Pakistan Endocrine Cases Collection (PECC) 7th Ed 2023

Pakistan Endocrine Society
Pakistan Endocrine Cases Collection (PECC) 2023

Submission Email: [email protected]
Questions, Answers & Discussions
CHIEF EDITOR
Dr. Ibrar Ahmed
FCPS (Med), FCPS (Endocrine), FRCP (London)
Assistant Professor & Divisional Head
Department of Diabetes & Endocrinology
Lady Reading Hospital Peshawar.
EDITORS
Dr. Suleman Elahi Malik Dr. Sumera Batool
MTI Khyber Teaching Hospital, Aga Khan Hospital,
Peshawar Karachi
Dr. Mussarat Riaz Dr. Urooj Lal Rehman

Baqai Institute of Diabetes and Jinnah Postgraduate Medical
Endocrinology, Karachi Centre (JPMC), Karachi
Dr. Zareen Kiran Dr. Amena Moazzam Baig
Dow University of Health Sciences, Services Institute of Medical
Karachi Sciences, Lahore
Dr. Sidrah Lodhi Dr. Saima Askari

King Edward Medical University, Baqai Institute of Diabetes and
Lahore Endocrinology, Karachi
Dr. Erum Sohail Dr. Nadeem Naeem

Endocrinology Jinnah Postgraduate Memon Medical Institute Hospital
Medical Centre (JPMC), Karachi Karachi
Dr. Shaista Kanwal Dr. Tejhmal Rehman

MTI Hayatabad Medical Complex, Royal Surrey County Hospital,
Peshawar Guildford, United Kingdom
Dr. Nasir Siddique

Northampton General Hospital,
Northampton, United Kingdom
The Voice of Clinical Endocrinologists
www.pakendosociety.org
The Voice of Clinical Endocrinologists
The Pakistan Endocrine Society is Pakistan’s eminent and active organization

working to advance the clinical practice of endocrinology. It was founded in 2001 and
is one of the prime representative body of eminent endocrinologist of Pakistan.
The Society earned national reputation for excellence in the quality of holding meeting
and CME programs and tried to improve public health through practice and science of
endocrinology.
Visit us at: www.pakendosociety.org
The statement and opinion expressed in this publication are the opinion of individual
authors. The endocrine society is not responsible or liable for the errors, omissions or
inaccuracies.
Copyright @ 2019 by the Pak Endocrine Society, endocrine unit Lady Reading
Hospital Peshawar. No part of this publication may be reproduced, stored in a retrieval
system, posted on the Internet, or transmitted in any form, by any means, electronic,
mechanical, photocopying, recording, or otherwise, without written permission of the
publisher.
Request for permission of publication should be directed to the Endocrine Society

Publications Department : by sending an email for permission to
[email protected] or [email protected]
ISBN: 978-969-23386-0-8
National Library of Pakistan
PRESIDENT’S MESSAGE
Moment of Joy for me and Pakistan Endocrine Society for the efforts, our members made in
keeping the Pakistan Endocrine Society viable in the circle of medical fraternity.
The knowledge is a key to success and in my opinion passing knowledge to all is one of the
main pillars in the establishment of enlightened society.
PECC is the project we have initiated five years back which help our junior colleagues
understanding, what we can do in our limited resources for our patients.
This year we had support of Endo- Hub a joint venture of PES and Getz which help our
fellows to come forward and improve their presentation skills. Through this project they go
through the day to day cases thoroughly which help in their capacity building.
I must congratulate my fellows who participated in compiling the fourth edition of PECC. I
hope this activity will move forward with more inputs from our fellows. It will be a golden
feather in cap of academic activities of Pakistan Endocrine Society.
“Order unity and continuity are human invention just as truly as catalogues and
encyclopedias”
Dr. Ibrar Ahmed

FCPS (Med), FCPS (Endocrine), FRCP (London)
Consultant Endocrinologist/Assistant Professor
Lady Reading Hospital Peshawar.
President
3
FOREWORD
Endocrinology remains a complex discipline of medicine and has long piqued the interest of
physicians in this sub speciality. You will travel through the intriguing world of
endocrinology in the pages that follow.
Science of Endocrinology, encompass numerous physiological processes, which is

frequently referred to as the "master control system" of the body. This book explores the
breadth and depth of some of these Endocrine cases, which pose scenarios confounding
clinicians in their clinical practices.
Endocrinology encompass clinical chalanges from delicate balance of insulin which

regulates blood sugar to the profound balance of hormones and their effect on
metabolism.
The instances discussed in these pages are more than just medical conundrums; they offer a
glimpse into the struggles that committed medical professionals face to eradicate suffering
of patients.
These Case reports presented by narratives, will leave you with some insights of this
intricate subject. Each one of these cases will provide readers a fresh perspective on the
complex presentation of Endocrine disorders and their significant impact on our health and
well being.
I am sure this book will help physicians to solve some riddles surrounding Endocrine
disorders and will learn about the complexity of hormone diseases.
I applaud the authors of this book for their commitment to the practise of medicine as both
an art and a science. For students, doctors, and academics alike, their rigorous
documenting and perceptive analysis of these instances serve as an invaluable resource,
providing a greater understanding of the struggles and victories of the endocrinologist's
journey.
Therefore, whether you are an experienced endocrinologist looking to broaden your

knowledge, a medical student just starting out in this fascinating subject, or just an avid
reader interested in human biology, this book is for you.
Dr. S. Abbas Raza

Tamgha-i-Imtiaz: By Government of Pakistan
President - ISE (International Society of Endocrinology) - (2022 – 2024)
Past President (2017 – 2019) and Founder Vice-President:
South Asian Federation of Endocrine Societies - SAFES
Founder and Past President: American Association for
Clinical Endocrinologist (AACE) Pakistan Chapter- Feb 2015
Past President: Pakistan Endocrine Society – PES - 2010 -2012
Lifetime Achievement Award: Pakistan Endocrine Society
5
CASES Pakistan
Endocrine
Case
Collection
2023
Question
Answers
Discussion
Case 1
Primary Hyperparathyroidism with Maxillary and

Phalangeal Brown Tumors
Authors:
Dr. Rajesh Jamna Dass ([email protected])
Dr. Zareen Kiran ([email protected])
Dr. Muhammad Uzair Abdul Rauf ([email protected])
Dr. Muhammad Umer Khan ([email protected])
Dr. Nazish Fatima ([email protected])
(National Institute of Diabetes and Endocrinology, DUHS, Karachi)
Case Summary
A 30-year-old female, married, resident of Karachi presented on 8th December 2022 in OPD
at National Institute of Diabetes & Endocrinology (NIDE), Dow University of Health Sciences
with complaints of painless swelling of proximal part of left index finger for last one year and
generalized body ache with weakness & easy fatigability for last 6 months and gradual
onset, progressive, painless swelling over left side of face for last 3 months. Patient also
reports documented weight loss 20kg in last one year.
On examination: BP:109/63mmHg, Pulse:84/min, Height:149cm, Weight:49kg

(BMI:19.4Kg/m 2), visible swelling over left maxillary region measuring 4 x 3 cm, soft in
consistency, non-tender. Hand examination showed non-tender, soft in consistency
swelling of proximal phalanx of index finger of left hand. Rest of systemic examination is
unremarkable.
9
Investigation:
Corrected serum calcium: 12.3mg/dl (8.6-10.2mg/dl)

Serum phosphorus: 2.5mg/dl (2.5-4.5mg/dl)
Serum creatinine: 0.42mg/dl (0.6-1.1mg/dl)
Serum alkaline phosphatase: 617 U/L (42-98)
25-Dihydroxyvitamin Vitamin-D: 4.75ng/ml (on 15/11/2022)
25-Dihydroxyvitamin Vitamin-D: 67.44ng/ml (on 08/12/2022)
(After Inj.Cholecalciferol 200,000IU x 3 doses)
24-Hour Urinary calcium: 388mg/24 hours (100-300mg/24hours)
Serum Intact PTH: 892.4pg/ml (15-65pg/ml)
Serum TSH: 1.91Uiu/L (0.4-4.2Uiu/l)
Serum Magnesium: 1.9mg/dl (1.6-2.6mg/dl)
Imaging studies:
¡ X-ray skull & paranasal sinuses: numerous small lucent foci throughout calvarium
representing “Salt & Pepper” appearance.
¡ X-ray Hand showed an expansile lytic lesion involving lateral cortex of distal end of
proximal phalanx of 2nd digit with significant thinning of overlying cortex.
¡ Ultrasound neck showed a well-defined homogenous lesion inferior to the right

lobe of thyroid gland, appears hypoechoic in comparison to thyroid measuring 1.1
x 0.6cm with no evidence of cervical lymphadenopathy.
¡ Parathyroid scintigraphy showed a functioning parathyroid adenoma over lower

part of right lobe of thyroid gland.
¡ CT scan paranasal sinuses showed an expansile lucent lesion with internal cystic
and solid density involving the left maxilla.
10
A B
C D E
A. Left maxillary swelling

B. Left index finger proximal phalanx swelling
C,D & E: Radiological features of metabolic bone disease
Q: What is most likely diagnosis in this patient?
a. Primary Hyperparathyroidism
b. Tertiary Hyperparathyroisim
c. Giant cell tumor of bone
d. Osteosarcoma
e. Metastatic Bone disease
Answer: (a) Primary Hyperparathyroidism
11
Discussion:
Primary hyperparathyroidism (PHPT) is a disorder of parathyroid glands which is
characterized by abnormalities in calcium, phosphate, and bone metabolism caused by
increased secretion of parathormone (PTH) resulting in hypercalcemia and
hypophosphatemia. (1) The disorders has different presentations including recurrent renal
stones (10-25%), peptic ulcers, mental changes, and less frequently, extensive bone
(3)
resorption (10-20%), resulting in multiple fibrotic cystic lesions (brown tumors). The bone
disease osteitis fibrosa cystica was first described by von Recklinghausen in 1891, but the
etiological link between the disease and parathyroid neoplasms was not established until
[1]
1925.
Bone brown tumor, also known as osteitis fibrosa cystica, has three stages of development,
initially, elevated PTH secretion stimulates osteoclasts resorbtion of bone while collagen
fibers form in bone marrow. In the second phase, known as the stage of fibrotic osteitis,
trabecular bone is absorbed and bone marrow is replaced by loosened fibrosis,
hemosiderin-containing macrophages, microfracture hemorrhage area and reactive
woven bone. As hyperparathyroidism and hemorrhage goes on, cystic degeneration
eventually occurs, leading to the final stage of disease (fibrous cystic osteitis). Cysts are
actually the result of intra-bone hemorrhage and tissue degeneration, filled with a large
number of osteoclasts, macrophages and fibroblasts that are engulfed with hemosiderin.
(2)
Hemorrhage and hemosiderin lead to brown appearance, so it's called brown tumor.
Radiographic features described in hyperparathyroidism are mainly beacuse to bone

resorption, which could be subperiosteal, subchondral, subligamentous, cortical, and
trabecular. Subperiosteal bone resorption gives a lace-like irregularity to the cortical
margin, subchondral bone resorption results in pseudo-widening of the joint space.
Cortical bone resorption gives rise to the appearance of intracortical tunneling and
scalloping along the endosteal margins. Trabecular bone resorption results in spotty
deossifcation and indistinct trabecular pattern. In the skull, this is
seen as the granular “salt and pepper” appearance.(3)
Histologically, brown tumors are characterized by fibroblastic vascular stroma and several
osteoclast-like multinucleated giant cells often interspersed with hemorrhagic infiltrates
(4)
and hemosiderin deposits.
Clinically, brown tumors may present as asymptomatic, small swelling in the jaw bone or as
a painful exophytic mass.. The diagnosis has to be confirmed by establishing elevated serum
calcium and PTH levels because histological features alone are not sufficient as it may
resemble any giant cell tumor. The parathyroid technetium scintigraphy is one of the most
(5
preferred imaging modality to localize diseased parathyroid glands prior to surgery
12
Brown tumors are one of the most pathognomonic features of primary

hyperparathyroidism; however, they are rarely seen in clinical practice. Brown tumors have
been reported to occur in 1.5% to 4.5% of patients with primary or secondary
hyperparathyroidism. Brown tumor is difficult to diagnose because it is uncommon in
clinical practice, and its clinical symptoms and imaging finding are easily confused with
malignant bone tumors, leading to delayed treatment and economic losses for patients. In
this case, patient was eventually diagnosed with brown tumor secondary to PHPT and
(6)
underwent surgical resection of the parathyroid.
This type of case is seldom seen in epidemiology. The patient disease may be delayed for a
long time due to unclear diagnosis. Through reflection of whole process of diagnosis and
treatment of this case and literature review, for patients with multiple bone pain, screening
of cervical ultrasound, PTH, serum calcium and phosphorus should be performed to
exclude multiple bone destruction caused by PHPT. As for brown tumor lesions, generally,
there is no need for surgical treatment, but a small number of patients with large lesions still
(7)
need surgical resection and implanting bone cement to restore function. If early diagnosis
and treatment of hyperparathyroidism are undertaken, the prognosis is excellent in most
patients. Resendiz-Colosia et al. have shown that all of their 20 cases of maxillofacial brown
tumor that were followed up for = 2 years had spontaneous regression after
parathyroidectomy. In 90% of the cases, regression was clinically complete and mostly
within 4-20 months. (8)
References:
1. Nagaraj C, Oommen R, Jacob PM, Irodi A. Solitary phalangeal brown tumour in primary
hyperparathyroidism: Report of a rare presentation. Indian Journal of Nuclear Medicine: IJNM: The
Official Journal of the Society of Nuclear Medicine, India. 2012 Apr;27(2):107.
2. Hong WS, Sung MS, Chun KA, Kim JY, Park SW, Lee KH, Lim HW, Lim YS, Yoo WJ, Chung MH. Emphasis on
the MR imaging findings of brown tumor: a report of five cases. Skeletal radiology. 2011 Feb;40:205-
13.
3. Sahan MH, Guner S, Guner SI. Radiological findings in the primary hyperparathyroid case with
multiple brown tumors: a case report. Eastern Journal of Medicine. 2008;13(1/2):30.
4. Reséndiz-Colosia JA, Rodríguez-Cuevas SA, Flores-Díaz R, Juan MH, Gallegos-Hernández JF, Barroso-
Bravo S, Gómez-Acosta F. Evolution of maxillofacial brown tumors after parathyroidectomy in primary
hyperparathyroidism. Head & Neck: Journal for the Sciences and Specialties of the Head and Neck.
2008 Nov;30(11):1497-504.
5. Al-Gahtany M, Cusimano M, Singer W, Bilbao J, Kovacs K, Marotta T. Brown tumors of the skull base:
case report and review of the literature. Journal of neurosurgery. 2003 Feb 1;98(2):417-20.
6. Guney E, Yigitbasi OG, Bayram F, Ozer V, Canoz Ö. Brown tumor of the maxilla associated with primary
hyperparathyroidism. Auris Nasus Larynx. 2001 Nov 1;28(4):369-72.
7. Choi JH, Kim KJ, Lee YJ, Kim SH, Kim SG, Jung KY, Choi DS, Kim NH. Primary hyperparathyroidism with
extensive Brown tumors and multiple fractures in a 20-year-old woman. Endocrinology and
Metabolism. 2015 Dec 1;30(4):614-9.
8. Martinez-Gavidia EM, Bagan JV, Milian-Masanet MA, de Miguel EL, Pérez-Vallés A. Highly aggressive
brown tumour of the maxilla as first manifestation of primary hyperparathyroidism. International
journal of oral and maxillofacial surgery. 2000 Dec 1;29(6):447-9.
13
Case 2
A Case of Charcot Neuro Arthropathy

Authors:
Dr. Ihsan Bashir Shaikh
Endocrine Fellow
[email protected]
Dr. Saima Askari

Consultant Endocrinologist & Assistant Professor
[email protected]
Dr. Musarrat Riaz

Consultant Endocrinologist & Associate Professor of Medicine
[email protected]
(Baqai Institute of Diabetology and Endocrinology, Karachi Pakistan)
Case Summary
A 45 years old male patient Mr. Bilal with T1DM of over 25 years duration (on basal-bolus
regimen) presented to the foot clinic with two months history of painless, swollen, and
warm right foot. During this 2-month period, he took multiple courses of Antibiotics
prescribed by GPs suspected as a case of diabetic foot infection. He also had a past history of
treated Diabetic foot infection. This patient had a history of poor glycemic control despite
the basal Bolus regimen with an average HbA1c of 10% over several years. He had no history
of other comorbid.
On Examination:
He had a red, hot, swollen right foot with no open wound or signs of trauma / break and no
tinea Pedis, all pedal pulses were readily palpable with ABI of 1.1, his touch and vibration
sense were intact. Skin temperature was recorded with a calibrated infra-red skin
thermometer demonstrating a significantly raised temperature of right foot as compared
to left foot. Right foot 34.7-36°C and 30.9-31°C with no signs of any systemic infection.
Physical Examination and left foot examination was unremarkable. A clinical diagnosis of
charcots neuroarthropathy was proposed and a plan X ray of Right foot and lab work up was
sent.
14
X-rays showed a destructive change in the mid-foot consistent with the diagnosis of Charcot
Neuropathy(CN).
Labs:
Date Tests name Results Reference range

5/10/22 Complete blood count:
Hb: 12.2 g/dl 11.1-13.8 g/dl

MCV: 87fl 76-96 fl
WBC: 8.0*1000/ul 4.0-11.0*1000/ul
PLT: 290*1000/ul 150-400*1000/ul
5/10/22 Serum Electrolytes
Sodium: 140 mEq/L 136-145 mEq/L

