AAP January 2022 Complete Issue Pediatrics in Review

JANUARY 2022
Vol. 43 No. 1
www.pedsinreview.org
Central Nervous
System Tumors
in Children
Care of the
Immigrant Child
Human
Immunodeficiency
Virus Preexposure
Prophylaxis in
Adolescents and
Young Adults
Visual Diagnosis
Chest Mass in a
Newborn Infant
A LOOK AHEAD AT THE AAP CME SCHEDULE
The Best Pediatric CME/CPD for the Best Pediatric Care
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Pediatrics in Review
COMMENTARY ••
•••
• •
•
•
1 Thank You
Joseph A. Zenel, Joseph Puskarz, Heidi Willis
MOC
•
•
• •
••
•••
ARTICLES To learn how

to claim MOC
3 Central Nervous System Tumors in Children points, go to:
Katherine C. Pehlivan, Megan R. Paul, John R. Crawford https://publications.
aap.org/journals/
16 Care of the Immigrant Child pages/moc-credit.
Karla Fredricks, Fernando Stein
28 Human Immunodeficiency Virus Preexposure Prophylaxis in Adolescents and

Young Adults
Megan E. Brundrett
INDEX OF SUSPICION
37 Rash in a 2-month-old Premature Infant
Margaret Urschler, Mary Anne Jackson, Mary Tyson, Barbara Pahud
41 Migratory Arthralgia in a 3-year-old Girl

Carol Fries, Andrew M. Long, Bethany A. Marston, Jeffrey R. Andolina
45 Feeding Intolerance in a 3-month-old

Alexander Gipsman, William Dufficy, Jessica Goldstein
49 Hives and Fever in a 13-year-old Boy

Thang V. Truong, Blake Gruenberg, Daisy A. Ciener, Ryan Butchee
IN BRIEF
54 Knee Trauma
Rachel Levene, Daniel M. Fein, Jennifer P. Grossman
58 Hypothermia and Cold Injury in Children

Lynn McDaniel
ONLINE
e1 Chest Mass in a Newborn Infant
Brenda T. Wu, Rebecca Stein-Wexler, Su-Ting T. Li
Answer Key appears on page 60.
Pediatrics in Review® (ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. It is published
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Pediatrics in Review
Editor-in-Chief Associate Editor, CME
Joseph A. Zenel, Sisters, OR Rani Gereige, Miami, FL
Deputy Editor Editorial Fellow
Hugh D. Allen, Houston, TX Kriti Puri, Houston, TX
Associate Editor, Index of Suspicion Managing Editor
Lynn Garfunkel, Rochester, NY Heidi Willis
Associate Editor, Visual Diagnosis Editorial Associate
Mark F. Weems, Memphis, TN Josh Sinason
Associate Editor, In Brief Medical Copyeditor
Henry M. Adam, Bronx, NY Lisa Cluver
Associate Editor, In Brief
Janet R. Serwint, Baltimore, MD
EDITORIAL BOARD
Robert D. Baker, Buffalo, NY Thomas C. Havranek, Bronx, NY
Peter F. Belamarich, Bronx, NY Kengo Inagaki, Ann Arbor, MI
Eyal Ben-Isaac, Los Angeles, CA Bert Emil Johansson, El Paso, TX
Roger L. Berkow, Atlanta, GA Stephanie Lauden, Columbus, OH
Theresa Auld Bingemann, Rochester, NY Neal S. LeLeiko, Providence, RI
Rebecca C. Butterfield, Albany, NY Priya Mahajan, Mission Viejo, CA
Heather Campbell, Washington, DC Katie A. Meier, Cincinnati, OH
Cynthia Christy, Rochester, NY Jennifer S. Read, Burlington, VT
Stephen E. Dolgin, New Hyde Park, NY Jennifer A. Reed, Sioux Falls, SD
Daniel M. Fein, Bronx, NY E. Steve Roach, Austin, TX
Catherine Forster, Washington, DC Samantha Vergano, Norfolk, VA
John G. Frohna, Madison, WI Melissa Weddle, Portland, OR
Linda Y. Fu, Washington, DC Miriam Weinstein, Toronto, ON
Timothy Garrington, Aurora, CO Shan Yin, Cincinnati, OH
Nupur Gupta, Boston, MA Shabana Yusuf, Houston, TX
PUBLISHER American Academy of Pediatrics

Sandy L. Chung, President
Mark Del Monte, Chief Executive Officer/Executive Vice President
Mary Lou White, Chief Product Officer/Senior Vice President, Membership, Marketing and Publishing
Mark Grimes, Vice President, Publishing
Joseph Puskarz, Director, Journal Publishing
The journal extends special thanks to the following question writers and ancillary reviewers who contributed to this issue:
Steven Ciciora, MD
Shweta Shah, MD
Brian Stotter, MD
CME/MOC INFORMATION:
The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.
The AAP designates this journal-based CME activity for a maximum of 36.0 AMA PRA Category 1 Credit(s)™. Physicians should
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www.pedsinreview.org, where you will view additional information, complete your CME quizzes, and claim credit online.
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COMMENTARY
Thank You
We are still in a pandemic, largely following the same pattern of events described for the first wave, second wave, and
third wave of the H1N1 influenza A virus, also known as the Spanish flu, that swept the world from 1918 through 1920.
If history repeats itself, and it usually does, we only have six months to a year more to endure. Hang in there.
I welcomed 2021 with its pandemic in Pediatrics in Review a year ago, encouraging pediatricians to “learn more, teach
more, act more, and become more.” Pediatricians did so valiantly, despite the increasing challenges of a questioning
public. Those challenges and what it took for pediatricians to face them in 2021 was recognized and applauded by the
American Academy of Pediatrics, whose Chief Executive Officer, Mark Del Monte, JD, wrote, “I want to take a moment
to personally thank you, and echo the appreciation shared by members of the AAP Board of Directors … for continuing
to do your job in unbelievable circumstances.”
One disheartening circumstance was people from all parts of society doubting the science from which we base our
care. Back in 1918, western society questioned the reliability of science’s recommendations for managing the Spanish
flu. Physicians overcame the public's distrust over time, and we can do the same today by staying current on our medi-
cal knowledge while teaching and guiding all who care for children. We need to persevere.
Today’s news frequently reports how society is changing its values in part due to our coping with social distancing.
Workplace structure and hours are disputed. Our future pediatricians may question how we practice medicine. Medical
schools and residencies have transformed the way we educate students and residents. Teleconferences and telemedicine
are increasingly used in teaching and in patient care, and it is difficult to predict how long this will continue after the
pandemic is over. But it is certain how we practice pediatrics will change.
It has never been a better time for Pediatrics in Review to publish what pediatricians need to know and understand.
The journal needs to be relevant for today’s and tomorrow’s practice. On behalf of our editorial board at Pediatrics in
Review, I thank our readers for their confidence in us, for reading and using our journal, and for caring for children in
the face of the Covid-19 pandemic. Your suggestions, constructive criticisms, and submissions keep our journal readable
and practical. Because of you, the journal continues to grow and has expanded to 2.7 million online readers worldwide,
downloading more than 700,000 articles annually.
New this year is the introduction of a chronic, complex care feature, acknowledging a growing need for pediatricians
to know how to care for the increasing number of children in our practices with complex, chronic needs. These children
deserve to become successful adults; the journal hopes to help. This quarterly feature may become a more frequent fea-
ture in the future.
Our "Index of Suspicion" (IOS) is probably our most popular feature. Your case submissions continue to be numer-
ous such that we published two IOS bonus supplements this past year to accommodate the many excellent patient pre-
sentations we accepted and believed had educational and practical value for our readers. We occasionally receive a
number of well-written cases that discuss the same disease yet demonstrate different aspects of that same disease. This
coming year, we may group these cases into a “case series” that will serve as a continuing medical education review
complete with CME questions.
In November 2021, AAP Publishing created the website AAP Publications (https://www.aappublications.org/). If you
haven't noticed, Pediatrics in Review relocated over 4,000 journal articles to that site. This new site now integrates all
AAP journals, AAP News, Point-of-Care Solutions, and books, making it possible for you to access many AAP pediatric
titles, including Pediatrics in Review, from a single location. Also integrated are the Pediatrics in Review’s CME quiz ques-
tions with the review articles to make them more accessible for you to claim credit. Pediatrics in Review is still available
at www.pedsinreview.org. The new platform gives the editors of Pediatrics in Review greater flexibility to provide you
with value-added content to support you in your daily practice.
Vol. 43 No. 1 JANUARY 2022 1

As history predicted, the pandemic is resolving, and the Thank you for hanging in there.
new year is promising. While 2021 was a tough year, Pedi-
atrics in Review continued to create, support, and adapt, Joseph A. Zenel, MD, Editor in Chief, Pediatrics in Review,
inspired by pediatricians who held their ground. It is Joseph Puskarz, Director, Journal Publishing, and
because of you children benefited during this challenging Heidi Willis, Managing Editor, CME Journals
time. All of us at Pediatrics in Review say thank you.
2 Pediatrics in Review
ARTICLE
Central Nervous System Tumors

in Children
Katherine C. Pehlivan, MD,* Megan R. Paul. MD,† and John R. Crawford, MD, MS†,‡
*Department of Pediatrics, Division of Hematology-Oncology, New York Medical College, Valhalla, NY
†
Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children’s Hospital, San Diego, CA
‡
Department of Neurosciences, University of California and Rady Children’s Hospital, San Diego, CA
EDUCATION GAP
The role of the pediatrician is crucial in both the diagnosis and

management of pediatric brain tumors, the most common solid tumor of
childhood. Awareness of the presenting signs and symptoms of brain
tumors can lead to timely diagnosis, and understanding the late effects of
brain tumor treatment improves long-term management of childhood
brain tumor survivors.
OBJECTIVES After completing this article, readers should be able to:
1. Recognize the presenting symptoms and physical examination findings

suggestive of a childhood brain tumor and how these findings depend
on tumor location.
2. Review common brain tumor pathologies affecting children.
3. Understand how molecular genetics plays a role in the diagnosis and
treatment of childhood brain tumors. AUTHOR DISCLOSURE: Drs Pehlivan,
Paul, and Crawford have disclosed no
4. Recognize the late affects associated with the treatment of childhood financial relationships relevant to this
article. This commentary does contain a
brain tumors.
discussion of an unapproved/
investigative use of a commercial
product/device.
INTRODUCTION
ABBREVIATIONS
Brain tumors are the most common solid malignancy in children and represent
ATRT atypical teratoid rhabdoid tumor
the leading cause of pediatric cancer-related deaths. Five thousand new brain CNS central nervous system
tumors are diagnosed yearly in the United States in children ages 0 to 19 years, CN cranial nerve
CSF cerebrospinal fluid
with an incidence of approximately 6 per 100,000 children. (1) Childhood brain CT computed tomography
tumors, more than half of which are malignant, vary in terms of biology, prog- HGG high-grade glioma
nosis and treatment. Presenting signs and symptoms depend on tumor location, ICP intracranial pressure
LGG low-grade glioma
growth rate, and presence of obstructive hydrocephalus. Making the initial diag- MRI magnetic resonance imaging
nosis of a brain tumor can be difficult because early symptoms, such as head- NF neurofibromatosis
aches or vomiting, are nonspecific to brain tumors and more frequently are NGGCT nongerminomatous germ cell
tumor
associated with other etiologies, leading to delays in diagnosis. The pediatrician OS overall survival
plays a crucial role in the timely diagnosis of patients with brain tumors as well WHO World Health Organization

as recognizing late effects resulting from tumor therapies.
This review summarizes the presenting features on history
and physical examination, tumor classification of common
tumor types, genetic brain tumor predisposition syndromes,
general management strategy, and late effects of therapy.
PRESENTATION OF BRAIN TUMORS IN CHILDREN

Signs and symptoms of a pediatric brain tumor can be non-
Figure 1. Presenting features of childhood brain tumors based on tumor
specific, insidious, intermittent, and dependent on location location. The presenting symptoms in the child with a brain tumor differ
within the central nervous system (CNS) and the anatomical based on the anatomical location of the tumor. Here, various anatomical
regions of the brain are highlighted and correlated to common constella-
pathways affected. Although headache is the most common tions of presenting symptoms suggestive of a lesion in that region of the
presenting complaint overall, it is present in only approxi- brain.
mately one-third of the children presenting with brain

patients presenting with supratentorial tumors. Instead, seiz-
tumors, and, in the absence of other symptoms or physical
ures were present in one-third of patients, along with focal
examination findings, is not in itself predictive of a brain
tumor. Elevated intracranial pressure (ICP) is present in neurologic deficits such as weakness or sensory deficits on
approximately half of all children with brain tumors. In addi- the contralateral side if there is involvement of the cortical
tion to headache, it can cause nausea/vomiting, abnormali- motor or sensory regions, respectively. (2) In cases of brain-
ties of gait and coordination, and papilledema. Vital sign stem tumors, children can present with crossed findings of
abnormalities associated with increased ICP, known as the ipsilateral facial weakness and contralateral hemiparesis.
Cushing triad (bradycardia, hypertension, abnormal respira- More than 75% of patients with brainstem tumors present
tions), are late signs of acutely increased ICP but can be with abnormal gait and coordination, whereas cranial nerve
absent in those with chronically elevated ICP. In young chil- (CN) palsies are present in more than half. Headache, how-
dren with an open fontanelle, macrocephaly, especially when ever, is not common in patients with brainstem tumors and
progressive, can be suggestive of hydrocephalus and a poten- is present in less than one-quarter at the time of diagnosis.
tial mass-occupying lesion. (2) Thalamic tumors can cause coordination and motor difficul-
Presenting symptoms depend on tumor location (Fig 1), ties or hemiplegia. (2)
and certain constellations of symptoms can point to specific Patients with pituitary tumors or optic pathway tumors
lesion locations. Table 1 lists commonly overlooked signs often present with visual deficits. It is not uncommon for
and symptoms that can lead to a delayed diagnosis. Wilne even severe visual deficits in children to go unrecognized by
et al analyzed presenting features of more than 4,000 child- the patient, parents, or pediatrician. (3) Because patients
hood brain tumors and found that for posterior fossa with neurofibromatosis (NF) type 1 are at increased risk for
tumors, three-quarters presented with nausea and vomiting, optic pathway glioma, they should have yearly ophthalmol-
two-thirds with headache, three-fifths with abnormal gait ogy evaluations. Children with pituitary or hypothalamic
and coordination, and one-third with papilledema. (2) In tumors often present with endocrine abnormalities, such as
contrast, headache, nausea, and vomiting were rare in failure to thrive, excessive thirst, or central obesity.
Table 1. Initial Presenting Signs and Symptoms Leading to Diagnosis of Brain Tumors in Various Locations
SIGNS AND SYMPTOMS TUMOR LOCATION
Early-morning vomiting, recurrent vomiting, enlarging head Posterior fossa, ventricular system
circumference
Failure to thrive, anorexia Suprasellar region, hypothalamic
Visual complaints, abnormal eye movements Optic pathway, suprasellar region, brain stem, posterior fossa
Tics, tremors, movement disorder Basal ganglia, thalamus, midbrain
Early handedness Cortex, subcortical, brain stem, spinal cord
Facial nerve palsy Brain stem, cerebellar pontine angle
Hearing loss Cerebellar pontine angle
Precocious puberty, nocturnal enuresis Suprasellar region
Head tilt, torticollis Cerebellar pontine angle, cervicomedullary junction
Reproduced with permission from American Academy of Pediatrics, adapted from Crawford J. Childhood brain tumors. Pediatr Rev.
2013;34(2):63–78.
Children with spinal cord tumors most commonly pre- tumors along the optic pathways. A fundoscopic examina-
sent with back pain, present at diagnosis in approximately tion can be difficult in young or uncooperative children,
two-thirds of cases. Spinal cord tumors may occur in extra- warranting referral to ophthalmology for a dilated exami-
dural, intramedullary, and extramedullary intradural loca- nation. Vision should be assessed by confrontation in the
tions. Although some children may present with scoliosis, 4 quadrants of each eye because different patterns of
most will not. Spinal cord compression causes signs such visual field deficits will suggest varying tumor locations.
as gait and coordination abnormalities, focal weakness, or In younger children, assessment of visual fields can be
bowel and bladder dysfunction. (2) performed using a colorful object for central fixation and
introducing a second object in the periphery and watching
ROLE OF THE NEUROLOGIC EXAMINATION for the eyes to track to that object.
A comprehensive neurologic examination (summarized in Eye movements are controlled by CNs III, IV, and VI.
Table 2) is crucial to identify abnormalities that might be The nuclei of CNs III and IV are located in the midbrain,
suggestive of a CNS tumor. A normal neurologic examina- whereas the nucleus of CN VI is in the pons, and brainstem
tion does not exclude the diagnosis of a brain or spinal tumors can lead to abnormalities of extraocular movements.
cord tumor and must be correlated with symptoms. Large pineal tumors can cause Parinaud syndrome, charac-
terized by upgaze palsy, convergence-retraction nystagmus,
Mental Status and poorly reactive pupils due to compression of the rostral
Patients with acute hydrocephalus can display dramatic midbrain. Nystagmus can also be seen in patients with cere-
changes in their mental status, with increased sleepiness, bellar tumors or optic pathway tumors.
decreased energy, and decreased responsiveness. How- CN V, the trigeminal nerve, has 3 divisions that give sensa-
ever, those with chronic hydrocephalus might show only tion to the face. The trigeminal nucleus is located in the pons,
subtle signs, such as slowly declining school performance. as is the nucleus of CN VII (the facial nerve), which controls
facial movement. Facial asymmetry or decreased facial sensa-
Cranial Nerves tion should raise concern for a mass in this region. Hearing in
A fundoscopic examination of the optic nerve, CN II, is each ear should be assessed to look for CN VIII dysfunction.
crucial to assess for papilledema and optic nerve pallor, The lower CNs (CNs IX, X, XII) exit from the medulla
which can reveal information about hydrocephalus or and are involved in phonation, swallowing, and tongue
Table 2. Key Components of the Neurologic Examination in a Child with Suspected Central Nervous System
Tumor
EXAMINATION PERTINENT FINDINGS SUGGESTIVE OF TUMOR
Mental status (alertness, speech) Encephalopathy, progressive neurocognitive decline
Cranial nerve II (visual fields, fundoscopic examination) Visual field deficit, papilledema, optic nerve pallor
Cranial nerves III, IV, VI (extraocular movements, efferent pupillary Nystagmus (upgaze in particular), gaze paralysis in any direction,
function) mid-position, poorly reactive pupils
Cranial nerve V (facial sensation) Asymmetry or change in facial sensation in anatomical distribution
of V1, V2, V3
Cranial nerve VII (facial symmetry, movement) Facial weakness (upper vs lower motor neuron distribution)
Cranial nerve VIII (hearing, balance) Decreased hearing to finger rub (unilateral or bilateral), vertigo
Cranial nerves IX, X, XII (palate elevation, swallowing, tongue Drooling, dysphagia, asymmetrical palate
movements)
Motor examination (bulk, tone, proximal and distal strength) Early handedness, delayed motor milestones, pronator drift, focal
changes in tone with associated atrophy
Sensory examination Sensory deficits in a focal anatomical distribution
Reflexes (biceps, triceps, brachioradialis, patellar, Achilles) Hyperreflexia with Babinski sign
Coordination (finger to nose testing, mirror testing, rapid finger Dysmetria, overshoot on mirror testing, marked asymmetry of finger
and toe tapping) and/or toe tapping (must be differentiated from weakness)
Gait (heel, toe, tandem straight line) Wide-based unsteady gait, inability to perform straight-line test,
circumduction of gait
A thorough neurologic examination includes assessment of mental status, cranial nerves, motor and sensory function, reflexes, coordination,
and gait. Examples of abnormal findings according to each examination component that might suggest a central nervous system mass or
lesion are listed. These abnormalities should be interpreted within the clinical context but can suggest a need for imaging or further
evaluation.
Reproduced with permission from American Academy of Pediatrics, adapted from Crawford J. Childhood brain tumors. Pediatr Rev.
2013;34(2):63–78.

movement. Palatal asymmetry, change in voice quality, or altered mental status, or concern for increased ICP war-
unilateral glossal atrophy raises suspicion for a medullary rant expedited evaluation, best managed initially in the
lesion. CN XI, the accessory nerve, has the most distal emergency department. Although magnetic resonance
nucleus, also in the medulla, and innervates the trapezius imaging (MRI) with and without contrast is the gold stan-
and sternocleidomastoid musculature. dard imaging technique for optimal visualization for brain
tumors and is often needed for neurosurgical planning, in
Motor Function, Sensation, Reflexes the unstable child, a computed tomographic (CT) scan
Motor function, sensation, and reflexes should be assessed may be the best initial imaging choice. CT scans can pro-
with special attention to comparison with the contralateral find- vide information regarding acute hydrocephalus, impend-
ings. Asymmetry can indicate a lesion affecting corticospinal ing herniation, or acute hemorrhage, all of which
tracts (motor), spinothalamic tracts (temperature, pain, light represent neurosurgical emergencies. They can also show
touch), or dorsal columns (proprioception, vibratory sense). the anatomical location of a mass, lesion size, presence of
Asymmetrical hyporeflexia can indicate lower motor neuron hydrocephalus, and whether the mass is compressing
injury, whereas hyperreflexia and the presence of a Babinski other brain structures, thereby helping to triage and plan a
reflex are indicative of upper motor neuron dysfunction. In timeline for MRI, surgery, or other sedated procedures.
acute upper motor neuron injury, reflexes may be absent. When choosing the optimal initial imaging study for a
young child who would require anesthesia to complete an
Gait and Coordination MRI, the relative risks of anesthesia compared with the
Patients with cerebellar tumors can present with a wide- risk of exposure to ionizing radiation from a CT scan,
based ataxic gait and difficulty with tandem gait. A hemipa- which could be completed without sedation, must be
retic gait can suggest a tumor involving cortical motor areas, weighed while taking into account the degree of suspicion
the thalamus, or the brain stem. Patients with cerebellar or for an abnormality and individual risk factors specific to
brainstem tumors may exhibit abnormal coordination, eli- that patient. (5)
cited by testing rapid alternating movements, finger to nose MRI with and without contrast is generally the pre-
testing, or finger (pointer to thumb) and toe tapping (on the ferred imaging modality for diagnosis and follow-up of
floor) or asking a child to mirror the examiner's finger as brain tumors. MRI allows for more detailed characteriza-
the examiner moves the finger laterally and/or vertically. tion of the tumor itself and the surrounding anatomy,
with more specialized sequences for visualization of
Skin Examination edema, relationship to CNs, blood vessels, and perfusion.
Although not technically part of the neurologic examination, a Furthermore, MRI does not expose children to ionizing
skin examination is important to assess for dermatologic man- radiation so is preferred over CT for repeated studies, as
ifestations of underlying tumor predispositions such as NF would be needed to follow a brain tumor. Most patients
type 1 (predisposed to low-grade gliomas [LGGs], especially in with a brain tumor require a spinal MRI to evaluate for
optic pathways), NF type 2 (predisposed to acoustic schwanno- evidence of leptomeningeal disease.
mas and meningiomas), tuberous sclerosis complex (predis- When a diagnosis of a brain tumor is made based on
posed to subependymal giant cell tumors), or, more rarely, imaging, in the absence of a neurosurgical emergency,
constitutional mismatch repair deficiency syndrome. Patients patients should be managed in concert with neuro-oncol-
with constitutional mismatch repair deficiency syndrome have ogy teams preoperatively. Early neuro-oncology consulta-
a genetic defect in genes responsible for repairing a specific tion allows for additional baseline neurologic examination,
type of DNA damage known as mismatch repair. Abnormali- can help inform surgical planning based on the working
ties in these genes (MLH1, MSH2, MSH5, PMS2) make it differential diagnosis and postoperative treatment options,
more difficult for the body to repair normally occurring DNA and facilitates an opportunity for clinical trial enrollment
damage, leading to mutations and predisposing these patients where presurgical consent may be required.
to many types of cancers at an early age, including brain
tumors, most commonly high-grade gliomas (HGGs). (4) TREATMENT OVERVIEW OF PEDIATRIC BRAIN
TUMORS
ACUTE MANAGEMENT The care of the pediatric neuro-oncology patient requires a
The child with a suspected brain tumor might require multidisciplinary team–based approach. In addition to an
urgent interventions. Those with unstable vital signs, excellent primary care pediatrician, this team includes
neuro-oncology, neuro-surgery, neurology, neuro-radiol-
ogy, radiation oncology, genetics, endocrinology, ophthal-
mology, audiology, neuropsychology, physical medicine
and rehabilitation, palliative care, and social work.
Upfront treatment of pediatric brain tumors generally
includes surgery, radiotherapy, chemotherapy, or a combina-
tion of these modalities. For most tumor types, maximal
safe surgical resection is pursued to obtain diagnosis and as
the first step in definitive treatment. Some notable excep-
tions to this include tumors in eloquent locations where
resection would result in significant morbidity or mortality.
These locations include the brain stem, optic pathways, thal-
amus, internal capsule, sensory and motor cortices, visual
cortex, or Broca and Wernicke areas, which are important
for receptive and expressive language. In some cases, a small
needle biopsy of these areas can be performed to obtain tis-
sue for diagnostic purposes. For germ cell tumors, tumor
markers can be diagnostic, obviating the need for upfront
surgery. Some patients with low-grade–appearing lesions are
followed with observation alone.
Although some low-grade tumors can be treated with
resection only, many low-grade and most high-grade tumors
require additional postsurgical treatment. The standard of Figure 2. Magnetic resonance imaging (MRI) features of pediatric brain
care for postsurgical management of pediatric brain tumors tumors with associated clinical presentation. A. MRI with contrast reveals a
heterogeneously enhancing mass of the posterior fossa. The patient pre-
is constantly evolving based on emerging preclinical and sented with several days of early-morning vomiting. Examination demon-
clinical data. In many cases, enrollment in an open clinical strated papilledema, ataxia, and dysmetria. Diagnosis: medulloblastoma. B.
Fluid-attenuated inversion recovery MRI sequence demonstrates a right-
trial is considered the standard of care. There are a variety of sided, posterior, cortically based tumor. The patient presented with a new-
clinical trial consortia and cooperative groups with open pro- onset focal seizure. Neurologic examination was normal. Diagnosis: dysem-
broplastic neuroepithelial tumor. C. MRI with contrast demonstrates an
tocols focused on pediatric brain tumors. A complete list of enhancing mass involving the optic chiasm and tracts. The patient pre-
sented with several months of blurred vision. Examination revealed multiple
open clinical trials can be found on clinicaltrials.gov. cafe au lait macules, axillary freckling, bilateral pale optic nerves, and poor
visual acuity. Diagnosis: optic pathway glioma, neurofibromatosis type 1. D.
Noncontrast MRI reveals a large hypointense mass involving the pons. The
CLASSIFICATION AND TREATMENT OF patient presented with several weeks of double vision, facial weakness, and
PEDIATRIC BRAIN TUMORS poor coordination. Examination revealed bilateral sixth and seventh nerve
palsies, bilateral dysmetria, and diffuse hyperreflexia with clonus. Diagnosis:
There are more than 30 unique pathologies of CNS diffuse intrinsic pontine glioma. E. Postcontrast MRI reveals a large suprasel-
lar tumor and hydrocephalus. The patient presented with several months of
tumors in children. MRI characteristics of some common headaches, double vision, and increasing difficulty seeing objects on the
childhood brain tumors are shown in Fig 2. The advent of television. Examination revealed bitemporal hemianopsia and papilledema.
Diagnosis: craniopharyngioma. F. T2-weighted MRI reveals a large right fron-
molecular genetics has enhanced our understanding of tal mass with mass effect. The patient presented with 2 weeks of headache
the biologic behavior of brain tumors, has changed tumor and left-sided weakness. Examination demonstrated left hemiparesis and
acute encephalopathy. Diagnosis: high-grade glioma.
classification systems, and has had treatment implications.
or nodular desmoplastic. Overall, medulloblastoma has 5-
Medulloblastoma year overall survival (OS) of approximately 70%. (6)
Medulloblastoma is the most common malignant brain Treatment depends on age at presentation, extent of
tumor in children and is of embryonal origin. It generally resection, and presence of metastatic disease. Recent trials
presents as a posterior fossa mass and, due to its location, are accounting for molecular subtype in treatment deci-
is often associated with obstructive hydrocephalus. Staging sions. Generally, treatment involves maximal tumor resec-
includes an MRI of the spine and a lumbar puncture look- tion, craniospinal radiotherapy, and chemotherapy. Young
ing for malignant cells in the cerebrospinal fluid (CSF). patients undergo high-dose chemotherapy with autologous
Histologically it is classified as classic, large cell anaplastic, stem cell rescue to avoid or delay irradiation.

