THE JOURNAL OF PEDIATRICS • www.jpeds.

com GRAND
ROUNDS
Early Diagnosis in Dedicator of Cytokinesis 8 (DOCK8) Deficiency
Deidre R. Chang, MD1, Jennifer Toh, MD2, Gabriele de Vos, MD3, and Tatyana Gavrilova, MD2

A
22-month-old boy was admitted to the hospital with Genetic testing revealed normal karyotype analysis and a ho-
a 1-week history of fever, oral lesions, right eye swell- mozygous nonsense mutation in the dedicator of cytokinesis
ing and eyelid crusting, rhinorrhea, nasal congestion, 8 (DOCK8) gene (c.1294C>T; p.R432X), confirming DOCK8
vomiting, and diarrhea. Findings of the physical examina- deficiency. Given the severity of disease, the patient was re-
tion revealed ulcerations throughout the oral mucosa, right ferred for evaluation for hematopoietic stem cell transplant
eyelid swelling, erythema, discharge, and crusting (Figure); (HSCT). Seven months later, while receiving antiviral treat-
dysmorphic nail changes; and coarse facial features, includ- ment for cutaneous HSV, he successfully received an unmodified
ing a large, bulging forehead and facial hirsutism. Direct fluo- allogeneic HSCT from his human leukocyte antigen-matched
rescent antibody and culture of oral ulcers were positive for brother after busulfan and cyclophosphamide cytoreduction
herpes simplex virus (HSV) type 1, and acyclovir was given conditioning. After transplantation, he developed nausea and
intravenously for herpetic gingivostomatitis, dermatitis, and vomiting; endoscopy showed mild graft-vs-host disease that
keratitis. improved following budesonide therapy. Sequelae include re-
History revealed that he was born at term in the US to sidual scarring of the right cornea from HSV keratitis and
nonconsanguineous parents from Ecuador and had a normal uveitis, low-grade Epstein-Barr virus viremia, and hypertension.
newborn screen. Family history was notable for 2 brothers who
died at 3 and 5 months of age in Ecuador with respiratory dis-
tress. He has one healthy living brother. The patient had mul-
Pathogenesis and Clinical Presentation
tiple visits to the emergency department for upper respiratory
Hyper-IgE syndrome (HIES) encompasses a spectrum of
tract infections from the first month of life, recurrent otitis
primary immunodeficiencies characterized by elevated serum
media, hirsutism, short stature, failure to thrive (fifth percen-
IgE concentrations, hypereosinophilia, and atopic dermati-
tile for weight and below the fifth percentile for height), and
tis. Patients are susceptible to recurrent infections involving
developmental delay.
the skin and respiratory tract. Those with autosomal-dominant
His hirsutism initially was attributed to the overuse of topical
(AD) HIES have a mutation in the human signal transducer
corticosteroids prescribed by his general pediatrician, but it re-
and activator of transcription 3 (STAT3) gene, which leads to
mained unchanged after their discontinuation. At 7 months
downregulation of inflammatory responses and anti-
of age, he was referred to an endocrinologist for failure to thrive,
inflammatory responses, resulting in cold abscesses of the skin
lack of weight gain from 5 months of age, short stature, and
and destructive inflammation in the lung, with development
hirsutism. Findings of the evaluation were unremarkable, and
of pneumatoceles. Patients develop nonimmune complica-
poor growth was attributed to dietary restrictions due to food
tions that affect teeth, bone, and connective tissue.1 AD HIES
allergies. He then was referred for allergy/immunology
also affects T-helper 17 cells, which are critical for protection
evaluation.
against extracellular bacteria and fungi, increasing suscepti-
An initial evaluation for severe atopic dermatitis (extend-
bility to Staphylococcus and Candida species infections.2
ing from the ears and fingertips) and food allergies led to the
Both AD HIES and autosomal-recessive HIES (including
advice to avoid cow’s milk and eggs, given elevated specific IgE
DOCK8 deficiency and phosphoglucomutase 3 mutations) are
levels. He had substantial improvement of atopic dermatitis.
considered combined immunodeficiencies, although the clini-
Outside records revealed an absolute eosinophilic count ranging
cal manifestations differ.3 Patients with DOCK8 deficiency have
from 1400 to 3300 cells/mm3 (normal 100-500 cells/mm3) and
recurrent, severe cutaneous viral infections including HSV,
a persistently elevated erythrocyte sedimentation rate ranging
human papillomavirus, and molluscum contagiosum infec-
from 70 to 80 mm/h. Previous total serum IgE concentra-
tions, and have high rates of malignancy and mortality, em-
tions were >2000 IU/mL above the normal cut-off level of the
phasizing the importance of early referral for HSCT. Patients
assay (Immulite 2000; Siemens Corp, Washington, DC). At the
also experience severe atopic features, such as wheezing, food
request of the immunologist, a sample was further diluted to
allergies, hay fever, and a predisposition to anaphylaxis.4 Typi-
reveal a value of 9092 IU/mL (normal for age 0.31-29.5 IU/mL),
cally, atopic eczema manifests in infancy and other symptoms
which prompted genetic testing.