Potassium: 4.2 mEq/L 3.8-5.2 mEq/L
Chloride: 99 mEq/L 96-107 mEq/L
Bicarbonate: 26 mEq/L 22-29 mEq/L
5/10/22 Serum Creatinine: 0.73mg/dl 0.6-1.1mg/dl
5/10/22 HBA1C: 10.6%
5/10/22 TSH: 2.2mIU/ml 0.4-4.2mIU/ml
15
The patient was then managed for CN and over a 6 months period a total of seven total
contact casts (TTC) were applied. The 1st one was for 1 week, then second for 2 weeks and
monthly these after. At this stage his CN had become quiescent. Subsequently he has been
provided with bespoke foot wear and orthoses to prevent ulceration over the planter
rocker sole deformity.
Q. Charcot joint in seen in all of the following conditions except:

a. Diabetes
b. Leprosy
c. Syringomyelia
d. Arthrogryposis multiplex congenita
e. Syphilis
Answer: (d)
This patient was diagnosed with diabetic Charcot neuro arthropathy of right foot.
Discussion:
Diabetic Charcot neuroarthropathy (CN) is uncommon and has a reported prevalence
between 0.08% and 13% but there are no definitive epidemiological studies on Charcot
foot. It is a condition mostly affecting the bones, joints and soft tissues of the foot and ankle.
It is an acute localized protracted inflammatory condition resulting from the interaction of
several component factors (diabetes, polyneuropathy, trauma and metabolic
abnormalities of bone) which, in turn, may lead to varying degrees and patterns of bone
destruction, subluxation, dislocation and deformity. Its pathogenesis is not fully
understood but peripheral sensory and sympathetic neuropathy is considered to be
predisposing factors.
The classical clinical presentation of an acute CN is a red/pink/dark (depending on skin

colour), swollen, warm/hot foot with mild to moderate pain, if any at all. This clinical
presentation closely resembles that of infection with cellulitis, deep vein thrombosis, or
even acute gout, thus it is possible to initially misdiagnose acute CN for any of the former.
The temperature difference between the affected and contralateral limb can differ by
several degrees, not uncommonly by 4-7°C. This difference in skin temperature is used as a
marker of resolving of the acute phase, thus when the skin temperatures of the two limbs
are = < 1°C, immobilisation of the affected limb can be gradually be removed
16
Another clinical feature is the presence of very good and possibly exaggerated arterial flow.
Characteristically, the pedal pulses when palpated are very strong and often 'bounding'.
Ankle pressures are frequently abnormally high, demonstrating the presence of medial wall
calcification, which is a common feature of CV. In the early onset of CN, X-ray examination
may appear normal but later, bony destruction becomes evident and the bones have a
'fluffy' appearance. The most frequent site for diabetic CN is the mid-foot area but it can
occur in the ankle, rear or forefoot. In those with foot deformity, approximately 60% are in
the tarsometatarsal joints (medial joints affected more than lateral), 30%
metatarsophalangeal joints and 10% have ankle disease.
Prompt detection and treatment are essential due to the potentially devastating
consequences of a Charcot foot. The current treatment of Charcot foot consists of
prolonged immobilization and total physical off-loading, either with a total contact cast or a
removable walker cast. Generally speaking, the off-loading process works best when it
begins as soon as possible. Off-loading allows the injured foot to heal as well as stops the
underlying deteriorating tissue damage.
STAGES OF CHARCOT FOOT
Stage 0 Stage 1 Stage 2 Stage 3

Prodromal Period Development Coalescence Reconstruction
Swelling Debris formation at Lessening of edema Further repair and

Local warmth articular margins Absorption of fine debris remodeling of bone
Mild erythema Fragmentation of Healing of fractures fusion and rounding of
Clinical instability subchondral bone Fusion and coalescence of large fagments
Radiographic changes Subluxation larger fragments Revascularization
are absent or minimal Dislocation Loss of vascularity Diminution of sclerosis
Erosion of articular cartilage Sclerosis of bone Restoration of stability
Bone resorption Increased bone density
Osteolysis and osteopenia Exuberant ossification
Disorganization and Deformity
fragmentation of bone
Soft tissue edema
increased joint mobility
Resorption of bone Repair
17
Brodsky Classification
Involves tarsometatarsal and naviculocuneiform joints.
Type 1 60%
Collapse leads to fixed rocker bottom foot with valgus angulation
Involves subtalar, talonavicular or calcaneocuboid joints.
Type 2 10%
Unstable, requires long periods of immobilization (up to 2 years)
Involves tibiotalar joint
Type 3A Late varus or valgus deformity produces ulceration and osteomyelitis of 20%
malleoli
Follows fracture of calcaneal tuberosity
<
Type 3B Late deformity results in distal foot changes or proximal migration of
10%
the tuberosity
<
Type 4 Involves a combination of areas 10%
<
Type 5 Occurs solely within forefoot
10%
References:
1. Jansen RB, Svendsen OL. A review of bone metabolism and developments in medical treatment of the
diabetic Charcot foot. Journal of Diabetes and its Complications. 2018 Jul 1;32(7):708-12.
2. Hastings MK, Johnson JE, Strube MJ, Hildebolt CF, Bohnert KL, Prior FW, Sinacore DR. Progression of
foot deformity in Charcot neuropathic osteoarthropathy. The Journal of bone and joint surgery.
American volume. 2013 Jul 7;95(13):1206.
3. Harris A, Violand M. Charcot neuropathic osteoarthropathy (Charcot joint). StatPearls [Internet]

Treasure Island FL: StatPearls Publishing. 2020.(last accessed via internet on 31st March 2023)
18
Case 3
Case of Immune Mediated Diabetes,

Presenting as DKA
Authors:
Dr. Rukhshanda Jabeen Dr. Wasfa Aijaz
Consultant Endocrinologist & Associate Professor Medical Officer
[email protected] [email protected]
Dr. Erum Sohail Dr. Inshirah Rana

Senior Registrar Endocrinology Postgraduate trainee
Email: [email protected] [email protected]
Dr. Fahmeeda Jan Dr. Tazeen Khalid

Endocrine fellow Endocrine fellow
[email protected] [email protected]
(Jinnah Postgraduate Medical Centre JPMC, Karachi)
Case Summary
A 35-year-old female, no known co-morbids, single, resident of Thatta, admitted from
emergency department in Feb 2023, with presenting complain of recurrent vomiting,
restlessness and drowsiness for 1 day. She was an offspring of consanguineous parents. She
had no history of using steroids or any other medication. There was no family history of
diabetes or any other chronic illness. At the time of presentation, she was drowsy
(GCS=14/15) with a pulse rate 86/min; her respiratory rate was 20/m and blood pressure
was 120/70 mmHg. She was afebrile while her body mass index (BMI) was calculated to be
2
17.8 kg/m . There were no signs of acanthosis nigricans and rest of the systemic
examination was within normal limits. Fundoscopy was normal.
On arrival in emergency department, her random blood glucose was 590mg/dl. Arterial
blood gases analysis revealed pH 6.9, HC03 3.9, PCO2 17 and PO2 55 (High Anion Gap
Metabolic Acidosis). Further Investigations showed hemoglobin 9.6g/dl; mean corpuscular
volume 71.2fl, hematocrit 32.1, white blood count 17.5 with predominant neutrophils,
platelets 331. Her chemistry showed sodium138mEq/L potassium 2.8mEq/L chloride
103mEq/L urea 48 mg/dl and creatinine 0.99mg/dl. Her urine sample was positive for
glucose and 3+ for ketones with trace protein, while her HbA1c was 13.0 %. Anti GAD
Antibody was 1472.50 IU/ml (range <10). Chest Xray and ECG findings were normal.
19
How will you classify her according to recent classification?

a) Severe insulin deficient diabetes
b) Severe insulin resistant diabetes
c) Severe autoimmune Diabetes
d) Mild obesity related Diabetes
e) Mild age related Diabetes
Answer: (C)
Discussion:
LADA, or latent autoimmune diabetes of adults, shares characteristics of both type 1 and
type 2 diabetes but, are relatively uncommon form of Diabetes. It is frequently
misdiagnosed as type 2 diabetes, given that it typically affects adults aged 30 and over and
progresses more slowly than type 1 diabetes. LADA is characterized by the presence of
auto-antibodies that attack the pancreas' insulin-producing cells, similar to type 1 diabetes.
However, unlike type 1 diabetes, LADA patients still produce some insulin, which can
conceal the autoimmune attack and create difficulties in making an accurate diagnosis
(1,2).
Currently, the diagnosis of LADA relies on three criteria, which include an onset of diabetes
in adulthood, the detection of islet autoantibodies such as autoantibodies to glutamic acid
decarboxylase 65 (GADA 65)/islet cell cytoplasm (ICA)/tyrosine phosphatase like protein
(IA-2A)/insulin (IAA), and the absence of insulin dependency for a minimum of six months
after diagnosis(3).
Our patient presented with symptoms of DKA, which is quiet rare as, LADA patients usually
don't have insulin dependency at time of diagnosis.
Autoimmunity seems to be the first pathological factor in LADA. Although T1D is

characterized by a cluster of islet cell auto-antibodies, LADA patients are mainly
characterized by positive anti-GAD antibodies. In our patient, GAD antibodies were
positive, however, other antibodies couldn't be checked due to affordability issues (4).
Based on the new classification of diabetes, it appears that this patient may fall under the
category of severe autoimmune diabetes (SAID). This classification was determined by
analyzing six variables that are typically used to define different types of diabetes, including
the presence of the islet autoantibody glutamic acid decarboxylase GAD65-Ab, age at
diagnosis, BMI, and measures of insulin sensitivity and secretion. The researchers identified
five distinct clusters of type 2 diabetes, each with unique characteristics related to the risk
of diabetic complications and the underlying pathophysiology. These clusters were
categorized as severe autoimmune diabetes (SAID), severe insulin-dependent diabetes
(SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes, and mild
age-related diabetes (5,6).
20
References:
1. Hernandez M, Mollo A, Marsal JR, Esquerda A, Capel I, Puig-Domingo M, Pozzilli P,et al. Insulin
secretion in patients with latent autoimmune diabetes (LADA): half way between type 1 and type 2
diabetes: action LADA 9. BMC Endocrine Disorders. 2015 Dec;15(1):1-6.
2. Carlsson A, Sundkvist G, Groop L, Tuomi T. Insulin and glucagon secretion in patients with slowly
progressing autoimmune diabetes (LADA). The journal of clinical endocrinology & metabolism. 2000
Jan 1;85(1):76-80.
3. Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Rolandsson O, Colman PG, Harrison LC. Latent
autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005 Nov;48:2206-12.
4. Sørgjerd EP. Type 1 diabetes-related autoantibodies in different forms of diabetes. Current diabetes
reviews. 2019 Jun 1;15(3):199-204.
5. Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-
onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables.
The lancet Diabetes & endocrinology. 2018 May 1;6(5):361-9.
6. Costanzo MC, von Grotthuss M, Massung J, Jang D, Caulkins L, Koesterer R, et al. The Type 2 Diabetes
Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.
Cell Metabolism. 2023 Mar 16.
21
Case 4
A case of 46XX Congenital Adrenal Hyperplasia

Reared as a Male
Authors:
Dr. Fahmeeda Jan
Endocrine fellow
[email protected]
Dr. Urooj Lal Rehman

Assistant Professor Endocrinology
[email protected]
Dr. Tazeen Khalid
Endocrine fellow
[email protected]
(Jinnah Postgraduate Medical Centre JPMC, Karachi)
Case Summary
A 26 years old gentleman presented to the outdoor endocrine clinic with complaints of
atypical genitalia. The patient had initially presented 10 years back and wasworked up at
that time. His blood works, ultrasound and karyotyping was done which was46XX. The
patient had been informed about his diagnosis 10 years back and asked to follow up but he
never re visited and carried on as a male. He had now come to the clinic as he wished to get
married.
There was no history of any particular drug intake, or admissions in the hospital since
childhood.
On examination a man with a height of 149 cm and weight 52 kg, BMI was 23.4. He had a
fully grown beard and no apparent facial or skeletal deformity, androgenic pattern of pubic
hair and a deep voice. Blood pressure was 125/80 and a regular pulse.
His genital examination showed Prader stage 4 virilization; marked clitoromegaly with a
vaginal orifice and empty scrotal sac
His hemoglobin was 15.2 g/dl and serum potassium was 3.9 mEq/l. Rest of the renal and
liver function tests were within the normal range.
22
His hormonal Profile showed
Testosterone: 13.50 nmol/L (0.52-2.43)

FSH: 4.75mIU/ml (1.4-15.4)
LH 2.01mIU/ml (1.2-7.8)
Estradiol: 70.45 pg/ml (10-50)
Prolactin: 13.38 ng/ml (3-23)
Cortisol: 11.7 µg/dl
ACTH: 65.5 pg/ml (<46)
17OH Progesterone: 16.14 ng/ml (0.15-2.0)
Karyotype was 46XX

Pelvic imaging showed bilateral ovaries with fallopian tubes and uterus.
What is the next best step in the management of this patient?

a) Testosterone therapy
b) Hysterectomy with salpingo-oophorectomy
c) Genital Prosthetic surgery
d) Psychiatric evaluation and counselling
e) Gonadotrophin therapy
Answer: (d)
Discussion:
Congenital adrenal hyperplasia (CAH) is a group of disorders with a defect in one of five
enzymes involved in adrenal steroidogenesis. CAH is the most common disorder of sex
development. It occurs with an incidence ranging from 1 in 5000 to 1 in 15,000 in the United
States and Europe. (1).
The virilizing form of 21-hydroxylase CAH comprises of a whole spectrum of virilization in

46, XX individuals ranging from none to complete virilization to an extent that in rare cases
the external genitalia are entirely male, without testes.
The available outcome data on sexual identity in 46 XX CAH patients suggests that there
may be a relationship between the degree of virilization of the external genitalia and sexual
identity. Therefore, it may not be appropriate to manage all 46,XX CAH patients on the same
pattern regardless of the degree of genital virilization. It is important to tailor management
strategies to the specific needs of each patient based on their individual characteristics and
clinical presentation. This may involve a combination of medical and psychological
interventions, and a multidisciplinary approach involving endocrinologists, psychologists,
and other healthcare professionals may be necessary to ensure the best possible outcomes
for patients with 46 XX CAH.
23
The actual percentage of 46 XX patients with CAH born with Prader 4-5 genitalia is
unknown, and it is expected to occur more frequently in patients with severe enzyme
deficiency. The relationship between gender identity and quality of life has not been
adequately studied in such situations, though it is well known that those with gender
identity disorders have significant quality-of life problems. Further, it is quite possible that
quality of life for the virilized 46 XX CAH patient starts from the initial gender assignment,
ensuring a firm basis for a secure gender identity. This is consistent with a stable gender
identity being an important factor in quality of life.
There is also agreement on those outcome factors that are gauged to assess quality-of-life
outcomes for 46 XX CAH patients such as self-esteem, body image, interpersonal
relationships, sexual identity and fertility. (2)
Although substantial evidence following this pattern is incomplete, there are many areas of
evidence that support it. Most importantly, although the incidence of gender dysphoria in
completely virilized 46, XX patients raised as males is unknown, a much higher incidence of
gender dysphoria has been reported in those patients who were assigned female,
regardless of karyotype. In summary, male gender of rearing may be a practical option for
parents whose children are born with congenital adrenal hyperplasia, a 46 XX karyotype
and male genitalia, although positive parental and other support, and counseling are
needed for adjustment. (3)
(A) As the patient is fully androgenized, both phenotypically and biochemically,

testosterone therapy is not indicated here. (B) Although hysterectomy and bilateral
salpingo-opherectomy are almost always performed during childhood in 46 XX CAH
patients, it should be delayed till the patient sexual identity is identified(C) Genital
prosthetic surgery would be the eventual surgery in our patient, is he carries on as a male,
but definitely not the next step. (D) According to the most recent consensus, surgeries
leading to permanent infertility should not be performed in patients with sex development
disorders unless their sexual identity is confirmed (4). All of the above options are preceded
by first identifying the sexual orientation of the patient, his quality of life and the sex that he
wishes to carry on with. (E) Gonadotrophin therapy might be a rare option only if the
patient wishes to carry on as a female with functional ovaries, which is unlikely in our
patient and hence not an option.
24
References:
1. Suharibawa IG, Daryanto B. A Case Report: 46, XX Congenital Adrenal Hyperplasia (CAH). The Pan
African Medical Journal. 2018 Aug 11(ARTISSUE).
2. Lee PA, Houk CP. Review of outcome information in 46, XX patients with congenital adrenal
hyperplasia assigned/reared male: what does it say about gender assignment?. International Journal
of Pediatric Endocrinology. 2010 Dec;2010:1-7.
3. Houk CP, Lee PA. Approach to assigning gender in 46, XX congenital adrenal hyperplasia with male
external genitalia: replacing dogmatism with pragmatism. The Journal of Clinical Endocrinology &
Metabolism. 2010 Oct 1;95(10):4501-8.
4. Savaþ-Erdeve Þ, Aycan Z, Çetinkaya S, Öztürk AP, Baþ F, Poyrazoðlu Þ, Darendeliler F, Özsu E, Þýklar Z,
Demiral M, Unal E. Clinical Characteristics of 46, XX Males with Congenital Adrenal Hyperplasia.
Journal of clinical research in pediatric endocrinology. 2021 Jun;13(2):180.
25
Case 5
Carcinoid Syndrome
Authors:
Dr. Nasir Siddique
Consultant General Internal Medicine / Endocrinology & Diabetes
[email protected]
(Northampton General Hospital UK)
Professor Khurshid Ahmad Khan

Professor of Endocrinology and Diabetes
(Fatima Memorial Hospital Lahore)
Case Summary
48/F admitted following GP referral with low K-1.5 Reported being unwell for 4 months,
anxious, puffy face, neck swelling, polyuria, bulging of eyes.PMH-Nil Observations: RR-14,
sats-98% on A, HR-102, BP-157/104(178/119), T36.6, CBG11.4 Appeared flushed, anxious
and puffy
Investigations
Serum Sodium 143mmol/l Serum Potassium 1.5mmol/l Urea 5.4 Creatinine 50 ?HB 15.6
gm / L Platelets 122,000 White cells count 7200
Chest xray showed a opacification in right cardiophrenic region
CT Thorax showed 46 mm well-demarcated heterogonous mass arising from mediastinum

adjacent to the right atrium. A branch of Right pulmonary artery enters the lesion at the
apex.
Endocrine profile showed : Cortisol-611 Post dexamethasone cortisol-285 Plasma

aldosterone-<72pmol/L(100-800)
Plasma Renin-0.3 pmol/ml/hr(0.5-3.1) Low aldosterone with low to low-normal PRA

26
48/F admitted following GP referral with low K-1.5 Reported being unwell for 4 months,
anxious, puffy face, neck swelling, polyuria, bulging of eyes.PMH-Nil Observations: RR-14,
sats-98% on A, HR-102, BP-157/104(178/119), T36.6, CBG11.4 Appeared flushed, anxious
and puffy
What is likely diagnosis ?

a) Cushing syndrome
b) Cushing Disease
c) Atypical Carcinoid
d) Liquorice ingestion
E) Diuretic abuse
Answer: (C)
Discussion :
Atypical carcinoids are ACTH-secreting lung carcinoids represent the principal cause of
ectopic Cushing syndrome and considered aggressive early recognition and surgical
resection. Pulmonary carcinoids have a favorable outcome. Most common presenting
complaints are non-specific, such as weight-gain, fatigue, lethargy, and depression. Low K
levels are found in approximately 10% of patients with CD and approximately 90% of
patients with ectopic Cushing's.
On further investigations, echocardiography showed well-circumscribed mass attached to

right atrium. From pericardial reflection asymmetric thickening of the right atrial wall was
noted. CT head showed no abnormal findings and it was considered possible hormone-
secreting lung mass so plan was made resection of lung mass with staging tests
Hypertension, High blood glucose, Hypokalemia, unsuppressed dexamethasone test and
low ARR were suggestive of hypercortisolism though typical clinical features of Cushing's
syndrome were not present Possible ectopic ACTH-driven Cushing's syndrome was
diagnosed based on above findings and pituitary venous sampling was not deemed
necessary . Finally , Right middle lobectomy in 10 days Histology showed Atypical
carcinoid-T2bN0Post-surgical Octreotide/PET scan- normal 5HIAA and Dexamethasone
suppression test normal
Need corrections
References :
Clinl Med case report 2012; 5: 4348. Published online 2012 Apr23. doi: 10.4137/CCRep.S9227 (PMCID:
PMC3342021PMID: 22563250 )
27
Case 6
Constitutional Delay of Growth and Puberty
Authors:
Dr. Nadeem Naeem