Table 3. The Four Major Consensus Molecular Subgroups of Medulloblastoma
SUBGROUP
VARIABLE WNT SHH GROUP 3 GROUP 4
Frequency 10% 30% 25% 35%
5-y overall survival 95% 75% 50% 75%
Rate of metastases 5%–10% 10%–15% 40%-45% 30%–50%
Age group Children Infants, adults Infants, children Children, adults
Medulloblastoma is divided into 4 major molecular subgroups with clinical and prognostic implications. These subgroups are beginning to
be integrated into clinical trial designs to impact risk stratification and treatment considerations. However, there is molecular and clinical
heterogeneity even within these subgroups. (7)(8)
Medulloblastoma has been classified into 4 principle rhabdoid tumors in other locations, most commonly the
molecular subgroups: WNT (wingless), SHH (sonic hedge- kidneys. Germline variants are more common in younger
hog), group 3, and group 4 (Table 3). (7) WNT-driven patients, and approximately two-thirds are sporadic. (11)
medulloblastomas are rarely metastatic and have the best Staging includes MRI of the brain and spine and lumbar
overall prognosis, with greater than 90% OS. Current clin- puncture for CSF cytology. Treatment involves surgical resec-
ical trials are focused on reducing therapy in this subtype. tion, radiotherapy, and chemotherapy, with or without triple
SHH-driven tumors have a bimodal distribution present- tandem autologous stem cell transplant. Recent clinical trial
ing most commonly in infants or adolescents and young data showed improved survival outcomes compared with his-
adults. They have an intermediate prognosis, although torical controls achieved with a regimen including radiotherapy
association with p53 mutations portends a poor prognosis. for patients as young as 6 months and 3 cycles of high-dose
(9) Group 3 and group 4 tumors are known as non-WNT, chemotherapy with autologous stem cell rescue for all patients.
non-SHH medulloblastoma subtypes. Although immuno- (12) A meta-analysis including 130 patients with ATRT saw that
histochemical studies can differentiate WNT and SHH survival correlated most strongly when patients were treated
medulloblastoma from the non-WNT and non-SHH with regimens that included high-dose chemotherapy with
medulloblastoma subtypes, other molecular methods, autologous stem cell rescue. Treatment modalities of radiother-
such as methylation studies, are needed to distinguish apy and intrathecal chemotherapy also lead to a statistically sig-
group 3 from group 4 tumors. Group 3 tumors can pre- nificant improvement in OS in this cohort. (10)
sent in very young children, often have MYC amplifica- ATRT tumors have also been classified based on molec-
tion, are commonly metastatic at presentation, and have ular characteristics into 3 subgroups: ATRT–tyrosine
the poorest outcomes overall of any subgroup. Recent data (ATRT-TYR), ATRT–sonic hedgehog (ATRT-SHH), and
suggest that group 3 tumors might benefit from intensi- ATRT–myelocytomatosis oncogene (ATRT-MYC), but fur-
fied chemotherapy concurrent with radiotherapy. Group 4 ther research is needed to delineate the prognostic and
tumors are the most common subgroup overall, present- clinical implications of these subgroups. (13)
ing in children and adults and, similar to group 3 tumors,
more commonly present in males than in females. (7) Ependymoma
Group 4 tumors have an intermediate prognosis. Ependymoma represents the third most common brain
tumor in children and arises from the ependymal cells lin-
Atypical Teratoid Rhabdoid Tumor ing the ventricles or the central canal of the spinal cord.
Atypical teratoid rhabdoid tumors (ATRTs) are also embry- Two-thirds of ependymomas present in the posterior
onal tumors but can present in the posterior fossa or fossa, with the remainder in the supratentorial region or
supratentorial region. These tumors have a very poor prog- spinal cord. For pediatric ependymoma as a whole, OS at
nosis, with 3-year OS of approximately 25%. Survival 10 years is approximately 64%, but cases achieving gross
trends improve with older age at diagnosis, with those total resection followed by radiotherapy fare significantly
older than 3 years faring better than younger patients. (10) better. Molecular subtype and gain of chromosome 1q has
Histologically, the loss of INI1, encoded by SMARCB1, is important prognostic implications as well. (14)
pathognomonic. Up to 35% of patients with ATRT have a Ependymoma is treated with maximal surgical resec-
germline mutation in SMARCB1 (or rarely SMARCA4), tion followed by focal radiotherapy, except for spinal dis-
which predisposes them to the development of malignant ease, in which gross total resection without adjuvant
radiotherapy can be curative. The role of chemotherapy in are driven by alterations in the mitogen-activated protein
ependymoma remains under clinical investigation. Studies kinase pathway, most commonly KIAA1459-BRAF fusions
have also explored the use of postoperative chemotherapy (33%), BRAF V600E single-nucleotide variants (17%), and
to delay or omit radiotherapy in patients younger than 3 NF type 1 alterations (17%). (16) MEK inhibitors have shown
years, but outcomes were inferior to regimens involving activity against mitogen-activated protein kinase–activated
radiotherapy for children older than 12 months. (15) pediatric LLGs, and BRAF inhibitors have shown promise
Ependymoma has been divided into 9 molecular sub- in BRAF V600E–altered tumors. (18)(19)
groups, with 3 subgroups for each anatomical location:
spinal, supratentorial, and posterior fossa. Only 6 of the High-Grade Gliomas
molecular subtypes generally affect children. Pediatric In contrast to LGGs, pediatric HGGs have a dismal prog-
ependymoma of the spine is divided into the SP-MPE sub- nosis. HGGs include hemispheric high-grade tumors (ana-
type (myxopapillary, usually World Health Organization plastic pleomorphic xanthoastrocytoma, glioblastoma),
[WHO] grade I) and the SP-EPN subtype (anaplastic, brainstem tumors (diffuse intrinsic pontine glioma), and
WHO grade II/III). Both spinal subtypes have a relatively nonbrainstem diffuse midline gliomas.
good prognosis. In the posterior fossa, patients with PF- Treatment of pediatric HGGs is challenging. Hemi-
EPN-A have a worse prognosis than those with PF-EPN-B, spheric tumors may be amenable to surgical resection.
and in the supratentorial compartment, those with RELA Resection is typically followed by radiotherapy and chemo-
fusion-driven disease (ST-EPN-RELA) have poorer OS than therapy for these tumors, as a Children’s Cancer Group
those with YAP1 fusion-positive disease (ST-EPN-YAP1). study showed improved survival when chemotherapy was
Both PF-EPN-A and ST-EPN-RELA are associated with added to radiotherapy compared with radiotherapy alone.
10-year OS less than 50% and 10-year progression-free Nonetheless, no specific chemotherapy regimen has
survival of approximately 20%. (14) emerged as a clearly superior standard of care for upfront
pediatric HGGs. (20) In contrast, for midline tumors such
Low-Grade Gliomas as diffuse intrinsic pontine glioma, adding chemotherapy
Pediatric LGGs are a heterogenous group of tumors that to radiotherapy has not been shown to prolong survival
encompass several distinct WHO histologies, including beyond the median 9- to 12-month OS and the 10% two-
astrocytic tumors (juvenile pilocytic astrocytoma being the year OS achieved with radiotherapy alone. Several open
most common), oligodendroglial tumors (such as oligo- molecularly based and immunotherapy-driven clinical tri-
dendroglioma), and mixed glioneuronal tumors (including als are currently accruing patients, hoping to improve out-
dysembryoblastic neuro-epithelial tumors). When grouped comes for these patients. (21)(22)
together, LGGs represent the most common brain tumor Molecular studies in pediatric HGGs demonstrate that
in children and can present in many anatomical locations. the biology of pediatric HGGs differs from that of adult glio-
LGGs are less likely to metastasize to other parts of the blastomas. Histone mutations H3.1K27M and H3.3 K27M
CNS axis than their malignant counterparts, and in some in midline tumors, and H3.3G34R.V in hemispheric
cases gross total resection can be curative. However, resec- tumors, highlight the influence of epigenetics in pediatric
tion is not always possible in certain anatomical locations, HGGs and portend a poor prognosis. Infant HGGs are bio-
such as in the brain stem or with optic pathway gliomas, logically distinct from HGGs in older children, with signifi-
common in patients with NF type 1. LGGs have a relatively cantly improved survival. NTRK fusions are more common
favorable prognosis, with OS of 92.5% and progression- in children younger than 1 year, and TRK inhibitors under
free survival of 67% reported in a study of 1,000 LGGs investigation are showing promising results. (23)(24)
with median follow-up of 15.9 years. (16)
Classically, when medical therapy is needed for LGGs, Germ Cell Tumors
the first-line regimen consists of traditional chemotherapy CNS germ cell tumors represent approximately 1% of
with either carboplatin/vincristine or procarbazine, lomus- pediatric brain tumors and are categorized as pure ger-
tine, vincristine, and thioguanine, although other chemo- minomas and nongerminomatous germ cell tumors
therapy regimens have demonstrated responses as well. (17) (NGGCTs). They most commonly arise in the pineal re-
Radiotherapy is not routinely used in the upfront manage- gion but can also present in the suprasellar region, fourth
ment of LGG due to concerns for late effects. Study of the ventricle, thalamus, or basal ganglia. NGGCTs secrete
molecular landscape of LGGs has demonstrated that most a-fetoprotein (yolk sac) or human chorionic gonadotropin

(choriocarcinoma) or both (immature teratomas or mixed), therapy for the management of a brain tumor. (28)(29)
which can be detected in peripheral blood and/or CSF. Table 4 summarizes selected germline syndromes associ-
Pure germinomas can cause modest elevation of human ated with specific brain tumor types.
chorionic gonadotropin in the CSF but do not secrete
a-fetoprotein. In some cases, diagnosis can be made based ACUTE AND EARLY EFFECTS OF TREATMENT
on CSF and serum tumor markers, whereas biopsy is Although the treatment of different tumor types varies sig-
required when tumor markers are inconclusive. Germino- nificantly, each of the commonly used treatment modali-
mas have a better overall prognosis, with OS greater than ties confers their own risks and acute toxicities.
90% compared with 60% to 70% for NGGCTs. Accord- Major risks of neurosurgery include bleeding, stroke,
ingly, germinomas are commonly treated with 4 cycles of infection, and damage to nearby structures, as well as
chemotherapy (carboplatin/etoposide) followed by radio- morbidity dependent on tumor location. For example, pos-
therapy to the tumor bed and whole ventricles, whereas terior fossa syndrome affects an estimated 8% to 30% of
NGGCTs are generally treated with 6 cycles of chemo- patients who undergo resection of large posterior fossa
therapy (carboplatin/etoposide alternating with ifosfa- tumors. Posterior fossa syndrome is characterized by a
mide/etoposide) and craniospinal radiotherapy in many combination of mutism or significant language impair-
cases, although studies are examining whether radiother- ment, with emotional lability and irritability or motor dys-
apy can be reduced in select patients with NGGCTs to function occurring within 2 weeks of cerebellar injury.
minimize toxicity associated with craniospinal radiother- Signs and symptoms can take months to resolve, and
apy. (25)(26) unfortunately many are left with residual deficits. (37)(38)
Patients with supratentorial tumors are at greater risk for
Craniopharyngioma postoperative seizures and are often started on prophylac-
A craniopharyngioma is a suprasellar tumor arising from tic antiepileptic medications. Children with suprasellar
the remnants of the Rathke pouch containing cystic and tumors are at increased risk for postoperative visual defi-
solid components. Histologically, they are classified as cits and hormone dysfunction.
benign tumors and are divided into adenomatous and pap- Radiotherapy treats tumors by directing high-energy
illary subtypes. Due to their location they can severely protons or photons at a tumor target to damage DNA.
impair visual, hormonal, and cognitive function. Optimal Radiation is fractionated over several weeks to achieve a
treatment strategy for craniopharyngioma is controversial; total dose to the target. Photons are waves without mass,
some centers perform a more aggressive primarily neuro- meaning that when concentrated at a point to a certain
surgical approach in an attempt to avoid radiotherapy, and dose, they also deliver radiation “scatter” at a lower dose
others perform an initial subtotal resection followed by on both the entrance and exit side of the wave. Protons
upfront radiotherapy. (27) have mass, so the radiation is designed to “stop” within
the target tissue, releasing the highest amount of energy
TUMOR PREDISPOSITION SYNDROMES at that point, minimizing the scatter that exits beyond the
There are several germline mutations that predispose chil- target. Acute adverse effects of radiotherapy are mostly
dren to specific types of childhood brain tumors in the due to the radiation absorbed in off-target tissues. With
context of tumor predisposition syndromes. Knowledge of both proton and photon radiotherapy, patients can develop
these syndromes is important to the primary care physi- local skin reactions, which generally worsen over the treat-
cians who follow these patients longitudinally. In the child ment period. Patients receiving intracranial radiotherapy
who presents with a brain tumor, especially in the context often experience headache or nausea. Craniospinal radio-
of other personal history of tumors, family history of therapy can cause myelosuppression due to the dose
tumors at a young age, or characteristic dermatologic find- received by the vertebral body bone marrow and can harm
ings, it is important to consider further evaluation for the growth plates of the vertebral bodies, resulting in loss
these cancer predisposition syndromes. Children with a of adult height (worse in younger children). Proton radio-
known family history of cancer predisposition syndromes therapy is becoming increasingly preferred over photon
might require genetic screening for the presence of these radiotherapy, particularly for patients who require cranio-
syndromes, and specific tumor surveillance if found to spinal radiotherapy, because it avoids scatter to several
harbor one of these mutations. Furthermore, the presence important anterior midline organs, such as the esophagus,
of certain underlying syndromes may alter the choice of mediastinum, heart, breast tissue, and intestines. For
Table 4. Selected Tumor Predisposition Syndromes Associated with Childhood Brain Tumors
GENES KNOWN BRAIN TUMORS OTHER ASSOCIATED BRAIN TUMOR
SYNDROME TO BE INVOLVED ASSOCIATED TUMOR TYPES SURVEILLANCE
Rhabdoid tumor SMARCB1, SMARCA4 Atypical teratoid rhabdoid Extracranial malignant Consider screening if age <5
predisposition tumor rhabdoid tumors y or symptomatic (30)
Gorlin PTCH1, SUFU Medulloblastoma (sonic Basal cell carcinomas PTCH1: Screen if symptomatic
hedgehog subgroup) SUFU: Consider screening if
age <5 y or symptomatic (30)
Familial APC Medulloblastoma, Colon cancer, osteomas, Screen if symptomatic (28)
adenomatous astrocytoma, fibromatosis, others
polyposis (Turcot ependymoma
type 2)
Li-Fraumeni TP53 Glioma, medulloblastoma, Sarcomas, adrenocortical Annual screening from birth
choroid plexus carcinoma carcinoma, breast cancer, (31)
others
Neurofibromatosis NF1 Low-grade glioma, optic Malignant peripheral nerve Yearly clinical assessment and
type 1 glioma, astrocytoma sheath tumor, ophthalmology; screen if
neurofibroma, leukemia vision loss or other symptoms
of brain tumor (32)
Neurofibromatosis NF2 Schwannoma, meningioma, Malignant peripheral nerve Screen brain every 1–2 y and
type 2 astrocytoma, sheath tumor, spine every 2–3 y if age
ependymoma neurofibroma >10 y or symptomatic (33)
Schwannomatosis SMARCB1 (mosaic Schwannoma, meningioma SMARCB1: malignant SMARCB1: screen brain/spine
or hypomorphic) peripheral nerve sheath at diagnosis, every 2–3 y
LZTR1 tumors, rarely other after age 10 y
rhabdoid tumors LZTRI: screen brain/spine at
LZTR1: other tumors diagnosis, every 2–3 y after
uncommon age 15–19 y (33)
Germline Rb Pineoblastoma, primitive Retinoblastoma, Periodic brain MRI until age
retinoblastoma neuroectodermal tumor osteosarcoma, others 5 y (34)
Simpson-Golabi- GPC3, GPC4 Medulloblastoma Wilms tumor, No established guidelines,
Behmel hepatoblastoma, screen if clinically indicated
neuroblastoma,
gonadoblastoma
Constitutional MLH1, MSH2, Astrocytoma, glioblastoma, Leukemia, gastrointestinal Brain MRI every 6 mo from
mismatch repair PMS2, MSH6 ganglioglioma, tumors, others time of diagnosis (4)
deficiency, Lynch meningioma,
syndrome (Turcot medulloblastoma,
type 1) hemangioblastoma
Tuberous sclerosis TSC1, TSC2 Subependymal giant cell Renal angiomyolipoma, Surveillance brain MRI every
complex astrocytoma cardiac rhabdomyoma, 1–3 y until age 25 y (35)
fibroma, hamartoma
Von Hippel Lindau VHL Hemangioblastoma Pheochromocytoma, Screen brain/spine every 2 y
paraganglioma, renal cell after age 8 y or if
carcinoma symptomatic (36)
Brain tumor surveillance recommendations are created by consensus groups and change over time. The imaging modality of surveillance is
typically brain MRI with and without contrast. Many syndromes also include guidelines for screening for extra–central nervous system
tumors, not reviewed here. It is strongly recommended to refer to the most up-to-date guidelines when caring for a patient with a cancer
disposition syndrome and to refer families for genetic counseling when available. MRI=magnetic resonance imaging.
patients receiving focal radiotherapy, proton therapy may A small percentage of patients might experience radia-
spare irradiation to important structures or result in a sig- tion necrosis, especially in areas treated to high total doses
nificantly smaller overall radiation field, depending on of radiation or that have been irradiated again. In some
tumor location. Comparison plans showing the radiation cases, radiation necrosis is discovered based solely on imag-
field and dose for a proton plan versus a photon plan can ing findings, but symptomatic patients may require medical
be helpful to evaluate relative advantages of proton over management with corticosteroids or bevacizumab, or fur-
photon based on the brain structures that would receive a ther intervention such as surgery. Research is ongoing into
given dose with each plan. Primary limitations to the use other strategies for treatment of radiation necrosis, such as
of proton therapy are the restricted number of proton the use of laser interstitial thermal therapy. (39)
radiotherapy centers, requiring some patients to travel By targeting rapidly dividing cells, chemotherapy medi-
long distances for therapy, as well as the relative cost of cines kill fast-growing tumor cells but also have off-target
treatment compared with photon radiotherapy. effects on other cell types with high turnover rates, such

as hair, gastrointestinal tract, and bone marrow. Alopecia,
although not painful or medically toxic, can be psychologically
difficult for patients and parents. Nausea and vomiting affect
most patients and, especially when combined with mucositis,
contribute to poor appetite and weight loss during therapy.
Myelosuppression leads to anemia, thrombocytopenia, and
leukopenia. Children are supported with red blood cell and
platelet transfusions. Leukopenia causes immunocompro-
mise, making children more prone to opportunistic infec-
tions. Patients are maintained on pneumocystis prophylaxis
(trimethoprim-sulfamethoxazole is first line) throughout treat-
ment and for at least 6 months after chemotherapy. Fever in
the oncology patient is a medical emergency, and neutropenic
patients with fever are admitted to the hospital for broad spec-
trum antibiotic therapy due to the risk of life-threatening
infection. Vaccine response is impaired during chemotherapy
and shortly after, so routine vaccinations should be deferred
Figure 3. Potential late effects of chemotherapy and radiotherapy in the
during chemotherapy because development of antibodies treatment of childhood brain tumors. Even when therapy for brain tumors
may be inadequate and live virus vaccines are strictly contrain- results in cure and long-term survival, the late effects of therapy can be
significant. Most organ systems throughout the body can experience late
dicated. However, immunocompromised children should still effects related to the consequences of therapy. For this reason, it is impor-
receive yearly influenza vaccination. tant that survivors of childhood brain tumors be followed lifelong for
screening and management of these late effects.
In addition to the shared toxicities of chemotherapy medi-
cines, individual chemotherapies carry drug-specific adverse
are caring for more survivors with late effects of cancer
effects. Some commonly used chemotherapy medicines in
therapy. Figure 3 shows the multitude of late effects that
patients with pediatric brain tumor include vincristine (asso-
can impact patients treated for pediatric brain tumors. The
ciated with constipation, peripheral neuropathies, hypore-
number and severity of late effects depend on many fac-
flexia, and jaw pain), cisplatin and carboplatin (associated
tors, including tumor location, age at treatment, treatment
with renal toxicity and ototoxicity), and cyclophosphamide
modalities, and intensity of treatment.
(associated with hemorrhagic cystitis).
Survivors of childhood brain tumors, especially those
Novel targeted therapies have distinct mechanisms of
who have received radiotherapy, are at high risk for neuro-
action from traditional chemotherapy and thus different
cognitive impairment. Studies have shown a decreased IQ
adverse effects. MEK inhibitors, for example, are known to of approximately 10 to 15 points, with radiotherapy at a
cause frequent dermatologic toxicity and gastrointestinal younger age correlating to worse deficits. The domains
adverse effects and also carry a risk of cardiac toxicity, most affected are executive function, processing, and
prompting frequent cardiac surveillance for patients working memory. (40)
receiving therapy. TRK inhibitors, on the other hand, carry Cranial radiotherapy also significantly increases the risk
an increased risk of weight gain and long bone fractures. of cerebrovascular disease, including stroke, moya-moya
Immunotherapy medicines such as PD-1/PD-L1 inhibi- syndrome, cavernomas, and aneurysms, which often man-
tors activate the patient's immune system to better recog- ifest years after therapy. The Childhood Cancer Survivor
nize and attack tumor cells and thus present a different Study showed that survivors of CNS malignancy had a
array of toxicities. Patients taking immunotherapy medi- 30× increased risk of stroke compared with a sibling con-
cines are at increased risk for development of autoim- trol group. Stroke risk correlated with radiation dose and
mune disease and should be closely monitored for increased over time from completion of therapy, with a
autoimmune-mediated processes, including dermatitis, cumulative incidence greater than 1% in survivors of brain
thyroiditis, pancreatitis, and colitis. tumors 10 years after treatment. The imaging findings of
radiation-induced vascular infarction can overlap with
FOLLOW-UP AND LATE EFFECTS those of tumor recurrence, so the cumulative risk over
As advancements in treatment have improved the survival time is important to consider when interpreting follow-up
rates of patients with pediatric brain tumors, pediatricians imagining in survivors of brain tumor. (41) Concurrent
hypertension and diabetes significantly further increased appropriately for mental health services, educational assis-
stroke risk, underscoring the importance of screening for, tance, and psychosocial support. (40)
and treating, these comorbidities in childhood cancer sur-
vivors. (42) FUTURE DIRECTIONS IN PEDIATRIC NEURO-
Patients who have had surgery or radiotherapy involv- ONCOLOGY
ing the hypothalamic-pituitary axis can experience endo- Recent advances in pediatric neuro-oncology have
crinopathies, including growth hormone deficiencies, enhanced understanding of tumor biology and molecular
hypothyroidism, adrenal insufficiency, and sex hormone
determinants of disease. Molecularly based clinical trials
deficiencies. Certain chemotherapy medications also con-
will promote even greater knowledge regarding molecular
tribute to risk of infertility in survivors of cancer. Those
predictors of disease severity, response to therapy, and
with hypothalamic injury from tumor, surgery, or radio-
molecularly based treatment strategies, helping to define
therapy are at risk for hypothalamic obesity. (40)
the role of novel targeted agents in pediatric neuro-oncol-
Many survivors of childhood brain tumor experience
ogy (eg, MEK inhibitors, TRK inhibitors, SHH inhibitors).
high-frequency sensorineural hearing loss as well.
Unanswered questions remain, such as whether these are
Although it can occur in the acute phase of therapy, it can
most effective as single agents, in combination with one
also manifest as a late effect in children who have received
another, or in combination with cytotoxic chemotherapy.
cisplatin chemotherapy or radiotherapy to structures in
Duration of treatment and duration of response once treat-
the inner ear or auditory nerve. Otoprotective agents may
ment is suspended also remain to be determined, as well
be used in select patients to decrease the risks of certain
as long-term adverse effects of their use in children.
patients receiving platin-based chemotherapy. Many of
Immunotherapy is another area of active research.
these children require hearing aids and other accommoda-
Immunotherapy approaches such as blinatumomab and
tions long-term.
chimeric antigen receptor T cells drastically improved sur-
Unfortunately, even after surviving brain cancer, chil-
vival in relapsed acute lymphoblastic leukemia, and the
dren are at increased risk for a secondary malignancy. Cer-
addition of antibody therapy in high-risk neuroblastoma
tain chemotherapy agents, such as alkylating agents (eg,
significantly improved survival in this population. Resear-
cyclophosphamide, lomustine, temozolomide) and topo-
chers hope that similar gains in survival might be seen
isomerase inhibitors (eg, etoposide) are known to pre-
dispose patients to secondary leukemia later in life. with the integration of immunotherapy in the treatment
Radiotherapy is also a risk factor for the development of a of childhood brain tumors. Several different agents are
secondary malignancy within the radiation field. Underly- currently under investigation to enhance immune cell acti-
ing genetic disorders, such as congenital mismatch repair vation and function against brain tumors, including
deficiency of p53 mutations, can further increase this risk. agents such as PD-1 and PD-L1 inhibitors or CD47 inhibi-
In a study of more than 34,000 survivors of childhood can- tors. Chimeric antigen receptor T cells are also in clinical
cer with median follow-up of 21 years, approximately 2% of trials for certain pediatric CNS malignancies expressing
survivors died of secondary malignancies, accounting for specific targets. Vaccine studies for CNS tumors are also
nearly 20% of late mortality in this cohort. However, all- being investigated.
cause late mortality and rate of secondary malignancy in Research is also ongoing to minimize morbidity associ-
cancer survivors has decreased over time due to efforts to ated with diagnosis and treatment of pediatric brain
decrease the toxicity of therapy and improve survivorship tumors. Some studies are looking to decrease chemother-
care. (43) apy and radiotherapy in tumor types with excellent sur-
Brain tumor treatment also takes a toll on the psycho- vival outcomes, such as WNT-driven medulloblastoma and
logical health of survivors, who report higher rates of CNS germ cell tumors. Research is also ongoing to inves-
depression and lower rates of life satisfaction than their tigate the utility of liquid biopsy as a minimally invasive
peers. In addition, they are less likely to report having technique that might be used not only to make a diagno-
close friends, being married, attending college, and being sis, but also to monitor response to therapy or detect early
employed. Even compared with other childhood cancer relapse. (44) Liquid biopsy involves the isolation of circu-
survivors, survivors of childhood brain tumors have signif- lating tumor DNA or proteins from body fluids such as
icantly poorer psychosocial outcomes. It is imperative for CSF, blood, or plasma, which could potentially decrease
providers to be aware of these disparities and refer the need for surgical interventions.