AD Autosomal dominant From the 1Department of Pediatrics, St. Barnabas Hospital, Bronx, NY; 2Division of
Allergy and Immunology, Children’s Hospital at Montefiore, Bronx, NY; and 3Division
DOCK8 Dedicator of cytokinesis 8 of Allergy and Immunology, Jacobi Medical Center, Bronx, NY
HIES Hyper-IgE syndrome The authors declare no conflicts of interest.
HSCT Hematopoietic stem cell transplant
HSV Herpes simplex virus 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org10.1016/j.jpeds.2016.08.081

FLA 5.4.0 DTD ■ YMPD8627_proof ■ September 23, 2016

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

diagnosis of DOCK8 deficiency. Recurrent viral infections,

failure to thrive, atopy, such as food allergies, and atopic der-
matitis, eosinophilia, and elevated serum IgE concentrations
should prompt suspicion for underlying immunodeficiency in-
cluding DOCK8 deficiency.14 Referral to a specialist in allergy/
immunology or genetics to facilitate testing should be prompt,
because early diagnosis and HSCT can be curative. Early di-
agnosis also is important to prevent DOCK8 deficiency-
associated malignancy and vasculitis. In addition, persistent
cutaneous viral infections typically resolve only after trans-
plantation. Pediatricians can play a central role in early
Figure. A, Herpetic dermatitis and mucositis of the eyelids. detection.
B, Oral ulcers of herpetic gingivostomatitis. Patients with DOCK8 deficiency have more severe atopic
features than do patients with AD HIES.2 Differentiating
DOCK8 deficiency from severe atopic dermatitis may be chal-
manifest throughout childhood years.5 Coarse facies classi-
lenging, because the skin manifestations and clinical features
cally is seen in AD HIES and not in DOCK8 deficiency, and
are similar. Assessment of lymphocyte subsets should be evalu-
reports of coarse facies in patients with DOCK8 deficiency, are
ated to distinguish this difference. An elevated serum IgE level
hypothesized to be the result of other genetic mutations or
in the setting of CD3+, CD4+, and naïve CD8+ T-cell lym-
severe eczema.6 Another autosomal-recessive form of HIES
phopenia, with normal total B lymphocyte percentage but low
characterized by phosphoglucomutase 3 mutations leads to a
memory B lymphocyte value, is strongly associated with
syndrome of increased serum IgE levels, severe atopy, immune
DOCK8 deficiency.15
deficiency, autoimmunity, and motor and neurocognitive
impairment.7 The defining difference in presentation between
patients with phosphoglucomutase 3 mutation and DOCK8 Management, Prognosis, and Long-Term
deficiency seems to be motor and neurocognitive impair- Outcome
ment in the former.
Mutations of the DOCK8 gene appear to cause the loss of Previously, the prognosis of patients with DOCK8 deficiency
protein expression in patients with DOCK8 deficiency, which was very poor. When therapy was limited to prophylactic an-
leads to varied and widespread manifestations. DOCK8 is a tibiotics and sometimes interferon-alpha 2b therapy for treat-
member of the DOCK180 superfamily of guanine nucleo- ment of viral infections,16 Aydin et al9 reported an overall
tide exchange factors, which are involved with intracellular sig- survival probability of patients with DOCK8 deficiency to be
naling involving Rho GTPases. DOCK8 protein is involved in 87% at 10 years of age, 47% at 20 years of age, and 33% at 30
cytoskeletal rearrangement and cell migration.8 Mutations lead years of age, with age-related event-free survival being 44%,
to T-cell lymphopenia and dysfunction.9 DOCK8 also is found 18%, and 4%, respectively. Seventeen percent of patients ex-
in B-lymphocytes, natural killer cells, and dendritic cells, which perienced malignancy, and 58% had severe, life-threatening
often are affected. DOCK8 protein regulates the integrity in infections.9 These results echo the urgency of early diagnosis
shape of lymphocytes, prevents cell breakdown, and pro- and curative HSCT, especially to avoid opportunistic infec-
motes antiviral immunity in the skin through CDC42 and p21- tions and malignancies that are associated with greater mor-
activated kinase.10 This mechanism of immunodeficiency may bidity and mortality.17 Transplantation following myeloablative
explain the significant cutaneous viral infections and multi- conditioning followed a short course of immunosuppression
system manifestations of patients with DOCK8 deficiency. to decrease the likelihood of graft-vs-host disease results in re-
Additional explanations of the multisystem manifesta- versal of the clinical phenotype of DOCK8 deficiency and re-
tions included elevated levels of IgE in plasma, defective pe- constitution of immunologic function.18 ■
ripheral B-lymphocyte tolerance checkpoints, and decreased
and functionally impaired T regulatory cells.11 T regulatory cells Submitted for publication Feb 22, 2016; last revision received Aug 1, 2016;
accepted Aug 24, 2016
are a subset of T lymphocytes that regulate the immune system.
Reprint requests: Deidre R. Chang, MD, Department of Pediatrics, St.
Specific functions include modulating tolerance to self anti- Barnabas Hospital, 4422 Third Avenue, Mills Building, 4th Floor, Bronx, NY
gens and preventing autoimmune disease. Dendritic cells prime 10457. E-mail: [email protected]
T lymphocytes, and the impairment of these cells to migrate
to target sites may be the cause of the decreased T-cell References
regulation.12,13
1. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al.
STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608-
Diagnosis
19.
2. Boos AC, Hagl B, Schlesinger A, Halm BE, Ballenberger N, Pinarci M, et al.
Genetic sequencing of the DOCK8 gene and examination of Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-
DOCK8 protein expression by flow cytometry confirm based sensitization pattern. Allergy 2014;69:943-53.