HOD Diabetes and Endocrinology
Dr. Sumair Ahmad
Post Graduate resident Medicine
(Memon Medical Institute, Karachi)
Case Summary
15-year-old boy presented in the OPD for being relatively short as compared to his class
fellows and lack of beard and penile growth. He has got 2 sisters and 1 brother, all three of
normal height.No history of altered bowel habits or fatigue. School Performance is ok and
no family history of late growth.
On Examination, he is well below mid parental height, SPL is 5 cm and both testes are 5ml,
soft in consistancy, no sexual hairs and sparse ambisexual hairs, sense of smell is present.
Labortery Test Results:
Serum Testosterone= 120ng/dl (300 to 900), FSH=1Miu/ml(1 to 13), LH=1.5Miu/ml(1to 9),

Celiac Screen= Negative, TSH=Normal, CBC=Normal, bone age=12.5 years, IGF1=Normal.
Low dose Testosterone started and after every 6 months axis recovery was checked by
stopping testosterone and getting serum levels after 1 month. During this period SPL
increased to 8 cm, testicular size to 7 ml and height by 16 cm in 18 months.
After 3 cycles 1 month post dose serum testosterone level is 435ng/dl.
28
What is the most probable Diagnosis?
a) Androgen Insesnsitivity Syndrome

b) Constitutional Delay of Growth and Puberty
c) Growth Hormone Deficiency
d) Hypergonadotrophic Hypogonadism
e) Hypogonadotrophic Hypogonadism
Answer: (b)
Discussion:
Short stature is a term applied to a child whose height is 2 standard deviations (SD) or more
below the mean for children of that sex and chronologic age.
The most common causes of short stature beyond the first year or two of life are familial
(genetic) short stature and delayed (constitutional) growth. Familial short stature is
differentiated by measuring Mid Parental Height.Children with CDGP are usually of normal
size at birth. However, a downward shift in growth rate begins at three to six months of age
that is parallel to that seen in most normally growing children in this age group but tends to
be more severe and prolonged resulting is a growth curve that remains below, but parallel
to, the third percentile for height. In addition to a low preadolescent height velocity, they
tend to have delayed pubertal maturation. This leads to a marked height discrepancy during
the early teenage years compared with their peers but is followed by catch-up growth when
they do enter puberty.
It is very difficult to differentiate delayed growth by CDGP from Delayed Puberty due to
Hypogonadism. That is the reason treatment is started considering Hypogonadism and axis
recovery is checked after every 6 months which usually doesnt recover in Hypogonadism.
In severe cases growth hormone stimulation testing may be necessary but in mild cases
IGF1 has got sufficient sensitivity to exclude.
References:
1) Soliman AT, De Sanctis V. An approach to constitutional delay of growth and puberty. Indian Journal of
Endocrinology and Metabolism. 2012 Sep 1;16(5):698-705.
2) Herman-Giddens ME, Steffes J, Harris D, Slora E, Hussey M, Dowshen SA, Wasserman R, Serwint JR,
Smitherman L, Reiter EO. Secondary sexual characteristics in boys: data from the Pediatric Research in
Office Settings Network. Pediatrics. 2012 Nov;130(5):e1058-68.
3) Stamou MI, Georgopoulos NA. Kallmann syndrome: phenotype and genotype of hypogonadotropic
hypogonadism. Metabolism. 2018 Sep 1;86:124-34.
4) Harrington J, Palmert MR. An approach to the patient with delayed puberty. The Journal of Clinical
Endocrinology & Metabolism. 2022 Jun;107(6):1739-50.
29
Case 7
Premenopausal Hyperandrogenism
Authors:
Dr. Nadeem Naeem

HOD Diabetes and Endocrinology
Dr. Muhammad Rafay
Post Graduate resident Medicine
(Memon Medical Institute, Karachi)
Case Summary
An 18-year-old girl presents in the Endocrine OPD with complaints of oligomenorrhea,
increased facial and body hairs, acne and weight gain of gradual onset for last 3 years. Her
age of Menarche is 13 years and from start her periods are not regular. She remained under
treatment of gynecologists and using OCPs with minimal effect on her Hirsutism.
Labortery test results:
Testosterone: 197ng/dl (8 to 60ng/dl)
17-hydroxyprogesterone:312ng/dl (less than 200ng/dl)
ACTH stimulated 17-hydroxyprogesterone: 783ng/dl
Ultrasound Pelvis: Right Ovarian volume 13ml, otherwise normal
Fasting Insulin, TSH, Prolactin are within normal range.
30
What is the most probable Diagnosis?
a) Androgen-secreting tumor
b) Cushing's Disease
c) Nonclassic congenital adrenal hyperplasia
d) Ovarian hyperthecosis
e) Polycystic ovary syndrome
Answer: (C)
Discussion:
Elevated serum concentrations of androgens in women are referred to as
hyperandrogenemia, which can manifest as hirsutism, acne, androgenetic alopecia, and
virilization. Polycystic ovary syndrome (PCOS) is the most common cause of hirsutism.
Other causes of androgen overproduction occuring less frequently include: Nonclassic
congenital adrenal hyperplasia(NCCAH), Androgen-secreting tumors, Ovarian
hyperthecosis and Cushing's Disease.
Nonclassic congenital adrenal hyperplasia presents clinically similar to that of PCOS and it
should always be ruled out because not only there are risks that offspring could be affected
with the more severe classic 21-hydroxylase deficiency, but also fertility management is
different than PCOS.
17-hydroxyprogesterone is the screening test to differentiate between these two entities.
A value less than 200 ng/dL in the early follicular phase makes this diagnosis unlikely and a
value of greater than 200 ng/dL strongly suggests the diagnosis, which may be confirmed by
a high-dose (250 mcg) corticotropin (ACTH) 1-24 (cosyntropin) stimulation test. The
response to cosyntropin is exaggerated, with most patients having values exceeding 1000
ng/dL specially in NCCAH due to 21-hydroxlase deficiency.
A Stimulated value of less than 1000ng/dl can be found in uncommon forms of NCCAH.
Uptodate Topic Review:
Ø Evaluation of premenopausal women with hirsutism.

Ø Etiology and pathophysiology of polycystic ovary syndrome in adolescents
Ø Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal
hyperplasia due to 21-hydroxylase deficiency
Ø Uncommon congenital adrenal hyperplasias
31
References:
1) Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women:

experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004;
89:453.
2) Carmina E, Rosato F, Jannì A, et al. Extensive clinical experience: relative prevalence

of different androgen excess disorders in 950 women referred because of clinical
hyperandrogenism. J Clin Endocrinol Metab 2006; 91:2.
3) Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003; 349:776.
4) Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase

deficiency: from clinical investigation to molecular definition. Endocr Rev 1991;
12:91.
5) Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase

deficiency: from clinical investigation to molecular definition. Endocr Rev 1991;
12:91.
32
Case 8
Luteoma of Pregnancy
Authors:
Dr. Nasir Siddique
Consultant General Internal Medicine / Endocrinology & Diabetes
[email protected]
(Northampton General Hospital UK)
Professor Khurshid Ahmad Khan

Professor of Endocrinology and Diabetes
(Fatima Memorial Hospital Lahore)
Case Summary
A 27-year-old, primigravida, 26 weeks, was referred to Endocrine Clinic due to recent
excessive growth of hair over the face and back as well as a change in her voice from the last
few weeks. She was diagnosed as having polycyclic ovarian syndrome (PCOS) at the age of
18 years which was well treated at that time, and she had regular periods before becoming
pregnant. Her examination revealed excessive hairs over the chin, abdomen, and back with
the deepening of the voice and mild clitoromegaly. Her cousin was recently diagnosed with
an adrenal incidentaloma of 4 cm, so she was concerned about the same condition in her.
She was only on iron tablets during her pregnancy.
Investigations revealed.
Total Testosterone 8.6 nmol/l(0.5-2.4nmol/l)
LH 6 IU/L(2-9IU/L), FSH 5.4 IU/L (<1IU/L)
DHEAS Normal
Ultrasound abdomen and pelvis showed normal Foetal growth and bilateral solid ovarian
masses of 2.7 cm with no further characteristics given.
33
What is the most likely diagnosis?
a) Relapse of polycyclic ovarian Syndrome

b) Adrenal carcinoma
c) Cushing Syndrome
d) Luteoma of Pregnancy
e) Non-Classical CAH
Answer: (d)
Discussion:
As this lady had gestational hyperandrogenism as evidenced by solid bilateral masses which
were more suggestive of Luteomas as a benign condition of pregnancy. Luteomas are
common during pregnancies and are non-neoplastic with aggravating hyperandrogenism
of pregnancy and rarely can become symptomatic. Furthermore, these Luteomas are
managed conservatively as they regress themselves in the postpartum period. This can be
polycyclic ovaries relapse but hyperandrogenism and virilization do not fit with PCOS.
REFERENCE :
1. Gestational Hyperandrogenism in Developmental Programming Christopher Hakim, Vasantha

Padmanabhan, Arpita K. Vyas Author Note Endocrinology, Volume 158, Issue 2, 1 February 2017, Pages 199212,
https://doi.org/10.1210/en.2016-1801
34
Case 9
Diabetic Foot Osteomyelitis
Authors:
Dr. Arwa Hatim
Consultant Diabetologist
[email protected]
Dr. Saima Askari

Consultant Endocrinologist & Assistant Professor
[email protected]
Dr. Musarrat Riaz

Consultant Endocrinologist & Associate Professor of Medicine
[email protected]
(Baqai Institute of Diabetology and Endocrinology, Karachi Pakistan)
Case Summary
A 42-year-old male, with a known case of hypertension and T2DM for 10 years on a basal-
bolus insulin regimen, having uncontrolled DM (HbA1c of 9.4),presented to the foot clinic
with a non-healing ulcer on the left big toe for 3 months. The patient had developed an
infected callus 3 months back for which he had visited a nearby GP and was advised
antibiotics. Initially, he responded, and the wound healed however 2 weeks later it got re-
infected. Callus removal along with antibiotics was started. His wound dressing was being
done regularly but he was noncompliant with medicines hence wound was not healing.
Examination:
He had a red, swollen, sausage-like left big toe with a small ulcer on the planter's surface.
Probe to bone was present. His foot pulses were palpable bilaterally with absent
monofilament and vibration senses. The rest of the physical examination was
unremarkable. He was advised baseline labs and an X-ray of the foot.
35
“ X-ray foot revealed bone lytic lesions with bony erosion and loss of bone cortex
in the proximal phalanx showing osteomyelitis (DFO-Diabetic Foot Osteomyelitis) .”
36
Labs:
The patient was managed by the removal of

infected bone fragments. Bone culture &
sensitivity (C/S)was sent and antibiotics were
given accordingly for 2 months. Daily wound
dressing and proper pressure offloading were
also done. The wound improved gradually and
almost healed in a duration of 6 months.
37
Features of osteomyelitis on Xray include all except:

a) loss of bony cortex with erosion
b) narrowing of joint space
c) periosteal elevation
d) bone sclerosis
e) presence of sinus tract from bone to soft tissue
Answer : (b)
The patient was diagnosed with diabetic foot osteomyelitis, DFO.
Discussion:
Diabetic foot osteomyelitis (DFO) is a serious limb-threatening complication of diabetes
occurring in >20% of moderate infections and in almost 50% to 60% of severe infections.,
DFO most commonly involves the forefoot. It usually results from long-standing, non-
healing ulcers and is associated with a high risk of lower extremity amputations.
The diagnosis of DFO is usually based on a combination of clinical features, laboratory

findings, and microbiological and radiological evaluation. Many of its adverse outcomes are
related to delayed diagnosis or inadequate management. Clinicians should suspect DFO if
the infected ulcer is wide, deep, and overlies a bony prominence. The ulcer has visible bony
fragments, non-healing despite adequate off-loading, or when a toe is erythematous and
indurated (the so-called sausage toe appearance.) An open wound positive probe-to-bone
test is highly diagnostic of bone infection. A highly elevated ESR (>70mm/hr) on laboratory
findings also favors osteomyelitis.Any patient suspected of osteomyelitis should initially
undergo plain X-rays although X-rays can be negative in the first few weeks of infection.
Characteristic X-ray findings of DFO include:

Ø Periosteal elevation
Ø Loss of bony cortex with bony erosion
Ø Focal loss of cortical trabecular pattern
Ø Bone sclerosis
Ø Presence of sinus tract from bone to soft tissue
Ø Presence of sequestrum, involucrum and cloacae.
The gold standard for diagnosis of osteomyelitis is the bone biopsy. Most cases of DFO are
polymicrobial, with Staph. Aureus being the most commonly isolated pathogen.
The management of DFO still remains controversial. The guidelines broadly recommend
specific conditions for surgical or medical approaches combined with conservative surgery.
Conservative surgery is a procedure in which only the infected soft tissues and bone
fragments are removed without any amputation.
38
Antibiotic therapy is widely used in combination with surgical procedures (conservative or

amputation), however, there are cases where DFO can be treated successfully by antibiotic
therapy alone. The International Working Group of Diabetic Foot IWGDF suggested at least
6 weeks of antibiotic therapy if the infected bone is not removed.
Consider surgical intervention in cases of osteomyelitis accompanied by:

Ø Spreading soft tissue infection
Ø Destroyed soft tissue envelope
Ø Progressive bone destruction on X-ray
Ø Bone protruding through the ulcer
References:
1. Medical Versus Surgical Treatment for the Management of Diabetic Foot Osteomyelitis: A Systematic
Review AroaTardáguila-García1 , Irene Sanz-Corbalán 1,*, Josep M. García-Alamino 2 , Raju Ahluwalia
3 , Luigi Uccioli 4 and José Luis Lázaro-Martínez 1
2. José Luis Lázaro-Martínez, AroaTardáguila-García, José Luis García-Klepzig, Diagnostic and

therapeutic update on diabetic foot osteomyelitis, Endocrinología, Diabetes y Nutrición (English ed.),
Volume 64, Issue 2, 2017, Pages 100-108, ISSN 2530-0180,
https://doi.org/10.1016/j.endien.2017.03.003.
update). Diabetes Metab Res Rev. 2020 Mar;36 Suppl 1:e3280. doi: 10.1002/dmrr.3280. PMID:
32176444.
3. Laura giurato, marcomeloni, Valentina Izzo, Luigi Uccioli, Osteomyelitis in diabetic foot: A
Comprehensive Overview, World J Diabetes. 2017 Apr 15; 8(4): 135-142
4. Lipsky BA, Senneville É, Abbas ZG, Aragón-Sánchez J, Diggle M, Embil JM, Kono S, Lavery LA, Malone
M, van Asten SA, Urbanèiè-Rovan V, Peters EJG; International Working Group on the Diabetic Foot
(IWGDF). Guidelines on the diagnosis and treatment of foot infection in persons with diabetes
(IWGDF 2019
39
Case 10
Hyperandrogenism with Polycystic

Ovarian Morphology
Authors:
Dr. Sidrah Lodhi

Assistant Professor of Endocrinology
[email protected]
Dr. Fawad Ahmad Randhawa

Associate Professor of Endocrinology
[email protected]
(King Edward Medical University, Lahore)
Case Summary
An 18-year-old girl is referred by a general physician for review. She had a history of
secondary amenorrhea for 2 years. She attained menarche at the age of 12 years. In the first
3 years post-menarche, the cycles were irregular with a cycle length of 37 to 65 days. In the
fourth year, she only menstruated thrice spontaneously. Thereafter, she did not have
menstrual bleeding. She also reports hirsutism and alopecia. On examination, her height is
148.5cm and she is 11 cm shorter than her sister with midparental height of 160cm. Her
sister had her menarche at 15 years of age. Further examination shows male pattern
baldness and Ferriman Gallway score was calculated to be of 10. Examination of external
genitalia reveals normal labia with prominent clitoris (length not measured due to patient's
discomfort). Pelvic ultrasound reveals bilateral increased ovarian volume with polycystic
ovarian morphology.
40
Hormonal profile was advised:
Which of the following investigation is most likely to have the highest diagnostic yield in
this girl?
a) ACTH stimulated 17-OH Progesterone

b) Basal Serum Cortisol
c) Basal DHEA-S
d) GnRH stimulated Testosterone
E) Urinary â-hCG
Answer : (a)
Discussions:
In a young patient with amenorrhea/oligomenorrhea combined with features of
hyperandrogenism and polycystic ovarian morphology, the differential includes polycystic
ovarian syndrome (PCOS), Cushing's syndrome, and non-classical congenital adrenal
hyperplasia (NCCAH). Rare causes include androgen-secreting tumors of ovarian or adrenal
origin. Polycystic ovarian syndrome is a diagnosis of exclusion. Raised testosterone level
and raised LH/FSH ratio (>2.5) are detectable in this condition but the same biochemical
picture may be present in other hyperandrogenic disorders as well.
In this patient, there are no additional clinical indicators of Cushing's syndrome. The
screening tests for this condition are dexamethasone suppression test, 24-hour urinary free
cortisol, or late-night salivary cortisol (Currently not available in Pakistan) with the limited
value of basal serum cortisol in the diagnostic algorithm for Cushing's.
41
NCCAH is a definite possibility in this patient. The clinical indicators are short stature and
possible clitoromegaly both of which indicate androgen exposure early in life. Considering
that 21-á-hydroxylase deficiency is the most common cause of CAH, testing for 17-OH
Progesterone offers the best chance of being diagnostic. If basal levels are unequivocal, an
ACTH stimulated level or the sum of basal and stimulated 17-OH-Progesterone increase the
diagnostic yield. It is important to diagnose this condition and differentiate it from PCOS as
this is a lifelong condition with definite chances of being passed on to offspring, especially in
societies with high rates of intrafamilial marriages.
The diagnostic algorithm for secondary amenorrhea is given below1

Secondary Amenorrhea
- absence of menses for 6months in a previously regular woman
-absence of menses for 12months in a previously irregular woman
Differential:
Pregnancy
-intrauterine
-ectopic
Order: Positive Tumor
hCG -trophoblastic
-ovarian germ cell
Gestational Trophoblastic Disease
Negative -choriocarcinoma
-hydatidiform mole
Order
Thyroid Stimulating Leutinizing Normal Follicle Stimulating Normal