CONCLUSIONS
including tumor pathology, tumor genetics, ana-
Although pediatric neuro-oncology is a specialized and tomical location, and treatment.
rapidly evolving field, patients often initially present to
their primary care pediatricians. It is essential for pediatri- • Based on strong evidence, treatment of childhood
cians to be familiar with presenting signs and symptoms, brain tumors with radiotherapy and chemotherapy
relevant physical examination findings, and acute manage- places survivors at increased risk for neurocognitive
ment of pediatric brain tumors. Knowledge of common deficits, neurovascular complications, endocrine
tumor types and their treatments, as well as acute and late dysfunction, secondary malignancies, impaired
effects of therapy, is also important as pediatricians con- psychosocial functioning, and other late effects.
tinue to follow these medically complex patients during
therapy and beyond as essential members of the neuro-
oncology team. Acknowledgment
This work was funded by the Gordon Fellowship in Pedi-
atric Neuro-Oncology Celebrating Futures Fund.
Summary
• Based on strong evidence, brain tumors are the References for this article can be found at
most common solid tumors in children and the DOI: 10.1542/pir.2020-004499.
most common cause of childhood cancer death.
• Based on strong research evidence, patterns of To view teaching slides that accompany this article, visit
symptoms and physical examination findings at 10.1542/pir.2020-004499.
presentation in a child with a brain tumor vary
with tumor location.
• Based on research evidence and consensus, brain

Childhood Brain
tumors are managed by a combination of surgery, Tumors
chemotherapy, or radiotherapy, depending on Katherine C. Pehlivan, MD1
Megan R. Paul, MD2
tumor type, location, dissemination, and age. John R. Crawford, MD2,3
• Based on research evidence as well as consensus, 1.

2.
3.
Department of Pediatrics, Division of Hematology-Oncology and Stem Cell Transplantaon, New York Medical College, Valhalla, NY
Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children's Hospital
Department of Neurosciences, University of California and Rady Children's Hospital, San Diego, CA
the morbidity and mortality associated with child-

hood brain tumors are determined by many factors,
PIR QUIZ
1. An 8-year-old boy presents with early-morning vomiting, headache,

and increased clumsiness. On physical examination, vision and extraocular
movements are normal and there is no facial asymmetry or hemiparesis. The
physician wants to rule out a brain tumor. Based on his signs and
symptoms, which of the following is the most likely location of a brain
tumor in this patient?
A. Brain stem.
B. Pituitary gland.
C. Posterior fossa.
D. Spinal cord.
E. Suprasellar region.
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ARTICLE
Care of the Immigrant Child

Karla Fredricks MD, MPH, FAAP*,† and Fernando Stein, MD, FAAP, FCCM‡,†
*
Global and Immigrant Health and
‡
Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX
†
Texas Children’s Hospital, Houston, TX
EDUCATION GAP
Because 3% to 4% of children in the United States are foreign-born, it is

highly likely that most pediatric providers will encounter these children in
their practice, and thus, important for all clinicians to understand best
practice guidelines for their care. Immigrant health curricula are not
standardized across US pediatric health professional training programs,
leading to variable levels of competency in currently practicing providers.

1. Describe national guidelines for the care of the immigrant child.
2. Use concepts from the national guidelines to implement practical
improvements in clinical service delivery for immigrant children, at both
the facility and individual levels.
3. Offer solutions for personal and professional obstacles that can arise
when caring for immigrant children.
INTRODUCTION
AUTHOR DISCLOSURE: Drs Fredricks and
There are approximately 2.5 million immigrant children in the United States, (1)
Stein have disclosed no financial
defined by the American Academy of Pediatrics (AAP) as “those born outside relationships relevant to this article. This
the United States to non–US citizen parents.” (2) This heterogeneous group commentary does not contain a
includes children from countries all around the world, with the top 4 countries
of origin being Mexico (18%), India (8%), China (5%), and the Philippines (3%). product/device.
(3) Most immigrant children come to the United States with 1 or both parents
for 1 or more of a myriad of reasons, including economic opportunity, educa- ABBREVIATIONS
tional attainment, family reunification, and/or safe haven from violence or per- AAP American Academy of Pediatrics
secution. In general, immigrants to the United States tend to be healthier than CDC Centers for Disease Control and
their US-born counterparts (known as the healthy immigrant paradox), but this Prevention
HEADSS
advantage tends to decrease over time. (4)(5) Although the exact reasons for this Home, education, activities, drugs,
are unknown, the effects of poverty (25% of immigrant children live below the suicidality/homicidality, sex
federal poverty level) (3) and lack of health insurance coverage (18%–33% of for- IOM International Organization for
Migration
eign-born children are uninsured, depending on immigration status) (6) likely ORR Office of Refugee Resettlement
play a large role. To mitigate this health decline and provide immigrant children UIC unaccompanied immigrant child
with the highest quality of care possible, the AAP recom- Community
mends specific core competencies for all pediatric health- In the same way that health services providers should
care providers. (2) This paper offers practical advice to work together to ensure a holistic approach, pediatric prac-
achieve these standards for all foreign-born children and tices should also collaborate with nonmedical community
concludes with helpful tips for caring for special immi- organizations that serve children. Schools, child care cen-
grant subpopulations as well as immigrant child health ters, community centers, social service organizations, and
practitioners themselves. places of worship can be invaluable partners in the mis-
sion to protect children’s health. This partnership should
be bidirectional, with medical practices sharing public
CONSTRUCTING THE MILIEU health information that community organizations can use
to educate their beneficiaries and community organiza-
Practice Environment
tions helping to identify children without a medical home
To create a practice environment that is welcoming to all
and directing them to medical practices.
patients, it is helpful to have a visual reflection of diversity.
For example, employing staff members and providers who
TAKING THE HISTORY
come from the varying communities served by your prac-
tice can help a family feel more comfortable. In addition, Language and Communication
At the start of the encounter, it is important for the pro-
any people depicted in artwork should represent a variety
vider to establish which language(s) the caregiver and
of different backgrounds, and signage should, when possi-
child are most comfortable speaking (this can differ
ble, include the most common languages spoken in the
between the two). If the provider is not fluent in the pre-
local community. Language services, either through a
ferred language of the caregiver and/or child, a certified
phone/video line or in person, should be available at all
medical interpreter should be used (ie, not a family mem-
visits. Furthermore, offering regular trainings for pro-
ber, a friend, or the child). Best practices for working with
viders and staff on cultural humility and implicit bias can
an interpreter include 1) maintaining eye contact with the
help everyone work together to create a positive experience
caregiver or patient while talking, 2) pausing every 1 to 2
for every patient.
sentences to allow the interpreter to translate, 3) position-
ing the interpreter next to the provider, and 4) speaking
directly to the caregiver or patient (eg, saying to the care-
Services Offered
giver, “Your child is growing well” instead of telling the
The gold standard for any pediatric primary care practice
interpreter, “Please tell the caregiver that their child is
is to be a “medical home,” where children and families
growing well”). (10)(11)
can receive comprehensive services and care coordination.
(7)(8)(9) As such, it is helpful to have a holistic view of Preface
health and employ staff who can support patients accord- With any new patient, introducing oneself and the
ingly. Depending on the population served, recommended involved clinical staff properly is key to establishing rap-
resources could be social work, referral coordination, port. It is also beneficial to describe the flow of the visit so
nutrition, and/or financial counseling. For the uninsured that families know what to expect. This can be particularly
population with limited income, having a sliding scale dis- important for children new to the United States because
count or charity care program would also be beneficial. many countries around the world do not use a similar pre-
Although these options are most often found at Federally ventive care approach (eg, apart from receiving vaccines,
Qualified Health Centers or other low-cost clinics, private children in developing countries might go to a health facil-
practices could help expand access for uninsured children ity only when they are ill). Normalizing (eg, saying, “These
by developing similar programs for a subset of their are questions I ask all new patients”) and framing (eg,
patients. Complementary services such as behavioral stating, “I only ask these questions because it helps me
health, dentistry, optometry, and pharmacy should be co- understand how to better care for your child”) are 2 tech-
located with primary care providers or, if not available niques that can help the caregiver and patient feel more
within the clinic, efficient referral pathways should be cre- comfortable. (12)(13) In addition, providers should let fami-
ated to ensure that patients are able to easily access these lies know that the information obtained remains only in
services at neighborhood organizations. the medical record (which is not shared with government

authorities), and they can choose not to answer a question that are recommended for use in the foreign-born
at any time without experiencing negative repercussions. population can be found through the National Child Trau-
matic Stress Network (https://www.nctsn.org/resources/
Medical Record Review measures-are-appropriate-refugee-children-and-families).
Caregivers often possess medical records for the child but (18) All children should also be screened for social deter-
might not offer to share them unless asked. Therefore, minants of health, including (but not limited to) housing,
inquiring whether families brought any past medical environmental exposures (eg, cigarette smoke, firearms,
paperwork with them (including vaccination records) and pets), interpersonal violence, food insecurity, and care-
should be done early in the visit. Children who are new to giver employment. (19)(20)(21)
the United States might have important health informa-
tion from their home country, countries through which CONDUCTING THE PHYSICAL EXAMINATION
they passed on their journey, predeparture medical visits Routine Measurements
(eg, through the International Organization for Migration Vital signs and anthropometric measurements, as well as
[IOM], US Embassy, or US Department of State), or hearing and vision testing, should be completed as recom-
another health facility in the United States (eg, clinic, mended in the AAP Bright Futures guidelines. (16) Fur-
urgent care, hospital, immigration facility/shelter, or thermore, children younger than 3 years who never
health department). received newborn screening—and for whom there is
parental or provider concern for hearing loss—should be
Questions referred to audiology. For foreign-born children 3 years
One of the first questions for all new patients, regardless and older, vision and hearing testing should be conducted
of background, should be, “Where was the child born?” at the first opportunity, regardless of whether they are cur-
Whether the child was born outside of the United States rently the age at which screening is typically conducted in
will determine whether an immigrant-focused framework the practice.
should be applied to the visit. If the child was born in the
United States, a typical history should be conducted Expectation Setting
according to AAP and individual practice guidelines. If the While the patient is still clothed, it is important to explain
child was born outside of the United States, specific ques- to the caregiver and patient what the physical examination
tions should be covered in addition to the typical history entails and how it will proceed. This might be the first
(Table 1). (14) time that the child has been fully assessed in the standard
manner for US healthcare. Specifically, the caregiver and
Screening patient should be informed that the routine health mainte-
Through the Bright Futures periodicity schedule, the AAP nance visit in the United States includes an examination
sets forth guidelines for when to screen children for devel- of the external genital area. Many children from develop-
opmental delay, psychosocial/behavioral concerns, sub- ing countries have never had a complete “head to toe”
stance use, and depression (https://downloads.aap.org/ examination by a medical professional because any visits
AAP/PDF/periodicity_schedule.pdf). (16) As appropriate to health facilities might have focused only on the present-
for age, screening of immigrant children should be initi- ing concern. If the caregiver or patient is not comfortable
ated at the first available opportunity. Foreign-born chil- with this full physical review and has no specific concerns
dren should also be asked about trauma exposure, if not about the genital area, this portion of the examination can
already part of routine practice, because they experience be deferred until the second visit. However, this should be
higher rates of trauma than native-born children. (17) considered an option only if follow-up can be ensured
Immigrant adolescents should be screened for depression, (due to the potential for missing conditions such as imper-
anxiety, and posttraumatic stress disorder in addition to a forate hymen or undescended testes, among other congen-
HEADSS (Home, Education, Activities [including employ- ital or acquired conditions).
ment], Drugs, Suicidality/homicidality, Sex [including
questions about menstrual history, consensual sex, sexual Physical Examination
abuse, and child marriage]) assessment that covers their The patient should change into a gown for the physical
experience in previous countries and the United States. examination. As the examination is conducted, the pro-
Tools to assist with screening for mental health concerns vider should talk through every aspect with the patient
Table 1. Special Considerations While Taking the History of Immigrant Children
Birth history In what type of facility (hospital, clinic, home) was the child born? Did the
mother undergo any laboratory testing while pregnant? If so, are the
results available? Did the child undergo any laboratory testing or other
screening in the newborn period? If so, are the results available?
Medical/surgical history Did the child have a blood transfusion? Do they have any tattoos or
traditional scarification? Was the male child circumcised? If so, in what
setting? Did the female child have any procedures to alter the genital
area, such as female genital mutilation or cutting? (15)
Family history Is there any history of human immunodeficiency virus, hepatitis B, hepatitis
C, tuberculosis, or hemoglobinopathies in the family?
Exposure history What type of work did the child’s caregiver(s) do before coming to the
United States? What type of work does he or she perform in the United
States?
Social history With whom was the child living in their home country? With whom did
they travel to the United States? By what mode of transportation did
they travel to the United States? Through what countries did they pass?
When did they arrive in the United States? Were they ever separated
from their caregiver? Were they ever detained? How long was the
journey to the United States?a
Nutrition history What was the child’s typical diet before coming to the United States? What
is the child’s typical diet now? Was there a time in the child’s life that
the caregiver worried that there would not be enough food for the
child? If so, does the caregiver still worry about that?
Education history What was schooling (if any) like before coming to the United States? Did
the child have any learning challenges when being taught in his or her
preferred language? If so, what were they?
a
The questions related to immigration are asked solely for the purpose of eliciting historical details that might require fur-
ther follow-up, such as a need for particular infectious disease testing based on regional exposure or more detailed assess-
ments for sequelae of trauma; they are not asked to determine immigration status. A child’s immigration status should
generally not be written in the medical record, especially if the child is undocumented. However, clinics that focus specifi-
cally on the care of newly arrived children might have the expertise to accurately denote the designation of an immigrant
child with legal status, as might a provider working with an immigration attorney for a particular child.
and caregiver to help them feel as comfortable as possible. be given to certain areas for immigrant children (Table 2).
The provider should approach the physical examination as (14)
he or she would a newborn examination, as if no medical
provider has ever fully evaluated the child before. There LABORATORY TESTING
might be unaddressed or undiagnosed abnormalities Children who are born in other countries often do not
found on examination that, with proper intervention or receive the same laboratory screenings that US-born chil-
follow-up, can be prevented from causing problems in the dren receive as neonates and throughout childhood, and
future. In addition to the standard physical examination neither do their mothers during the prenatal period. If the
recommendations for all children, special attention should mothers and/or children were tested, it is unlikely that
Table 2. Special Considerations During the Physical Examination of Immigrant Children

EXAMINATION TYPE ASSESSMENT FOR
Eyes Strabismus, coloboma, ptosis, nystagmus, cataracts, conjunctival
pallor
Teeth Visible caries, significant malalignment
Neck Goiter
Heart Murmurs/gallops/rubs while seated and supine
Skin Birthmarks, nevi, scars, tattoos
Skeleton Bony deformities, scoliosis, polydactyly, clubfoot, evidence of
rickets (genu varum/valgum, rachitic rosary, frontal bossing/
delayed closure of fontanelle, and flared wrists/ankles)
External genitalia Tanner stage, female genital mutilation or cutting, imperforate
hymen, undescended testes, inguinal hernias
General Wasting, stunting

the results are available or easily attainable. One nota- residing in the United States, (16) as well as targeted testing
ble exception is the case of children who enter the based on concerns arising during the history and physical
United States through the Refugee Resettlement Pro- examination, such as dietary deficiencies, abnormal physical
gram. Most receive all the recommended laboratory findings, or risk factors for infectious disease. In addition,
tests within the first 90 days of arrival in the United providers can consider screening for conditions such as
States, and the results should be available on request. sickle cell trait and glucose-6-dehydrogenase deficiency,
In addition, a review of their overseas medical exami- depending on family history and region of origin. Further
nation paperwork might reveal that they were given recommendations for screening can be found in the AAP
presumptive treatment for certain conditions immedi- Immigrant Child Health Toolkit (https://www.aap.org/
ately before departure and thus do not require addi- en-us/advocacy-and-xpolicy/aap-health-initiatives/Immigrant-
tional screening or presumptive treatment (see the Child-Health-Toolkit/Pages/Immigrant-Child-Health-Toolkit.
Refugees subsection later herein). In the absence of aspx) and the Centers for Disease Control and Prevention
medical records that contain these results, screening (CDC) Domestic Refugee Guidelines (https://www.cdc.gov/
laboratory studies should be considered for all asymp- immigrantrefugeehealth/guidelines/domestic/
tomatic foreign-born children, especially those from domestic-guidelines.html). (14)(22)
Africa, the Middle East, Asia, Latin America, and the
Caribbean (Table 3). Symptomatic
Symptomatic children should receive testing and treat-
Asymptomatic ment for their presenting condition either before or at the
Routine screening tests should be added by age as recom- same time as their screening is conducted, whichever is
mended in the AAP Bright Futures guidelines for all children medically appropriate. For children who present with fever
Table 3. Recommended Laboratory Testing of Asymptomatic Immigrant Children

Baseline laboratory tests for all children Complete blood cell count with differential count (focus on anemia,
eosinophilia)
Lead (age 0–16 y, pregnant or breastfeeding females at any age)a
Interferon-c release assay (first-line at any age: interferon-c release
assay, second-line: tuberculin skin test)a
HIV (antibody test for age $18 mo, RNA test for age <18 mo)
Syphilis (EIA, VDRL test, or RPR test at any age or FTA-ABS test if $12
mo old)
Hepatitis B surface antigen
Hepatitis C antibody (if positive, would need confirmatory RNA test if
age <18 mo)
Strongyloides serology (IgG) (see Table 4 for optional presumptive
treatment)
Ova and parasite stool test, 2–3 samples collected on 2–3 different
days (although presumptive treatment is preferred over testing, if
possible [see Table 4])
If <12 mo of age, add: Newborn screen
If <6 y of age,b add: Thyrotropin thyroid stimulating hormone (TSH)
Free thyroxine (T4)
If adolescent, add: Pregnancy test for females (urine beta hCG)
Gonorrhea/chlamydia for males and females (urine nucleic
amplification test)
If lived in sub-Saharan Africa (excluding Lesotho), add: Schistosoma serology (IgG) (see Table 4 for optional presumptive
treatment)
If lived in Latin America and received a blood transfusion or organ Chagas serology (IgG for Trypanosoma cruzi)
transplant while there, are pregnant, are immunosuppressed, or
mother has a known diagnosis of Chagas disease, add:
EIA=enzyme immunoassay, FTA-ABS=fluorescent treponemal antibody absorption, hCG=human chorionic gonadotropin, HIV=human immu-
nodeficiency virus, IgG=immunoglobulin G, RPR=rapid plasma reagin, VDRL, venereal disease research laboratory test.
a
Consider repeating at the follow-up visit (see the Laboratory Testing subsection under the Follow-up Visit section), even if initially normal
and no known exposures since the previous test. Other repeated testing to be determined by new exposures.
b
Unpublished consensus guidelines from Andrew Bauer, MD, The Thyroid Center, Division of Endocrinology and Diabetes, Perelman School
of Medicine, University of Pennsylvania; Jennifer Barker, MD, Sharon Travers, MD, Philip Zeitler, MD, Maggie Chan, MD, University of Colo-
rado School of Medicine, Children’s Hospital Colorado, Department of Pediatric Endocrinology; Janine Young, MD, Division of General Pedi-
atrics, Denver Health, University of Colorado School of Medicine.
within the first 4 months of arrival in the United States treatment given for these conditions (Table 4).(14)(22) For
from a malaria-endemic area, malaria testing should be children who are uninsured or underinsured, discount pric-
performed as part of the evaluation. After 4 months, ing might be available for medications through prescription
malaria should remain on the differential diagnosis but assistance programs.
testing performed only if indicated by the presence or
absence of other symptoms (eg, fever plus headache or Vaccinations
fever plus vomiting and diarrhea would be more consis- Vaccinations given in other countries can be accepted if
tent with malaria, whereas fever plus cough or rhinorrhea the dates are written in ink (or typed) on an official immu-
is less likely related to malaria). nization form, the timing of administration and vaccine
type are acceptable per CDC guidelines, (23)(24) and the
record contains the patient’s correct name and date of
TREATMENT
birth. If the child’s previous immunization record meets
Medications
all the preceding criteria, they will require only any catch-
Aside from medicine needed to treat identified concerns, a
up vaccinations not already administered (can test for
multivitamin with iron should be considered for all chil-
immunity before going directly to administering vaccines,
dren, especially those between 6 months and 6 years of if possible and desired). If the child does not have an
age. (14) Newly arrived children might not have had access attainable immunization record or the record is not
to a wide variety of nutritious foods before coming to the acceptable, there are 2 options: 1) serum testing can be
United States and can benefit from supplementation. performed to assess for immunity (available for hepatitis
In addition, presumptive treatment should be given to A, hepatitis B, measles, mumps, rubella, and varicella)
all children older than 12 months for soil-transmitted hel- and vaccines given only if not immune or for diseases for
minths (Table 4). This is preferable because stool tests for which serologic evidence of immunity is not possible; or
ova and parasites have poor sensitivity and the medications 2) all vaccinations can be administered as if the child has
are generally well tolerated. However, if treatment is contrain- never received any immunizations, per the CDC catch-up
dicated, stool for ova and parasites should be analyzed with 2 schedule. The latter option might be the most practical for
to 3 stool samples from different days. Stool testing is not an situations in which the child is uninsured because the lab-
effective screen for strongyloidiasis and schistosomiasis, so oratory cost might be prohibitive, the vaccines can be
either serum testing should be performed or presumptive given without charge through the Vaccines for Children
Table 4. Presumptive Treatment Options for Immigrant Children

AGE/WEIGHT
RECOMMENDATIONS (IF NO
OTHER
DISEASE CONTRAINDICATIONS) MEDICATION AND DOSAGE CONTRAINDICATIONS
Soil-transmitted helminth $12 mo of age Albendazole: 12–23 mo of age: Pregnancy, allergy to
infection: first line 200 mg po once; $24 mo of albendazole, known
age: 400 mg po once cysticercosis or
neurocysticercosis, seizures
of unknown etiology
Soil-transmitted helminth $2 y of age Pyrantel pamoate: 11 mg/kg po Allergy to pyrantel pamoate
infection: second line of pyrantel base daily × 3 d;
maximum 1,000 mg/dose
Strongyloidiasis $15 kg in weight Ivermectin: 0.2 mg/kg po daily × Pregnancy, breastfeeding an
2d infant <1 wk old, allergy to
ivermectin, from a Loa
loa–endemic country,
known cysticercosis or
or neurologic disorders of
unknown etiology
Schistosomiasis $4 y of age Praziquantel: 40 mg/kg po Allergy to praziquantel, known
divided into 2 doses × 1 d cysticercosis or
or neurologic disorders of
unknown etiology
po=by mouth.

Table 5. Select Immigrant-Focused Organizations in the United States
Organization Website
American Immigration Council https://www.americanimmigrationcouncil.org
International Refugee Assistance Project https://refugeerights.org
Migration Policy Institute https://www.migrationpolicy.org
National Immigration Law Center https://www.nilc.org
Protecting Immigrant Families https://www.protectingimmigrantfamilies.org
RAICES: The Refugee and Immigrant Center for Education and Legal Services https://www.raicestexas.org
United We Dream https://unitedwedream.org
Young Center for Immigrant Children’s Rights https://www.theyoungcenter.org
program, (25) and the benefits to ensuring coverage for United States, with the exception of the visit immediately
vaccine-preventable illnesses greatly outweigh the minimal after their establishment of care. If the next routine visit
risk to the child of receiving vaccinations. would be more than 6 months after the initial visit, a fol-
low-up should be scheduled for 1 to 6 months in the
RECOMMENDATIONS AND REFERRALS future. This visit is necessary to check on referrals or
Families who are new to the United States would benefit issues from the first visit, review any medical records that
from anticipatory guidance on how the health care system have been received in the interim, do additional laboratory
works, including explanations about primary care providers, testing and vaccinations (as needed), and identify new
the concept of a medical home, preventive care, the referral concerns.
process, and appropriate use of urgent care as well as emer-
gency departments and 9-1-1. They should also be connected
History and Screening
This time should be used to discuss how the child is
to services to meet their comprehensive health needs, either
adjusting to American culture, review how he or she is
within the same facility or as an external referral. For example,
doing in school (if applicable), reassess the social determi-
any child 12 months and older should be linked to a dentist.
nants of health (see the Screening section previously
Referrals should also be made for children with behavioral
herein), and ask about any new issues. Screening for men-
health, optometry, or other subspecialty concerns. Finally,
tal health and trauma should also be repeated because it
families should be informed of resources for which they are
can capture new concerns or yield previously unrevealed
eligible that can alleviate health risks caused by social circum-
information that the patient is now more comfortable
stances. These resources can include federal supports such as
sharing. A second HEADSS assessment should be com-
the Special Supplemental Nutrition Program for Women,
pleted for adolescents as well.
Infants, and Children (aka WIC; open to all children <5 years
of age whose families meet income requirements) and the
Physical Examination
Supplemental Nutrition Assistance Program (aka SNAP; open
A focused physical examination should be conducted to
only to lawful permanent residents, US citizens, and grantees
follow up on any abnormalities noted at the first visit or
of humanitarian relief whose families meet income require-
to evaluate new concerns revealed in the history. If the
ments) as well as local resources, including food banks, legal external genital examination was normal at the first
organizations, housing support, domestic violence hotlines, visit, there are no current, related complaints, and the
utility and rental assistance, recreation/community centers, child is at least 3 years old, this region does not need to
English-language classes, and job training. Immigrant-specific, be addressed and can be examined on a once yearly
nationwide, nongovernmental organizations can also offer schedule. If, however, all 3 conditions are not met, the
resources and/or information for providers and families genital area should be examined at this follow-up visit.
(Table 5). Weight and height/length should also be checked to
determine whether the child is growing well. On the
FOLLOW-UP VISIT other side of the spectrum from undernutrition and fail-
Timing ure to thrive, some newly arrived children who initially
Immigrant children should be seen on the same routine present with a body mass index within normal limits
preventive care schedule as children who were born in the experience rapid weight gain due to overindulgence in
the typical American diet. It is important to identify extensive vetting abroad—to have a well-founded fear of
these children and discuss interventions (eg, how to persecution or harm if they were to return to their coun-
select healthier foods and beverages, recommendations tries of origin. Before arrival in the United States, refu-
for exercise, and limiting screen time) with their care- gees receive predeparture medical examinations, usually
givers before the children develop weight-related health by the IOM. The US Refugee Resettlement Program is
problems. the formal process by which they come to the United
States and are resettled into communities by local agen-
Laboratory Testing cies. (29) Refugee children are typically able to receive
For children up to 6 years of age, a second lead level Medicaid and have case managers who assist their fami-
should be measured 3 to 6 months after the first visit lies with finding health services, among other supports.
(even if the first level was normal). The reason for Furthermore, refugees generally receive their first set of
repeated testing is to assess the current environmental postarrival laboratory screenings and vaccinations at a
exposure because the first level can reflect the previous liv- health department, community health center, or aca-
ing environment in newly arrived children. If a child of demically affiliated clinic within their first 90 days in
any age was experiencing severe stress, malnutrition, para- the United States. Records from this visit should be
sitic infection, or untreated human immunodeficiency requested (if not immediately available) to avoid repeat-
virus infection at the initial visit, a repeated tuberculosis ing laboratory tests and vaccinations unnecessarily. In
test should be performed. It is recommended to do an addition, previous records from countries of origin or
interferon-g release assay if at all possible, although a transit should be reviewed—such as the medical infor-
tuberculin skin test can be used if the interferon-g release mation from the predeparture examination conducted
assay is not feasible. (26)(27)(28) Other tests might be by the IOM—to look for any laboratory and radiology
warranted, as well, depending on specific disease pro- results as well as any presumptive treatment and vacci-
cesses and new risk factors (eg, testing for sexually trans- nations given.
mitted infections might be needed if sexual activity or
abuse has occurred or been revealed since the original Unaccompanied Immigrant Children
visit). Most children without a parent or legal guardian who arrive
in the United States and do not have a previously approved
Treatment form of admittance are transferred to the custody of the
If presumptive treatment was prescribed for parasites, the Office of Refugee Resettlement (ORR). Although unaccom-
provider should ensure that it was taken. In addition, the panied immigrant children (UIC) are not considered refu-
efficacy of any ongoing medications should be assessed gees, the ORR (under the Department of Health and
and refills prescribed, as needed. The multivitamin recom- Human Services) is the branch of the US government tasked
mended at the first visit can be either continued or with covering the basic needs of these children while the
stopped after 6 months of treatment, depending on the government assesses potential “sponsors” (usually parents or
diet of the child. Catch-up or routine vaccinations should other family members) to assume guardianship. Within the
be given per the CDC timetable. first 24 hours of entry into ORR care in a shelter (where
If there are no issues identified or continuing vacci- most UICs are placed) or foster home, every child receives a
nation delays that necessitate more frequent follow-up, psychological evaluation and, within 48 hours of entry, an
the child can then be scheduled for his or her next pre- initial medical examination. Typically, ORR-affiliated shelters
ventive care visit per the routine Bright Futures guide- contract with external pediatric-trained practitioners to come
lines. (16) into the shelter to provide preventive and acute care,
although some hire full-time, in-house providers and others
SPECIAL CIRCUMSTANCES take the UICs to an outside clinic. The initial medical exami-
Refugees nation consists of a full history and physical examination,
Children who arrive in the United States as refugees are vaccinations, and testing for tuberculosis. Adolescents 13
generally with a parent or guardian, although a small years and older are also tested for human immunodeficiency
subset are “unaccompanied refugee minors” and placed virus, and children at any age are screened for sexually trans-
with foster families. Refugees in the United States have mitted infections if they disclose sexual abuse or activity (any
been predetermined—through months to years of disclosure of abuse that occurred in the United States must