2 Chang et al

FLA 5.4.0 DTD ■ YMPD8627_proof ■ September 23, 2016

■■ 2016 GRAND ROUNDS

3. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin
Combined immunodeficiency associated with DOCK8 mutations. N Engl Immunol 2014;134:1365-74.
J Med 2009;361:2046-55. 12. Krishnaswamy JK, Singh A, Gowthaman U, Wu R, Gorrepati P, Sales
4. Hill HR, Quie PG. Raised serum-IgE levels and defective neutrophil che- Nascimento M, et al. Coincidental loss of DOCK8 function in NLRP10-
motaxis in three children with eczema and recurrent bacterial infec- deficient and C3H/HeJ mice results in defective dendritic cell migra-
tions. Lancet 1974;1:183-7. tion. Proc Natl Acad Sci USA 2015;112:3056-61.
5. Koskenvuo M, Kainulainen L, Vanto T, Lukkarinen H, Lahteenmaki P, 13. Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, et al.
Ruuskanen O. Severe atopy and allergy—rare hyper-IgE syndrome caused DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migra-
by the DOCK8 mutation as underlying condition. Duodecim 2015;131:541- tion during immune responses. Blood 2012;119:4451-61.
4. 14. Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC,
6. Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC, et al. Cuta- Glocker C, et al. The extended clinical phenotype of 64 patients with
neous manifestations of DOCK8 deficiency syndrome. Arch Dermatol dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol 2015;136:402-
2012;148:79-84. 12.
7. Zhang Y, Yu X, Ichikawa M, Lyons JJ, Datta S, Lamborn IT, et al. Autosomal 15. Janssen E, Tsitsikov E, Al-Herz W, Lefranc G, Megarbane A, Dasouki M,
recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation et al. Flow cytometry biomarkers distinguish DOCK8 deficiency from
defects to atopy, immune deficiency, autoimmunity, and neurocognitive severe atopic dermatitis. Clin Immunol 2014;150:220-4.
impairment. J Allergy Clin Immunol 2014;133:1400-9, 9 e1-5. 16. Boztug H, Karitnig-Weiss C, Ausserer B, Renner ED, Albert MH, Sawalle-
8. Singh AK, Eken A, Fry M, Bettelli E, Oukka M. DOCK8 regulates pro- Belohradsky J, et al. Clinical and immunological correction of DOCK8
tective immunity by controlling the function and survival of RORgammat+ deficiency by allogeneic hematopoietic stem cell transplantation follow-
ILCs. Nat Commun 2014;5:4603. ing a reduced toxicity conditioning regimen. Pediatr Hematol Oncol
9. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, 2012;29:585-94.
et al. DOCK8 deficiency: clinical and immunological phenotype and 17. Keles S, Jabara HH, Reisli I, McDonald DR, Barlan I, Hanna-Wakim R,
treatment options—a review of 136 patients. J Clin Immunol 2015;35:189- et al. Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue
98. of severe herpetic infections with IFN-alpha 2b therapy. J Allergy Clin
10. Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, Immunol 2014;133:1753-5, e3.
et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral im- 18. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock
munity. J Exp Med 2014;211:2549-66. H, et al. Matched related and unrelated donor hematopoietic stem cell
11. Janssen E, Morbach H, Ullas S, Bannock JM, Massad C, Menard L, et al. transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant
Dedicator of cytokinesis 8-deficient patients have a breakdown in 2015;21:1037-45.

Early Diagnosis in Dedicator of Cytokinesis 8 (DOCK8) Deficiency 3

FLA 5.4.0 DTD ■ YMPD8627_proof ■ September 23, 2016