Normal Prolactin Normal
Hormone (TSH) Hormone (LH) or Low Hormone (FSH) or Low Order:
Estrodiol
High
High High
Ovarian Failure High Low
Order: Hyperprolactinemia
fT4 Pituitary Dysfunction
Differential:
Prolactinoma Order Normal Differential:
Drugs (Rx) - Shaheen’s Syndrome
Low or Normal - Functional hypothalmic
amenorrhea (ie stress
induced)
Order: - Anorexia
thyroid
autoantibodies
17- Hypothalmic Amenorrhea
hydroxyprogesterone Cortisol Testosterone
High
Normal High
High Highly
Elevated
Hypothyroidism Moderately
Congenital Adrenal Cushing’s Disease Elevated
Hyperplasia (CAH)
Malignancy
Differential:
- ovarian tumor
- adrenal tumor
Polycystic Ovary
Syndrome (PCOS)
References:
1. Roberts-Wilson TK, Spencer JB, Fantz CR. Using an algorithmic approach to secondary amenorrhea:
avoiding diagnostic error. Clinica Chimica Acta. 2013 Aug 23;423:56-61.
2. McClintock, A., Kaminetzky, C.P. (2020). Approach to Secondary Amenorrhea. In: Mookherjee, S.,
Beste, L.A., Klein, J.W., Wright, J. (eds) Chalk Talks in Internal Medicine. Springer, Cham.
3. Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. American family
physician. 2013 Jun 1;87(11):781-8.
42
Case 11
Precocious Puberty
Authors:
Dr. Shaista Kanwal

Specialist Registrar
(Department of Endocrinology,
MTI-Hayatabad Medical Complex, Peshawar)
Case Summary
A 6-years young girl, referred by the gynecologist to the department of endocrinology for
assessment and workup for precocious puberty. She initially presented to the department
of gynecology with 4 months history of abdominal pain, abdominal swelling, and
progressive breast enlargement. She also reported recent weight gain with no increase in
height, low mood, and loss of appetite. There was no history of vaginal bleeding. She
belonged to Afghanistan and was born through normal vaginal delivery and the pregnancy
was uneventful with no postnatal complications. She was product of non-consanguineous
marriage and was full term at the time of birth, weighing 2.25kgs. Routine neonatal
laboratory investigations were unremarkable. She was of normal intelligence and had
normal developmental milestones. There was no history of vomiting, headache or visual
disturbance. Family history was unremarkable for any thyroid disorder, precocious puberty
or any other autoimmune disorder. There was no history of any drug intake.
On physical examination she was pale with dry skin and some facial puffiness. Her height
was 98cm (<3rd centile, SDS of 3.4) and weight was 22 kg (50th centile). She had distended
abdomen with no organomegaly, however there was tenderness in both iliac fossa. She had
Tanner's stage B3 for breast development and Tanner's stage P2 for pubic hair. Her external
genitalia were normal. There was no expressive galactorrhea.
43
On workup, her bone age was 4 years at the time of consultation revealed on the Xray left
wrist. Abdominal ultrasound was unremarkable whereas pelvic ultrasound revealed a
uterine size of 5.4 × 3.2 × 3.6 cm and enlarged ovaries with multi cystic appearance with
right ovarian size of 7.9 × 5.2 cm and left ovarian size of 4.2 × 3.9 cm. The largest cyst in the
left ovary measured about 28 × 34 × 36 mm and largest right ovarian cyst was about 57.8 ×
45.2 × 63.2 mm.
Hormonal profile was as follows:
LH: 0.12 mIU/ml (1.78.6)
FSH: 8.1 mIU/ml (1.512.5)
Serum Prolactin: 177 ng/ml (4.49-19.5)
Estradiol: 58 pg/ml (< 29 pg/ml)
Which of the following is the most probable diagnosis?
a) Estrogen-secreting tumor
b) Ovarian cyst
c) McCune-Albright syndrome
d) Exogenous estrogen exposure
e) Primary hypothyroidism
Answer: (e)
44
Discussion:
The common presentation of primary hypothyroidism is usually in the form of nonspecific
features like gain in weight, reduced concentration, weakness, depressive symptoms,
lethargy, short stature in children and menstrual irregularities in females.Very rarely, it may
present in an unusual form like Van Wyk Grumbach (VWG) Syndrome. For the first time this
syndrome was reported by Van Wyk and Grumbach in three girls, whose presentation was
with precocious puberty; precocious thelarche and galactorrhea but with delayed bone age
along with hypothyroidism. Importantly, there were no axillary and pubic hair. Moreover,
there is incomplete isosexual precocious puberty in VWGS. The patient described in this
case report breast development in the absence of uterine bleeding, suggesting an
incomplete isosexual precocious puberty. Furthermore, an estrogen secreting ovarian
tumor was initially suspected because of precocious puberty with enlarged ovaries
presence of delayed bone age on X ray of the wrist leads to the suspicion of primary
hypothyroidism, proven further on performing thyroid function tests. Radiological studies
in VWGS usually reveals enlarged ovaries with multiple cysts due to development of the
follicles, an enlarged uterus of puberty and delayed bone age instead of advanced bone age
as expected in a case of sexual precocity. Biochemical findings in VWGS include low free
thyroxine (T4) along with raised thyroid stimulating hormone (TSH), prolactin and
oestradiol.
The exact mechanism of sexual precocity in VWGS is unknown however, Van Wyk and
Grumbach postulated that the increased production of TSH, prolactin, gonadotropins and
estradiol might be because of the overlap of hormones in the pituitary feedback
mechanism. Moreover, a common alpha subunit is shared by TSH, FSH and LH which are all
glycoprotein hormones however, they have unique beta subunit conferring specificity to
each hormone. Due to this molecular homology, they have a tendency to cross react.
Furthermore, there is possibility that ovarian hypersensitivity to the gonadotropins could

be either directly from the hypothyroid status or indirectly due to raised prolactin level.
Prolactin also sensitizes ovaries to gonadotropins and promotes maturation of the follicles.
In primary hypothyroidism, TRH levels are high due to absence of negative feedback by the
thyroid hormones, this high TRH leads to thyrotroph hyperplasia and increased prolactin
secretion.
A unique characteristic feature of isosexual precious puberty produced by primary

hypothyroidism is retarded growth with a delay in the bone age, paradoxical to rest of the
causes of precocious puberty where there is advancement in bone age. This is because of
the extremely low levels of thyroid hormones. Although the exact pathogenesis is still not
clear, the treatment approach is quite straightforward. All the symptoms and signs
regresses with thyroid hormone replacement. There is resolution of the hormonal
derangements and reduction in the ovarian cyst sizes or even regression of these cysts
altogether. Timely diagnosis and treatment are of paramount importance because it can
save the patient from unnecessary investigations or interventions.
45
References:
1. Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile
hypothyroidism: an example of hormonal overlap in pituitary feedback. The Journal of Pediatrics.
1960 Sep 1;57(3):416-35.
2. Baranowski E, Högler W. An unusual presentation of acquired hypothyroidism: the Van Wyk-

Grumbach syndrome. Eur J Endocrinol. 2012 Mar;166(3):537-42. doi: 10.1530/EJE-11-0494. Epub
2011 Dec 14. PMID: 22170796.
3. Reddy P, Tiwari K, Kulkarni A, Parikh K, Khubchandani R. Van Wyk Grumbach Syndrome: A Rare
Consequence of Hypothyroidism. Indian J Pediatr. 2018 Nov;85(11):1028-1030. doi:
10.1007/s12098-018-2704-2. Epub 2018 May 19. PMID: 29777468.
4. Riaz M, Ibrahim MN, Laghari TM, Hanif MI, Raza J. Van Wyk Grumbach Syndrome. J Coll Physicians
Surg Pak. 2020 Dec;30(12):1332-1334. doi: 10.29271/jcpsp.2020.12.1332. PMID: 33397063.
5. Biswas M, Sinha MK, Das MK, Sarkar S. Van Wyk-Grumbach syndrome with hemangioma in an infant. J
Pediatr Endocrinol Metab. 2018 Sep 25;31(9):1057-1060. doi: 10.1515/jpem-2018-0049. PMID:
30028725.
6. Marr A, Hardy K, Curtis J. A 14-year-old girl with short stature, incomplete puberty and severe
menstrual bleeding. Paediatr Child Health. 2018 Apr;23(2):85-88. doi: 10.1093/pch/pxx113. Epub
2017 Nov 23. PMID: 29686489; PMCID: PMC5905373.
7. Razi SM, Gupta AK, Gupta DC, Gutch M, Gupta KK, Usman SI. Van Wyk-Grumbach Syndrome with
Kocher-Debré-Sémélaigne Syndrome: Case Report of a Rare Association. Eur Thyroid J. 2017
Feb;6(1):47-51. doi: 10.1159/000448993. Epub 2016 Oct 4. PMID: 28611948; PMCID: PMC5465749.
46
Case 12
Hypokalemia
Authors:
Dr. Niktash Khan Hadi
Fellow Endocrinology
Dr. Shaista Kanwal
Specialist Registrar
(Department of Diabetes and Endocrinology,

MTI-Hayatabad Medical Complex, Peshawar)
Case Summary
A 22-year-old male presented to the emergency in anxious state with sudden onset
weakness in all limbs, vomiting and abdominal distention. Initial investigations revealed
severely low potassium ( K+ : 1.8mEq/l). Potassium replacement was commenced. Patient
subsequently deteriorated with quadriparesis and respiratory failure. He was shifted to ICU
and placed on ventilator support with continuous intravenous potassium supplementation
via central line. Once the patient was stabilized and weaned off ventilator, he was stepped
down to Endocrinology unit for further hypokalemia investigations.
History revealed previous admission to medical ward with limb weakness however it was
not as severe as current admission There was no documented evidence of hypokalemia. He
had had no history of chronic illness but did complain of arthralgias and gritty eyes. He
denied use of any medications or illicit drug use and there was no relevant family history. He
was normotensive and physical examination was unremarkable.
47
Biochemical results are as below;

· Serum magnesium: 2 mg/dl (1.58-2.55)
· Urinary electrolytes
· Spot Urine K+ : 46 mEq/L
Na+: 75 mEq/L
Cl- : 100 mEq/l
· Urine ph: > 7 (5-7)
· Urine calcium: 8mmol/24hr ( 2.5-7.5mmol/24)
· Urine anion gap: 21 (0-10)
· Arterial blood gases:
· PH: 7.35
· HCO3:14 mmol/L
· PCO2: 34 mmHg
· Anion gap: 12mEq/L
· Serum aldosterone: 13.5 ng/dl (2.52-39.2)
Serum aldosterone/renin ratio: 0.1 ng/uIU/mL (normal < 2.5)
· U/S abdomen: Bilateral renal calculi
· Anti Ro (Anti SSA): positive
· Anti La (Anti SSB): positive
Looking at the clinical picture above, which of the following test would you do to confirm
the probable diagnosis:
a) Ammonium chloride acidification test

b) Thyroid function test
c) HCO3 loading test
d) Diuretic screening
e) CT Abdomen
Answer: (a)
48
Explanation:
Hypokalemia is a common clinical problem, the likely cause of which can usually be
determined from history. Most of the causes of extra renal potassium loss have significant
history and may not need extensive investigations. If a patient has history of diarrhea,
vomiting, thyrotoxicosis and periodic paralysis, or has recently used antibiotics such as
aminoglycosides, diuretics , high dose insulin, beta agonists or antifungal agents; then
further investigations may not be needed. In this patient, history did not reveal any clue.
The examination was normal with normal blood pressure ruling out all causes of
Renin/aldosterone dysfunction (Rules out option E). With euvolemic status and no history
of drug use/abuse, furosemide use is least likely (Rules out option D). Patient is Clinical and
biochemically euthyroid (rules out option B)
Such patients need further diagnostic evaluation which include assessment of:
1) Urinary potassium excretion
2) Acid-base status
This patient has excessive potassium loss in urine with blood gases suggestive of metabolic
acidosis with respiratory compensation. With high suspicion of renal tubular acidosis as
cause of persistent hypokalemia, further tests were ordered to differentiate between distal
and proximal RTA. A high urine anion gap, persistently high urine pH and U/S showing renal
calculi is indicative of distal RTA.(Rules out option C).
Further testing reveals positive antibodies for Sjogren's syndrome, which has a strong
association with distal RTA. Distal RTA confirmed by ammonium chloride acidification test.
Distal renal tubular acidosis (dRTA) is the classical form of RTA characterized by a failure of
acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct
of the distal nephron. It leads to relatively alkaline urine, due to the kidney's inability to
acidify the urine to a pH of less than 5.5. Clinical features include: Normal anion gap
metabolic acidosis/acidemia with Hypokalaemia, Urinary stone formation (related to
alkaline urine, hypercalciuria, and low urinary citrate), Nephrocalcinosis (deposition of
calcium in the substance of the kidney), Bone demineralisation (causing rickets in children
and osteomalacia in adults)
The diagnosis of distal RTA can be made by the observation of a relatively alkaline urinary
pH of greater than 5.3 in the face of a systemic acidemia (usually taken to be a serum
bicarbonate of 20 mmol/L or less). In cases with borderline acidosis and normal to low
normal bicarbonate levels, failure to acidify the urine following an oral acid loading
challenge is often used as a test. The test usually performed is the ammonium chloride test,
in which ammonium chloride capsules are used as the acid load. More recently, an
alternative test using furosemide and fludrocortisone has been described
49
Treatment involves correction of the acidemia with oral sodium bicarbonate, sodium
citrate or potassium citrate. This will correct the acidemia and reverse bone
demineralisation. Hypokalaemia and urinary stone formation and nephrocalcinosis can be
treated with potassium citrate tablets which not only replace potassium but also inhibit
calcium excretion and thus do not exacerbate stone disease as sodium bicarbonate or
citrate may do.
References:
1. Mohebbi N, Wagner CA. Pathophysiology, diagnosis and treatment of inherited distal renal tubular
acidosis. Journal of Nephrology. 2018 Aug;31(4):511-22.
2. Both T, Hoorn EJ, Zietse R, van Laar JA, Dalm VA, Brkic Z, Versnel MA, van Hagen PM, van Daele PL.
Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome. Rheumatology. 2015 May
1;54(5):933-9.
3. Shavit L, Chen L, Ahmed F, Ferraro PM, Moochhala S, Walsh SB, Unwin R. Selective screening for distal
renal tubular acidosis in recurrent kidney stone formers: initial experience and comparison of the
simultaneous furosemide and fludrocortisone test with the short ammonium chloride test.
Nephrology Dialysis Transplantation. 2016 Nov 1;31(11):1870-6.
50
Case 13
Thyroid Dysfunction with Immune

Check Point Inhibitors
Authors:
Dr. Sidrah Lodhi
Assistant Professor of Endocrinology
[email protected]
Dr. Rana Sohail

Assistant Professor of Surgery
[email protected]
(King Edward Medical University, Lahore)
Case Summary
A 74-year-old lady was referred by oncologist for evaluation of deranged thyroid function
tests. She has a history of recurrent hepatocellular carcinoma on background of
decompensated cirrhosis due to chronic hepatitis C infection. Previously, she has
undergone TACE twice. At present, a new nodule has been detected which is not amenable
to TACE. She was started on Sorafenib but was intolerant.
The oncologist then switched her to Atezolizumab; the first dose was administered 9 days
before presentation. Patient started experiencing palpitations 6 days after receiving
injection Atezolizumab.
Thyroid function tests were advised:
TSH <0.001 0.5- 4.5 mIU/L

FT3 9.5 pmol/L 3.1 -6.0 pmol/L
FT4 69.7 11.0 23.0 pmol/L
51
Patient is hypertensive and blood pressure is controlled with combination of Valsartan and
Bisoprolol. She also has bronchial asthma for which she has been prescribed inhaled
budesonide/formeterol and Montelukast.
In-clinic examination revealed blood pressure of 131/82 mmHg and pulse of 82/min.
Thyroid & chest examination is unremarkable.
Q. What is the next step in management of this patient?
a. Continue same treatment till further investigation

b. Discontinue Atezolizumab
c. Initiate Carbimazole / methamizole
d. Initiate Propylthiouracil
e. Switch Bisoprolol to Diltiazem
Answer: (a)
Discussion:
Immunotherapy, a newer mode of treatment in various malignancies, includes anticancer
vaccines, oncolytic virus, bi-specific T-cell and immune checkpoint inhibitors (ICIs). Cancer
cells avoid being killed by immune escape mechanisms such as regulation by immune
checkpoints, the inhibitory pathways preventing unrestricted immune response. Immune
checkpoints are essential for protecting healthy tissue and preventing autoimmunity.
ICIs inhibit these pathways leading to activation of immune system against malignant cells.
ICIs are monoclonal antibodies directed against CTLA-4 (cytotoxic T-lymphocyte-associated
antigen 4), PD-1 (programmed death 1) or PD-L1 (PD-1 ligand). Currently used anti-CTLA-4
are ipilimumab and tremelimumab, anti-PD-1 are pembrolizumab, nivolumab,
cemiplimab, dostarlimab, retifanlimab and anti-PD-L1 are atezolizumab, durvalumab,
avelumab.
While changing the outlook of cancer treatment and survival, ICIs also cause specific
immune-related adverse effects (irAEs) affecting virtually all organ systems similar to
autoimmune diseases. Genetic and environmental factors predispose to IrAEs. Endocrine
irAEs are seen in up to 40% patients and amongst these thyroid is a frequent target. The
severity of IrAEs is in accordance with Common Terminology Criteria for Adverse Events
(CTCAE) (annexure)
52
Various mechanisms may underlie thyroid involvement. Expression of CTLA-4 in prolactin

and TSH secreting cells of anterior pituitary and PD-1 & PDL1 in thyroid cells may point to
the pathophysiologic mechanisms. ICI- induced endocrinopathies are irreversible in nearly
50% and may occur at any time after initiation of ICIs or even after discontinuation of
therapy. Studies suggest favorable response to ICIs in patients developing irAEs. Baseline
testing and periodic monitoring of endocrine function is recommended. Risk factors for
irAEs include dose of ICIs, combination therapy with ICIs, pre-existing autoimmune
disorders and obesity.
Additional risk factors for thyroid-related irAEs include female gender, ethnicity, raised anti-
TPO & and anti-thyroglobulin antibodies at baseline, high baseline TSH, prolonged
treatment, anti-PD-1 or anti-PD-L1 use and renal cell carcinoma. Thyroid function tests
should be measured before initiation of ICIs and then every 6-8 weeks thereafter. As irAE,
thyroid dysfunction may present as hypothyroidism, thyrotoxicosis, hyperthyroidism and
even thyroid storm. PD-L1 inhibitors, such as atezolizumab and avelumab, have a
predilection in inducing hypothyroidism, while the PD-1 and CTLA-4 inhibitors can cause
both hypothyroidism and hyperthyroidism.
Hypothyroidism, the more frequent manifestation, usually occurs in the context of