be reported to child protection authorities, as it is for all chil- the United States while their asylum claim was processed.
dren). If there are abnormalities identified through the initial Because these children are living in US communities and
medical examination or known, preexisting conditions, the accessing local health-care, it is important to recognize
children are referred to local subspecialists. While in ORR whether they have a history of detention, to assess for any
custody, UICs are covered by health insurance, and ORR— signs or symptoms of resultant trauma, and to facilitate con-
as well as shelter staff, by officially designated extension— nections to mental health services, as needed. In addition,
has medical decision-making authority on their behalf. (30) note that immigration policies change over time and families
However, healthcare providers are encouraged to contact the could again be held in detention in the future.
UIC’s parent or other family member, as appropriate, to be
PROTECTING THE PEDIATRIC PRACTITIONER
sure that an accurate health history is obtained and those
who know the minor best are able to contribute to the for- As a result of the everyday challenges of caring for immigrant
mulation of their medical plan of action. children and families, frontline practitioners working with this
When UICs are released from ORR care to live with their population are at high risk for burnout. Care must be taken
sponsors, the health insurance coverage they previously to prevent the compassion fatigue that can result from burn-
received is terminated. In 6 states (Washington, Oregon, Cali- out as well as recognize and intervene when it is beginning to
manifest. Although self-care such as yoga and meditation
fornia, Illinois, New York, and Massachusetts) and the District
have proved to be beneficial in decreasing stress, interventions
of Columbia, children are eligible to receive public health
that increase resilience and self-efficacy have been shown to
insurance coverage regardless of immigration status. If the
be more effective in alleviating burnout. (34) An important
child will be living in one of the remaining 44 states, it is
avenue through which to build this resilience in practitioners
likely that he or she will be uninsured (unless the sponsor
for immigrant children is through advocacy. This can come in
can provide private insurance coverage). Thus, access to care
the form of contacting elected officials on a particular topic or
can be a challenge, and these children typically require finan- writing resolutions on immigrant-related issues for state medi-
cial assistance programs and/or charity care to meet their cal societies. (35) Practitioners can also join professional organ-
health needs. If the sponsor and child do not bring the izations, such as the AAP, in raising awareness about the
records of vaccinations and laboratory results from ORR to structural injustices that form the root of health inequities in
their new health facility after release, they can be requested at immigrant children and supporting legislation to reform the
the ORR website (https://www.acf.hhs.gov/orr/resource/ system. Although the societal, environmental, and economic
unaccompanied-childrens-services). challenges facing immigrant populations are staggering, medi-
cal professionals can partner in their advocacy with organiza-
Families in Detention tions and individuals that address factors across the spectrum
Before spring 2021, there was a small but significant minority of social determinants of health. It is this fortifying, action-ori-
of children who arrived in the United States with a parent or ented collaboration of health professionals, social workers,
guardian and were placed in family detention together. There educators, politicians, faith leaders, service organizations, legal
were 3 such facilities in the United States, with a total capacity advocates, and immigrant parents, among others, that is the
of approximately 3,700 individuals within family units. (31) ultimate antidote to burnout and the fuel to keep the fire
Although the medical services varied among facilities, children burning on behalf of immigrant children for as long as they
continue to come.
and adults generally did not receive any screening other than
a rapid examination for scabies, lice, and varicella. The fami-
lies had access to health care on site for acute needs and hos-
Summary
pital referral for emergencies only. Occasionally and without a
predictable pattern, family detention centers conducted tuber- • Based on strong research evidence, immigrant
culosis testing or full physical examinations of children but children in the United States are a heterogeneous
did not typically give vaccinations. (32) population, the care of which requires specialized
Per the Flores Settlement Agreement, children should not clinical knowledge of particular global health
be held in detention for more than 20 days. (33) Although concerns as well as cultural humility in its
this limit was violated at times, most families who were approach. (2)
placed in these detention facilities were eventually released, • Based on strong research evidence, the gold
and most of them went on to stay with friends or family in standard for immigrant children (as it is for US-
born children) is to receive health services in a followed closely in the postmigration period to
medical home that can provide referral support, build trust and rapport between practitioner and
care coordination, and community connection. patient, assess for acculturation concerns, ensure
(7)(8)(9) compliance with Centers for Disease Control and
• Based on some research evidence as well as Prevention (CDC) and American Academy of
Pediatrics guidelines, monitor chronic conditions,
consensus, the history of an immigrant child should
and address any new issues. (2)(14)(22)
include information related to premigration, during
migration, and postmigration to elicit risk factors to • Based on some research evidence as well as
guide screening, physical examination, diagnostic consensus, children who were admitted to the
evaluation, and treatment. (14) United States as unaccompanied immigrant children
or refugees, as well as those who experienced family
• Based on some research evidence as well as
detention, are subpopulations of immigrant children
consensus, immigrant children typically have not
who require particular understanding of their
received care equivalent to US-born children in
unique, respective circumstances. (29)(30)(31)(32)(33)
their country of origin and could have been
exposed to pathogens uncommon in the United • Based on some research evidence as well as
States. Therefore, in addition to following expert opinion, pediatric practitioners working
standard guidelines for all children in the United with immigrant children are at high risk for
States, immigrant children at any age might need burnout and can mitigate that risk by building
laboratory studies, physical examinations, and resilience through advocacy. (34)(35)
vaccinations that were previously missed as well
as targeted testing or presumptive treatment for
specific exposures. (14)(22) References for this article can be found at
DOI: 10.1542/pir.2020-000729.
• Based on some research evidence as well as
consensus, immigrant children should be

PIR QUIZ
1. You are seeing a 4-year-old girl who recently immigrated to the United
States with her family from Somalia. Her father has a position at your local
university and has been in the United States for a year. The girl, her mother,
and 2 siblings arrived last week from Somalia and are establishing care with
you. The father and the girl’s 8-year-old sister speak English, Somali, and
Italian. The girl, her mother, and her younger brother speak Somali and
Italian. A family friend drove the mother, your patient, and the older sister to
the clinic. The family friend speaks Somali and English. You do not speak
Somali and there are no colleagues or staff members in your practice who
speak Somali. However, you do speak Italian at a beginner level. Which of
the following is the best option to communicate with the family?
A. Ask the older sister to translate in Somali in person. REQUIREMENTS: Learners can
take Pediatrics in Review quizzes
B. Ask the adult family friend to translate in Somali in
and claim credit online only at:
person. http://pedsinreview.org.
C. Ask to reschedule the visit to a time when the father
can attend the visit. To successfully complete 2022
D. Communicate with the family in Italian. Pediatrics in Review articles for
E. Use a certified interpreter who speaks Somali. learners must demonstrate a
minimum performance level of
2. A 5-year-old boy and his family have been placed in your city by a refugee 60% or higher on this
organization. A care coordinator for the refugee organization set up the assessment. If you score less
appointment with you for a health supervision evaluation. The mother is confused than 60% on the assessment,
you will be given additional
by why her son needs an evaluation because he is not ill. Your medical assistant
opportunities to answer
asked the boy to undress and put on a gown for the examination. The mother questions until an overall 60%
was upset because she does not want her son’s genitals to be seen. Which of the or greater score is achieved.
following is the most appropriate approach that you should take in this situation?
This journal-based CME activity
A. Call the care coordinator from the refugee organization
is available through Dec. 31,
and ask for guidance. 2024, however, credit will be
B. Discuss the concept of the health supervision visit recorded in the year in which
compared with the sick care visit. the learner completes the quiz.
C. Reprimand the medical assistant for asking the boy to
put on the gown.
D. Reassure the mother that you have seen the genitals
of many young boys.
E. Tell the mother that this is a required examination to
2022 Pediatrics in Review is
stay in the country.
Maintenance of Certification
3. A 2-year-old girl recently emigrated from Bolivia with her family. Her (MOC) Part 2 credits by the
physical examination findings are normal. Her height and weight are at American Board of Pediatrics
the 10th percentile. Her mother brings an immunization record in the
child’s name with the correct date of birth, and the paperwork Review subscribers can claim up
documents that her immunizations are up to date. In addition to ordering to 30 ABP MOC Part 2 points
routine laboratory studies, which of the following is the most appropriate upon passing 30 quizzes (and
additional plan in the management of this patient? claiming full credit for each
quiz) per year. Subscribers can
A. Add ova and parasite stool testing to the laboratory
panel. early as October 2022. To learn
B. Add measles serology to the laboratory panel. how to claim MOC points, go
C. Prescribe pyrantel pamoate for 3 days. to: https://publications.aap.org/
D. Refer the girl for a nutritional evaluation. journals/pages/moc-credit.
E. Start immunizations on a catch-up schedule.
4. An 18-month-old boy is brought to the clinic by his parents to establish care as
the family recently immigrated from India. Physical examination is unremarkable.
You obtain the laboratory testing recommended for asymptomatic immigrant
children, and treat the entire family presumptively for intestinal parasites. The
family reports that he had received vaccines before and they do have the child’s
medical records with them at home but forgot to bring them to the clinic today.
In planning follow-up visits for this child, you request the family to send you the
records and discuss the future visit schedule and what will be done at the next
appointments. Which of the following is the most appropriate follow-up plan for
this patient?
A. Add measles serology to the laboratory panel.
B. Follow-up at 2-years of age as per the US schedule and then yearly
afterwards.
C. Follow-up in 4–6 weeks for record review and appropriate immunizations.
D. Give the 2-months vaccines today and follow-up in 2 months for next set of
vaccines.
E. Next time he requires immunizations is at 4–5 years of age.
5. A 5-year-old boy and his family are refugees from Sudan, and he is seeing you
for a first visit. Your evaluation shows average growth and normal physical
examination findings. You discuss laboratory studies with the family. You
would like to order a complete blood cell count, interferon-c release assay,
hepatitis C antibody, and hepatitis B surface antigens today. You schedule
the patient for a follow-up visit in 3 months. You are most likely to order
which of the following additional laboratory studies?
A. Chagas serology today.
B. Human immunodeficiency virus testing at the next visit.
C. Lead level today and repeated at the next visit.
D. Newborn screen at the next visit.
E. Urinalysis and culture.

ARTICLE
Human Immunodeficiency Virus

Preexposure Prophylaxis in Adolescents
and Young Adults
Megan E. Brundrett, MD, MPH*
*
Division of Primary Care and Infectious Disease, Nationwide Children’s Hospital, Columbus, OH
PRACTICE GAPS
Pediatricians should be able to identify youth at higher risk for human

immunodeficiency virus acquisition and teach human immunodeficiency
virus prevention strategies, including preexposure prophylaxis.

1. Identify youth at higher risk for human immunodeficiency virus (HIV)
acquisition.
2. Understand how to teach and develop an HIV prevention strategy for at-
risk patients.
3. Initiate and manage preexposure prophylaxis for youth at higher risk for
HIV acquisition.
4. Understand the special considerations when prescribing preexposure
prophylaxis for minors.
ABSTRACT
AUTHOR DISCLOSURE Dr Brundrett has
Human immunodeficiency virus (HIV) prevention holds the promise of disclosed no financial relationships
decreasing the burden of HIV infections worldwide. Access to HIV prevention relevant to this article. This commentary
does contain a discussion of an
services, including preexposure prophylaxis (PrEP), is a key strategy in
unapproved/investigative use of
reducing HIV transmission, but it continues to be underused. PrEP, a once- commercial products.
daily medication for HIV prevention, is approved for adolescents. A
pediatrician’s role is critical in identifying and increasing access for adolescents ABBREVIATIONS
and young adults to PrEP services and reducing HIV acquisition in youth.
ART antiretroviral therapy
CDC Centers for Disease Control and
Prevention
CrCl creatinine clearance
FDA Food and Drug Administration
HIV INFECTIONS HIV human immunodeficiency virus
HIV-1 and HIV-2 are the viruses that cause HIV infection, with HIV-1 causing PrEP preexposure prophylaxis
STI sexually transmitted infection
most infections worldwide, including in the United States, which is the focus of TAF tenofovir alafenamide
this article. These viruses are enveloped, single-stranded retroviruses that TDF tenofovir disoproxil fumarate
predominantly target CD41 T lymphocytes. The virus enters Services, provides support and financial resources to these
the cell by binding with a cellular coreceptor, which results communities. It also includes support to seven states
in envelope fusion with the cell wall. In the CD41 T lympho- where at least 10% of new diagnoses are in rural areas,
cyte, the virus uses reverse transcriptase to create HIV DNA which typically have less access to HIV care. The overarch-
and integrate into the cellular DNA. It then replicates, releasing goal is a 75% reduction in new HIV infections by
ing HIV virions. Ultimately, this process leads to CD41 lym- 2025 and at least a 90% reduction by 2030. (7)
phocyte death and, if left untreated, immunosuppression
from widespread CD41 lymphocyte cell destruction. ADOLESCENT AND YOUNG ADULT HIV CARE
Globally, in 2019 there were 1.7 million newly infected CONTINUUM
individuals with HIV and 38 million people living with The HIV care continuum identifies 4 areas as stepwise
HIV. (1) In the United States there were almost 37,000 indicators to overall HIV control: awareness of HIV diagno-
persons newly diagnosed as having HIV infections in sis, being seen within 30 days of diagnosis, continuing in
2019, of which 21% were youth aged 13 to 24 years. (2) care, and maintaining viral suppression. Compared with
Worldwide, HIV infections in youth predominantly occur older adults, fewer young people living with HIV are linked
in women, acquired through heterosexual contact, with to care, retained in care, or achieve viral suppression. (8)
the largest number of new infections in sub-Saharan Viral suppression is achieved when an individual is receiv-
Africa. (3)(4) In contrast, in the United States, most newly ing antiretroviral therapy (ART) and the number of copies
acquired HIV infections in this age group occur in gay of HIV is less than 200 per mL of blood or has reached an
and bisexual young men. Male-to-male sexual contact is “undetectable” level that is too low to be quantified per the
the leading risk factor of HIV acquisition, followed by het- assay used. The overall HIV viral suppression rate in the
erosexual contact, predominantly in females, with a lesser United States is estimated to be 56% and includes individu-
portion attributed to injection drug use. (2) als who are aware and unaware of their diagnosis. (5)(8) In
Although the incidence of HIV in youth has decreased youth aged 13 to 24 years, the estimated overall viral sup-
slightly during the past 10 years, there continue to be signifi- pression rate is only 30%. (8) Lower rates of viral suppres-
cant racial, ethnic, gender, and geographic disparities in HIV sion lead to an increased potential for transmission to
acquisition in the United States. Black/African American and others and higher community viral load.
Latino youth are disproportionately affected by HIV. In 2018, Youth are also the most likely group to be unaware of their
of new HIV infections in youth, 52% were in Black/African HIV infection status. The Centers for Disease Control and Pre-
American individuals, although they represent 14% of the vention (CDC) estimates that 4 in 7 people aged 13 to 24 years
general population, compared with 17% in white youth, who are unaware that they are living with HIV, and this unaware-
compose 53% of the population. (5) At the end of 2017, of ness increased from 2014 to 2018. (8) Not knowing one’s HIV
females (aged 13–24 years) living with HIV, 62% were Black infection status delays entry into care, leads to potentially sicker
compared with 13% who were white. (5) Latino gay and bisex- patients at the time of diagnosis, and decreases the number of
ual young men had a 13% increase in the incidence of HIV individuals who are taking ART and are virally suppressed.
diagnoses between 2010 and 2017, and the overall rates in These factors lead to increased deaths attributable to HIV in
Black/African American and white gay and bisexual individu- youth compared with older aged groups. In 2017, 48.6% of
als declined or remained stable. (5) Transgender men and deaths in youth (aged 13–24 years) diagnosed as having HIV
women are also disproportionately affected. In the United were directly related to HIV, which in most cases was prevent-
States in 2017, the HIV prevalence was 14.1% in transgender able if had been identified and treated. (9)
women and 3.2% in transgender men compared with less
than 0.5% in the total adult population. (5)(6) HIV PREVENTION STRATEGIES
Regionally there are differences, with the southern Components of HIV prevention plans include being regularly
United States having the highest rates of new HIV diagno- tested for HIV, getting tested and treated for sexually transmitted
ses. (2) Greater than 50% of new HIV diagnoses occur in infections (STIs), using barrier protection (condoms) during all
48 US counties, Washington DC, and San Juan, Puerto types of sexual activity, and knowing a sexual partner’s HIV sta-
Rico. End the HIV Epidemic: A Plan for America focuses on tus. For people who inject drugs, needle exchange programs that
these regional differences and the unique aspects of these offer clean needles and elimination of needle sharing with others
areas and modes of transmission. (7) This focused strat- help prevent HIV acquisition. Understanding when and how to
egy, led by the US Department of Health and Human access postexposure prophylaxis if one has a known exposure to

HIV is another important prevention strategy, but such strategies of PrEP. Protective levels of tenofovir diphosphate were found
must be initiated within 72 hours of HIV exposure. in colorectal tissue at 7 days compared with up to 21 days for
If an individual seronegative for HIV is in a sexual vaginocervical tissue. (14) This suggests that women are not
relationship with a partner living with HIV, knowing the fully protected until 3 weeks after taking PrEP daily. This is
partner’s viral load and adherence to ART is important to an important aspect when counseling new PrEP patients.
understanding one’s own risk of HIV acquisition. Indi- In 2017, a demonstration project evaluated the safety,
viduals living with HIV who have been virally suppressed acceptability, and adherence of TDF/emtricitabine and moni-
for at least 6 months and are taking ART as prescribed tored patterns of risk behavior in youth. (15) They enrolled
have no risk of transmitting the virus sexually to others, 78 healthy young men aged 15 to 17 years who reported sex-
(10) including during unprotected sex. This prevention ual activity with other men and did not require parental con-
strategy is the basis for the U=U, Undetectable = Untrans- sent to participate. Eligibility included self-report risk of HIV
mittable, campaign, a public awareness effort to improve acquisition via any of the following risk behaviors in the past
education and reduce the stigma of HIV. 6 months: unprotected anal intercourse with an HIV-sero-
positive male partner or a male partner of unknown HIV sta-
PREEXPOSURE PROPHYLAXIS tus, anal intercourse with at least 3 different partners, or an
Preexposure prophylaxis (PrEP) should be part of an HIV pre- STI. (15) Due to known adverse effects of TDF/emtricitabine
vention strategy in patients at high risk for acquiring HIV. The use, the exclusion criteria included a glomerular filtration
US Preventative Services Task Force recommends that PrEP rate less than 75 mL/min, active hepatitis B, positive hepati-
be offered to those at risk for HIV, noting substantial net bene- tis B surface antigen, or a history of fractures.
fit. (11) In the current Food and Drug Administration (FDA) Although TDF/emtricitabine has been used for years as
approved PrEP, nucleoside reverse transcriptase inhibitors part of ART in children and adolescents living with HIV,
block the transformation of HIV RNA to DNA, inhibiting its there were questions about the safety of using this medica-
ability to integrate into the host cell’s DNA and replicate, there- tion in adolescents younger than 18 years for PrEP. The
fore preventing HIV replication and, ultimately, infection. most common adverse effects of TDF/emtricitabine use are
In 2012, the FDA approved the use of tenofovir diso- mild gastrointestinal upset, headache, and weight loss. How-
proxil fumarate (TDF)/emtricitabine for individuals 18 ever, nephrotoxicity and bone loss have been reported in
years and older as chemoprophylaxis for HIV. It was long-term use of TDF/emtricitabine. (16) The nephrotoxicity
approved as a combination fixed-dose tablet taken orally is related to damage of the proximal tubules with subsequent
daily for those at high risk of HIV acquisition (Table 1). In development of Fanconi syndrome or type IV renal tubular
2018, the FDA extended approval to adolescents weighing acidosis. (13) TDF/emtricitabine therapy is recommended
at least 77 lb (35 kg) for the same indications. only in patients with an estimated creatinine clearance
Efficacy of PrEP is directly correlated with medication (CrCl) greater than 60 mL/min/1.73 m2 (>1.00 mL/s/m2).
adherence and differs by sex and mode of sexual activity. (16) In adult PrEP trials there were some mild elevations in
PrEP is estimated to be approximately 99% effective at pre- creatinine level that resolved after discontinuation of the
venting sexually transmitted HIV for individuals who are medication and no reported renal adverse effects in the dem-
adherent to their regimen and more than 74% effective at pre- onstration project in youth. (13)(15)(17)
venting transmission via injection drug use. (12) Post hoc Bone mineral density loss during adolescence, a period of
analysis of data from several PrEP trials has shown that ade- significant growth and bone development, has been a con-
quate intracellular tenofovir diphosphate levels ($700 fmol/ cern. It was shown in adult PrEP trials that any bone loss is
mL in dried blood samples) correlate with daily PrEP use and reversible after discontinuation of TDF/emtricitabine, and no
92% to 100% protection from HIV. (13) The concentration of increase in fractures or osteoporosis has been reported. (13) In
tenofovir differs in colorectal mucosa versus the lower female the demonstration project, bone mineral density was studied
genital tract. The TDF active metabolite, tenofovir diphos- via dual-energy x-ray absorptiometry and showed a significant
phate, concentration is 10 times higher in colorectal tissue increase in bone mineral density over 48 weeks in the partici-
than in the lower genital tract in females. (14) By extrapolating pants, which would be expected in growing adolescents. After
data from PrEP trials and pharmacokinetic/pharmacodynamic 48 weeks, the total body z score was decreased (–0.20) from
studies, it has been determined that women must be 100% baseline, which was statistically significant. However, there
adherent to daily PrEP to be effective, whereas men might were no fractures associated with TDF/emtricitabine use. (15)
need to take only 4 tablets per week to achieve the advantages At this time, there is no recommendation that patients taking
Table 1. Youth with Recommended Indications for Preexposure Prophylaxis Use
Young man or transgender woman engaging in sex with male partners in the past 6 mo or plans to be sexually active in the near future
and 1 of the following:
Is having anal sex without condoms (receptive or insertive)
Has had syphilis, gonorrhea, or chlamydia diagnosed in the past 6 mo
Heterosexual young person sexually active in the past 6 mo or plans to be sexually active in the near future and 1 of the following:
Is a young man who has sex with both men and women
Does not use condoms with partners of unknown HIV status who might be at higher risk, such as known injection drug user or
bisexual male partner
In a relationship with an HIV-seropositive partner
Diagnosed as having syphilis or gonorrhea in the past 6 mo
Injection drug use – any sharing of equipment/syringes in the past 6 months
Commercial sex work
Exchange of sex for drugs or goods
HIV=human immunodeficiency virus.

Reprinted with permission from Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the
United States – 2017 update: a clinical practice guideline. Available at: https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf.
Accessed June 24, 2021.
Table 2. Open-ended Questions for Expanded Sexual History

Partners Can you tell me how many sex partners you had in the past 12 mo?
Are your partners men, women, or both?
Sexual practices People have different sexual practices, eg, do you have vaginal sex, anal sex, or oral sex?
When you have anal sex are you on the top (insertive) or bottom (receptive) or both?
Protection from STIs How do you protect yourself from STIs?
How is your partner protecting you from STIs?
History of STIs Have you or your partner ever been diagnosed as having or treated for an STI?
Pregnancy prevention Are you currently trying to become pregnant?
How are you currently preventing pregnancy when you have sex?
How is your partner preventing pregnancy when you have sex?
STI=sexually transmitted infection.
TDF/emtricitabine need routine dual-energy x-ray absorptiom- Care Act have a 25% higher prevalence of PrEP use compared
etry scans, but they could be considered if an individual has with states that did not. (21) Most commercial insurance pro-
other risk factors for bone loss. grams cover PrEP, but there can be associated copays, poten-
Tenofovir alafenamide (TAF), a prodrug of tenofovir, tially reducing access. For uninsured patients Ready, Set, PrEP
more rapidly delivers the active metabolite tenofovir diphos- is a national program that offers access to free PrEP for those
phate into peripheral blood mononuclear cells at a dose 10 who qualify. (22) Although PrEP use has increased, there are
times less than TDF. With TAF, there is less circulating notable disparities. The southern United States has a lower
tenofovir in the plasma, decreasing bone and renal expo- number of PrEP users relative to the number of new HIV
sure with subsequent fewer nephrotoxic and bone adverse diagnoses compared with the northeast. (23) PrEP uptake in
effects. (18)(19) In 2019 the FDA approved TAF/emtricita- youth is lower compared with older age groups. Awareness of
bine for PrEP, expanding the options for individuals with PrEP varies, making HIV education and prevention in the pri-
baseline renal dysfunction. Adolescents with a body weight mary care setting essential. (23)(24) Adolescents, especially in
of at least 35 kg were included in this approval. TAF/emtri- rural areas, might have access to primary care only, making
citabine is approved only for sexual transmission in men this the primary source of comprehensive HIV prevention
and transgender women. It is not approved in cisgender information, including PrEP.
women, vaginal receptive intercourse, and injection drug
use. This is because these populations were not studied in WHO SHOULD BE OFFERED PREP?
the trials supporting its effectiveness for PrEP. (19)(20) As health care providers, understanding who is at increased
risk for HIV acquisition can lead to targeted HIV prevention
CURRENT PREP USE education and access to PrEP. In the United States, PrEP is
Despite the increase in options and access, PrEP uptake has recommended for anyone at higher risk for HIV acquisition
not matched the need. State Medicaid programs cover PrEP, (Table 1). (11)(25) In the adolescent population it is difficult to
and states that expanded Medicaid through the Affordable obtain an accurate and complete sexual and drug history due

to multiple factors, such as time constraints, lack of privacy, management for youth in areas with fewer resources. For
concerns for confidentiality, and provider or patient hesitancy. those uncomfortable with providing PrEP in the general
During preventive care visits, there should be adequate time pediatrician’s office, referral to a pediatric infectious dis-
for patients to discuss confidential topics without a parent or ease specialist for patients younger than 18 years is an
guardian in the room. A thorough sexual history is essential option. Or for youth who are 18 years and older it might
for many aspects of adolescent care, including family plan- be acceptable to refer to adult infectious disease or local
ning and contraception, screening for STIs, and identifying health department programs or to transition the patient to
risks of HIV acquisition. For an expanded sexual history adult primary care services. It is important to know the
many use the CDC’s 5 P’s method—partners, sexual practi- local PrEP providers, often available on health department
ces, protection from STIs, past STIs, and pregnancy preven- websites, and ensure that there are no excessive barriers
tion. (26) Open-ended, neutral questions should be asked to for the youth to obtain PrEP services when referring.
allow the adolescent an opportunity to express one’s self in a Before PrEP initiation, a history, physical examination,
safe and nonjudgmental environment (Table 2). (27) and laboratory evaluation are necessary (Table 3). All patients
must have a confirmed negative HIV test result within 7
CONFIDENTIALITY AND LEGAL BARRIERS TO days of being prescribed PrEP. The antiretrovirals used in
PREP IN ADOLESCENTS PrEP provide only partial treatment for HIV, creating poten-
Adolescents at high risk for acquiring HIV might require con- tial viral resistance if the patient has acquired HIV before
fidential services and request to make decisions about HIV starting PrEP. The preferred HIV screening test is a fourth-
prevention on their own. These individuals can be homeless, generation antibody/antigen test using a serum sample sent
in the foster care system, or unwilling to disclose their sexual to a laboratory, but an antibody-only test can be used. If
practices, sexual orientation, or drug use with their parent/ using rapid point-of-care testing, it should be a finger-stick
guardian present. Minor consent for treatment and confidenti- blood sample, not an oral fluid sample due to decreased sen-
ality are important issues that practitioner’s face when offering sitivity compared with blood tests. (25) An assessment of the
HIV prevention services. There are no states that explicitly patient should include reviewing for any signs and symp-
prohibit autonomous consent for PrEP in minors. There are toms of acute HIV infection in the past 30 days, including
16 states that allow minor consent for HIV prevention serv- recent illnesses, fevers, chills, myalgia, pharyngitis, and rash.
ices. (28) Other states have a variety of statutes that can allow If the history or physical examination findings suggest a pos-
for STI and/or HIV testing and STI treatment in minors. sible acute HIV infection, a viral load (HIV-1 quantitative
Understanding the statutes in the state one is practicing is RNA) should be completed at the time to rule out an acute
essential. A quick reference on the CDC website can be used infection that could be missed, especially on antibody testing
to help determine minor consent laws (https://www.cdc.gov/ alone. (25) If history reveals that the individual has a known
hiv/policies/law/states/minors.html) but should be cross refer- HIV exposure in the past 72 hours, postexposure prophylaxis
enced with state and local regulations. (17)(28) for 4 weeks should be initiated and then transitioned to
Even a minor’s access to HIV prevention services and PrEP PrEP after confirming a negative HIV test result.
does not guarantee confidentiality of services. Minors are typically Renal function and hepatitis B infection status need to
on a parent/guardian’s insurance plan. Billing documentation in be assessed at the start of PrEP therapy (Table 3). An esti-
explanation of benefits might disclose services rendered, or a mated CrCl greater than 60 mL/min/1.73 m2 (>1.00 mL/
minor might have trouble accessing the medication at a pharmacy s/m2) is required for individuals using TDF/emtricitabine
because of cost or transportation issues. Respecting the autonomy due to the risk discussed earlier. TAF/emtricitabine can be
of the adolescent, within the extent of the law, is important. used to an estimated CrCl greater than 30 mL/min/1.73 m2
When appropriate and with the adolescent’s permission, involving (0.50 mL/s/m2). Both TDF/emtricitabine and TAF/emtricita-
the parent/guardian in the HIV prevention plan can increase pro- bine are active antiviral agents against hepatitis B. Hepatitis B
tective behaviors and reduce risk behaviors. (17)(29) infection status needs to be determined at the start of PrEP by
checking hepatitis B surface antigen, core antibody, and sur-
INITIAL PREP MANAGEMENT face antibody. Chronic hepatitis B infection is not a contrain-
Prescribing and managing PrEP in the primary care set- dication to using PrEP; however, for these individuals there is
ting is feasible and often the best option for patients a potential risk of hepatitis flare when PrEP is discontinued.
because of familiarity, access, and established relation- In these cases, the patient’s transaminase levels should be fre-
ships. This might be the only option for PrEP quently monitored after discontinuation of PrEP. (16)(30) If an
Table 3. Initiation of Preexposure Prophylaxis
TDF 300 MG/EMTRICITABINE 200 MG TAF 25 MG/EMTRICITABINE 200 MG
VARIABLE BY MOUTH DAILY BY MOUTH DAILY
Eligible patients by risk of HIV acquisition Receptive or insertive anal intercourse Receptive or insertive anal intercourse
Insertive vaginal intercourse Insertive vaginal intercourse
Receptive vaginal intercourse
Injection drug use
Laboratory recommendations HIV-1/2 Ab/Ag HIV-1/2 Ab/Ag
HIV-1 RNA quantitative (if concern for acute HIV-1 RNA quantitative (if concern for
HIV infection) acute HIV infection)
Creatinine and estimated CrCl >60 mL/min/ Creatinine and estimated CrCl >30 mL/
1.73 m2 (>1.00 mL/s/m2) min/1.73 m2 (>0.50 mL/s/m2)
Hepatitis B surface antigen Hepatitis B surface antigen
Hepatitis B surface antibody Hepatitis B surface antibody
Hepatitis B core antibody Hepatitis B core antibody
Hepatitis C antibody Hepatitis C antibody
Bacterial STIs Bacterial STIs
Syphilis Syphilis
Pregnancy test
Other considerations HPV vaccine series HPV vaccine series
Contraception management
Ab=antibody, Ag=antigen, CrCl=creatinine clearance, HIV=human immunodeficiency virus, HPV=human papillomavirus, STI=sexually trans-
mitted infection, TAF=tenofovir alafenamide, TDF=tenofovir disoproxil fumarate.
individual is not immune to hepatitis B, a vaccination series man or transgender female and has the risk factor of sexual
should be offered. Hepatitis C antibody testing is recommended, acquisition only, TAF/emtricitabine can be used due to the
especially in patients reporting a history of injection drug use. improved adverse effect profile compared with TDF/emtricita-
Screening for bacterial STIs (gonorrhea, chlamydia, and bine. TDF/emtricitabine is the only PrEP medication approved
syphilis) at initiation of PrEP is also recommended because for females, vaginal receptive intercourse, and injection drug
they share the same risk factors for acquisition with HIV. use. (20)(25) Behavior risk reduction counseling should be
Samples for gonorrhea and chlamydia should be collected given, as well as instructions on the use of PrEP, including
from all areas that the individual engages in sexual activity, dosing, days until effectiveness, and adverse effects. PrEP is
including pharyngeal, urethral, rectal, and vaginal. Nucleic FDA-approved as a once-daily oral medication. The CDC PrEP
acid amplification testing is the preferred method due to sen- guidelines require HIV testing every 3 months while a patient
sitivity. Self-collected samples have been shown to be equiva- is receiving PrEP, and a negative HIV test result should be
lent to provider obtained samples and can be more confirmed before each new prescription; therefore, a maximum
comfortable for some patients to obtain. (25) Syphilis testing
of 90 days should be prescribed at one time.
is recommended because there is an increased risk of acquir-
ing HIV if currently infected with syphilis. Human papilloma-
FOLLOW-UP PREP MANAGEMENT AND
virus vaccination series should be offered in nonpregnant
ADHERENCE
patients if not previously vaccinated.
In the demonstration study, adherence, measured by tenofovir
Women should be tested for pregnancy before initiating
PrEP. This is an opportunity to discuss family planning and diphosphate levels, was significantly better in the first 3
contraception. There are no interactions between current months, when the participants returned every 4 weeks. Ini-
PrEP therapy and hormonal contraception. The use of PrEP tially, of the 72 participants, adherence rates were 54% at 4
in pregnancy is not contraindicated, and risk should be weeks, 47% at 8 weeks, and 49% at 12 weeks. There was a
assessed to determine the need for PrEP during pregnancy. If significant drop in adherence when follow-up was spaced to 3-
a woman is attempting to conceive with a partner living with month intervals. At 24, 36, and 48 weeks, adherence rates
HIV, then PrEP can be advised in this situation and can be were 28%, 17%, and 22%, respectively. (15) In this study, the
continued throughout the pregnancy depending on risk. (25) decline in adherence suggests that closer follow-up or other
If the individual’s HIV test result is negative, PrEP can models of engagement might be needed to ensure that adher-
be prescribed. The use of TDF/emtricitabine or TAF/emtri- ence is maintained. These adolescents were also enrolled in
citabine depends on patient factors, including sex, sexual practi- the study without parental consent. Adherence might differ if
ces, and other risk behavior (Table 3). If the patient is a young there is parental/guardian involvement in the HIV prevention

plan and support for PrEP. Larger peer networks have been it would be administered intramuscularly every 8 weeks
potentially related to increased odds of PrEP awareness and instead of taking an oral daily pill. (33)(34)
uptake. (31) This idea can be leveraged for improved adher-
ence with peer navigators or support groups.
Summary
In most cases, a visit or check-in with the patient after 1
month of therapy is beneficial. This visit can be used to • Based on strong research evidence (grade A),
recheck an HIV test result (especially if HIV antibody–only preexposure prophylaxis (PrEP) is recommended to
testing was completed initially), evaluate adverse effects of the prevent human immunodeficiency virus (HIV) in
medication, and review adherence and adherence strategies. If persons with higher risk of HIV acquisition. PrEP is
a patient is using TDF/emtricitabine, renal function should be Food and Drug Administration–approved for adole-
assessed. Follow-up intervals will vary with each patient, scents with a weight of 77 lb or greater ($35 kg).
remembering that adherence can decline if visits are spaced to • The indications for PrEP are as follows: Young men
the maximum allowed of 3 months. At follow-up visits, behav- and transgender women engaging in anal sex with
ioral risk reduction counseling and reviewing adherence to male partners without a condom and/or who have
PrEP are important. At least every 3 months HIV testing needs had syphilis, gonorrhea, or chlamydia in the previous
to be completed, following the same testing guidelines as the 6 months. Heterosexual youth sexually active in the
initial HIV test, as well as an assessment for acute HIV signs previous 6 months without condoms with partners
and symptoms. (25) Screening for STI risk factors (unprotected at higher risk for HIV, such as bisexual male partner,
sex, multiple sex partners, etc) and symptoms should prompt known injection drug use, known HIV infection, and/
appropriate testing. It is recommended to screen for bacterial or diagnosed as having syphilis or gonorrhea in the
STIs at least every 6 months even in asymptomatic individu- previous 6 months. Youth actively using injection
als. (25) Pregnancy tests should be completed every 3 months drugs who are sharing needles and/or equipment.
if a patient is not using a long-acting contraceptive method. If • Youth have increased barriers to PrEP, including
the patient is taking TDF/emtricitabine, evaluation of renal minor consent laws, confidentiality, lack of transpor-
function every 6 months is necessary, or yearly if taking TAF/ tation, and fewer financial resources. Clinicians
emtricitabine. Any vaccination series that were started, should be aware of these barriers and address them
such as human papillomavirus series, hepatitis A or B, to increase access and improve adherence.
should be completed at appropriate intervals. Impor-
tantly, the need for HIV prevention with PrEP can
change over time. HIV acquisition risk should be evalu- Acknowledgments
ated annually, and PrEP can be discontinued when a Thank you to Dr Alex R. Kemper for his review of the
patient is no longer at higher risk. Except for manuscript.
patients with active hepatitis B infections, PrEP can be References for this article can be found at
DOI: 10.1542/pir.2020-002048.
discontinued at any time without the need for further
monitoring.
THE FUTURE OF PREP To view teaching slides that accompany this article, visit
Adherence, simplicity, confidentiality, and ease of use of 10.1542/pir.2020-002048.
PrEP are paramount to ensuring that PrEP is reaching those
at higher risk for HIV. There is evidence that using on-
HIV Preexposure Prophylaxis in Adolescents and Young Adults
demand PrEP (2 tablets 2–24 hours before a sexual encoun-
ter, 1 tablet 24 hours after the first dose, and 1 tablet 24
hours after the second dose) is effective for male-to-male sex-
ual contact, but this is not FDA-approved. (32) Long-acting Megan E. Brundrett, MD, MPH1
1Division of Primary Care and Infectious Disease, Nationwide Children's Hospital, Columbus, OH
injectable forms of PrEP using the integrase inhibitor cabote-
gravir has been one of the most promising alternatives for
the future of chemoprophylaxis for HIV. Currently in trials,
PIR QUIZ
1. A 17-year-old boy is seen in clinic for a routine sports physical. He is healthy,

takes no medications, and his immunizations are up to date. Social history reveals
intermittent marijuana use with friends and current sexual activity, with age of
first intercourse at 16 years. Which of the following is the most appropriate next
step in management?
A. Complete human immunodeficiency virus (HIV) prevention counseling.
B. Obtain further information about past and current sexual activity.
C. Obtain testing for gonorrhea, chlamydia, HIV, and syphilis.
D. Proceed to physical exam without further testing.
E. Start HIV preexposure prophylaxis after a negative HIV
antibody/antigen serum test. REQUIREMENTS: Learners can
take Pediatrics in Review quizzes
2. A 17-year-old girl is seen in the office as she found out this morning and claim credit online only at:
that her male sexual partner she has been in a relationship with for 3 http://pedsinreview.org.
months tested positive for HIV. They have vaginal intercourse 4–6 times a
week without condoms. Last intercourse was last night. She is well- To successfully complete 2022
Pediatrics in Review articles for
appearing with a normal physical examination and has no other health
concerns. She has no history of sexually transmitted infections (STIs). A learners must demonstrate a
long-acting hormonal contraceptive implant was placed 4 months ago. In minimum performance level of
addition to obtaining a fourth-generation antibody/antigen HIV test, which 60% or higher on this
of the following is the most appropriate next step in management? assessment. If you score less
than 60% on the assessment,
A. Obtain CD4 lymphocyte enumeration. you will be given additional
B. Return in 72 hours to obtain CD4 lymphocyte enumeration. opportunities to answer
C. Return in 72 hours to start preexposure prophylaxis (PrEP). questions until an overall 60%
or greater score is achieved.
D. Start postexposure prophylaxis today.
E. Start preexposure prophylaxis today. This journal-based CME activity
is available through Dec. 31,
3. Which of the following states explicitly prohibits autonomous consent
2024, however, credit will be
for PrEP in minors? recorded in the year in which
A. Alaska. the learner completes the quiz.
B. Florida.
C. Kansas.
D. None.
E. North Dakota.
2022 Pediatrics in Review is

Maintenance of Certification
(MOC) Part 2 credits by the
American Board of Pediatrics
Review subscribers can claim up
to 30 ABP MOC Part 2 points
upon passing 30 quizzes (and
claiming full credit for each
quiz) per year. Subscribers can
early as October 2022. To learn
how to claim MOC points, go
to: https://publications.aap.org/
journals/pages/moc-credit.

4. A 17-year-old boy is seen in the office for an adolescent wellness exam.
He has been sexually active since age 15 years. A detailed sexual history is
gathered. He has had both male and female partners in the past. He was
treated for gonorrhea at the health department 6 months ago and uses
condoms intermittently. He has oral sex and insertive and receptive anal sex.
HIV prevention strategies are discussed, and he is interested in starting PrEP.
Last sexual encounter was over 2 weeks ago. On review of systems, he
endorses a 3-day history of extreme fatigue and myalgias and he has a sore
throat. He denies any diarrhea, night sweats, swollen lymph nodes, rashes,
or fevers. Which of the following is the most appropriate next step in
management?
A. Check HIV antibody/antigen test and start HIV postexposure
prophylaxis immediately.
B. Defer PrEP initiation labs due to current health concerns and check
for gonorrhea, chlamydia, syphilis, and HIV antibody/antigen test.
C. Obtain hepatitis B serologies, creatinine, HIV antibody/antigen testing,
and quantitative polymerase chain reaction for HIV RNA; check for gonorrhea,
chlamydia, syphilis.
D. Obtain hepatitis B serologies, creatinine, HIV antibody/antigen testing in preparation
to start PrEP.
E. Start PrEP immediately.
5. A 17-year-old girl is seen in the clinic for follow-up after beginning PrEP
approximately 3 months ago with TDF/emtricitabine due to a history of
intravenous drug use. She has been adherent to her PrEP regimen.
Laboratory testing at her initial visit was negative for HIV, hepatitis B, STIs,
pregnancy and her renal function was normal. She has an intrauterine
device (IUD) for contraception. Immunizations are up to date, including
human papillomavirus (HPV). She is well-appearing and has no current
health concerns. She has a week of medication left from her prior
prescription and would like a refill. Which of the following laboratory tests
should be obtained today and results reviewed prior to renewing her PrEP
prescription?
A. CD4 lymphocyte enumeration.

B. Hepatitis B surface antigen.
C. HIV antibody/antigen serum test.
D. Pregnancy test.
E. Rapid plasma reagin (RPR) test.
INDEX OF SUSPICION
Rash in a 2-month-old Premature Infant

Margaret Urschler,* Mary Anne Jackson, MD, FAAP, FIDSA, FPIDS,*† Mary Tyson, MD, Barbara Pahud, MD, MPH†
*University of Missouri–Kansas City School of Medicine, Kansas City, MO
†
Department of Infectious Diseases, Children’s Mercy Hospital, Kansas City, MO
PRESENTATION
An 82-day-old girl presents with a 4-day history of a generalized rash without
other systemic symptoms. She was born at 32 weeks’ gestation of a dichorionic tri-
amniotic pregnancy. Her neonatal course was uncomplicated, and she was dis-
charged along with her 2 brothers at 47 days of life. The rash began with 1- to 3-
mm papules and vesicles on the anterior neck and then spread to her face and scalp
over the next 24 hours, with spread of macules, papules, and pustules over the next
several days to the chest, torso, and lower extremities (Fig). The infant appears well,
is afebrile, is not scratching, and is not irritable. The infant’s mother denies expo-
sure to anyone with rash. The infant does not attend child care, but her 4-year-old
sibling does. Her parents and siblings report being healthy, and the 2- and 4-year-
old siblings are both fully immunized for age per recommended guidelines. Vari-
cella is suspected based on the rash characteristics; her mother reports having had
varicella (chickenpox) as a child. The patient is referred to infectious diseases for
further evaluation.
Differential Diagnosis
Diagnosis depends on history and physical examination findings to differentiate
chickenpox from other diseases associated with vesiculopapular lesions, includ-
ing rash progression and distribution, the presence of pruritus or pain, expo-
sures, previous varicella or vaccine history, and presence of other systemic
features (Table).
Diagnosis
Varicella is traditionally a clinical diagnosis and is easily recognized in the set-
ting of a significant exposure and classic exanthema. In this patient, the diagno-
sis was more difficult because a specific exposure was not initially ascertained. AUTHOR DISCLOSURE: Dr Pahud has
In most infants beyond 28 weeks’ gestation with a positive maternal varicella- been an investigator on clinical trials
funded by GlaxoSmithKline and Alios
zoster virus (VZV) history, one could assume that the newborn is immune via
Biopharma/Janssen and has received
transplacental transfer of antibody; in this case, it seems that the infant had honoraria from Merck, GlaxoSmithKline,
incomplete immunity. Because fewer current clinicians have seen varicella, clini- Alios Biopharma/Janssen, Pfizer, Sequiris,
and Sanofi Pasteur for service on advisory
cal comfort with diagnosis might be less than in the prevaccine era. Vaccines
boards and for nonbranded
have decreased the incidence of VZV up to 95%, including an 80% decline in presentations. Drs Urschler, Jackson, and
varicella incidence in infants. (1) As a result, not all providers are able to diag- Tyson have disclosed no financial
nose wild-type VZV because atypical presentations due to vaccination or partial relationships relevant to this article. This
commentary does not contain a
immunity can mimic other diseases. Each year in the United States, VZV vacci- discussion of an unproved/investigative
nation prevents more than 3.5 million cases of chickenpox. (1) Breakthrough use of a commercial product/device.

on her extremity 2 weeks before the infant’s presentation.
We suspect that the infant’s preterm birth and possibly the
placental chorionicity (number of placentae in a multiple
gestation pregnancy) influenced the presence and magnitude
of transplacental varicella antibody, resulting in her mild var-
icella presentation. IgG transplacental varicella antibody is
clearly influenced by gestational age. In this case of a dichor-
ionic triamniotic pregnancy (2 placentas, 3 amniotic sacs),
our patient had her own placenta and her brothers shared a
placenta. Umbilical cord antibody concentrations are known
to be lower in monochorionic twin pregnancies (fetuses
share a single placenta) compared with dichorionic twin
pregnancies (each fetus has a placenta), theoretically result-
ing in a higher IgG transfer in our patient, who had her
own placenta. (3) However, despite this, our patient was
affected by VZV more than her brothers, who shared a pla-
centa. The triplet brothers developed vesicles localized to
their scalps about 3 weeks after their sister’s infection.
Although varicella infection generally confers lifelong immu-
nity, a history of varicella is not a contraindication to vaccina-
tion, and vaccination should be considered in all 3 infants
because their disease could have been modified by partial
immunity that is not fully protective.
The Condition
After exposure, primary varicella occurs in up to 90% of
those susceptible after an incubation period of 10 to 21 days.
The classic exanthema occurs in 3 to 4 crops of lesions. Mac-
ules appear first, followed by papules and vesicles, on the face
and scalp and then involving the chest, back, and extremities,
with crusting after 4 to 7 days. Complications of primary vari-
Figure. Photographs of the patient with rash taken on days 2 and 3 after
illness onset. cella include bacterial superinfections, pneumonia, encepha-
litis, thrombocytopenia, or rarely, glomerulonephritis, arthritis,
or hepatitis. Herpes zoster (HZ) infection, or shingles, is a
disease after varicella vaccination can occur when VZV
reactivation of a latent varicella infection and is characterized
disease presents more than 42 days after vaccination; it is
by grouped vesicular skin lesions in dermatomal distributions
often a mild illness with fewer, atypical (maculopapular) associated with pain and itching. HZ lesions contain active
skin lesions and a faster recovery. (2) virus, and any susceptible person in contact with the rash blis-
Polymerase chain reaction of a vesicular lesion or scab ters is at risk for chickenpox infection. Maternal HZ likely
is very sensitive and specific for VZV and can distinguish accounts for the patient exposure.
the vaccine strain from the wild-type strain. Immunoglob- Largely regarded as an invariable and benign infection
ulin G (IgG) serology assays are available and specific for of childhood, in the prevaccine era nearly all individuals
VZV but have low sensitivity to detect vaccine-induced acquired natural infection by adulthood. Complications occurred,
immunity. (2) and on average 100 children died of varicella each year. If a
woman develops primary varicella during the first 20 weeks of
DISCUSSION pregnancy, congenital varicella, manifest as eye, limb, and neu-
Polymerase chain reaction from a skin lesion was obtained rologic abnormalities, might rarely occur. Since the varicella
for herpes simplex virus and VZV, and testing confirmed vaccine was introduced in 1995, there has been a 97%
VZV infection. The suspected exposure was the patient’s decrease in primary varicella cases. Vaccine coverage is cur-
mother, who later revealed a history of a dermatomal rash rently greater than 90%, and vaccine immunity occurs in
Table. Differential Diagnosis
RASH
PROGRESSION PAINFUL
DISEASE RASH DISTRIBUTION EXPOSURE PRURITUS LESIONS OTHER CLUES DIAGNOSIS
Varicella Macules, followed by Scalp and face, then 10–21 d after 11 – In neonate, no VZV PCR of skin
papules, vesicles; crust chest and torso, exposure to maternal lesion
after 4–7 d then extremities varicella or herpes history of
zoster varicella or
varicella
vaccine or
history of birth
before 28–32
weeks’
gestation
HSV Vesicular cropped lesions Presenting area and 7–14 d after exposure – 1/– Can occur after HSV PCR of skin,
areas of trauma to mother with exposure to blood, and
from, eg, scalp primary genital other contacts CSF
electrode herpes at delivery with herpes
labialis
Scabies Vesiculopapules Palms and soles Adult with typical 1111 – Skin scraping
scabies
Contact dermatitis Vesicular usually Area of contact Psoralen (citrus) or 11111 1 Handling limes or
extremities urushiol (poison outdoor
ivy) plants activity
Atopic dermatitis Erythema Face, neck, and Vesicles when co- 11111 11 Family history Coxsackie virus
extensor surfaces infection with eczema or HSV PCR
Coxsackie virus or from skin
HSV lesion
Impetigo Vesiculopapules Mouth, face, or Others in family with – 1 Staphylococcus Bacterial culture
diaper area skin abscesses aureus or GAS skin lesion
Sweet syndrome Erythematous nodules or Arms, legs, trunk, – 111 Consider Skin biopsy
plaques (5) face, or neck underlying
primary
immunologic
or genetic
disorder
Langerhans cell Vesiculopapules; may Head, neck, ears, – 1111 Liver, spleen, Skin biopsy
histiocytosis resemble seborrhea diaper area bone marrow
(6) involvement
Vol. 43 No. 1
CSF=cerebrospinal fluid, FH=, GAS=group A Streptococcus, HSV=herpes simplex virus, PCR=polymerase chain reaction, VZV=varicella-zoster virus. “1” indicates presence of this symptom, “ ” indi-
cates absence of this symptom, and “1/ ” indicates symptom may be present or absent.
JANUARY 2022
39
90% of those immunized with 1 dose of vaccine and in 97% sent within a 10-day window if they have an underlying con-
of those with 2 doses; vaccine immunity is long-lasting. dition that places them at risk for severe complications of
Transplacental transport of IgG antibodies from the varicella. Based on the recommendations in the Red Book 2021
pregnant woman to her unborn baby begins at approximately on the management of exposures to VZV, the 2 triplet sib-
17 weeks’ gestation and continues until close to term. (4) The lings would not be candidates for varicella zoster immune
increase of the fetal IgG concentration between 29 and 41 globulin. (2) But some experts might recommend preemptive
weeks is double the concentration between 17 and 28 weeks. antiviral therapy in this case. In addition, because of the safety
(4) For VZV specifically, studies have shown that the fetal of varicella vaccine and the concern that subclinical infection
IgG–maternal IgG concentrations are equal between 32- and might not confer immunity, immunization of the 2 triplets
36-weeks’ gestation (4) and after birth; these antibodies wane should be considered.
after 3 to 6 months. Premature infants are at increased risk
for vaccine-preventable diseases, including VZV, compared
Lessons for the Clinician
with term infants due to decreased transplacental transfer of
IgG antibodies. Generally, infants born before 28 weeks are • Varicella-zoster virus and herpes zoster require a high
considered susceptible to varicella and those born between index of suspicion since disease prevalence and inci-
28 and 32 weeks are thought to be at risk because of lower dence have decreased. Laboratory methods are increas-
antibody concentrations. (4) Antibodies in term infants may ingly used to help with diagnosis because clinical
be present for up to 6 months, and, even if present, antibod- recognition of the disease is less common since vac-
ies wane faster in preterm infants compared with those born cine introduction.
at term. (4) • When clinicians identify an exposure history, to either
primary varicella or shingles, they need to consider
Treatment whether the patient is susceptible to varicella based on age,
Antiviral therapy is not recommended in children with mild vaccination history, and, for premature infants, whether
disease. Antiviral therapy in the form of acyclovir or valacyclo- transplacental immunity is likely.
vir is typically reserved for patients at greater risk for moderate • Premature infants are at risk for varicella because trans-
to severe disease, including unvaccinated children older than placental transport of immunoglobulin G antibodies can
12 years, those with chronic cutaneous or pulmonary diseases, be absent in those born before 28 weeks’ gestation and
patients receiving long-term salicylate therapy, or patients inadequate for protection in those born between 28- and
receiving courses of corticosteroids or who are otherwise 32-weeks’ gestation.
immunocompromised. Supportive therapy for any child with
VZV includes keeping fingernails short to prevent trauma Acknowledgments
from scratching, frequent baths, use of calamine lotion to Thank you to the family for giving permission to present
reduce pruritis, and acetaminophen use if febrile. Aspirin this case and to the Medical Writing Center at Children’s
should not be given to these patients due to the risk of Reye Mercy Hospital for their review of this manuscript.
syndrome. (2)
Varicella zoster immune globulin should be given for References for this article can be found at
susceptible individuals with significant exposure who pre- DOI: 10.1542/pir.2020-003897.
INDEX OF SUSPICION
Migratory Arthralgia in a 3-year-old Girl