destructive thyroiditis after a variable period of subclinical or overt thyrotoxicosis. 30-40%
patients treated with anti-PD-1 or anti-PD-L1 may experience this form of thyroid
dysfunction, necessitating serial thyroid function testing. The onset is usually as grade 1 or 2
AE. Myxedema coma remains rare. Levothyroxine therapy may be initiated at lower dose in
patients with subclinical hypothyroidism. Ongoing destructive thyroiditis, monitored by
TFTs, requires frequent dose adjustment until full replacement therapy is required.
Thyrotoxicosis may occur either in the context of thyroiditis with follicular destruction or
because of autoantibody development (e.g. Graves' disease). The incidence of
hyperthyroid state with ICI use is 1-7% and appears at an average of 47 days after anti-PD-1
initiation. Graves' disease induced by ICI appears mostly at the beginning of the treatment
but onset may be delayed. Among patients with thyroiditis, the initial 3-6 weeks long phase
of thyrotoxicosis is usually followed by hypothyroidism.
Anti-thyroid receptor antibodies (TRAb) can differentiate between the two forms of
thyrotoxicosis while anti-thyroid peroxidase antibodies (anti-TPO) and anti-thyroglobulin
antibodies (anti-Tg) are seen in up to 80% patients with ICI-induced thyroid dysfunction.
Thyroid ultrasound (with comment on vascularity), scintigraphy, technetium or iodine
scanning, positron emission tomography scan (PET) with 18FDG uptake may also be used to
differentiate. Serial ultrasongraphic monitoring identifies changes in vascularity and
thyroid volume; increase indicating thyrotoxic state while shrinkage indicates fibrosis
requiring long term replacement therapy.
53
Treatment options are chosen considering the CTCAE grading. Watchful waiting is the best
strategy for asymptomatic patients. For grade 1 or 2 AEs, symptomatic treatment with beta
blockers is the best option while continuing ICIs. For grade 3 irAEs, ICI therapy should be
interrupted and oral corticosteroids (prednisolone 1-2mg/kg/day) is initiated. In patients
with grade 4 irAEs, it is advisable to give 1-2mg/kg/day intravenous methylprednisolone,
followed by oral prednisolone (1-2mg/kg/day), decreasing the dose after one month.
However, the benefits of high dose corticosteroid therapy are questionable.
Anti-thyroid therapy with methimazole or propylthiouracil may be considered in Grave's

disease. If euthyroidism is not achieved, radioiodine or thyroidectomy should be
considered. Spontaneous remission of Grave's disease without therapy is also possible.
After treatment with ICIs, thyroid eye disease (TED) may also develop with or without the
elevation of thyroid hormones. It is characterized by eye pain, conjunctival redness,
periorbital edema, proptosis and ophthalmoplegia. CTLA-4 and PD-1 gene polymorphisms
might be involved in the occurrence of TED. Mild cases are usually treated topically (e.g.,
artificial tears); more severe symptoms may require high doses of steroids.
In the index case, the patient is experiencing grade 1 irAE, so Atezolizumab therapy is to be
continued. Since the etiology of the thyrotoxic state is still not documented (thyroiditis or
Grave's disease), so initiation of anti-thyroid therapy is not indicated without further
testing. Propranolol is the beta-blocker of choice in hyperthyroidism since it also blocks the
peripheral conversion of T4 to T3. History of asthma precludes the use of propranolol.
There is ample evidence that cardio-selective beta-blockers like metoprolol and bisoprolol
are safe for use in patients with controlled mild to moderate reversible obstructive airway
disease. Switching from Bisoprolol to Diltiazem, a centrally acting non-dihydropyridine
calcium channel blocker, is unlikely to yield additional benefits. Therefore, the treatment of
patient should continue as such until further information is available.
Annexure: CTCAE Grading:
54
Common Terminology Criteria for Adverse

Table
Events Grade and Clinical Severity1
Grade Clinical severity
1 Mild; asymptomatic or mild symptoms; clinical
or diagnostic observations only; intervention
not indicated
2 Moderate; minimal, local or noninvasive
intervention indicated; limiting age-appropriate
instrumental ADL
3 Severe or medically significant but not
immediately life-threatening; hospitalization
or prolongation of hospitalization indicated;
disabling; limiting self-care ADL
4 Life-threatening consequences; urgent
intervention indicated
5 Death related to adverse event
ADL indicates activities of daily living.
References:
1. Chera A, Stancu AL, Bucur O. Thyroid-related adverse events induced by immune

checkpoint inhibitors. Frontiers in Endocrinology. 2022:2277.
2. US Department of Health and Human Services. Common Terminology Criteria for Adverse
Events (CTCAE) version 5.0. Published November 27, 2017.
55
ENDOHUB
The Pakistan Endocrine Society (PES), has undertaken a noteworthy project known as
ENDOHUB, aimed at presenting Endocrine Case Studies. This initiative by PES serves to
encourage young endocrinologists to showcase their unique endocrine cases to the
medical community, fostering a learning hub where they can exhibit their work and
learn from senior endocrinologists and colleagues.
ENDOHUB involves the selection of cases from various regions across Pakistan, followed
by a competition involving six Endocrine Fellows. Thus far, Four competitions have been
successfully organized, and Four winners have been honored with the free registration
of prestigious AACE MENA Conference.
ENDOHUB is supported by unrestricted grant from Getz pharma for all the logistics and
prize sponsorship for ENDOHUB winners.
The winners of all 4 sessions of ENDOHUB are as follows
· 1st Session Peshawar: Dr Humaira Hasnain Endocrine Fellow (Federal

Government Polyclinic Hospital, Islamabad)
nd
· 2 Session Karachi: Dr. Maria Wajid Endocrine Fellow (Aga Khan University
Hospital, Karachi)
· 3rd Session Bhurban: Dr Abrar Ali Endocrine Fellow (Aga Khan University
Hospital, Karachi)
th
· 4 Session Lahore: Dr Bushra Asif Sheikh Endocrine Fellow (Services Institute of
Medical Sciences, Lahore)
These proceedings exemplify the commitment of PES to promote professional

development, knowledge sharing, and recognition among young endocrinologists in
Pakistan.
59
Case 1
A Young Female Patient with Pregnancy and

Elbow Tuberosity Xanthomas
Presenter & Affiliation:
Dr. Muhammad Zahid Jamil

(Endocrinology Department, Jinnah Hospital, Lahore)
Case Summary
A 28-year-old female visited endocrine clinic Jinnah hospital Lahore with complaints of
tuberous swellings on both elbow tuberosities. These swellings were painless and gradually
increased in size over 1 year causing cosmetic concern to patient. Patient was having 8
months of gestation and gained significant weight over this time. Her past medical and
surgical history was unremarkable. She was not taking any medication other than folic acid
for her pregnancy.
There was no family history of such swellings. Her parents and siblings were alive and
healthy. There was no history of premature cardiovascular death or CHD in family. She was
non-smoker, non-alcoholic with a sedentary life style.
Local examination of elbows revealed multiple, large (3*3cm), non-tender, firm,

pedunculated swellings on tuberosities of both elbows as shown in picture 1.
60
On further examination, small peanut size swellings were also noted in front of both knees.
Her hands examination showed multiple small maculopapular orange colored skin lesions
in interdigital spaces and in palmar creases as shown in picture 2.
There were no features of hypothyroidism, Cushing syndrome or insulin resistance. Her

peripheral pulses were normal. There was no corneal arcus and both fundi were normal.
Workup:
Parameter Value Interpretation
Hemoglobin 13.0 g/dl 12.1-15.1
ALT 20 U/L 10-40
AST 15 U/L 20-48
Creatinine 0.8 mg/dl 0.5-1.4
Glucose (Fasting) 82mg/dl 70-99
TSH 1.8 mIU/mL 0.5-4.0
Calcium 9.0 mg/dl 8.2-10.2
Lipid profile Value Normal range

Total cholesterol 590 mg/d < 200
LDL-C 100 mg/dl < 100
HDL-C 42 mg/dl > 40
VLDL 400 mg/dl < 30
Triglycerides 480 mg/dl < 150 mg/dl
61
Management:
On the basis of typical clinical features, equimolar raised cholesterol and triglycerides and
absence of secondary causes of dyslipidemias, patient was diagnosed as familial
dysbetalipoproteinemia. Considering patient was having gestation, most of the lipids
lowering medications were contraindicated in this patient. Patient was counseled about
dietary modifications including low fat diet, moderate exercise and appropriate pregnancy
weight. Follow up was planned after gestation for any treatment modification.
Discussion:
Familial dysbetalipoproteinemia is autosomal recessive hyperlipidemia (type III)

due to Apo E lipoprotein impairing hepatic uptake of remnants of TGs rich
lipoproteins.1 It is a rare disorder of lipid metabolism with estimated prevalence of 1
2
in 10,000. Familial dysbetalipoproteinemia is associated with early onset CHD and
peripheral vascular disease. Typical clinical features include presence of orange-
tinged palmer striae and tuberous or tuberoeruptive xanthomas on elbows and
knees. Due to recessive nature of disease, a second triggering factor is usually
needed to precipitate typical biochemical abnormalities. Usual precipitating factors
include obesity, type 2 DM, hypothyroidism, beta blockers, thiazide diuretics or
OCPs. Family history is usually not present in these patients and diagnosis is
confirmed by genetic testing.
Management includes weight reduction by decreasing dietary intake of cholesterol,

fat and alcohol. Drug treatment includes fibrates or niacin in low doses or
combination in resistant cases. Some patients respond better to potent reductase
inhibitors (statins). An attempt should be made to identify contributing factors.
PCSK9 inhibitors have been described successful in recent studies.3
References:
1. Heidemann BE, Koopal C, Baass A, Defesche JC, Zuurbier L, Mulder MT, Roeters van Lennep JE, Riksen
NP, Boot C, Marais AD, Visseren FL. Establishing the relationship between familial
dysbetalipoproteinemia and genetic variants in the APOE gene. Clinical Genetics. 2022
Oct;102(4):253-61.
2. Vasanth Sathiyakumar MD, Jihwan Park MA, Peter P, Emily Brown MG, David Marais MD, Daniel Soffer
MD, Allan D, Seth S. Modern Prevalence of Dysbetalipoproteinemia (Fredrickson-Levy-Lees Type III
Hyperlipoproteinemia).
3. Busygina K, Waldmann E, Parhofer K. The Effect of PCSK9 inhibition in familial dysbetalipoproteinemia
(Type III hyperlipoproteinemia): 4 cases. Journal of the American College of Cardiology. 2018 Mar
10;71(11S):A1759-.
62
Case 2
DYSLIPIDEMIA
Dr. Javeria Javed

(MTI-Khyber Teaching Hospital, Peshawar)
Case Summary
A 22-year-old married girl presented to the emergency department with complaints of

severe epigastric pain, nausea, and vomiting. She had these symptoms for the last 3 days.
The pain was severe in onset radiating to back, not relieved with any medication. She had a
history of 3 episodes of acute pancreatitis in the last 3 years. Her father has type 2 diabetes
and one of her sisters has dyslipidemia. She has been married for the last 4 years but had no
conception.
On examination, she was pale and had a temperature of 100oF. She had tachycardia with a
pulse of 124 bpm. She had eruptive xanthoma above elbow joint. On abdominal
examination, there was moderate tenderness in the epigastrium. The rest of the systemic
examination was unremarkable.
Workup
Laboratory investigation revealed a TLC of 12.0 x 109/L, Hb 18.2 g/dl and Hct of 47%. Her
serum lipase was 527 U/L and serum amylase was 796 U/L, while serum LDH was 351 U/L
and serum corrected calcium was 7.9 mg/dl. Her lipid profile was ordered which revealed a
TGs of 928 mg/dl, total cholesterol of 1028 mg/dl, LDL-C of 25 mg/dl and HDL-C of 5 mg/dl.
Previous lipid profiles performed in the last 2 years also showed similar patterns. Her urine
R/E, fasting blood sugar, thyroid function tests and ECG were normal.
63
Considering the above clinical picture, a CT- Thorax, Abdomen and Pelvis was requested,
which revealed a bulky pancreas, with peripancreatic fluid collection extending into
bilateral paracolic gutter and a significant fat stranding was seen in surrounding mesentery.
These findings were suggestive of acute pancreatitis CTSI=7/10
Based on these findings, serum lipoprotein electrophoresis was ordered which showed
Dysbetalipoproteinemia with type III phenotype.
Discussion
Familial combined hyperlipidemia (FCHL) is generally characterized by elevations in plasma
levels of TGs (VLDL) and LDL-C. Measurement of apoB levels can help support the diagnosis
if they are substantially elevated relative to the LDL-C level including small dense LDL and
reduced plasma levels of HDL-C. Patients with FCHL have substantially elevated plasma
levels Of apoB, and high level LDL-C.
Familial chylomicronemia is a genetic deficiency or inactivity of lipoprotein lipase (LPL),

which results in impaired lipolysis and profound elevations in plasma chylomicrons, causing
familial chylomicronemia syndrome. Fasting TG levels are almost invariably >1000 mg/dL.
Fasting cholesterol levels are also elevated but to a lesser degree. Familial chylomicronemia
syndrome can be present in childhood or adulthood with recurrent episodes of severe
abdominal pain due to acute pancreatitis.
Familial hypercholesterolemia (FH) syndrome is an autosomal dominant condition and can

be present in childhood or adulthood with recurrent episodes of severe abdominal pain
due to acute pancreatitis. FH includes corneal arcus and/or tendon xanthomas, particularly
involving the dorsum of the hands and the Achilles tendons. The diagnosis of FH is generally
a clinical diagnosis based on substantial hypercholesterolemia with LDL-C >190 mg/dL in
the absence of a secondary etiology.
Familial hypertriglyceridemia (type IV familial dyslipidemia) is a disorder characterized by

the overproduction of very low-density lipoproteins (VLDL) from the liver. As a result, the
patient will have an excessive number of triglycerides and VLDL on the lipid profile that can
cause acute pancreatitis.
Familial Dysbetalipoproteinemia (also known as Type III hyperlipoproteinemia) is usually a

recessive disorder characterized by a mixed hyperlipidemia (elevated cholesterol and TGs)
due to the accumulation of remnant lipoprotein particles (chylomicron remnants and VLDL
remnants, or IDL).
64
ApoE is present in multiple copies on chylomicron remnants and IDL and mediates their
removal via hepatic lipoprotein receptors. Familial Dysbetalipoproteinemia (FDBL) is due to
genetic variants of apoE, most commonly apoE2, that result in an apoE protein with
reduced ability to bind lipoprotein receptors. The APOE gene is polymorphic in sequence,
resulting in the expression of three common Isoforms: apoE3, which is the most common;
and apoE2 and apoE4, which both differ from apoE3 by a single amino acid. Individuals who
carry one or two apoE4 alleles have an increased risk of Alzheimer's disease. ApoE2 has a
lower affinity for the LDL receptor; therefore, chylomicron remnants and IDL containing
apoE2 are removed from plasma at a slower rate. Individuals who are homozygous for the
E2 allele (the E2/E2 genotype) comprise the most common subset of patients with FDBL.
Approximately 0.5% of the general population are apoE2/E2 Homozygotes, but only a small
minority of these individuals develop hyperlipidemia characteristic of FDBL. In most cases,
an additional, sometimes identifiable, factor precipitates the development of
hyperlipoproteinemia. The most common precipitating factors are a high-fat diet, diabetes
mellitus, obesity, hypothyroidism, renal disease, HIV infection, estrogen deficiency, alcohol
use, or certain drugs. The disease seldom presents in women before menopause.
Patients with FDBL usually present in adulthood with hyperlipidemia, xanthomas, or

premature coronary or peripheral vascular disease. In FDBL, in contrast to other disorders
of elevated TGs, the plasma levels of cholesterol and TG are often elevated to a similar
degree, and the level of HDLC is usually normal or reduced. Two distinctive types of
xanthomas, tuber eruptive and palmar, are seen in FDBL patients. Tuberoeruptive
xanthomas begin as clusters of small papules on the elbows, knees, or buttocks and can
grow to the size of small grapes. Palmar xanthomas (alternatively called xanthomata Striata
palmaris) are orange-yellow discolorations of the creases in the Palms and wrists. Both
xanthoma types are virtually pathognomonic for FDBL. Subjects with FDBL have premature
ASCVD and tend to have more peripheral vascular disease than is typically seen in FH.
Initial evaluation with a fasting lipid profile should be completed. Increased total
cholesterol and increased triglyceride levels should raise suspicion. Levels of total
cholesterol and TG levels are usually within the range of 300-1000 mg/dL with an
approximate similar range or disproportionally high triglyceride, or low LDL-C levels
compared with TC. The presence of palmar xanthomas and tuberous xanthomas should
raise suspicion, as they are more commonly seen in levels >1000. Measurement of VLDL
and non-LDL are essential as well.
65
The definitive diagnosis of FDBL can be made either by the documentation of very high
levels of remnant lipoproteins or by identification of the apoE2/E2 genotype. A variety of
methods are used to identify remnant lipoproteins in the plasma, including “â-
quantification” by ultracentrifugation (ratio of directly measured VLDL-C to total plasma TG
>0.30), lipoprotein electrophoresis (broad â band), or nuclear Magnetic resonance
lipoprotein profiling. The Friedewald formula for Calculation of LDL-C is not valid in FDBL
because the VLDL particles are depleted in TG and enriched in cholesterol. The plasma
levels of LDL-C are actually low in this disorder due to defective metabolism of VLDL to LDL.
DNA-based apoE genotyping can be performed to confirm homozygosity for apoE2.
However, absence of the apoE2/E2 genotype does not strictly rule out the diagnosis of
FDBL, because other mutations in apoE can (rarely) cause this condition.
Patients with familial dysbetalipoproteinemia respond exceptionally well to dietary

therapy. Dietary therapy includes reducing saturated fat intake with replacement, including
unsaturated fat and long-chain polyunsaturated fatty acids.
Obesity is a modifiable risk factor in patients in whom reduction in weight can lead to lower
triglyceride levels. Evaluation and optimization of secondary risk factors including
hypothyroidism, type 2 diabetes mellitus and metabolic syndrome demonstrates an
improvement of triglyceride levels.
When dietary modifications are insufficient in optimizing lipid levels, statins with fibrates
are the mainstay of therapy and demonstrate an improvement in LDL levels. It is important
to focus on non-HDL cholesterol as LDL-C is usually low. Statin monotherapy leaves patients
hypercholesterolemic, and the addition of fibrates improves lipid profiles. Because FDBL is
associated with increased risk of premature ASCVD, it should be treated aggressively. Other
metabolic conditions that can worsen hyperlipidemia should be managed. Patients with
FDBL are typically diet-responsive and can respond favorably to weight reduction and to
low-cholesterol, low-fat diets. Alcohol intake should be curtailed.
Pharmacologic therapy is often required, and statins are the first line in management. In the
event of Statin intolerance or insufficient control of hyperlipidemia, cholesterol absorption
inhibitors, fibrates, and PCSK9 inhibitors are also effective in the treatment of FDBL.
66
Pharmacologic therapy is often required, and statins are the first line in management. In the
event of Statin intolerance or insufficient control of hyperlipidemia, cholesterol absorption
inhibitors, fibrates, and PCSK9 inhibitors are also effective in the treatment of FDBL.
References
1. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Harrison's principles of internal medicine,
19e. New York, NY, USA:: Mcgraw-hill; 2015.
2. Koopal C, Marais AD, Visseren FL. Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder.
Current Opinion in Endocrinology, Diabetes and Obesity. 2017 Apr 1;24(2):133-9.
3. Javvaji A, Can AS, Sharma S. Dysbetalipoproteinemia.
4. Heidemann BE, Koopal C, van Lennep JE, Stroes ES, Riksen NP, Mulder MT, Blackhurst DM, Visseren FL,
Marais AD. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol
measurement in Familial Dysbetalipoproteinemia. Clinica Chimica Acta. 2023 Jan 15;539:114-21.
5. Koopal C, Marais AD, Westerink J, van der Graaf Y, Visseren FL. Effect of adding bezafibrate to standard
lipid-lowering therapy on post-fat load lipid levels in patients with familial dysbetalipoproteinemia. A
randomized placebo-controlled crossover trial. Journal of Lipid Research. 2017 Nov 1;58(11):2180-7.
67
Case 3
PERRAULT SYNDROME
Dr. Humaira Hasnain