Carol Fries, MD,* Andrew M. Long, MD,† Bethany A. Marston, MD,† Jeffrey R. Andolina, MD*
*Department of Pediatrics, Pediatric Hematology/Oncology and
†
Department of Pediatrics, Pediatric Rheumatology, University of Rochester, Rochester, NY
PRESENTATION
A previously healthy 3-year-old girl presents to the pediatric rheumatology clinic for
evaluation of 5 to 6 weeks of arthralgia of the left wrist and right elbow. Initial atrau-
matic right elbow pain prompted her pediatrician to refer her to orthopedic surgery.
The orthopedic surgeon’s physical examination revealed decreased right elbow range
of motion (ROM), and initial laboratory evaluation was notable for an erythrocyte sed-
imentation rate of 33 mm/hr (reference range, 0–20 mm/hr), a C-reactive protein
level of 1.30 mg/dL (13 mg/L) (reference range, 0–1.0 mg/dL [0–10 mg/L]), and a
normal complete blood cell (CBC) count: white blood cell (WBC) count, 9,000/mL
(9.0 × 109/L) (reference range, 5,000–17,000/mL [5.0–17.0 × 109/L]); hemoglobin level,
12.3 g/dL (123 g/L) (reference range, 11.5–14.0 g/dL [115–140 g/L]); and platelet count,
442 × 103/mL (442 × 109/L) (reference range, 160–370 × 103/mL [160–370 × 109/L]).
Her symptoms improved after 3 days of immobilization, but recurrence of right
elbow pain another 2.5 weeks later prompted her orthopedic surgeon to refer her to
rheumatology with consideration for an inflammatory arthritis process.
On initial rheumatology evaluation the patient’s history is notable for arthral-
gia; in addition to recurrence of right elbow pain, she also developed left wrist
pain. There are no other reported symptoms, and review of systems is notable
for an absence of rash or constitutional symptoms: no fever, sweats, fatigue,
appetite suppression, weight loss, or changes in activity level. Examination reveals
subtle edema, tenderness to palpation with stiffening/guarding, and pain with left
wrist ROM. There is no swelling or frank reduction in ROM in the right elbow,
but she demonstrates guarding with hyperextension. She is otherwise well-appear-
ing, with no other noted physical abnormalities. Repeated laboratory evaluation
demonstrates improvement in inflammatory markers (erythrocyte sedimentation
rate, 16 mm/hr; C-reactive protein level, 0.9 mg/dL [9 mg/L]); left wrist radiogra-
phy is notable for sclerosis at the distal radius suspected to be the result of a heal-
ing occult fracture. A trial of twice-daily naproxen use is initiated for symptom
management.
DISCUSSION
Rheumatology follow-up approximately 5 weeks later (>10 weeks after initial pre-
AUTHOR DISCLOSURE: Drs Fries, Long,
sentation to orthopedic surgery) was conducted via telemedicine amid the early Marston, and Andolina have disclosed no
coronavirus disease 2019 (COVID-19) pandemic. Despite nonsteroidal anti-inflam- financial relationships relevant to this
article. This commentary does not
matory drug therapy, the patient experienced progression in arthralgia, with 2 days
contain a discussion of an unapproved/
of new right ankle pain at the time of follow-up but still no systemic symptoms. A investigative use of a commercial
presumed diagnosis of polyarticular juvenile idiopathic arthritis (JIA) was suspected product/device.

by her rheumatologist. Methotrexate therapy was planned, marrow infiltrative process. Acute lymphoblastic leukemia
and, in the meantime, a trial of systemic corticosteroids (ALL) is the most common pediatric malignancy, most
(prednisolone, 0.5 mg/kg per day) was initiated in an often presenting in children aged 2 to 5 years (5) with symp-
attempt to provide timely pain relief. However, a repeated toms related to the sequelae of disordered hematopoiesis.
CBC count revealed interval development of isolated normo- Diffuse bone pain is a common presenting symptom of
cytic anemia (hemoglobin level, 7.9 g/dL [79 g/L]), prompt- acute leukemia resulting from predominance of leukemic
ing discontinuation of prednisolone therapy after 3 days. blasts in the bone marrow regardless of circulating WBC
Another CBC count 3 days later revealed interval develop- count. Fevers and refusal to walk—a result of nonlocalizing,
ment of mild neutropenia (absolute neutrophil count, diffuse bone pain—are typical clinical features at leukemia
1.4 × 103/mL [1.4 × 109/L]; reference range, 1.5–8.0 × 103/mL presentation. Associated anemia often results in pallor and
[1.5–8.0 × 109/L]); the platelet count remained normal at fatigue and, when severe, can present with evidence of con-
307 × 103/mL (307 × 109/L). The patient’s symptoms rapidly gestive heart failure; thrombocytopenia precipitates bruis-
progressed during the next 3 to 5 days to include fatigue, ing, petechiae, and/or mucosal bleeding.
shortness of breath, pallor, refusal to bear weight, and wors-
ening pain now also involving her back, hips, and lower Actual Diagnosis
extremities. The insidious onset of the patient’s cytopenias and the
need for remote follow-up in the setting of the COVID-19
Differential Diagnosis pandemic resulted in a prolonged clinical course before
The clinical evaluation of migratory arthritis in pediatric definitive diagnosis. Details are depicted in Fig 1. Rapid
patients involves a detailed history and physical examina- symptom progression ultimately prompted an expedited
tion. JIA was the initially suspected diagnosis in this case, pediatric hematology/oncology evaluation. A follow-up CBC
but the inconsistent clinical course soon raised concern count revealed a rapid exacerbation in anemia (hemoglobin
for alternate etiologies. A broad differential diagnosis is level, 5.4 g/dL [54 g/L]) and neutropenia (absolute neutrophil
depicted in Table 1; distinguishing clinical features can count, 0.4 × 103/mL [0.4 × 109/L]) with 1% blasts noted on the
often help differentiate among these possibilities. differential count. Peripheral smear revealed few small- to
JIA typically presents with subacute onset of swelling intermediate-sized blasts with a high nuclear-cytoplasmic
and reduced ROM in 1 or more joints. In young children ratio, fine nuclear chromatin, and conspicuous nucleoli. An
with the oligoarticular JIA subtype, pain is usually absent. expedited bone marrow aspirate/biopsy revealed 77% lym-
The clinical diagnosis is based on the presence of persistent phoblasts with immunophenotype (CD341, CD191, CD101,
joint inflammation (characterized by swelling, limitation in CD79a1, HLA-DR1) consistent with the diagnosis of B-cell
ROM, warmth, and/or occasionally pain with palpation or ALL.
ROM) of at least 6 weeks’ duration. Characteristic labora-
tory findings (elevated inflammatory markers, antinuclear The Condition
antibody positivity) and imaging can support the diagnosis The prognosis of childhood ALL has dramatically improved
but are frequently absent. Symptoms are generally respon- in recent decades, with overall event-free survival greater than
sive to nonsteroidal anti-inflammatory drug therapy, cortico- 90% among affected children and adolescents. (6) At presen-
steroids, or disease-modifying antirheumatic medications tation, children with ALL undergo preliminary risk stratifica-
such as methotrexate. In patients with inconsistent features, tion based on numerous clinical and cytogenetic variables.
such as pain out of proportion to examination, severe noc- Assignment of National Cancer Institute risk group—stan-
turnal pain, significant cytopenias, or failure to respond to dard risk (SR) versus high risk (HR)—at diagnosis is deter-
typical therapies, further laboratory evaluation, imaging, and mined by the patient’s age (1–9.99 years is SR and $10
specialist consultation are indicated to evaluate for alternate years is HR) and presenting WBC count (<50,000/mL
etiologies. Radiographic imaging in JIA is typically unre- [<50 × 10/L] is SR and $50,000/mL [$50 × 109/L] is HR). (7)
markable but can display soft tissue swelling or periarticular Additional stratification into subcategories of treatment
osteopenia; the sclerotic lesions noted on this patient’s initial intensity (eg, SR-favorable, SR-average, SR-high) involves
wrist radiograph are atypical of JIA. the detection of favorable versus unfavorable cytogenetic
In the setting of concurrent cytopenia(s) or an otherwise features; the extent of leukemia involvement of sanctuary
unclear clinical picture, unexplained arthralgia and/or bone sites, namely, the central nervous system and testes; and,
pain in a child should prompt consideration for a bone most critically, leukemia responsiveness to early-phase
Table 1. Differential Diagnosis of Bone/Joint Pain in Children
TYPICAL AGE AT
DIAGNOSIS PRESENTATION CLINICAL FEATURES IMAGING FINDINGS (1)
Noninflammatory conditions
Injury (eg, fracture, dislocation, Any History of trauma, pain worsens Fracture, dislocation, soft tissue
ligamentous injury, muscle with activity, focal tenderness swelling
or tendon injury)
Orthopedic disease (eg, Adolescents and school-age Chronic joint pain typically Can have characteristic features
Osgood-Schlatter and Legg- children, respectively without swelling, worse with
Calve-Perthes disease) activity
Genetic or metabolic disease Any Variable; may have characteristic Can be normal or can have
(eg, Rickets, Ehlers-Danlos habitus (Marfan syndrome), characteristic findings (eg,
syndrome, Marfan syndrome, nutritional or developmental metaphyseal fraying in
OI) abnormalities rickets, osteopenia in OI)
Amplified musculoskeletal Any May have nonspecific Normal
pain syndrome, tenderness or hypermobile
hypermobility arthralgia, joints; nocturnal pain is
growing pains common; normal laboratory
values, including
inflammatory markers and
CBC count
Inflammatory conditions
Infectious (eg, septic arthritis, Any Fever, toxic appearance, refusal Soft tissue swelling, joint
osteomyelitis, skin and soft to bear weight, elevated effusion, bone marrow
tissue infection, Lyme inflammatory markers, edema on MRI
arthritis) leukocytosis
Rheumatologic School-age children Insidious onset, 1 or many areas Soft tissue swelling,
Juvenile idiopathic arthritis of joint swelling, restricted periarticular osteopenia,
(2) ROM, morning stiffness, fever, marginal erosions (severe
elevated inflammatory disease)
markers
Reactive arthritis Adolescents/young adults Usually oligoarticular, involves Normal/soft tissue swelling
large joints in a migratory,
asymmetrical pattern with a
preceding GI illness, uveitis,
urethritis
Other (eg, systemic lupus Subacute onset, polyarticular Usually normal
erythematosus, pain and joint swelling,
immunoglobulin A vasculitis) rashes, fevers, or other
specific findings
Malignant conditions
Acute leukemia (3) Peak: 2–5 y; can present at any Musculoskeletal complaints are Metaphyseal bands, periosteal
age common (38.3% of reaction, lytic lesions, focal
patients) (4) sclerosis
Asymmetrical, nocturnal pain,
pain out of proportion to
examination,
hepatosplenomegaly, anemia,
thrombocytopenia, evidence
of tumor lysis/elevated uric
acid
Osteosarcoma Peak: adolescents; can present Single focus, often localizes Sunburst pattern, periosteal
at any age away from joint, overlying lifting, Codman triangle, soft
soft tissue swelling tissue ossification
Ewing sarcoma Peak: adolescents; can present Single focus, often localizes Periosteal reaction with onion
at any age away from joint, overlying skin appearance, extension
soft tissue swelling into soft tissues
CBC=complete blood cell, GI=gastrointestinal, MRI=magnetic resonance imaging, OI=osteogenesis imperfect, ROM=range of motion.
chemotherapy as measured by minimal residual disease that single-agent corticosteroid treatment alone induced leuke-
evaluation at the end of the induction phase. (8) mia remission in more than half of patients. (9) However,
patients treated with corticosteroid monotherapy consistently
Treatment/Management demonstrated leukemia recurrence (10); multiagent combina-
Corticosteroids are an integral element of the multitherapy tion therapy is thus critical for sustained cure. Prolonged or
standard of care for ALL. In fact, historical data demonstrated intensive corticosteroid exposure before definitive leukemia

Figure 1. Clinical course. The patient’s symptoms, clinical evaluation(s), laboratory and imaging studies, and therapeutic interventions are shown over
time since presentation. The diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) was reached 83 days after initial clinical evaluation. ANA=antinu-
clear antibody, ANC=absolute neutrophil count, CRP=C-reactive protein, dsDNA Ab=double-stranded DNA antibody, ESR=erythrocyte sedimentation
rate, Hgb=hemoglobin, L=left, NSAID=nonsteroidal anti-inflammatory drug, R=right, SOB=shortness of breath.
diagnosis has been suspected to promote corticosteroid resis- morphology or cytogenetics, but minimal residual disease
tance and partially treat and mask other critically risk-stratify- assessment by multiparameter flow cytometry was positive at
ing features, such as presenting WBC count or central a level of 0.037%. Taken together with her disease’s favor-
nervous system involvement, thereby resulting in inadequate able cytogenetics, her final risk stratification remains SR-
risk stratification and wrongly assigned treatment intensity. average. Her excellent prognosis is estimated at approxi-
(11) To achieve meaningful and actionable clinical trial out- mately 95% long-term survival after completion of an
comes in the setting of such confounders, the Children’s approximately 2.3-year treatment course.
Oncology Group enforces rigorous enrollment criteria in all
their clinical trials, with strict guidelines surrounding the Lessons for the Clinician
acceptability of patients having undergone corticosteroid pre- • An evolving or inconsistent clinical picture should prompt
treatment. Our patient’s risk stratification was altered by the consideration for an oncologic etiology of arthralgia and
brief course of prednisolone administered in the week before cytopenia(s) in a pediatric patient, particularly with unex-
diagnosis: pretreatment prednisolone exposure precluded her plained imaging findings such as focal sclerosis.
from stratification to the lowest risk treatment arm of the SR • Clinicians should be mindful of the impact of glucocor-
group. ticoid therapy on the diagnosis and management of
lymphoid malignancies and should strongly consider
Patient Course consultation with a pediatric hematologist/oncologist
One day after bone marrow evaluation our patient was for- before initiating corticosteroid therapy in the setting of
mally enrolled in the current Children’s Oncology Group any diagnostic uncertainty.
SR B-cell ALL clinical trial. She began therapy with 3-drug • Barriers to in-person follow-up in the setting of the coro-
induction chemotherapy (dexamethasone, vincristine, and navirus disease 2019 pandemic might limit the compre-
polyethylene glycol–conjugated asparaginase). She toler- hensive clinical evaluation and prolong the time to
ated induction therapy well, with resolution in migratory diagnosis for pediatric patients with insidious leukemia
arthralgia and complete return to baseline activity level onset.
by day 4 of treatment. The cytogenetics of her leukemia
were favorable (trisomy 4 and 10). Her end-of-induction References for this article can be found at
bone marrow evaluation revealed no detectable disease by DOI: 10.1542/pir.2020-003657.
INDEX OF SUSPICION
Feeding Intolerance in a 3-month-old

Alexander Gipsman, MD,* William Dufficy, MD,* Jessica Goldstein, MD†
*
Department of Pediatrics and
†
Department of Pediatric Neurology, Rainbow Babies and Children’s Hospital, Cleveland, OH
PRESENTATION
A 3-month-old, previously healthy Amish boy presents to the emergency depart-
ment with decreased oral intake, fussiness, and concern for dehydration. Two
days before presentation the patient began to show less interest in breastfeeding.
He initially exhibited feeding cues, but his suck was weak and he appeared to
have difficulty swallowing. That same afternoon, his cry was weaker than usual.
The next day, his mother noticed “gurgling” sounds whenever he cried. He has
been fussy and difficult to console. He has not had fever, congestion, vomiting,
respiratory distress, sweating, or cyanosis with feeds.
Two weeks before presentation, the patient started stooling less frequently;
he previously stooled at least once daily, but now he stools once every 3 days.
There have been no sick contacts or recent travel. The family has been building
a house on the lot next to their current home, and dirt is frequently tracked
inside from the construction site. They can their own foods at home, including
vegetables, legumes, and meats. The patient has never consumed any canned
foods.
The patient was born at term via normal spontaneous vaginal delivery. He
has met all of his developmental milestones on time and is up to date on his
immunizations. He has no allergies, and his only medication is vitamin D. The
family history is notable for hypertrophic cardiomyopathy in 3 siblings, several
deaths from long QT syndrome on the maternal side of the family, and multiple
cousins with GM3 synthase deficiency.
The patient is afebrile with a heart rate of 147 beats/min, a respiratory rate
of 40 breaths/min, blood pressure of 110/70 mm Hg, and oxygen saturation of
97%. His weight is in the first percentile for age; at his most recent health
supervision visit 1.5 months ago, his weight was in the sixth percentile. On
physical examination he is fussy and crying, with audible gurgling that
resolves with bulb suction. He has dry mucous membranes and no rhinorrhea
or congestion. The patient is tachypneic but breathing comfortably. Lungs are
clear to auscultation bilaterally, and there are no retractions. The patient is
tachycardic, and the remainder of the cardiac examination findings are normal.
AUTHOR DISCLOSURE: Drs Gipsman and
Abdominal and skin examination results are normal. Neurologic examination
Dufficy have disclosed no financial
is notable for a weak suck, weak cry, and decreased axial tone and strength as relationships relevant to this article. Dr
evidenced by head lag and an abnormal vertical suspension test result. Grasp Goldstein serves on the AAP PREP
editorial board. This commentary does
reflex in the fingers and toes is normal. Pupils are equal, round, and briskly
not contain a discussion of an
reactive. They remain briskly reactive to light after being allowed to fully dilate unapproved/investigative use of a
several times over 2 minutes. Extraocular motions are intact, and no ptosis is commercial product/device.

present. Gag reflex, sensation, and deep tendon reflexes soil. Under specific conditions (restricted oxygen, pH > 4.6,
are normal. There are no tongue fasciculations. temperature of 77.0 F–98.6 F [25 C–37 C]), the spores pro-
Complete blood cell count, complete metabolic panel, and duce botulinum toxin, which is the most potent poison known
C-reactive protein and ammonia levels are normal other than to humankind. (3) The infantile form of botulism was first
a mildly decreased serum bicarbonate level of 20 mEq/L (20 described in 1976, (3) and it affects approximately 100 infants
mmol/L). Urinalysis shows 21 protein and 21 ketones. The annually in the United States. (4) Although there are 8 types of
patient is given a 20-mL/kg bolus of normal saline and is botulinum toxin, nearly all cases of infantile botulism have
started on maintenance fluids due to concern for dehydration. been caused by type A or B. (3) The median age at infection is
After completion of the fluid bolus, the patient’s tachycardia 16 weeks, and 99.8% of all reported cases of infantile botulism
and tachypnea resolve. have occurred in children younger than 1 year. (5) Experimental
data from mouse studies indicate that C botulinum spores are
Differential Diagnosis able to colonize the infant intestine more readily than the adult
The differential diagnosis for an infant with acute onset of intestine. This is thought to be due to a lack of gut microbiome
hypotonia includes infection, metabolic disorders, and neuro- diversity in the infant compared with adults, making them
muscular disorders. (1) Congenital heart disease should be more susceptible to botulism. (3) C botulinum spores colonize
considered in this patient as a possible cause of feeding the infant’s colon and produce neurotoxin, which is absorbed
intolerance due to his family history, in addition to his into the bloodstream. It then irreversibly binds to cholinergic
recently decreased growth velocity. The patient’s lack of fever, receptors in the presynaptic cell membrane at neuromuscular
overall well appearance, and laboratory results point against junctions.
an invasive infection such as encephalitis or meningitis. The light chain portion of the toxin enters the cytosol
Disorders of the neuromuscular junction considered in this of the neuron, where it inhibits release of acetylcholine into
case include spinal muscular atrophy, infantile botulism, and the neuromuscular junction (Fig 1). (3)(6)
myasthenia gravis. The acuity of onset of symptoms and The first sign of illness is almost always decreased stool
their localization to the upper extremities and cranial nerves frequency (>95% of cases). (6) Lethargy and poor feeding
make spinal muscular atrophy and congenital myasthenia usually follow, with increasing weakness that manifests as
gravis less likely. Infantile botulism typically presents with symmetrical, descending paralysis. Bulbar palsy is the hall-
acute-onset bulbar dysfunction in an afebrile infant with a mark of infantile botulism, presenting as weak cry, ptosis,
recent history of decreased stooling frequency, which were poor head control, and expressionless face. Pupillary constric-
all present in this patient. GM3 synthase deficiency is a rare tion may be brisk initially but slows with repetitive stimula-
condition that presents as hypotonia, poor feeding and tion. (3) Importantly, the patient is usually afebrile. There is
growth, and fussiness in the first 6 months after birth. (2) It a wide spectrum of illness severity, but most cases eventually
should be considered in this case given the patient’s symp- require hospitalization. Similarly, the acuity of presentation
toms, decreased growth velocity, and family history. An addi- varies; some cases present insidiously, and others progress
tional but less likely cause of bulbar dysfunction in this rapidly over hours before presenting as a completely “floppy”
patient would be a brainstem lesion because an acute insult infant. (7) Muscle weakness often progresses to affect the
to the central nervous system can initially present with hypo- diaphragm, with nearly 50% of patients requiring mechani-
tonia and bulbar dysfunction. cal ventilation during the hospital course at some point. The
peak of symptoms usually occurs within 1 to 2 weeks after
Actual Diagnosis: Infantile Botulism admission to the hospital in patients who are not treated
This patient presented with acute-onset bulbar dysfunction with antitoxin. With adequate supportive care (enteral nutri-
as evidenced by weak cry, weak suck, and gurgling in addition, respiratory support), complete recovery is the expected
tion to upper body weakness and hypotonia with a recent outcome; mortality is less than 1% in the United States. It
2-week history of decreased stool frequency. He was afe- may take patients several months to recover, and the rate of
brile and alert. Of note, he was exposed to a nearby con- clinical improvement depends on regeneration of damaged
struction site and his family canned their own foods at nerve terminals and motor endplates. There have been no
home. His symptoms were clinically consistent with infan- known cases of repeated infection in an infant who has
tile botulism. recovered from botulism. (3)
Clostridium botulinum is an obligate anaerobic spore– Honey consumption has been definitively associated
producing gram-positive bacillus that is naturally found in with approximately 20% of cases, and it is the only known
Figure 1. A. Normal neuromuscular junction. Acetylcholine (ACh)-containing vesicles bind to membrane fusion proteins (collectively referred to as the
SNARE complex) on the presynaptic terminal membrane, resulting in release of ACh molecules across the neuromuscular junction and binding to the
ACh receptor on the muscle cell. B. Neuromuscular junction affected by botulinum neurotoxin (BoNT). BoNT is endocytosed by the presynaptic neuron,
and the light chain targets the SNARE complex, preventing the ACh from being released from its vesicle and thus binding to the ACh receptor on the
muscle cell.
modifiable risk factor. Therefore, honey should not be fed results of the botulinum toxin assay, as it can take up to a
to children younger than 12 months. For most cases, no week to receive results.
source of C botulinum spores is identified; in such cases, A single dose (50 mg/kg) of BIG-IV neutralizes all botuli-
spores adherent to airborne dust particles are likely the num toxin that may be absorbed from the infant’s colon for 6
culprit. Therefore, lack of exposure to a known source of months, and it does not decrease the sensitivity of diagnostic
the organism should not impact diagnosis and treatment. testing. (3) The California Department of Health is the sole
Diagnosis is established by identification of C botulinum provider of BIG-IV in the world, and it may be obtained by
organisms and/or toxin in a stool sample of an infant with calling their 24-hour phone line at (510) 231-7600.
symptoms of botulism. Electromyography and nerve conduc- Besides prompt administration of BIG-IV, supportive
tion studies may be helpful; however, they are neither sensi- care is the cornerstone of treatment for infantile botulism.
tive nor specific for infantile botulism and should not be Careful monitoring of respiratory status is essential, while
anticipating the potential need for intubation and mechan-
relied on for diagnosis. If botulism is suspected, head imaging
ical ventilation if the diaphragm is affected. Enteral nutri-
and lumbar puncture are usually not required. (3)
tion, either by mouth or via nasogastric tube, is preferred
In 2003, the Food and Drug Administration (FDA)
over parenteral nutrition to avoid complications such as
approved a human-derived antitoxin (botulism immune
central line infections. Secondary infections are common,
globulin intravenous, or BIG-IV) for the treatment of infan-
including pneumonia (due to aspiration and airway
tile botulism developed by the California Department of
smooth muscle hypotonia), urinary tract infection (due to
Health Services. The approval was based on data from a 5-
bladder catheterization and hypotonia), and acute otitis
year randomized, double-blind, placebo-controlled trial.
media (due to Eustachian tube dysfunction). (9)
This seminal study showed that treatment with BIG-IV was
Caution should be taken before administering antibiotics
associated with a decrease in mean hospital stay by 3.1
to patients suspected of having infantile botulism due to
weeks, mean ICU care by 3.2 weeks, mean duration of the concern that their use may cause increased release of
mechanical ventilation by 2.6 weeks, mean duration of neurotoxin from lysed C botulinum organisms. (10) This
tube or intravenous nutrition by 6.4 weeks, and mean hos- applies to all classes of antibiotics because nearly all com-
pital charges by $88,600 per patient. (4) A subsequent 6- monly used agents have high activity against C botulinum
year open-label study showed similar results. No serious organisms. (11) Aminoglycosides in particular should be
adverse events were associated with BIG-IV therapy in avoided when possible because they have been shown to
these studies. Postlicensure data from 2003-2015 showed potentiate the action of botulinum toxin at the neuromus-
that the greatest decrease in length of stay is seen in cular junction. (12) Once BIG-IV has been administered, it
patients who receive BIG-IV within the first 3 days of hospi- is safe to give antibiotics to treat secondary infections
talization. (8) Therefore, treatment should be initiated because BIG-IV neutralizes all botulinum toxin present in
immediately if botulism is suspected without awaiting the blood. (3)

PATIENT COURSE • Lack of exposure to honey or other suspected sources of
The California Department of Health was called shortly after Clostridium botulinum should not impact the consider-
the patient was admitted, and BIG-IV was airmailed and ation of botulism in the differential diagnosis.
administered the following afternoon. His weakness and • Botulism immune globulin intravenous therapy dramati-
hypotonia plateaued and slightly improved after approximately cally decreases mean length of hospitalization, ICU care,
1 week, but progress was slow. He was discharged 14 days mechanical ventilation, and intravenous and tube feeding
after admission requiring nasogastric feeds. Two days after and mean patient cost.
discharge we received the stool study results showing type B • Treatment should be initiated as soon as possible when
toxin–producing C botulinum. At a follow-up appointment 23 botulism is suspected and should not be delayed to con-
days after discharge the patient had returned to his baseline firm the diagnosis.
and his examination findings were normal. • The California Department of Health should be con-
tacted to obtain BIG-IV by calling the 24-hour phone
Lessons for the Clinician line at (510) 231-7600.
• Botulism should be suspected in an afebrile infant with

acute-onset bulbar dysfunction and a recent history of References for this article can be found at
decreased stool frequency. DOI: 10.1542/pir.2020-002840.
INDEX OF SUSPICION
Hives and Fever in a 13-year-old Boy

Thang V. Truong, MD,*,† Blake Gruenberg, MD,‡ Daisy A. Ciener, MD, MS,‡ Ryan Butchee, MD*
*The Children’s Hospital at OU Medical Center, Oklahoma City, OK
†
University of Iowa Hospitals and Clinics, Iowa City, IA
‡
Vanderbilt University Medical Center, Nashville, TN
PRESENTATION
A 13-year-old previously healthy immunized boy presents to the pediatric emergency
department (ED) with fever, hives, and red-colored urine. He had no history of ana-
phylaxis, but earlier that morning he had an episode of angioedema, hives, and diffi-
culty breathing. His mother treated him with 25 mg of oral diphenhydramine and
0.3 mg of intramuscular epinephrine obtained from a sibling with a history of ana-
phylaxis. All of his symptoms improved by the time emergency medical services
arrived so he was not transported to a hospital. A couple of hours later he presented
to his pediatrician due to recurrence of hives. He was prescribed hydroxyzine and a
prednisolone course for presumptive allergic reaction symptoms. That night (12 hours
after intramuscular epinephrine administration), his hives were still visible but much
improved according to his mother. However, he became febrile to 101.9 F (38.8 C)
and also noticed red-colored urine, so he presented to the ED. He did not have nau-
sea, vomiting, or diarrhea. On arrival his vital signs are remarkable for hypoxia to
88% requiring oxygen at 2 L/min via nasal cannula and hypertension to 150/100
mm Hg. On physical examination he appears uncomfortable from pain and has mild
diffuse urticaria. He also has 2 dusky lesions on his abdomen surrounded by areas of
erythema that are distinctly different from his urticarial rash (Fig 1). These lesions are
tender to palpation, but the rest of his abdomen is soft, nontender, and nondistended.
He does not have any respiratory distress, wheezing, or angioedema. Initial laboratory
values (refer to Table 1 for normal values) are notable for a low platelet count of
100,000/mL (100 × 109/L) and a low hemoglobin level of 11 g/dL (110 g/L). The retic-
ulocyte count is elevated at 10.6% of red blood cells (RBCs) (0.11 proportion
of RBCs), and the lactate dehydrogenase level is elevated at 3,934 U/L (65.7
mkat/L). The peripheral blood smear shows that 25% of RBCs are schisto-
cytes. Also notable are elevated levels of blood urea nitrogen of 34 mg/dL
(12.1 mmol/L) and creatinine of 1.5 mg/dL (132.6 mmol/L). The coagulation
profile is abnormal, with a high international normalized ratio of 1.9, a high
D-dimer value of 5,781 mg/mL (31,657 nmol/L), and a prolonged activated par-
tial thromboplastin time of 39 seconds. The white blood cell count is elevated
at 24,000/mL (24 × 109/L), and the lactate dehydrogenase level is normal at
AUTHOR DISCLOSURE: Drs Truong,
302 U/L (5.0 mkat/L). A urine sample appears as shown in Figure 2. After Gruenberg, Ciener, and Butchee have
receiving the sample, the laboratory reports that his urine remains pigmented disclosed no financial relationships
despite multiple centrifugations and that a supernatant cannot be separated. relevant to this article. This commentary
does not contain a discussion of an
Therefore, dipstick and microscopy results cannot be reported that night unapproved/investigative use of a
using the available colorimetric urine analyzers. The urine myoglobin level, commercial product/device.

DISCUSSION
Differential Diagnosis
The differential diagnosis for dusky/erythematous skin lesions
and red-colored urine includes cellulitis, anaphylaxis, hemo-
lytic uremic syndrome (HUS), Henoch-Schonlein purpura,
nephritis syndrome, nephrolithiasis, pyoderma gangrenosum,
vasculitis, and systemic loxoscelism (brown recluse spider
bite). Although cellulitis can manifest as an erythematous
skin lesion, it typically does not have a dusky appearance or
result in red-colored urine. The patient does not meet the ana-
phylaxis criteria while in the ED because he only has hives
without respiratory or gastrointestinal involvement. He denies
a recent history of bloody diarrhea, making Escherichia coli
O157: H7–induced HUS unlikely. Nondiarrheal forms of
HUS, also known as atypical HUS, are exceedingly rare.
Henoch-Schonlein purpura is less likely because the patient
does not have purpura or a rash that localized to dependent
areas (lower extremities/buttocks). Nephritic syndrome should
be considered when hematuria and hypertension are found;
however, this does not explain his cutaneous skin findings or
evidence of hemolysis on laboratory testing. He denies colicky
abdominal or flank pain, making nephrolithiasis less likely. In
addition, renal ultrasonography did not show any stones or
Figure 1. Patient’s abdominal skin lesions found on examination at pre-
sentation to the emergency department. There are 2 dusky centers sur-
hydronephrosis. Pyoderma gangrenosum is an idiopathic dis-
rounded by erythema. order in which dark erythematous papules progress to
necrotic ulcers. The lesion of pyoderma gangrenosum typically
is not as well-demarcated and often has ragged, ribbon-like
however, is elevated to 1,962 mg/L (114 nmol/L). Chest ulcers. (1) It should be suspected in patients with preceding
radiography is normal. Renal ultrasonography shows trauma to the area or those who have other systemic ill-
increased renal parenchymal echogenicity but no hydro- nesses, such as inflammatory bowel disease, juvenile idi-
nephrosis or stones. At the time of admission, repeated opathic arthritis, and other rheumatologic arthritides, or
laboratory values are significant for a decreased hemo- leukemia, none of which is suggested in this patient’s
globin level of 7.8 g/dL (78 g/L) and an increased crea- history. Similarly, vasculitis is less likely in this patient
tine kinase level of 645 U/L (11 mkat/L). because he does not have any history of underlying
Table 1. Normal Laboratory Values in Order of Appearance in Manuscript

NORMAL VALUES IN
NORMAL VALUES IN SYSTEME
LABORATORY TEST CONVENTIONAL UNITS INTERNATIONAL (SI) UNITS
Platelets 150–400 × 103/mL 150–400 × 109/L
Hemoglobin 11.4–15.4 g/dL 114–154 g/L
Reticulocyte count 0.5%–2.5% of red blood cells 0.005–0.025 proportion of red blood cells
Lactate dehydrogenase 62–496 U/L 1.0–8.3 mkat/L
Blood urea nitrogen 7–17 mg/dL 2.5–6.1 mmol/L
Creatinine 0.8–1.1 mg/dL 70.7–97.2 mmol/L
International normalized ratio 0.9–1.2 0.9–1.2
D-dimer <0.24 mg/mL 1.3 nmol/L
Activated partial thromboplastin time 26.0–37.0 s 26.0–37.0 s
White blood cells 4,500–13,500/lL 4.5–13.50 × 109/L
Creatine kinase 58–391 U/L 1.0–6.5 mkat/L
Urine myoglobin 0–13.8 mg/L 0–0.8 nmol/L
Potassium 3.5–5.1 mEq/L 3.5–5.1 mmol/L
elastin-degrading metalloproteinases and causes apoptosis
of keratinocytes, resulting in neutrophil chemotaxis. (7)
Clinically, this manifests as localized pain, necrosis,
inflammation, and edema. Interestingly, there is no asso-
ciation between the severity of local tissue damage and the
development of systemic symptoms such as fever, emesis,
and myalgia. For reasons not yet fully understood, sys-
temic symptoms are relatively more common in children
than in adults. (8) In severe cases of systemic loxoscelism,
acute hemolysis, disseminated intravascular coagulation
(DIC), acute kidney injury (AKI), and rhabdomyolysis can
occur. (8)(9) If acute hemolysis is present, it typically occurs
within 7 days after local inoculation. (10) Phospholipase
D enzyme is also the driving mechanism behind hemolysis
via activation of complement pathways. (7)(11) Disseminated
intravascular coagulation, characterized by intravascular micro-
thrombi, also causes mechanical shearing of RBCs, further
contributing to hemolysis. In addition, the toxin from L reclusa
causes direct damage to renal tubular epithelial cells, leading
to AKI. Free hemoglobin (from hemolysis) and myoglobin
(from rhabdomyolysis) also directly damage the renal
tubules in a process known as pigmentary nephropathy.
(12)(13) The pigmented urine associated with systemic
Figure 2. The patient’s urine sample obtained in the emergency
department. loxoscelism can remain homogenously red/brown due to
hemoglobin and myoglobin not separating into a super-
natant after centrifugation. In contrast, RBCs can be sep-
connective tissue disease, recent infections, or exposure
arated from the rest of the urine specimen into a grossly
to offending medications.
clear supernatant in which cells are visible under micros-
copy. (14)(15) AKI, rhabdomyolysis, and acute hemolysis
The Condition and Patient’s Diagnosis can all lead to life-threatening hyperkalemia.
This patient has systemic loxoscelism caused by the toxin
of Loxosceles reclusa, or the brown recluse spider. These Treatment/Management
spiders are endemic to the midwestern and southern Systemic loxoscelism typically resolves in 1 week if no
United States. Certain distinguishing features of the further complications occur. Management of the local
brown recluse spider include a violin-shaped print on the bite includes conservative therapy such as cleaning the
anterior thorax as well as 3 pairs of 2 eyes as opposed to inoculated area copiously with soap and water, elevating
the typical 2 pairs of 4 eyes of other arachnid species. (2) the wound if possible to mitigate localized edema, using
As their name implies, they typically live in dark cool cool packs, managing pain, and updating tetanus vaccine
spaces inside homes but can also be found outside under if the patient has not received at least 3 doses of tetanus
dead foliage or logs. (3) Bites are more common from toxoid, with the last dose being administered within the
April to October. (4) Brown recluses rarely bite twice, but past 10 years. Patients should monitor the wound for
emerging case reports have reported multiple adjacent progression to necrosis, which typically occurs 10 days
inoculations. (5) The initial bite often goes unnoticed as it after inoculation. (16) No treatment has been proven to
is typically painless. The bite wound initially manifests as halt this progression if it occurs. Corticosteroids, intrave-
an erythematous macule with subsequent development of nous immunoglobulin, and dapsone have been studied
a dusky center within 24 hours. The bite wound pro- but have not shown consistent efficacy and are not rec-
gresses to central necrosis 10% of the time. (6) Local tis- ommended as the standard of care. (17) There is yet to
sue damage is attributed to the phospholipase D enzyme exist an antivenom in the United States. However, one is
in the toxin. This enzyme generates potent collagen/ available in South America as local Loxosceles species

Figure 3. Progression of the patient’s skin lesions throughout hospitalization and after discharge. The photograph on day 1 was taken by the patient’s
mother earlier that day before presentation to the emergency department. Day 7 and day 18 photographs were taken by the medical team during the
patient’s hospitalization. He was then discharged, and the day 21, 25, and 27 photographs were sent to the medical team by his mother.
(specifically Loxosceles laeta) cause a higher incidence of rhabdomyolysis includes the infusion of isotonic saline
systemic loxoscelism than its North American counter- (targeting a urine output of 4 mL/kg per hour) to miti-
part L reclusa. (18) In North America, therapies are gate progression to renal failure. (20) AKI, acute hemoly-
largely supportive for both local and systemic complica- sis, and rhabdomyolysis can lead to hyperkalemia and
tions of the brown recluse spider bite. Blood transfusion subsequent dysrhythmias, so close monitoring of electro-
is a cornerstone for patients who are severely anemic or lytes is necessary. Hyperkalemia is initially treated with
hemodynamically unstable. Plasma exchange has been calcium gluconate/chloride to stabilize the cardiac mem-
trialed for severe cases, and consultation with a hematol- brane, followed by albuterol and insulin with glucose to
ogist is prudent. (19) In children, management of drive potassium intracellularly. Urine alkalization along
with diuretics and polystyrene sulfonates can increase renal replacement therapy to intermittent dialysis to com-
renal and gastrointestinal clearance, respectively. Patients plete kidney recovery during his 18-day hospital admis-
with persistent hyperkalemia and AKI with progression sion. After discharge, his mother continued sharing
to renal failure might require dialysis. Coagulopathy photos of his abdominal lesions to keep the medical
management often includes vitamin K and/or targeted team updated with his healing progress (Fig 3). Wound
infusion of blood products. care therapists continued to follow him as an outpatient
until he made a complete recovery.
Patient Course
After his initial presentation and resuscitation, the
patient was admitted to the PICU. He progressed to Lessons for the Clinician
severe rhabdomyolysis, hemolysis, hyperkalemia, and
• In severe cases of systemic loxoscelism, acute hemolysis,
dysrhythmia. His potassium level, initially normal in the
disseminated intravascular coagulation, acute kidney
ED, rapidly increased to 7.1 mEq/L (7.1 mmol/L) in the
injury, and rhabdomyolysis can occur.
PICU. In addition, he had the onset of premature ventric-
• There is no association between the severity of local mani-
ular contractions and a widening QRS complex. His
hyperkalemia persisted despite treatment with calcium festations and the development of systemic symptoms.
gluconate, albuterol, insulin/glucose, bicarbonate, and • Urine supernatant that remains pigmented after centri-
diuretics. Due to anticipated progression to life-threaten- fugation is a result of either hemoglobinuria from acute
ing arrhythmias and cardiac arrest, the PICU team intu- hemolysis or myoglobinuria from rhabdomyolysis. In
bated him to facilitate timely and safe dialysis catheter contrast, hematuria due to hemorrhage in the urinary
placement. Nephrology was consulted, and he was placed tract can be separated via centrifugation.
on continuous renal replacement therapy for recalcitrant • Corticosteroids, intravenous immunoglobulin, and dap-
hyperkalemia and deteriorating renal function. His sone have inconsistent efficacy, and their use is not rec-
course was further complicated by hematemesis due to ommended. The standard of care is largely supportive,
his ongoing thrombocytopenia and coagulopathy. He was focusing on the complications of systemic loxoscelism.
given vitamin K and multiple blood product transfusions
along with a high-dose proton pump inhibitor. After 2 References for this article can be found at
days he was extubated and transitioned from continuous DOI: 10.1542/pir.2020-003848.

IN BRIEF
Knee Trauma
Rachel Levene, MD, ME Ed,* Daniel M. Fein, MD,* Jennifer P. Grossman, MD,*
*Division of Pediatric Emergency Medicine, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY
Over each of the 1st 4 months of the year, PIR will feature a mini-series of In Briefs
dealing with injuries to the extremities of children: knee, ankle, elbow, and hand.
Read and enjoy!
–Henry M. Adam, In Brief Associate Editor
The knee is the largest joint in the human body, making it particularly vulnerable to
injury. Acute injury can result in ligamentous sprains and strains, dislocations/sub-
luxations, and/or bony fractures either from direct trauma to the joint or indirect
stress on previously healthy tissue. Most injuries to the knee involve the surrounding
ligaments and/or tendons, with fractures composing an exceedingly small percentage
of injuries. Prepubescent children are at greater risk for bony injury because before
closure of the physis, tensile bone strength is less than that of ligament and tendon
attachments. Once the physis closes, bone tensile strength exceeds that of ligaments/
tendons, making ligamentous injury more common in postpubertal children.
Although not the subject herein, it is important to remember that aside from trau-
matic injury, knee pain can be a manifestation of infectious, rheumatic, or oncologic
pathology.
Sprains or tears of the anterior or posterior cruciate ligament or the medial
or lateral collateral ligament, meniscal tears, quadriceps tendon ruptures, patel-
lar tendon ruptures, and hamstring strains are soft tissue injuries that can result
from acute trauma to the knee.
Anterior cruciate ligament tears are the most common ligamentous knee AUTHOR DISCLOSURE: Drs Levene, Fein,
and Grossman have disclosed no financial
injury in children and skeletally immature adolescents. Typically, they occur dur- relationships relevant to this article. This
ing a sudden change in the rotational forces on the knee when the foot is fixed. commentary does not contain a
Patients will describe a “pop,” or their knee “giving out,” and present with an discussion of an unapproved/
acutely swollen knee with an effusion. Posterior cruciate ligament injuries are product/device.
rare, resulting from direct force on the tibial tubercle, which pushes the tibia
posteriorly relative to the femur. Medial and lateral collateral ligament injuries Injury: Knee. Baskin MN, Adams CM. In:
Shaw KN, Bachur RG, eds. Fleisher &
are more common in the skeletally mature patient and result from direct trauma
Ludwig’s Textbook of Pediatric Emergency
to the contralateral side of the knee: trauma at the lateral aspect causes medial Medicine. 7th ed. Philadelphia, PA: Wolters
collateral ligament injury, and medial trauma affects the lateral collateral liga- Kluwer; 2016:254–261
ment. (A list of maneuvers to assess ligamentous injury appears in Table 1.)
Knee Conditions. Cunill-De Sautu B,
Meniscal tears result from sudden twisting of the leg while bearing weight.
Gereige RS. Pediatr Rev. 2014;35(9):359–370
Patients, most commonly postpubertal, often describe their injury as a painful
“locked knee” or “torn cartilage.” Quadriceps and patellar tendon ruptures occur in Can the Ottawa Knee Rule Be Applied to
postpubertal children, typically older athletes, with an abrupt contraction of the quad- Children? A Systematic Review and Meta-
analysis of Observational Studies.
riceps muscles, as when landing from a high jump or with a sudden change in direc- Vijayasankar D, Boyle AA, Atkinson P. Emerg
tion at high velocity. As a result of the rupture, extension of the knee is limited. Med J. 2009;26(4):250–253
TABLE 1. Maneuvers to Assess Ligamentous Injury
INJURY MANEUVER EXAMINATION
Anterior cruciate ligament Lachman Patient supine, knee flexed to 15 ; stabilize femur; pull tibia
tear forward to assess for any anterior motion relative to femur,
while keeping thumb on tibial tuberosity. + = increased
movement compared with uninjured leg.
Anterior drawer Patient supine with hip flexed to 45 and knee flexed to 90 ; sit
on foot and wrap hand around hamstrings; push and pull
proximal part of the leg. 1 = increased forward drawer
compared with uninjured leg.
Pivot shift Extend knee; rotate foot internally; apply valgus force to knee
while flexing. 1 = subluxation of tibia.
Medial and lateral collateral Valgus and varus stress tests Valgus or varus pressure while the knee is either in full
ligament tears (respectively) extension or 30 flexion. 1 = pain/widened gap.
Patellar subluxation Patellar apprehension test Place gentle pressure at the medial aspect of the patella. 1 =
anxiety/resistance to maneuver.
Meniscal tear Apley compression With the patient prone, place the knee into 90 of flexion;
firmly grasp the heel and apply downward axial loading
force and rotate the leg medially. 1 = pain.
Apley distraction With the patient prone, stabilize the posterior thigh; place the
knee in 90 of flexion; lift the lower leg by the heel and then
rotate the leg medially and laterally. 1 = pain.
McMurray Place thumb and index finger on the patient’s medial and
lateral joint lines while the knee is passively flexed and
extended; rotate the lower leg. 1 = click/pain.
Thessaly Hold patient’s hands as patient stands with foot flat on the
ground and knee slightly flexed; internally and externally
rotate the knee 3 times. 1 = joint line discomfort, or sense
of knee locking/catching.
1 = A positive test/maneuver results in or indicates
The muscles most affected by an acute injury to the reduced or subluxated. Such patients can have slight
knee are the hamstrings. Diagnosis of a hamstring strain medial patella pain and are anxious during an attempt to
is clinical, manifesting with significant swelling, local ten- push the patella laterally (apprehension test). If subluxa-
derness, and sometimes overlying ecchymosis. tion is suspected, radiographs should be obtained to look
Dislocations of the knee joint in children are infrequent for an associated osteochondral fracture.
but serious limb-threatening injuries, occurring most fre- Young children and other skeletally immature patients
quently after physis closure. Typically, a significant traumatic are the most likely to sustain Salter-Harris–type physeal
force is involved, resulting in an overt deformity. Because fractures from direct trauma, as in contact sports or with
the dislocation can shear the popliteal artery, which is motor vehicle accidents. Physeal fractures most commonly
anchored firmly to either end of the joint, and can also dis- occur at the distal femoral epiphysis. Although rare, proxi-
rupt the peroneal nerve, evaluation of the limb’s neurovascu- mal tibial epiphyseal fractures can be limb-threatening
lar status is a crucial part of the physical examination. because the popliteal artery lies just posterior to the tibial
More common than dislocations of the knee joint, epiphysis. Sudden directional change can lead to tibial spine
patellar dislocations occur with forceful contraction of (intercondylar eminence) avulsion fractures in children 6 to
the quadriceps while the lower leg is abducted. Classically, 16 years of age because the tibial spine is not fully ossified
a “popping” sensation is described, and the patient has and thus weaker than the surrounding ligaments. Tibial
significant pain with the hip abducted, the knee held in tuberosity avulsions occur most often in adolescents when
the flexed position, and the patella laterally displaced. the knee’s extensor mechanism is challenged during sud-
Because the diagnosis is based on history and examina- den acceleration or deceleration, typically with jumping.
tion, the dislocation can be reduced before obtaining The tibial tubercle becomes swollen and painful, and the
radiographs by placing gentle pressure on the lateral patient is unable to fully extend the knee or perform a
aspect of the patella as the patient extends the knee. Post- straight leg raise. Patella fractures occur after direct trauma
reduction radiographs should be obtained to rule out an to the patella, such as falling on a flexed knee. They are rare
associated avulsion or patella osteochondral fracture. If the in young children because the patella does not ossify until 3
history suggests patellar dislocation but the patella is in to 6 years of age. Patellar avulsion fractures are more com-
anatomical position, the dislocation could have self- mon, resulting from forceful contraction of the quadriceps.

Table 2. Common Overuse Injuries
INJURY AGE, y INJURY DESCRIPTION
Osgood-Schlatter 11–15 Pain and swelling of the tibial tuberosity
from recurrent contractions of the
patellar tendon during knee extension
(jumping, squatting).
Sinding-Larsen-Johansson 11–15 Pain and swelling at the inferior aspect of
the patella from recurrent contractions
of the patellar tendon during knee
extension (jumping, squatting).
Patellofemoral dysfunction Teenagers Pain to the anterior superior aspect of the
knee from misalignment of the extensor
mechanism of the knee (increased
running mileage/intensity of training).
Patellar tendonitis Growth spurt Pain to the anterior inferior knee from
repetitive rapid knee extension
(jumping).
Prepatellar bursitis Adults Pain to the anterior patella from acute or
chronic trauma of the bursa (constant
kneeling).
Osteochondritis dissecans Teenagers Generalized pain, swelling, and sometimes
joint locking from separation of a small
area of the bone and overlying
cartilage.
Iliotibial band syndrome Older runners Lateral knee pain from repetitive
movement of the iliotibial band across
the lateral femoral condyle as the knee
flexes and extends (running).
Patellofemoral syndrome Teenagers Pain around the patella from cartilage
under knee damaged from injury or
overuse.
The patella is swollen, tender, and painful with extension. Avulsion fractures of the patella pole (patellar sleeve
Osteochondral fractures can accompany patellar dislocation fracture) can be missed easily on radiographs, and diagno-
or injury to a ligament or meniscus. If left untreated, they sis may necessitate more advanced imaging. Hip imaging
can lead to permanent defects and osteoarthritis. Nearly all should also be considered after careful examination
fractures of the knee are associated with swelling, signifi- because hip pathology frequently causes referred knee
cant pain, limited range of joint movement, and sometimes pain. If knee radiographs do not reveal a fracture but the
hemarthrosis. knee remains painful and swollen, damage to a ligament
Subacute overuse injuries can present with chronic or meniscus is likely. Emergent orthopedic consultation is
pain or acute worsening of pain. Table 2 lists the common indicated if neurovascular compromise is suspected, punc-
overuse injuries. ture or lacerations raise concern for violation of joint
Evaluation of an injury to the knee includes an attempt integrity, with laxity of the knee in any direction, and with
to locate point tenderness, assessment of range of motion nonlateral patellar dislocations.
and ligamentous laxity, presence of an effusion, and neu- Definitive management depends on the injury and
rovascular status of the lower leg. Laxity of the knee ranges from conservative treatment with rest, ice, com-
should be assessed in full extension and at 30 of flexion. pression, and elevation to urgent operative intervention.
The Ottawa Knee Rule is a highly sensitive clinical deci- Weightbearing status varies with the type of injury, and
sion tool to help guide the need for knee radiographs in analgesia and ambulatory aides should be provided as nec-
the setting of injury without a gross deformity. Anteropos- essary. If not indicated at the time of presentation, ortho-
terior and lateral radiographs of the knee (and a patellar pedic follow-up should occur within 1 to 2 weeks if
view if indicated) should be obtained only if any of the fol- symptoms do not improve.
lowing is present: patellar tenderness, tenderness at the
head of the fibula, inability to flex to 90 , and inability to COMMENT:
bear weight for 4 steps (regardless of limping), immedi- Our authors note that aside from trauma, knee pain can
ately with the injury and at presentation. result from infection or from rheumatoid and oncologic
disorders. Another category in the differential diagnosis is knee joint is particularly susceptible, especially in the first
joint laxity or hypermobility, which is, in fact, a relatively decade after birth. Affected children may be described as
common cause of recurrent knee pain in children. Genetic “double jointed,” and their pain typically occurs late in a
disorders of connective tissue, such as Marfan and Ehlers- day marked by vigorous exercise. The painful joint(s) can
Danlos syndromes, as well as syndromes such as trisomy show swelling, but not the redness and heat typical of
21 and William syndrome, are associated with joint laxity, inflammation. Recognition of BJHS, aided by the Beighton
but much more common than any of these is the so-called 9-point scale for hypermobility, can avoid unnecessary diag-
benign joint hypermobility syndrome (BJHS). More fre- nostic evaluation and expedite appropriate management:
quent in girls than in boys, possibly related to estrogen reassurance with patient education, muscle-strengthening
effects, and especially among children of African or Asian exercises, and pain control.
descent, BJHS probably reflects excessive ligamentous lax- –Henry M. Adam, MD
ity that allows range of motion beyond the normal. The Associate Editor, In Brief