(Federal Government Polyclinic Hospital, Islamabad)
Case Summary
A 20 years old female, resident of Mianwali, presented to endocrine OPD in October 2022
with complaints of primary amenorrhea and absent secondary sexual characteristics. She is
the first child of healthy consanguineous parents of Pakistani origin. She was born after an
uneventful pregnancy with normal birth weight and height. Developmental milestones
were normal during childhood. At the age of 12 years hearing problem was noticed and she
started using hearing aids after audiologic evaluation. She achieved age-appropriate
weight and height but did not develop secondary sexual characteristics or had menarche.
She never sought any medical or alternative treatment for this complaint.
There was no history of anosmia, galactorrhea, headache, visual problems, excessive

exercise or psychological stress, excessive weight loss or gain, polyuria or polydipsia, other
chronic illnesses. The was also no history of acne, hirsutism, hypertension, cyclical pelvic
pain, radiation exposure, recurrent ear infections or exposure to loud noise. She had no
neurological symptoms other than hearing loss and no history of learning difficulties.
Her mother achieved puberty at the age of 14 years. She has two younger sisters and a
brother. One sister is of 14 yrs. She has age-appropriate height and signs of thelarche and
pubarche but has not achieved menarche yet. The other sister is of 12 years and has no signs
of puberty. She is being worked up for short stature. Her brother is of 17 years and has
achieved age-appropriate height & puberty. All 3 siblings have photophobia and inability to
perceive colors since birth; diagnosed as cone-rod dystrophy (an autosomal recessive
condition). Her siblings have no history of hearing problems or any other chronic illnesses.
Patient's two maternal cousins have history of primary amenorrhea but no hearing or
neurological problems reported. No history of allergies, medication use, fractures or
surgeries. She is single, student of bachelor sciences, nonsmoker, non-addict, lives in a
nuclear family unit and belongs to a low to middle socioeconomic status.
68
On examination a young girl of average built, temperature 96 F, heart Rate 80/min, BP

110/70mmHg, Height 165cm, weight 55kg, BMI: 20 kg/m2. She exhibited normal growth
parameters and no dysmorphic features. There is no evidence of acne, hirsutism, striae,
increased pigmentation or vitiligo.
Her Tanner Stage is 1 (B1-P1) with normal female external genitalia and orifices. Visual
fields are full by confrontation method. She has impaired hearing bilaterally, and rest of
neurological exam was normal. Rest of systemic examination was unremarkable.
Workup:
Normal blood sugar, TSH and prolactin. Hematological and biochemical profile was normal.
Hormonal evaluation:
LH: 32.10 mIU/ml (NR: 2.4---12.6)
FSH: 61.5 mIU/ml (NR: 3.5---12.5)
Estradiol: < 5.00 pg/ml (NR: 12.5---166)
Ultrasound pelvis revealed small sized uterus and non-visualization of bilateral ovaries.
MRI pelvis with contrast confirmed the small sized uterus and bilateral absence of ovaries,
small caliber cervix and well visualized vaginal canal.
Sagittal and axial T2 Images:
69
Cytogenetic analysis showed 46XX karyotype.

Pure tone audiometry revealed bilateral moderate to profound sensorineural hearing
loss.
70
DXA scan showed osteoporosis as evidenced by Z score of -3.7 at femoral neck

and -4.0 at L1 to L4 region.
Neck
1.6
1.4
Scan Date: 26 November 2022 - A 11262206
1.0 DXA Results Summary:
T-Score
BMD
0.8 -1.0
Region BMD T- Z-
0.6 -2.5 2
(g/cm ) score score
0.4
Neck 0.523 -3.7 -3.7
0.2
20 25 30 35 40 45 50 55 60 65 70 75 80 85
Total 0.622 -2.9 -2.9
Age
Fracture Risk
Total BMD CV 1.0%
Not Increased Increased High
WHO Classification: Osteoporosis
103 x 126 Fracture Risk: High
NECK: 49 x 15
T-score vs. White Female: Z-score vs. White Female.

Source:Hologic
L1-L4
1.6
Scan Date: 26 November 2022 - A 11262205
1.4
1.0
Region BMD T- Z-
T-Score 2
BMD
(g/cm ) score score

-1.0
0.8
L1-L4 0.584 -4.5 -4.0
-2.5
0.6
0.4
Total BMD CV 1.0%
20 25 30 35 40 45 50 55 60 65 70 75 WHO Classification: Osteoporosis
Age Fracture Risk: High
Fracture Risk
Not Increased Increased High
79 x 129
Management: Low dose oral estrogen therapy was started with 3 monthly follow up to
monitor for signs of puberty and a plan to start cyclic estrogen & progesterone after 2 years
to mimic menstrual cycle. Daily calcium and vitamin D supplements advised. We scheduled
her for routine audiologist assessments. Detailed education of patient and her parents with
advice to avoid consanguineous marriages. Molecular genetic testing of patient and her
siblings is in plan.
Discussion:
Perrault syndrome is a rare clinically and genetically heterogeneous disorder with
autosomal recessive mode of inheritance [1]. Less than 100 cases have been reported in
literature so far [2]. First cases was reported by Perrault et al. in 1951 when they described
2 sisters with a syndrome comprising sensorineural deafness and ovarian dysgenesis. The
parents were cousins, suggesting autosomal recessive inheritance [3]. Bi-allelic variants of
eight genes are associated with Perrault syndrome (CLPP, ERAL1, GGPS1, HARS2, HSD17B4,
LARS2, RMND1, and TWNK). Variants of these eight genes only account for approximately
half of the individuals with clinical features of Perrault syndrome where the molecular
genetic base remains under investigation [1]. Dysfunction of mitochondrial protein
translation is considered to be the underlying pathogenesis of most cases. [1]
71
Perrault syndrome is characterized by sensorineural hearing loss in males and females and
ovarian dysfunction in females. Sensorineural hearing loss is bilateral and ranges from mild
and clinically unrecognized to profound. Ovarian dysfunction ranges from gonadal
dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary
ovarian insufficiency (POI). Fertility in affected males is reported as normal (although the
number of reported males is limited) [2]. Since the initial clinical description of Perrault
syndrome 70 years ago, the phenotype of some subjects may additionally involve
developmental delay, intellectual deficit and other neurological disabilities, which can vary
in severity in part dependent upon the genetic variants and the gene involved [1]
Gottschalk et al. in 1996 reported an 18-year-old man with neurosensory hearing loss and
his sister with neurosensory hearing loss, ovarian dysgenesis, and mental retardation,
generalized ataxia of the trunk and limbs, and saccadic dysmetria [4].
Pierce et al. (2010) noted that clinical heterogeneity of Perrault syndrome has prompted
classification into type I, which is static and without neurologic disease, and type II, which is
with progressive neurologic disease [5].
Chen, K et al. in 2017 reported 2 sisters with Perrault syndrome in a consanguineous

Chinese Han family; the 40-year-old proband presented with cerebellar symptoms and
signs and was later found to have POI and bilateral sensory neural hearing loss. They
identified homozygous missense variant in HSD17B4 gene [6].
Neyroud, A.S. et al. in 2023 investigated two French sisters, who's only clinical complaint
was premature ovarian insufficiency. They shared one known and one novel likely
pathogenic variant in the Perrault syndrome gene, LARS2. Subsequent audiologic
assessment revealed a mild bilateral hearing loss [7].
No formal diagnostic criteria has been published so far. Perrault syndrome is suspected
based on the clinical findings of SNHL in men and women and ovarian dysfunction in
women with a 46 XX karyotype. Diagnostic suspicion is supported by a family history of
parental consanguinity. It is confirmed by the presence of bi-allelic pathogenic variants in
one of eight genes [1]. However, in 60% of individuals with Perrault syndrome identified to
date, a molecular diagnosis could not be established. [2]
Management involves a multidisciplinary team including audiologists, endocrinologists,

neurologists and geneticists. Primary amenorrhea is treated in adolescents in the usual
manner, first to induce puberty and then to mimic the menstrual cycle and maintain bone
health. Assisted reproduction through in vitro fertilization using donor eggs is a
consideration for women with gonadal dysgenesis; oocyte cryopreservation can be
considered in women at risk for POI [2].
72
It is important to evaluate the older and younger siblings of a proband in order to identify
those who would benefit from early interventions. If the pathogenic variants in the family
are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known, screening of siblings should include
audiologic assessment in males and females and baseline measurements of serum LH, FSH
and estradiol in females [2]
Ths case is from a consanguineous family with an already diagnosed autosomal recessive
disorder i.e. cone-rod dystrophy in siblings of the proband with typical features of Perrault
syndrome and a younger sister with short stature and pubertal delay. None of the siblings
were found have sensorineural hearing loss. Genetic testing in this case is likely to help in
clarifying the genotype-phenotype correlation in various presentations of Perrault
syndrome.
References:
1- Faridi, R., Rea, A., Fenollar-Ferrer, C. et al. New insights into Perrault syndrome, a clinically and
g e n e t i c a l l y h e t e r o g e n e o u s d i s o r d e r. H u m G e n e t 1 4 1 , 8 0 5 8 1 9
(2022).https://doi.org/10.1007/s00439-021-02319-7
2- Newman WG, Friedman TB, Conway GS, Demain LAM. Perrault Syndrome. In: GeneReviews®.
U n i v e r s i t y o f W a s h i n g t o n , S ea t t l e , S e a t t l e ( W A ) ; 1 9 9 3 . P M I D :
25254289.https://europepmc.org/article/NBK/nbk242617#perrault.REF.lerat.2016.1354
3- Perrault, M., Klotz, B., Housset, E. Deux cas de syndrome de Turner avec surdi-mutite dans une meme
fratrie. Bull. Mem. Soc. Med. Hop. Paris 16: 79-84, 1951.https://omim.org/entry/233400#14
4- Gottschalk, M.E., Coker, S.B. and Fox, L.A. (1996), Neurologic anomalies of Perrault syndrome. Am. J.
Med. Genet., 65: 274-276. Https://doi.org/10.1002/(SICI)1096-8628(19961111)65:4<274::AID-
AJMG5>3.0.CO;2-P
5- Pierce, S. B., Walsh, T., Chisholm, K. M., Lee, M, K., Thornton, A. M., Fiumara, A., Opitz, J. M., Levy-
Lahad, E., Klevit, R. E., King, M.-C. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian
dysgenesis, hearing loss, and ataxia of Perrault syndrome. Am. J. Hum. Genet. 87: 282-288, 2010.
[PubMed: 20673864, images] [Full Text] https://pubmed.ncbi.nlm.nih.gov/21464306/
6- Chen, K., Yang, K., Luo, SS. et al. A homozygous missense variant in HSD17B4 identified in a
consanguineous Chinese Han family with type II Perrault syndrome. BMC Med Genet 18, 91 (2017).
Https://doi.org/10.1186/s12881-017-0453-0
7- Neyroud, A.S., Rudinger-Thirion, J., Frugier, M. et al. LARS2 variants can present as premature ovarian
insufficiency in the absence of overt hearing loss. Eur J Hum Genet 31, 453460 (2023).
Https://doi.org/10.1038/s41431-022-01252-1
73
Case 4
PRIMARY ALDOSTERONISM
Dr. Fatima Qayyum

(Capital Development Authority Hospital, Islamabad)
Case Summary
A 43 years old male patient, Mr. M who is a bank officer by profession, married with 2 kids
presented to endocrine OPD as diagnosed case of resistant hypertension since 2016.
According to his history, he experienced symptoms of headache since 2016. The headache
was generalized, moderate in severity that was affecting his quality of life and workplace
performance. It did not have any association with posture or timing of the day. There was no
history of visual symptoms, memory loss, change in body appearance, skin rash and joint
pains. The patient gave history of infrequent palpitation and exertional chest tightness with
no radiation to arm, neck or jaw. He was labelled as Essential Hypertension and was started
on beta blocker and an anxiolytic then and his symptoms improved only temporarily with
the prescribed medication. The patient had regular follow ups, and during his visits had a
raised blood pressure (BP) to 160-170 mmHg systolic and 90-100mmHg diastolic, despite
changed drug regimen consisting of three antihypertensive drugs: a calcium channel
blocker (Amlodipine 10mg), Angiotensin receptor blocker ( Valsartan 160mg) and a
hydrochlorothiazide of 12.5mg. On examination he was an adult male with average adult
2
built, weight of 68kg, height of 155cm and a Body Mass Index of 28.30 kg/m . His BP was
170/120mmHg with the current medication that included 10mg amlodipine and a
doxazosin 2mg twice a day. Pulse was 70 beats/min and regular. Temperature was 98ºF. His
abdominal examination and the rest of the systemic examination was unremarkable.
74
Workup:
Investigations showed normal blood counts, renal and liver function tests. His
investigations showed repeated hypokalemia with a potassium of 3.1mg/dL. His serum
Sodium was 134mg/dL. His electrocardiographic tracing showed a left ventricular
hypertrophy. His renal Doppler ultrasound for renal artery stenosis was a normal study. His
echocardiography showed a concentric left ventricular hypertrophy and a normal ejection
fraction of 60% and stress echocardiography was negative for exercise induced ischemia.
His 24 hour urinary metanephrine levels were 5.56 ug/24hrs (N: <261). His serum
aldosterone = 21.8 ng/dL {N: Supine (1.76- 23.2) and upright (2.52-39.2)}, Plasma renin
concentration = 0.9 pg/mL (N: 2.8- 39.9). Aldosterone to renin ratio was = 24.2 ng/mcl/ml
(normal: < 3.7). He was started on verapamil, doxazosin and hydralazine to control his blood
pressure and replaced with potassium, and then his serum aldosterone and plasma renin
were repeated again.
• His serum aldosterone= 22.9ng/dl {Supine (1.76- 23.2) and upright (2.52-39.2)}
• Plasma renin concentration was 2.158 pg/mL {Supine (2.8-39.9) upright (4.4-
46.1)}
• Aldosterone to renin ratio = 10.61ng/mcl/ml (normal: < 3.7)
In the presence of resistant hypertension with hypokalemia high aldosterone, low renin
level and, high aldosterone to renin ratio, he was labelled as a case of primary
aldosteronism.
CT Scan abdomen showed a tiny well defined fat attenuated lesion measurinf 3.0X2.7mm in
the medial limb of the right adrenal gland; may represent small right adrenal lipoma/
adenoma. Mild nodular thickening of the medial limb of the left adrenal gland measuring
about 8.8mm.
The adrenal venous sampling was planned to confirm primary aldosteronism and
determine lateralization if any.
ALDOSTERONE ng/dl CORTISOL mcg/dl ALDOSTERONE/CORTISOL RATIO
LEFT ADRENAL VEIN >100 27.60 3.62
RIGHT ADRENAL VEIN 9.57 24.40 0.39
INFERIOR VENA CAVA 22.20 22.10 1.00
75
The indices were calculated as follows:
1. Selectivity Index
a. Left selectivity index = 27.60/22.10 = 1.24
b. Right selectivity index = 24.40/22.10 = 1.10
2. Lateralization Index
Left AC Ratio/Right AC Ratio = 3.62/0.39 = 9.28
3. Contralateral suppression index
CSI = Non-dominant aldosterone/cortisol ÷ IVC aldosterone/cortisol
Important Considerations:
In this case, there were several considerations before proceeding for surgery. The main
question that arise are:
1. On the basis of Adrenal venous sampling report of Mr. M, what is the next step of
management?
2. What are the confirmatory steps for hyperaldosteronism?
3. What are the various confirmatory tests?
4. How to interpret the adrenal venous sampling report on the basis of Indices?
DISCUSSION:
1. Repeat Adrenal venous sampling to confirm proper cannulation of the adrenal
veins.
2. Case confirmation In most patients, an elevated PAC with a low renin level is not
sufficient to establish the diagnosis of primary aldosteronism, which must be
confirmed by demonstrating inappropriate aldosterone secretion with one of
several tests.
The exception to the requirement for confirmatory testing is the patient with all of
the following:
· Spontaneous hypokalemia
· Suppressed PRA (<1 ng/mL/hour) or PRC (below the lower limit of the reference
range)
· PAC =20 ng/dL (555 pmol/L)
· In this clinical setting, no diagnosis other than primary aldosteronism can explain
the findings. However, for all other patients, aldosterone suppression testing is
needed.
76
3. Establish aldosterone suppression. It can be done by the following tests:

· Oral sodium loading
· Saline infusion test An alternate method to suppress endogenous aldosterone
production is by the intravenous administration of 2 L of isotonic saline over four
hours (from 8 AM to 12 PM), ideally while the patient is seated. The PAC will fall
below 5 ng/dL in healthy individuals, whereas values above 10 ng/dL are consistent
with primary aldosteronism. False-negative rates may be as high as 30 percent, but
they appear to be lower if the test is performed with the patient seated rather than
recumbent.
· Other Other available confirmation tests include the fludrocortisone suppression
and captopril challenge tests.
77
Case-detection testing for diagnosis of primary aldosteronism
Consider testing for primary aldosteronism

in patients with any of the following:
HTN and hypokalemia
Resistant HTN (three drugs and
poor BP control)
Adrenal incidentaloma and HTN
Onset of HTN at a young age (eg, <.30 years)
Severe HTN (>150 mmHg systolic BP or
>100 mmHg diastolic BP)
Whenever considering secondary HTN
Case-detection testing:
Morning blood sample in seated patient*
PAC
PRA or PRC
PAC > 10 ng/dL (>277 pmol/L) PAC <10 ng/dL (<277 pmol/L)
AND OR
PRA > 1 ng/mL/hour
PRA (<1.0 ng/mL/hour) or PRC
(less than the lower limit of normal)
Does patient have Surgically curable

spontaneous hypokalemia and primary aldosteronism
PAC > 20 ng/dL (555 pmol/L)? is unlikely
Yes No
Confirmation testing: For suspected

primary aldosteronism
24-hour urine aldosterone, sodium,
Primary creatinine on a high-sodium diet
aldosteronism OR
Fludrocortisone suppression testing
OR
Saline suppression testing
78
4. Measurement of aldosterone in samples of adrenal venous blood, obtained by an

experienced interventional radiologist, is the criterion standard test to distinguish
between unilateral adenoma and bilateral hyperplasia. Unilateral disease is
associated with a marked (usually fourfold greater than contralateral adrenal)
increase in PAC on the side of the tumor, whereas there is little difference between
the two sides in patients with bilateral hyperplasia. Calculating indices on AVS
results report:
· SELECTIVITY INDEX: Determines if adrenal vein calnnulation is done

properly
SI= Adrenal Vein Cortisol/ Inferior Vena Cava vein cortisol
Interpretation: if > 3 indicates proper cannulation of both adrenal veins
· LATERALIZATION INDEX = Determines if production is unilateral or

bilateral
LI: Dominant adrenal vein Aldosterone/cortisol ÷ Non Dominant adrenal

vein aldosterone / cortisol
Interpretation: > 4 confirms lateralization
· CONTRALATERAL SUPPRESSION INDEX: Adjunctive value to determine if

production is unilateral or bilateral.
CSI= Non-dominant aldosterone/cortisol ÷IV aldosterone/cortisol
Interpretation: < 0.5 confirms lateralization.
79
Subtype evaluation of primary aldosteronism
Subtype testing
Adrenal CT scan
Normal, micronodularity, Unilateral hypodense nodule

bilateral masses, or atypical >1 cm and <2 cm in the setting of
unilateral mass (eg, >2 cm) marked primary aldosteronism
Surgery not Surgery Surgery Surgery not

desired desired desired desired
If >35 years, If <35 years,

consider consider
AVS
No lateralization Lateralization
with AVS with AVS
APA or PAH:
IHA or GRA: Pharmacologic
Unilateral laparoscopic
Pharmacologic therapy therapy
adrenalectomy
Refer to UpToDate topic on the diagnosis of primary aldosteronism for

details.
CT: computed tomography: AVS: adrenal venous sampling: IHA:

idiopathic hyperaldosteronism: GRA: glucocorticoid-remediable
80
REFERENCES:
1. Monticone S, D'Ascenzo F, Moretti C, et al Cardiovascular events and target organ damage

in primary aldosteronism compared with essential hypertension: a systematic review and
meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41.
2. Umakoshi H, Sakamoto R, Matsuda Y et al. Role of Aldosterone and Potassium Levels in

Sparing Confirmatory Tests in Primary Aldosteronism. J Clin Endocrinol Metab.
2020;105(4)
3. Ahmed AH, Cowley D, Wolley M. et al. Seated saline suppression testing for the diagnosis of
primary aldosteronism: a preliminary study. J Clin Endocrinol Metab. 2014 Aug;99(8):2745-
53.
4. Holland OB, Brown H, Kuhnert L, et al. Further evaluation of saline infusion for the diagnosis
of primary aldosteronism. Hypertension. 1984;6(5):717.
5. Daunt N Adrenal vein sampling: how to make it quick, easy, and successful. Radiographics.
2005;25 Suppl 1:S143
6. Young WF, Stanson AW, Thompson GB, et al Role for adrenal venous sampling in primary
aldosteronism. Surgery. 2004;136(6):1227
81
Case 5
HYPOTHALAMIC PITUITARY DYSFUNCTION IN

LANGERHANS CELL HISTIOCYTOSIS
Dr. Maria Wajid

(Aga Khan University Hospital, Karachi)
Case Summary
A 30 years old female was referred to endocrinology clinic in November 2022 from oncology
with complaints of headache for 4 years associated with polyuria and polydipsia and
secondary amenorrhea. Patient had recurrent, self-healing scalp lesions with oozing of
yellowish-brown sticky material first noticed 2 years back. Systemic review was
unremarkable. There was no associated weight change, nausea, vomiting, changes in
appetite, sleep, or dizziness on standing. Previous medical and surgical history was
unremarkable except for 3 LSCS. Drug history included on and off use of combined oral
contraceptives. The examination was unremarkable with stable vital signs, no goiter,
lymphadenopathy, skin nodules, hepatosplenomegaly, or stigmata of Cushing disease.
Visual fields were normal. Breasts were Tanner 5 with no expressive galactorrhea.
Work up:
Initial blood work sodium of 154meq/l, FSH 6.36 mIU/ml (1.4-9.9), LH 4.32 mIU/ml (1.7-15),
estradiol 21.4 pg/ml (19.5-144.2), TSH uIU/ml , FT4 1.28ng/dl, 8am cortisol 14 ug /dl &
prolactin of 25.6ng/ml (monomeric 10.2ng/ml).
Serum sodium was 147mmol/l with serum osmolality of 309mosm/kg (275-300) and urine
osmolality of 242mosm/kg (50-1400).
HRCT was unremarkable. Whole body PET/CT was negative.
CT scan of head was done on 6th nov 2022 which showed extra-axial infiltrating lesion along
convexity of bilateral parietal and occipital bones with heterogeneous appearance and
erosion of adjacent bones with focal extracranial extension into the subcutaneous tissues
of scalp. It was enhancing on post contrast examination and was associated with adjacent
dural enhancement. It was sparing the brain parenchyma and was not causing any mass
effect.
82
PRECONTRAST CT
POSTCONTRAST CT
MRI pituitary with gandolinium enhancement showed thickening of pituitary stalk with
absence of the posterior pituitary bright signal. There was no mass in the
seller-suprasellar area.
83
Management:
Patient underwent neuro navigation guided biparietal craniotomy and excision of lesion on
06/09/2022. Gram staining of the lesions didn't reveal any microorganism, numerous pus
cells were seen however culture was negative. Mycobacterium tuberculosis was not
detected by gene expert. Histopathology showed fibro collagenous tissue exhibiting a
neoplastic lesion composed of sheets of Langerhans's cells. Langerhan's cells had moderate
to abundant eosinophilic cytoplasm. Immunohistochemical stains were performed, and
the neoplastic cells show following reactivity pattern:
CD1a Positive
S100 Positive
CD68 Positive
Cyclin D1 Focal Positive
Final diagnosis of Langerhans cell histiocytosis was made.

Desmopressin at a dose of 0.05mg bid was initiated with marked improvement in polyuria
and polydipsia. Patient was given Primolut N (Norethisterone) for breakthrough bleeding.
Cladribine 5mg/m2 for 5 days every 3 weekly for 6 cycles was initiated by oncologist. MRI
was repeated in February 23 with marked reduction in thickening of pituitary stalk. The rest
of the MRI changes were unchanged.
84
DISCUSSION:
Langerhans cell histiocytosis (LCH) is a rare disease characterized by aberrant proliferation
of a specific dendritic cell belonging to the monocyte- macrophage system. Infiltration of
the hypothalamic-pituitary axis (HPA) has been reported in between 550% of autopsy
patients with LCH (1). LCH is a disease of childhood and is rarely reported in adults. In adults
skin, lung, bone involvement and DI are common, whereas liver, spleen, lymph nodes, and
bone marrow are frequently involved sites in children (2). Skull vault defects particularly
involving temporal bone or orbits with intracranial tumor extension are frequently
reported(3). Diabetes insipidus (DI) is the most common endocrine abnormality, reported
in 1550% of patients with LCH . Anterior pituitary deficiency in LCH has almost always been
associated with DI ; only a few cases have been noted in the literature of pituitary hormone
insufficiency without DI (4). DI can be the initial presentation of LCH; however, it usually
develops after about 12 months of diagnosis (5).
Anterior pituitary dysfunction may also occur in the absence of structural changes on
imaging and has been attributed to microinjury leading to vascular impairment and scarring
(6). Frequently noticed abnormalities on imaging include infundibular thickening, partial or
complete empty sella with a lack of posterior pituitary bright spot on T1-weighted MRI
sequences, or a pituitary mass lesion (3).
Treatment modalities are categorized as local treatment which includes radiotherapy or

systemic therapy involving glucocorticoid and/or cytotoxic drugs. It has been suggested
that none of the treatments currently available is able to alter the course of LCH or to
prevent its progression and the established endocrine abnormalities do not respond to
treatment (7). A study by Rosenzweig et al. suggested that radiotherapy to the HPA when
applied early for incipient DI may be effective with partial or even complete remission (8).
LCH in adults may run a relatively indolent course and a more conservative approach,
especially in elderly or debilitated patients, has been proposed (9). Thus, long term follow-
up with proper replacement of hormonal deficiencies may be as important in improving
quality of life as other more aggressive interventions.
85
REFERENCES:
1. Willman, C. L., Busque, L., Griffith, B. B., Favara, B. E., McClain, K. L., Duncan, M. H., & Gilliland, D. G.
(1994). Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. The New
England journal of medicine, 331(3), 154160.
https://doi.org/10.1056/NEJM199407213310303
2. Dunger, D. B., Broadbent, V., Yeoman, E., Seckl, J. R., Lightman, S. L., Grant, D. B., & Pritchard, J. (1989).
The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis.
The New England journal of medicine, 321(17), 11571162.
https://doi.org/10.1056/NEJM198910263211704
3. Grois, N. G., Favara, B. E., Mostbeck, G. H., & Prayer, D. (1998). Central nervous system disease in
Langerhans cell histiocytosis. Hematology/oncology clinics of North America, 12(2), 287-305.
4. Tabarin, A., Corcuff, J. B., Dautheribes, M., Merlio, J. P., Cochet, C., Maire, J. P., Louail, C., & Roger, P.
(1991). Histiocytosis X of the hypothalamus. Journal of endocrinological investigation, 14(2), 139145.
https://doi.org/10.1007/BF03350286
5. Maghnie, M., Villa, A., Arico, M., Larizza, D., Pezzotta, S., Beluffi, G., Genovese, E., & Severi, F. (1992).
Correlation between magnetic resonance imaging of posterior pituitary and neurohypophyseal
function in children with diabetes insipidus. The Journal of clinical endocrinology and metabolism,
74(4), 795800.
https://doi.org/10.1210/jcem.74.4.1548343
6. Maghnie, M., Genovese, E., Aricò, M., Villa, A., Beluffi, G., Campani, R., & Severi, F. (1994). Evolving
pituitary hormone deficiency is associated with pituitary vasculopathy: dynamic MR study in children
with hypopituitarism, diabetes insipidus, and Langerhans cell histiocytosis. Radiology, 193(2),
493499.
https://doi.org/10.1148/radiology.193.2.7972767
7. Kilpatrick, S. E., Wenger, D. E., Gilchrist, G. S., Shives, T. C., Wollan, P. C., & Unni, K. K. (1995).
Langerhans' cell histiocytosis (histiocytosis X) of bone. A clinicopathologic analysis of 263 pediatric
and adult cases. Cancer, 76(12), 24712484.
https://doi.org/10.1002/1097-0142(19951215)76:12<2471::aid-cncr2820761211>3.0.co;2-z
8. Rosenzweig, K. E., Arceci, R. J., & Tarbell, N. J. (1997). Diabetes insipidus secondary to Langerhans' cell
histiocytosis: is radiation therapy indicated?. Medical and pediatric oncology, 29(1), 3640.
https://doi.org/10.1002/(sici)1096-911x(199707)29:1<36::aid-mpo7>3.0.co;2-t
9. Gadner, H., Heitger, A., Grois, N., Gatterer-Menz, I., & Ladisch, S. (1994). Treatment strategy for
disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Medical and pediatric oncology,
23(2), 7280.
https://doi.org/10.1002/mpo.2950230203
86
Case 6
ISOLATED HYPOGONADOTROPIC HYPOGONADISM

WITH PARTIAL ANDROGEN INSENSITIVITY
Dr. Sohrab Khan

(Lady Reading Hospital, Peshawar)
Case Summary
A 5 years old child brought by his/her parents to endocrinology OPD at Lady Reading
Hospital Peshawar after noticing a swelling in perineal area. There was no history of
pregnancy related complications or any hospitalization since. The child has been reared as a
female. Patient's height was 110 cm, weight 20 kg, blood pressure 100/60mmhg in both
sitting and standing positions. There was no midline defect or no pigmentation of buccal
mucosa. Genital examination revealed ambiguous genitalia with micropenis,
clitoromegaly, Pereneal hypospadias, and empty non fused labioscrotal folds.
Workup:
Investigations showed HB 12.4 gm/dl, WBC 4500/mL, platelets 250,000/mL, sodium

134mg/dL ,potassium 4.2, creatinine 0.8.Further investigation done showed karyotype 46
XY, LH 0.06 miu /ml, FSH <0.001 miu /ml, TSH 2.4 miu/ml, prolactin 160 miu/l(normal), 9 am
cortisol 15, testosterone <0.07 ng/ml(o.08 to 0.48), AMH more than 23 and 17 hydroxyl
progesterone 0.28(normal).Ultrasound pelvis showed absent uterus and ovary ,bilateral
inguinal testis( right testes 4 ml, left testes 3 ml ).HCG stimulation done and testosterone
repeated after 72 hour was 1.73 ng/ml(testosterone and DHT done from outside lab after
HCG stimulation was 400(upper limit 290) and 90(upper limit 30).MRI pituitary was
unremarkable.
87
Management:
HYPOGONADOTROPIC HYPOGONADISM WITH PARTIAL ANDROGEN INSENSITIVITY
TREATMENT:
Multidisciplinary team (MDT) involving endocrinologist, plastic surgeon, urologist,

psychiatrist.
Sex of raring.
When family wants male sex of raring,
Human Chorionic Gonadotropin (HCG) for 6 months for possible testicular decent,
increasing testicular volume and androgen
Hypospadias repair, penile reconstructive surgery and orchiopexy.
High dose testosterone at 14 years
HCG and Follicle stimulating hormone (FSH) in case fertility is desired
When family wants female sex of raring,

Bilateral orchiectomy, hypospadias repair, vaginoplasty and other reconstructive surgery
Estrogen at the age of 14 for secondary sexual characteristics.
88
Discussion:
GONADOTROPIN DEFICIENCY(ISOLATED)
Not uncommon. Congenital. Kallman syndrome. isolated defect in GNRH secretion
associated with maldevelopment of olfactory centre, anosmia, hyposmia
Autosomal dominant, recessive, sporadic KAL1,FGFR1,FGF8,PROKR2 and PROK2.
Weight loss, emotional or physical stress
Mark obesity, anorexia nervosa
Autoimmune poly glandular syndrome (autoimmune hypopysitis).
Chronic illnesses (Sickle cell anemia, poorly controlled diabetes, malnutrition).
ANDROGEN INSENSITIVITY SYNDROME(AIS)

Due to mutation in androgen receptor. More than 800 mutations have been recorded.
COMPLETE ANDROGEN INSENSITIVITY SYNDROME(CAIS)

Mutation completely abolishes androgen receptors.
Cause of DSD in completely feminized 46 XY subjects.
Patient appear as normal female at birth and come to medical attention after primary
amenorrhea (normal breast development)
Diagnosis can be made in girls when inguinal hernia contains palpable gonad(testis)or
prenatally because of discordance between genotype and phenotype.
Absent pubic and axillary hairs, short blind ended vagina, absent uterus.
Testosterone in male range, Elevated gonadotropin, Anti Mullerian Hormone (AMH) male
range.
PARTIAL ANDROGEN INSENSITIVITY SYNDROME(PAIS):

Some degree of virilization, which range from predominantly female genitalia to
phenotypic male with hypospadias, micropenis to subjects with ambiguous genitalias.
Scanty pubic axillary hair develops at puberty, gynecomatia frequent.
Testosterone, gonadotropin, AMH in male range

Testicular response to HCG stimulation is good Poor genotype, phenotype correlation.
89
Case 7
A VERY TALL BOY GIGANTISM
Dr. Tehreem Shafqat

(Services Hospital, Lahore)
Case Summary
A 9-years old boy presented to the Endocrine clinic with concerns regarding rapid increase
in height for 6 months. His parents stated that he had a normal birth and developmental
history, and had an uneventful childhood till date. However, over the past 6 months, they
noticed that he was rapidly outgrowing his clothes and shoes, and had a remarkable growth
spurt. He also complained of early morning headaches, visual deterioration and
hyperhidrosis. Family history was negative for any tumors or syndromes. The boy's height
th
was above the 97 centile for his age. He did not have any signs of pubertal onset. There was
loss of temporal field of vision in his right eye, which was later confirmed on formal visual
field testing.
For work up of his diagnosis, a few baseline investigations were ordered which came out to
be normal, following which age-matched IGF-1 levels were done, which were significantly
elevated at 1099ng/ml suggesting GH excess. It was further confirmed on 75-g OGTT which
failed to suppress GH at 2-hr interval. Rest of the pituitary hormonal profile was normal.
Following clinical and biochemical evidence, a contrast enhanced pituitary MRI was
ordered, which showed a large pituitary mass about 5.5 x 4.2 x 5.8 cm extending into the
suprasellar space and abutting the optic chiasm, invading the cavernous sinuses and
encasing ICA bilaterally.
A Multi-Disciplinary Board meeting was held and Craniotomy was planned for debulking of
the large pituitary adenoma. He underwent surgery, but developed diabetes insipidus
during the post-op recovery period and was started on intranasal desmopressin, with
recovery of his newly developed symptoms. He was referred back to the endocrinologist for
assessment of his post-op hormonal status, but was lost to follow up. He presented again to
the Endocrine clinic after 6 months with the complaints of headache, weight gain and body
90
aches. A re-evaluation of his pituitary functions showed GH excess with new findings of
hypothyroidism and hypocortisolism. Pituitary imaging revealed persistence of mass lesion
with mild ventricular dilatation. He was started on weight-based dose of Thyroxin and
physiological dose of hydrocortisone. A repeat surgery was planned in the tumor board
meeting, but was refused by the guardians, hence a radiation oncologist was involved and
stereotactic radiotherapy was arranged. After the radiotherapy, he was started on
somatostatin analog, Octreotide LAR 20 mg once a month. He took the treatment for 8
months, with regular follow up visits for dose adjustment of Thyroxin and glucocorticoids.
His recent IGF-1 levels, although supra-normal, show significant improvement at 730.4
ng/ml. Currently, his growth velocity is about 7.2cm/year, with growth along the normal
growth curve. His overall quality of life has improved and he has returned to school. Future
plans for him include life-long follow-up, psychological and hormonal support for his
gradual transition to puberty.
91
Case 8
ADIPSIC DIABETES INSIPIDUS: NAVIGATING THE