IN BRIEF
Hypothermia and Cold Injury in Children

Lynn McDaniel, MD
University of Virginia, Charlottesville, VA
Accidental hypothermia is common and carries significant risk of morbidity and

mortality. Hypothermia, defined when the body temperature falls below 95 F
(<35 C), occurs when the body loses more heat than it can absorb or generate. It is
classified as mild, moderate, severe, or profound (Table). Environmental cold expo-
sure, near drowning, and immersion are common causes, as are trauma and intoxica-
tion. Hypothermia is not always easily diagnosed, so awareness of the presentation,
associated risks, and treatment is needed. Localized cold injury, of which frostbite is
the most commonly reported, is often seen with hypothermia, although it can occur
alone. This In Brief reviews accidental hypothermia: both generalized and local cold
injuries, their definitions, risk factors, presentations, and management.
Children are at increased risk for accidental hypothermia due to their greater body
surface area-to-mass ratio and less subcutaneous fat, which leads to greater heat loss.
Infants are particularly vulnerable due to immature thermoregulation and an inability
to shiver. Children with neurologic conditions are more prone to hypothermia due to
inability to avoid or escape a cold environment as well as difficulty with thermoregula-
tion. Exhaustion, hunger, dehydration, and lack of adequate clothing can contribute
to hypothermia in participants in outdoor sports, camping, and hiking. The epidemi- AUTHOR DISCLOSURE: Dr McDaniel has
disclosed no financial relationships
ology of accidental hypothermia in children shows that it is more common in boys, relevant to this article. This commentary
more prevalent in infants than in older children, and, in the United States, more does not contain a discussion of
common in the southern regions of the country. unapproved/investigational use of a
commercial product/device.
The most diagnostic sign of hypothermia is a low temperature. However, this
sign may be missed because most thermometers do not read below 93 F (34 C), Accidental Hypothermia. Brown DJA,
and oral and axillary temperatures are unreliable. Even rectal measurements may Brugger H, Boyd J, Paal P. N Engl J Med.
not reflect the true core temperature. 2012;367(20):1930–1938
Signs of mild hypothermia (89.6 F–95 F [32 C–35 C]) are shivering, pallor, acro-
Management of Accidental Hypothermia
cyanosis, and slurred speech. (Table) As the hypothermia becomes more severe, and Cold Injury. Petrone P, Asensio JA,
some signs may reverse, such as the skin becoming flushed instead of presenting Marini CP. Curr Probl Surg. 2014;51(10):417–431
with pallor. This can make recognition of the degree of hypothermia more difficult.
Hypothermia in Children: Clinical
Mental status worsens with more severe hypothermia and can range from clumsi-
Manifestations and Diagnosis. Corneli HM,
ness to confusion, progressing to stupor and a comatose state. Kadish H. UpToDate website. Available at:
A major problem in hypothermia is intravascular hypovolemia, which is caused https://www.uptodate.com/contents/
by extravasation, cold diuresis, and cold-induced thickening of the blood. Combined hypothermia-in-children-clinical-
manifestations-and-diagnosis. Accessed
with reduced cardiac output and drops in systemic vascular resistance, it can lead to May 2021
circulatory collapse. Victims of hypothermia are at increased risk for ventricular
fibrillation. Care to avoid triggers of ventricular fibrillation includes gentle handling Hypothermia in Children: Management.
and keeping the patient supine. Other potential complications include hypoglycemia Corneli HM, Kadish H. UpToDate website.
Available at: https://www.uptodate.com/
or hyperglycemia, hyperkalemia, metabolic acidosis or alkalosis, and coagulopathy contents/hypothermia-in-children-management.
with and without thrombocytopenia. Complications that can be seen in patients Accessed May 2021
Table. Degrees of Hypothermia with Clinical Correlation
CATEGORY TEMPERATURE, C CIRCULATORY METABOLIC NEUROLOGIC
Mild 32 to 35 Vasoconstriction Shivering Slurred speech
Pallor Increased metabolism Clumsiness
Acrocyanosis
Moderate 28 to <32 Vasodilation Respiratory depression Confusion
Flushed
Severe 24 to <28 Severely impaired circulation Severely impaired ventilation Loss of consciousness
Profound <25 Cardiovascular collapse Fixed pupils
Coma
more than 24 hours after rewarming include pulmonary Environmental risk factors for frostbite are similar to those
injury and infection, renal failure, and neurologic injury. for hypothermia. Frostbite tends to occur more commonly in
Prehospital management of hypothermic patients consists younger children than in infants, yet in teens it is frequently
of evaluating the patient’s ABCs (airway, breathing, and circu- related to intoxication, and overall it can be associated with
lation) and providing basic or advanced life support as needed. lack of supervision. Wind chill and damp clothing are contrib-
Conscious, shivering patients (mild hypothermia) can begin uting factors to cold injury. Extremities are most at risk; 90%
treatment in the field with ingestion of warm sweet drinks involve the hands and feet, and other common sites are the
and active movement. Passive rewarming, that is, removal of nose, cheeks, and ears.
wet clothing and use of warm blankets, should be performed. The damage to tissues in frostbite occurs in the freezing of
Active external rewarming by applying heat to the skin extracellular fluid and ice crystal formation, which damages the
with a heating pad, warm air, or warm water baths cellular membrane, causing intracellular dehydration and lead-
should be used in those with mild to moderate hypother- ing to cell death. The body attempts to warm the extremity by
mia. In patients with impaired consciousness who are breath- alternating cycles of vasoconstriction and vasodilatation, the
“hunting reaction.” This partial thawing and refreezing causes
ing and have a detectable pulse, careful movement of the
a thrombotic phase, leading to progressive dermal ischemia in
patients is required on transport because they are at risk for
capillary beds. Ischemia leads to increasing inflammatory
cardiac dysrhythmias. If there is no pulse, cardiopulmonary
mediators associated with edema, endovascular injury, and
resuscitation should be initiated and maintained while the
arrested blood flow to the area.
patient is transported to a hospital with extracorporeal mem-
In patients with a history of exposure to extreme cold,
brane oxygenation (ECMO) capabilities because this is often
numbness of the affected area is the first sign of frostbite.
required for optimal resuscitation. Severely hypothermic
Because frostbite injuries appear similar on presentation, stag-
patients, who experience hypothermia before hypoxemia,
ing is conducted only after rewarming. Superficial frostbite
have a greater likelihood of surviving cardiac arrest without
(first and second degree) is generally above the vascular plexus
neurologic impairment if ECMO rewarming is used. Timely
of the dermis and heals without substantial tissue loss. In
transport of patients to a hospital experienced in and capable
deep frostbite (third and fourth degree) the injury is full thick-
of treating hypothermia and its complications has greatly ness of skin and subcutaneous tissue and can involve muscle,
reduced its morbidity and mortality. tendons, and bone. Signs favorable for a superficial injury are
Localized hypothermia (cold injury) can be classified as normal skin color, clear blisters, and skin that compresses
frostbite (the most common type of freezing injury), frost- with pressure. Hard, noncompressible skin, cyanosis, and
nip, pernio (or chilblains), and immersion foot (trench foot). hemorrhagic blisters suggest deep injury.
Frostbite involves severe localized injury caused by freezing Initial management of frostbite involves protecting the
of the tissues, leading to cell death and tissue destruction. extremity or affected tissue from mechanical trauma in transport
Frostnip is defined as local cold injury where skin becomes to a hospital. Rewarming in the field can begin with immersion
white and numb yet reverses on warming. Pernio includes in warm water (98.6 F–102.2 F [37 C–39 C]) if there is no risk
rare localized inflammatory lesions due to damp cold expo- of refreezing before presentation to a hospital. It is important to
sure above freezing temperatures. Trench foot, also a non- avoid thawing before definitive warming can be done because
freezing cold injury, is associated with prolonged exposure refreezing can cause further damage. Once in-hospital care is ini-
to damp cold conditions, leading to injury of the sympathetic tiated, rewarming is best performed in a water bath at 104 F
nerves and vasculature of the feet. (40 C) for 15 to 30 minutes. Rewarming can be painful, so

attention to analgesia is important. Ibuprofen is recommended the field” while hiking in nature, at a swimming pool,
for control of pain and inflammation, although opioids might be or at the scene of a motor vehicle collision. Knowing
needed for severe pain. Daily hydrotherapy to promote debride- what to do emergently and when to refer for more spe-
ment and movement over the first few days is also needed. cialized care is key. Amazing advances have been made
White blisters are debrided and treated with aloe vera, as an in rewarming techniques for severe hypothermia. One
inhibitor of thromboxane, to reduce tissue necrosis. Hemor- study provided data that the rates of survival after
rhagic blisters should be left intact. Surgical care might be ECMO for patients who later are found to not have sig-
needed for debridement, although more aggressive debridement nificant neurologic impairment ranged from 47% to
or amputation might not occur until final demarcation, usually 63%, which reinforces the point that one cannot predict
after 1 to 3 months. the eventual outcome until the appropriate interventions
Hypothermia and cold injury can be common, and chil- and rewarming have been accomplished. One quote I
dren are at increased risk. It is not restricted to geographic read was particularly poignant: “No one is dead until
areas with extreme cold but can occur in more temperate they are warm and dead.” It is an important guideline to
climes, especially when caught unprepared for low overnight maintain cardiopulmonary resuscitation for prolonged
temperatures in damp clothing or prolonged immersion in periods in the field for patients with significant hypo-
cool waters. Therefore, a high index of suspension is needed thermia, unless there is clearly a lethal injury or a do
to appropriately diagnose and treat. not resuscitate order for the patient. The science of
interventions for hypothermia is evolving, and contin-
COMMENT: This In Brief addresses a fascinating topic ued research is needed to optimize care and outcomes
and one that is important for us as clinicians to know how for our patients.
to handle. We may encounter patients with hypothermia –Janet R. Serwint, MD
at work at our respective health-care facilities but also “in Associate Editor, In Brief
ANSWER KEY FOR JANUARY PEDIATRICS IN REVIEW

Central Nervous System Tumors in Children: 1. C; 2. A; 3. D; 4. B; 5. D.
Care of the Immigrant Child: 1. E; 2. B; 3. C; 4. C; 5. C.
Human Immunodeficiency Virus Preexposure Prophylaxis in Adolescents and Young Adults: 1. B; 2. D; 3. D; 4. C; 5. C.
VISUAL DIAGNOSIS
Chest Mass in a Newborn Infant

Brenda T. Wu, MD,* Rebecca Stein-Wexler, MD,† Su-Ting T. Li, MD, MPH‡
*
School of Medicine, University of California Davis, Sacramento, CA
†
Department of Radiology and
‡
Department of Pediatrics, University of California Davis Health, Sacramento, CA
PRESENTATION
A term, large-for-gestational age boy is transferred from an outside hospital with a
right anterior chest wall mass noted since birth. His mother is a healthy 33-year-
old gravida 4, para 4 woman with good prenatal care and normal prenatal labora-
tory values who had an uncomplicated pregnancy and elective cesarean delivery.
None of the patient’s siblings or family members have had similar masses.
On physical examination the patient is well-appearing and moving all 4 extremities
spontaneously without obvious limitations. Vital signs on admission to the hospital are
normal. There is a nontender, boggy, fluctuant, flesh-colored, grapelike mass from his
right nipple to the midaxillary line that extends to the right upper arm, with dimpling
of the skin throughout the right upper extremity (Fig 1). No bruit is heard over the
lesion. There is no palpable bony abnormality. Radial pulses are 21. Capillary refill is
less than 2 seconds. His lungs are clear to auscultation. The cardiovascular examina-
tion reveals a normal heart rate, rhythm, S1, and S2 and no murmurs. The abdomen
is soft, nontender, and nondistended, with no palpable masses or hepatosplenomegaly.
Chest radiography is normal. Complete blood cell count with differential
count is normal. Ultrasonography of the right superolateral chest shows a multi-
loculated fluid collection with undulating borders measuring 6 × 1.7 cm. Mag-
netic resonance imaging (MRI) with contrast of the chest and right upper
extremity reveals a multiloculated macrocystic mass in the superficial right chest
wall, additional cysts in the right arm, and a partially cystic right mediastinal
mass (Figs 2 and 3). MRI also shows multiple cysts in both kidneys (Fig 4).
Review of the findings from MRI and genetic testing reveal the diagnoses.
DIAGNOSIS
The differential diagnosis includes lymphatic malformation, venous malforma-
tion, vascular tumor, arteriovenous malformation, arteriovenous fistula, and cap-
illary malformation. The patient was diagnosed as having lymphatic
malformation. In addition, rapid genome sequencing revealed de novo patho-
genic variant of PKD1 mutation, supporting an incidental second diagnosis of
AUTHOR DISCLOSURE: Drs Wu, Stein-
autosomal dominant polycystic kidney disease (ADPKD).
Wexler, and Li have disclosed no financial
relationships relevant to this article. This
DISCUSSION commentary does not contain a
Lymphatic malformations are a type of vascular anomaly. The International Soci- investigative use of a commercial
ety for the Study of Vascular Anomalies stratifies vascular anomalies into vascular product/device.
Vol. 43 No. 1 JANUARY 2022 e1

Figure 1. Chest mass and right upper extremity dimpling.
tumors (benign, locally aggressive or borderline, and malig-

nant) and vascular malformations (simple, combined, anom-
Figure 3. Axial T1-weighted fat-suppressed gadolinium-enhanced mag-
alies of major named vessels, and vascular malformations netic resonance image shows the lobulated lesion appearing hypointense
associated with other anomalies). (1)(2) Lymphatic malforma- and the septae enhance.
tions are low-flow, nonmalignant vascular malformations of
the lymphatic system with dilated lymphatic channels or commonly occur in the head and neck regions, followed by
cysts thought to occur during lymphatic development. the extremities. (4) They are classified as macrocystic, micro-
Lymphatic malformations can affect 1 location or can be cystic, or mixed. Most are noted at birth or within the first 2
loculated and/or multifocal (eg, lymphangiomatosis). (3) years after birth.
Lymphatic malformation is an umbrella term that includes Superficial lymphatic malformations or deep vascular
all subtypes of lymphatic malformations, including cystic lesions may have no skin discoloration. In contrast, superficial
lymphatic malformations (macrocystic, microcystic, or mixed), arterial, capillary, or venous vascular anomalies can appear
generalized lymphatic anomalies such as kaposiform lym- red, pink, violaceous, or blue, depending on the mix of oxy-
phangiomatosis, channel-type lymphatic malformation, genated (arterial) or deoxygenated (venous) blood. Superficial
acquired progressive lymphatic anomaly (acquired progres- lymphatic malformations can have clear vesicles or pitting of
sive lymphangioma), and primary lymphedema. Lymphatic the skin or appear bruised if bleeding occurs within the mal-
malformations can affect any area of the body but most formation. Venous malformations are often bluish, soft, and
compressible papules. Capillary malformations are often pink,
red, or purple flat macules or patches. High-flow
Figure 2. Axial T2-weighted fat-saturated magnetic resonance image

delineates the lesion in the right anterior chest wall and in the right arm Figure 4. Coronal T2-weighted fat-saturated magnetic resonance image
consisting of hyperintense lobulations with thin hypointense septations. shows several predominantly subcortical hyperintense (arrows) renal
There is also a cyst (arrow) in the right mediastinal lesion. lesions, most numerous on the right.
e2 Pediatrics in Review
malformations, such as arteriovenous malformations and arte- of ADPKD being a separate etiology for renal cysts from that
riovenous fistulas, can have a palpable bruit or thrill. Vascular underlying the lymphatic malformations in the chest and
anomalies can cause overgrowth and swelling in the affected right upper extremity. Differentiation between renal lymphan-
area, which could cause pain. giomatosis and ADPKD can affect the treatment regimen and
Lymphatic malformations can be associated with other prognosis. A case report describing an infant with biopsy-
anomalies. Gorham-Stout syndrome, also known as vanishing proven bilateral renal lymphangiomatosis with 1-year follow-
bone disease, is a rare condition characterized by proliferation up suggests a self-limiting course in some patients, although
of lymphatic vessels adjacent to single or multiple bones, lead- it can expand before regression. (10) Successful treatment for
ing to osteolysis and resorption of bone, oftentimes the ribs, renal lymphangiomatosis with sclerotherapy has been
spine, pelvis, skull, clavicle, or jaw. (5) Several PIK3CA-related described. (3)(9)
overgrowth spectrum conditions also have lymphatic malfor- A case report describing an adult with comorbid lym-
mations, such as Klippel-Trenaunay syndrome, a rare congeni- phangiomatosis and ADPKD hypothesized a link between
tal syndrome characterized by cutaneous capillary ADPKD and lymphangiomas as cystic pathologies sharing
malformations (port-wine stain), vascular or lymphatic malfor- common genetic and congenital processes; however, no
mations, and limb overgrowth. (1)(6) Many patients with lym- genetic mechanism has been identified. (11)
phatic malformations have an activating somatic PIK3CA ADPKD is the most common hereditary kidney disease,
gene mutation. (7) This was not the case for our patient. with a prevalence of 1:1,000 to 1:2,500. Patients with
Diagnosis of vascular malformation or neoplasm is ADPKD develop cysts in the kidney parenchyma, which
often made clinically and confirmed by imaging. For ini- often leads to end-stage kidney disease by age 50 to 60
tial imaging, the 2019 American College of Radiology years. Our patient’s incidental diagnosis of ADPKD is atypi-
Appropriateness Criteria for Clinically Suspected Vascular cal for several reasons. There was no family history, he
Malformation of the Extremities deems magnetic reso- developed cysts in the neonatal period, and his presenting
nance angiography with and without contrast, MRI with complaint was lymphatic malformations. Our patient had a
and without contrast, computed tomographic (CT) angiog- de novo PKD1 mutation, the most common mutation seen
raphy with contrast, and duplex Doppler ultrasonography in ADPKD. Patients with PKD1 mutations have a less favor-
as appropriate for suspected vascular malformation of the able kidney prognosis than patients with PKD2 mutations,
extremity presenting with physical deformity. (8) However, who have end-stage kidney disease in their 70s and 80s.
because our patient also had a suspected abnormality in The Predicting Renal Outcomes in Polycystic Kidney Dis-
the chest wall, MRI or magnetic resonance angiography ease score combines predictive genetic factors with clinical
with and without contrast would be the best initial study information to predict risk of progression to end-stage kid-
to better evaluate deeper lesions than ultrasonography and ney disease for patients with ADPKD in patients older than
better evaluate soft tissue contrast than CT angiography. 35 years. (12) ADPKD is typically diagnosed using renal
The presence of renal cysts initially raised concern for ultrasonography in patients with an affected first-degree rel-
underlying lymphangiomatosis. Lymphangiomatosis is the ative. Genetic analysis can be useful in very young patients
term used to describe lymphatic malformations in multiple without a family history of ADPKD, as in our patient, who
organs. (3) It can affect any region of the body, although it is was found to have a de novo PKD1 mutation.
most common in the neck, axilla, retroperitoneum, and medi-
astinum. Renal lymphangiomatosis in pediatric patients is Treatment and Management
rare but should be included in the differential diagnosis for Symptoms from lymphatic malformations vary depending
conditions such as ADPKD, nephroblastomatosis, lymphoma, on location of involvement and extent of invasion. Man-
and hydronephrosis with perinephric urinoma. (9) Several agement varies depending on location, size and symptoms
case reports describe initial misdiagnosis of renal lymphangio- (including compression or obstruction of adjacent struc-
matosis as ADPKD. Imaging and genetic testing can help dif- tures), infection, and interference with quality of life,
ferentiate between renal lymphangiomatosis and ADPKD. In including cosmetic concerns. Generally, microcystic lym-
renal lymphangiomatosis, renal cysts are central in the renal phatic malformations are more challenging to treat than
sinus, whereas in ADPKD, renal cysts are peripheral and are macrocystic lymphatic malformations because they are
parenchymal, as was seen with this patient. (9) In addition, less accessible for aspiration or sclerosing. (1)
the patient’s rapid genome sequencing reveals de novo patho- Observation for potential spontaneous regression can be
genic variant of PKD1 mutation, which supports a diagnosis appropriate for small lymphatic malformations without

Five months later he presented with cough and was
diagnosed as having a parainfluenza infection. Chest radi-
ography revealed airway compromise; CT showed that the
intrathoracic extent had dramatically increased, resulting
in mediastinal shift and tracheal narrowing (Fig 5). Dark,
sanguineous fluid was drained from the lesion, and sclero-
therapy was performed using bleomycin. The postsclero-
therapy radiograph showed mass reduction and improved
lung expansion.
Persistent hypertension was treated with enalapril.
Repeated renal ultrasonography, compared with postnatal
imaging, showed an enlarging right cyst and a new left
cyst. Intrathoracic sclerotherapy was repeated 40 days
later. Further treatment will be required.
Figure 5. Coronal iohexol-enhanced computed tomographic scan shows

the intrathoracic lesion extending from the right apex to the level of the
diaphragm along with lobulated soft tissue in the axilla.
SUMMARY
• Magnetic resonance imaging/magnetic resonance
compromise of other systems. (13) Compression dressing is a
angiography without and with contrast is essential
conservative, first-line option for symptomatic treatment of
when an extensive lymphatic malformation is
lymphatic malformations limited to the extremities to prevent
suspected because ultrasonography often undere-
pain or growth of the malformation. (4) Treatment options for
stimates deep or intracavitary involvement.
large or symptomatic lymphatic malformations include sclero-
therapy, endovenous laser ablation, radiofrequency ablation, • Imaging findings, including ultrasonography,
and surgical resection. Drug therapy with sirolimus, sildenafil, computed tomography, and magnetic resonance
or propranolol has been described in case reports. Antibiotics imaging, can help distinguish autosomal dominant
should be used to treat infected lymphatic malformations. polycystic kidney disease (ADPKD) from renal
Clinical trials in adults with ADPKD show that angio- lymphangiomatosis because ADPKD lesions are
tensin-converting enzyme inhibitors and possibly vaso- more parenchymal and peripheral than the central
pressin antagonists decrease renal cyst growth. (14) A lesions typical of renal lymphangiomatosis. (6)
randomized controlled trial with tolvaptan, a selective • Genetic testing can help diagnose ADPKD in very
vasopressin antagonist, for pediatric ADPKD is underway young patients with bilateral renal cysts and no
for children aged 12 to 17 years; results are not yet avail- family history of ADPKD.
able. (15) Schaefer et al suggest angiotensin-converting
• Multiple specialists might need to be involved in the
enzyme inhibitors and angiotensin receptor blockers for
care of a patient with lymphatic malformation,
management of hypertension and proteinuria in the set-
including pediatricians, geneticists, surgeons,
ting of pediatric ADPKD. (15) In addition, there is limited
hematologist/oncologists, nephrologists, dermat-
evidence that statin therapy slows the progression of struc- ologists, radiologists, and interventional radiologists.
tural kidney disease in children and young adults with
• Treatment of lymphatic malformation depends on
ADPKD. (16)
the extent of symptoms and the degree of
encroachment on or obstruction of vital organs.
Patient Course
The patient was evaluated by a multidisciplinary team including • Extensive or multifocal lymphatic malformations
surgery, hematology/oncology, nephrology, genetics, and inter- can require multiple treatments.
ventional radiology; he was referred for sclerotherapy but was
lost to follow-up.
e4 Pediatrics in Review
9. Kashgari AA, Ozair N, Al Zahrani A, Al Otibi MO, Al Fakeeh K.
REFERENCES Renal lymphangiomatosis, a rare differential diagnosis for
1. Wassef M, Blei F, Adams D, et al; ISSVA Board and Scientific autosomal recessive polycystic kidney disease in pediatric patients.
Committee. Vascular anomalies classification: recommendations Radiol Case Rep. 2016;12(1):70–72
from the International Society for the Study of Vascular Anomalies. 10. Pickering SP, Fletcher BD, Bryan PJ, Abramowsky CR. Renal
Pediatrics. 2015;136(1):e203–e214 lymphangioma: a cause of neonatal nephromegaly. Pediatr Radiol.
2. International Society for the Study of Vascular Anomalies. ISSVA 1984;14(6):445–448
classification of vascular anomalies. Available at: http://www.issva. 11. Samuelson H, Giannotti G, Guralnick A. Jejunal lymphangioma
org/classification. Accessed February 17, 2020 causing intussusception in an adult: an unusual case with review of
3. Reinglas J, Ramphal R, Bromwich M. The successful management the literature. Ann Med Surg (Lond). 2018;34:39–42
of diffuse lymphangiomatosis using sirolimus: a case report. 12. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant
Laryngoscope. 2011;121(9):1851–1854 polycystic kidney disease. Lancet. 2019;393(10174):919–935
4. Langbroek GB, Horbach SE, van der Vleuten CJ, Ubbink DT, van 13. Gilony D, Schwartz M, Shpitzer T, Feinmesser R, Kornreich
der Horst CM. Compression therapy for congenital low-flow L, Raveh E. Treatment of lymphatic malformations: a more
vascular malformations of the extremities: a systematic review. conservative approach. J Pediatr Surg. 2012;47(10):
Phlebology. 2018;33(1):5–13 1837–1842
5. Nikolaou VS, Chytas D, Korres D, Efstathopoulos N. Vanishing bone 14. Jafar TH, Stark PC, Schmid CH, et al; ACE Inhibition in
disease (Gorham-Stout syndrome): a review of a rare entity. World J Progressive Renal Disease (AIPRD) Study Group. The effect of
Orthop. 2014;5(5):694–698 angiotensin-converting-enzyme inhibitors on progression of
6. Keppler-Noreuil KM, Rios JJ, Parker VE, et al. PIK3CA-related advanced polycystic kidney disease. Kidney Int. 2005;67(1):
overgrowth spectrum (PROS): diagnostic and testing eligibility 265–271
criteria, differential diagnosis, and evaluation. Am J Med Genet A. 15. Schaefer F, Mekahli D, Emma F, et al. Tolvaptan use in children
2015;167A(2):287–295 and adolescents with autosomal dominant polycystic kidney
7. Luks VL, Kamitaki N, Vivero MP, et al. Lymphatic and other disease: rationale and design of a two-part, randomized, double-
vascular malformative/overgrowth disorders are caused by somatic blind, placebo-controlled trial. Eur J Pediatr. 2019;178(7):
mutations in PIK3CA. J Pediatr. 2015;166(4):1048–1054.e5 1013–1021
8. Obara P, McCool J, Kalva SP, et al; Expert Panel on Vascular 16. Gimpel C, Bergmann C, Bockenhauer D, et al. International
Imaging. ACR Appropriateness CriteriaV R clinically suspected consensus statement on the diagnosis and management of
vascular malformation of the extremities. J Am Coll Radiol. autosomal dominant polycystic kidney disease in children and young
2019;16(11S):S340–S347 people. Nat Rev Nephrol. 2019;15(11):713–726

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JANUARY 2022

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ARTICLES To learn how

28 Human Immunodeﬁciency Virus Preexposure Prophylaxis in Adolescents and

41 Migratory Arthralgia in a 3-year-old Girl

45 Feeding Intolerance in a 3-month-old

49 Hives and Fever in a 13-year-old Boy

58 Hypothermia and Cold Injury in Children

Answer Key appears on page 60.

PUBLISHER American Academy of Pediatrics

Vol. 43 No. 1 JANUARY 2022 1

Central Nervous System Tumors

The role of the pediatrician is crucial in both the diagnosis and

OBJECTIVES After completing this article, readers should be able to:

1. Recognize the presenting symptoms and physical examination ﬁndings

Vol. 43 No. 1 JANUARY 2022 3

PRESENTATION OF BRAIN TUMORS IN CHILDREN

mately one-third of the children presenting with brain

Vol. 43 No. 1 JANUARY 2022 5

Vol. 43 No. 1 JANUARY 2022 7

Vol. 43 No. 1 JANUARY 2022 9

Vol. 43 No. 1 JANUARY 2022 11

Vol. 43 No. 1 JANUARY 2022 13

• Based on research evidence and consensus, brain

• Based on research evidence as well as consensus, 1.

the morbidity and mortality associated with child-

1. An 8-year-old boy presents with early-morning vomiting, headache,

Vol. 43 No. 1 JANUARY 2022 15

Care of the Immigrant Child

Because 3% to 4% of children in the United States are foreign-born, it is

OBJECTIVES After completing this article, readers should be able to:

Vol. 43 No. 1 JANUARY 2022 17

Table 2. Special Considerations During the Physical Examination of Immigrant Children

Vol. 43 No. 1 JANUARY 2022 19

Table 3. Recommended Laboratory Testing of Asymptomatic Immigrant Children

Table 4. Presumptive Treatment Options for Immigrant Children

Vol. 43 No. 1 JANUARY 2022 21

Vol. 43 No. 1 JANUARY 2022 23

Vol. 43 No. 1 JANUARY 2022 25

E. Start immunizations on a catch-up schedule.

Vol. 43 No. 1 JANUARY 2022 27

Human Immunodeficiency Virus

Pediatricians should be able to identify youth at higher risk for human

OBJECTIVES After completing this article, readers should be able to:

Vol. 43 No. 1 JANUARY 2022 29

HIV=human immunodeﬁciency virus.

Table 2. Open-ended Questions for Expanded Sexual History

STI=sexually transmitted infection.

Vol. 43 No. 1 JANUARY 2022 31

Vol. 43 No. 1 JANUARY 2022 33

1. A 17-year-old boy is seen in clinic for a routine sports physical. He is healthy,

2022 Pediatrics in Review is

Vol. 43 No. 1 JANUARY 2022 35

A. CD4 lymphocyte enumeration.