COMPLEX UNION OF POLYURIA AND ADIPSIA
Dr. Abrar Ali

(Aga Khan University hospital, Karachi)
Case Summary
45-year-old female patient who was electively admitted, under the care of the
neurosurgical team. The primary reason for her admission was the planned resection of a
suprasellar mass. The patient presented with concerning progression of symptoms of
ongoing headaches and visual blurriness that started three months before her admission.
These symptoms prompted her initial evaluation at an external healthcare facility, where
neuro-imaging revealed hydrocephalus along with a large suprasellar lesion, suspicions of
craniopharyngioma. To address her condition, the patient underwent the placement of an
external ventricular drain (EVD) as an initial measure. Furthermore, a thorough hormonal
workup confirmed the existence of multiple anterior pituitary hormone deficiencies, which
necessitated the initiation of hormone replacement therapy. In addition, the patient's
medical history includes a recent diagnosis of diabetes mellitus, managed with a basal
bolus insulin regimen. Her medication list also includes levothyroxine for thyroid hormone
replacement and hydrocortisone to address corticosteroid deficiencies. Importantly, her
Past surgical and Family history is unremarkable. On neurological examination, the patient
exhibited a bitemporal hemianopia on confrontation method, while the rest of the systemic
examination was found to be unremarkable
92
Baseline Investigations Normal values

FT4 0.83 0.89-1.76 ng/dl
TSH 0.9 miu/ml 0.4-4.2 miu/ml
IGF-1 74 .10 ng/ml 92-249 ng/dl
GH 0.12 ng/ml 2.0-5.0 ng/ml
Prolactin 27 ng/ml 3-14.7 ng/ml
Monomeric prolactin 12.0 ng/ml 3.1-13.0 ng/ml
FSH <0.3 mIU/ml 1.4-15.4 miu/ml
LH <0.07 miu/ml 1.2-7.8 miu/ml
8 am Cortisol 1.0 ug/ml 5-18 ug/ml
A solid cum cystic lesion in the

suprasellar region measuring 25 x 25 x
18 mm (CC x TR x AP) with internal foci
of calcification.
Overall findings are suggestive of
Craniopharyngioma.
It is causing mass effect on the
foramina of Monro and resulting in
ballooning of frontal horn.
93
Patient underwent transcranial resection of suprasellar lesion and Histopathology later

showed: Craniopharyngioma, WHO grade 1
Patient started to have polyuria with large volumes of urine postoperatively soon after the
surgery. (Day 0). Although pre-operatively her sodium concentrations were within normal
range (137), her sodium levels were increased (within 2 hours) after the procedure and
increased further over the next 6-8 hours in the range of 148 to 155 mmol/L and in tandem
with a low urine osmolality <130 mosm/L and higher serum osmolality > 320.
Endocrinology was involved and a diagnosis of transient DI was considered and she was
started on desmopressin 0.1 mg stat and as needed (Na>148 & U.O>200ml) along with IVF
hydration @ 125cc/hr (half strength saline) and Sodium monitoring every 6 hourly with
strict Iinput and Output charting. To which she responded well and her polyuria settled. On
Post op day 1, She started to develop polyuria again 16 hours after the first dose of
desmopressin, with a urine output of 200 mL/hour initially and 300-400 ml/hour
subsequently in later hours and her sodium concentrations up trended to 157 mmol/L.
Patient received another dose of desmopressin 0.1mg 24 hours later along with IVF
hydration with D5W bringing sodium level to 151-153 mmol/l. On Post operative Day 2,
Patient was transitioned to general care by primary neurosurgical team. Her IV fluid
discontinued and sodium turned out to be 159 mmol/l and patient had also developed
polyuria again around 14-16 hours later. Here, despite her blood investigations showing
rising sodium levels up to 159 mmol/L, patient was alert and calm this prompted to think of
adipsia and upon questioning, patient verbalized that she felt no thirst during this period of
hypernatraemia and Her oral intake documented in that period of time was only 400ml/hr
for 12 hours consistent with adipsia. A diagnosis of ADIPSIC DI was made. Hence, fluids had
to be regulated to maintain sodium balance. Patient was shifted back to special care unit
(HDU) and IVF restarted at 125 cc/hr to compensate lossess and a fixed oral fluid intake of 2-
3L was advised. Desmopressin 0.1mg once daily fixed dose started. Her sodium levels
gradually returned to 152 Meq/L. On post-operative day 3, patient started to develop
polyuria again after 12 hours of desmopressin so it was increased to 0.1mg BID. IVF
hydration discontinued plus daily water oral intake of 2.5-3 L encouraged. Her sodium levels
also remained static throughout day but peaked again during early morning hours as
patient did not take enough free water during that period of time so family was engaged in
active patient management and counselled for water balance. On Post-operative day 5,
patient was transitioned to general ward with careful monitoring of IO charting and Urine
output, which remained static and sodium levels remained well regulated. With this regime
of desmopressin, and a regulated fluid intake of around 3 L/day, her sodium concentrations
were maintained within the range of 140-150 mmol/L without major fluctuations or
cognitive symptoms and patient was discharged in stable condition.(Sodium 140 meq/l on
discharge). Patient and family was educated for water balance management.
94
Discussion:
Central diabetes insipidus (CDI) is characterized by an absent or impaired AVP release in
response to rising osmolality, leading to hypotonic polyuria. While CDI alone is uncommon,
the combination of CDI and disordered thirst is even more rare(~100 cases reported in the
literature). Two critical mechanisms help maintain normal water balance:
1) Arginine vasopressin (AVP) secretion and

2) Thirst.
The major input to both AVP production and thirst response is a change in osmolality that
results in an osmotic control within a very narrow range. Anatomically, both are located in
very close proximity within the hypothalamus.
Adipsic diabetes insipidus (ADI) proves to be challenge for clinicians. While those
individuals with intact thirst will increase water consumption to maintain eunatremia
despite relative AVP deficiency, patients with ADI are unable to sense rising osmolality and
can quickly develop severe osmolar disturbances leading to marked increases in morbidity
and mortality. Treatment success relies on close observation, frequent reassessment of
water balance, and patient and family dedication to adherence. Adipsia can be diagnosed
when thirst is absent and/or spontaneous drinking does not occur in the setting of
hypernatremia (sodium >150 mEq/L) and/or hyperosmolality (serum osmolality > 310
mOsm/kg). Again, this may be accomplished by water deprivation or a hypertonic stimulus.
Thus, it is important to obtain osmolality above that range to make the diagnosis.
Fixed DDAVP dosing is the key component to success. Doses may vary but are reported most
commonly as 100 to 250 mcg orally twice daily or 3 to 10 mcg intranasally twice daily. Fixed
DDAVP dosing is intended to achieve a daily urine output between 1.5 and 2 L. This volume
is equivalent to the obligate daily intake in most temperate climates. Eunatremia is then
achieved by varying the daily water intake based on adjustments for daily weight
changes(from a target weight while euvolemic and eunatremic). Weight gain is managed by
reducing the prescribed water-intake and weight loss by increasing intake on a 1 kg = 1 L
basis.
95
Case 9
UNCONTROLLED OSMOTIC SYMPTOMS IN TYPE 1

DIABETES MELLITUS WOLFRAM SYNDROME
Dr. Fasih Iqbal

(Hayatabad Medical Complex, Peshawar)
Case Summary
A 21-year-old patient named, Wasif khan from Afghanistan, presented to our OPD with 5
years history of poorly controlled type 1 diabetes with an HBA1C of 13 percent and RBS of
512 mg/dl, old record consistent with poor control.
He was complaining of osmotic symptoms, however every time it was attributed to his poor
glycemic control and is rational to think like that too.
However this time ,the attending doctor asked the patient in extempore about why he is
having such a bizarre control ,upon which patient reacted as if he couldn't listen properly,
after which the attending doctor immediately showed him a word to read out to check his
visual acuity ,in which the patient failed .
Work up was initiated that showed bilateral sensory neural deafness and optic atrophy
besides partial cranial diabetes insipidus on water deprivation test .Patient also had gross
deformity of urinary tract including thin walled distended ureters and bladders .
Patient was given desmopressin ,optimal hydration plan together with ophthalmic and
ocular support .
Insulin dose was titrated to his need and patient placed on long term follow up plan.
Important to note, genetic testing couldn't be performed due to economic as well as lack of
testing facility in this part of the world.
96
Laboratory Reference Ranges
Reference ranges very among laboratories. Conventional units are listed first with Sl units in parentheses.
Lipid Values Thyroid-stimulating immunoglobulin ------------------- <120% of basal activity

High-density lipoprotein (HDL) cholesterol Thyroperoxidase (TPO) antibodies -------------------- <2.0 IU/mL (<2.0 kIU/L)
Optimal ------------------------------------------- >60 mg/dL (>1.55 mmol/L) Thyroxine (T)4 (fr ee) ------------------------ 0.8-1.8 ng/dL (10.30-23.17 pmol/L)
Normal ------------------------------------ 40-60 mg/dL (1.04-1.55 mmol/L) Thyroxine (T)4 (to tal) -------------------- 5.5-12.5 µg/dL (94.02-213.68 nmol/L)
Low ------------------------------------------------ <40 mg/dL (<1.04 mmol/L) Free thyroxine (T)4 in dex ----------------------------------------------------------- 4-12
Low-density lipoprotein (LDL) cholesterol Triiodothyronine (T)3 ( free) ------------------- 2.3-4.2 pg/mL (3.53-6.45 pmol/L)
Optimal ----------------------------------------- <100 mg/dL (<2.59 mmol/L) Triiodothyronine (T)3 ( total) ------------------- 70-200 ng/dL (1.08-3.08 nmol/L)
Low ------------------------------------ 100-129 mg/dL (2.59-3.34 mmol/L) Triiodothyronine (T)3 r everse ------------------ 10-24 ng/dL (0.15-0.37 nmol/L)
Borderline-high --------------------- 130-159 mg/dL (3.37-4.12 mmol/L) Triiodothyronine uptake, resin --------------------------------------------- 25%-38%
High ------------------------------------ 160-189 mg/dL (4.14-4.90 mmol/L) Radioactive iodine uptake --- 3%-16% (6 hours); 15%-30% (24 hours)
Very high --------------------------------------- >190 mg/dL (>4.92 mmol/L)
Non-HDL cholesterol
Endocrine Values
Optimal ---------------------------------------- < 130 mg/dL (<3.37 mmol/L)
Borderline-high ---------------------- 130-159 mg/dL (3.37-4.12 mmol/L)
Serum
High -------------------------------------------- > 240 mg/dL (>6.22 mmol/L)
Aldosterone ---------------------------------------- 4-21 ng/dl (111.0-582.5 pmol/L)
Total cholesterol
Alkaline phosphatase ------------------------------ 50-120 U/L (0.84-2.00 µkat/L)
Alkaline phosphatase (bone-specific) ------------------- < 20 µg/L (adult male):
Borderline-high ---------------------- 200-239 mg/dL (5.18-6.19 mmol/L)
< 14 µg/L (premenopausal female); < 22 µg/L (postmenopausal female)
High -------------------------------------------- > 240 mg/dL (>6.22 mmol/L)
Androstenedione -------------- 65-210 ng/dL (2.27-7.33 nmol/L) (adult male);
Triglycerides
80-240 ng/dL (2.79-8.38 nmol/L) (adult female)
Antimullerian hormone ---------------------- 0.7-19.0 ng/mL (5.0-135.7 pmol/L)
Borderline-high --------------------- 150-199 mg/dL (3.88-5.15 mmol/L)
(male, > 12 years);
High ---------------------------------- 200-499 mg/dL (5.18-12.92 mmol/L)
0.9-9.5 ng/mL (6.4-67.9 pmol/L) (female, 13-45 years);
Very high------------------------------------- > 500 mg/dL (>12.95 mmol/L)
<1.0 ng/mL (<7.1 pmol/L) (female, >45 years)
Lipoprotein (a) --------------------------------------- < 30 mg/dL (<1.07 µmol/L)
Calcitonin ------------------------------- < 16 pg/mL (<4.67 pmol/L) basal, male);
Apolipoprotien B ------------------------------------ 50-110 mg/dL (0.5-1.1 g.L)
< 8 pg/mL (<2.34 pmol/L) (basal, female);
< 130 pg/mL ( <37.96 pmol/L) (peak calcium infusion, male);
Hematologic Values < 90 pg/mL ( <26.28 pmol/L) (peak calcium infusion, female);
Erythrocyte sedimentation rate -------------------------------------------- 0-20 mm/h Carcinoembryonic antigen ------------------------------- < 2.5 ng/mL (<2.5 µg/L)
Haptoglobin ------------------------------------------ 30-200 mg/dL (300-2000 mg/L) Chromogranin A ----------------------------------------------- <93 ng/mL (<93 µg/L)
Hematocrit ----------------------------------------------41 %-50% (0.41-0.51) (male); Corticosterone --------------- 53-1560 ng/dL (1.53-45.08 nmol/L) (>18 years)
35%-45% (0.35-0.45) (female) Corticotropin (ACTH) ----------------------------- 10-60 pg/mL (2.2-13.2 pmol/L)
Hemoglobin A1c ---------------------------------------- 4.0%-5.6% (20-38 mmol/mol) Cortisol (8 AM) ----------------------------------- 5-25 µg/dL (137.9-689.7 nmol/L)
Hemoglobin ------------------------------------ 13.8-17.2 g/dl (138-172 g/L) (male); Cortisol (4 AM) ------------------------------------ 2-14 µg/dL (55.2-386.2 nmol/L)
12.1-15.1 g/dL (121-151 g/L) (female) C-peptide ----------------------------------------- 0.9-4.3 ng/mL (0.30-1.42 nmol/L)
International normalized ratio --------------------------------------------------- 0.8-1.2 C-reactive protein ------------------------------ 0.8-3.1 mg/L (7.62-29.52 nmol/L)
Mean corpuscular volume (MCV) ------------------------ 80-100 µm3(80 -100 fL) Cross-linked N-telopeptide of type 1 collagen --------------------------------------
3 9
Platelet count ----------------------------------- 150-450 x 10/µL (150-450 x 10/L ) 5.4-24.2 nmol BCE/mmol creat (male);
Protein (total) -------------------------------------------------- 6.3-7.9 g/dL (63-79 g/L) 6.2-19.0 nmol BCE/mmol creat (female)
Reticulocyte count ------------------ 0.5%-1.5% of red blood cells (0.005-0.015) Dehydroepiandrosterone sulfate (DHEA-S)
9
White blood cell count -------------------------- 4500-11,000/µL (4.5-11.0 x 10/L) Patient Age Female Male
18-29 years 44-332 µg/dL 89-457 µg/dL
Thyroid Values (1.19-9.00 µmol/L (2.41-12.38 µmol/L)
Thyroglobulin --- 3-42 ng/mL (3-42 pg/L) (after surgery and radioactive 30-39 years 31-228 µg/dL 65-334 µg/dL
iodine treatment: <1.0 ng/mL [<1.0 µg/L]) (0.84-6.78 µmol/L (1.76-9.05 µmol/L)
Thyroglobulin antibodies ---------------------------------- < 4.o IU/mL (<4.0 klU/L) 40-49 years 18-244 µg/dL 48-244 µg/dL
Thyrotropin (TSH) ------------------------------------------------------ 0.5-5.0 mlU/L (0.49-6.61 µmol/L (1.30-6.61 µmol/L)
97
Patient Age Female Male Patient Age Female Male
50-59 years 15-200 µg/dL 35-179 µg/dL 26-30 years 117-321 ng/mL 117-321 ng/mL
(0.41-5.42 µmol/L) (0.95-4.85 µmol/L) (15.3-42.1 nmol/L) (15.3-42.1 nmol/L)
> 60 years (15-157 µg/dL) 25-131 µg/dL 31-35 years 113-297 ng/mL 113-297 ng/mL
(0.41-4.25 µmol/L) (0.68-3.55 µmol/L) (14.8-38.9 nmol/L) (14.8-38.9 nmol/L)
Deoxycorticosterone ----------- < 10 ng/dL (<0.30 nmol/L) (>18 years) 36-40 years 106-277 ng/mL 106-277 ng/mL
1,25-Dihydroxyvitamin D3 ----------- 16-65 pg/mL (41.6-169.0 pmol/L) (13.9-36.3 nmol/L) (13.9-36.3 nmol/L)
Estradiol ----------------------- 10-40 pg/mL (36.7-146.8 pmol/L) (male); 41-45 years 98-261 ng/mL 98-261 ng/mL
10-180 pg/mL (36.7-660.8 pmol/L) (folicular, female); (12.8-34.2 nmol/L) (12.8-34.2 nmol/L)
100-300 pg/mL (367.1-1101.3 pmol/L) (midcycle, female); 46-50 years 91-246 ng/mL 91-246 ng/mL
40-200 pg/mL (146.8-734.2 pmol/L) (luteal, female); (11.9-32.2 nmol/L) (11.9-32.2 nmol/L) .
<20 pg/mL (<73.4 pmol/L) (postmenopausal, female) 51-55 years 84-233 ng/mL 84-233 ng/mL
Estrone ------------------------ 10-60 pg/mL (37.0-221.9 pmol/L) (male); (11.0-30.5 nmol/L) (11.0-30.5 nmol/L)
17-200 pg/mL (62.9-739.6 pmol/L) (premenopausal female); 56-60 years 78-220 ng/mL 78-220 ng/mL
7-40 pg/mL (25.9-147.9 pmol/L) postmenopausal female) (10.2-28.8 nmol/L) (10.2-28.8 nmol/L)
a-Fetoprotein --------------------------------------------- <6 ng/mL (<6 µg/L) 61-65 years 72-207 ng/mL 72-207 ng/mL
(9.4-27.1 nmol/L) (9.4-27.1 nmol/L)
Follicle-stimulating hormone (FSH) -------------------------------------------
66-70 years 67-195 ng/mL 67-195 ng/mL
1.0-13.0 mlU/mL (1.0-13.0 IU/L) (male);
(8.8-25.5 nmol/L) (8.8-25.5 nmol/L)
<3.0 mIU/mL (<3.0 IU/L) (prepuberty, female);
71-75 years 62-184 ng/mL 62-184 ng/mL
2.0-12.0 mIU/mL (2.0-12.0 IU/L) follicular, female);
(8.1-24.1 nmol/L) (8.1-24.1 nmol/L)
4.0-36.0 mIU/mL (4.0-36.0 IU/L) (midycycle, female);
76-80 years 57-172 ng/mL 57-172 ng/mL
1.0-9.0 mIU/mL (1.0-9.0 IU/L) (Iuteal, female);
(7.5-22.5 nmol/L) (7.5-22.5 nmol/L)
>30 mlU/mL (>30 IU/L) (postmenopausal, female)
>80 years 53-162 ng/mL 53-162 ng/mL
Free fatty acids ------------------------ 10.6-18.0 mg/dL (0.4-0.7 nmol/L)
(6.9-21.2 nmol/L) (6.9-21.2 nmol/L)
Gastrin ----------------------------------------------- <100 pg/mL (<100 ng/L)
Growth hormone (GH) --- 0.01-0.97 ng/mL (0.01-0.97 (µg/L) (male); Insulinlike growth factor binding protein 3 -------------------------- 2.5-4.8 mg/L
0.01-3.61 ng/mL (0.01-3.61 µg/L) female) Insulin --------------------------------------------1.4-14.0 µlU/mL (9.7-97.2 pmol/L)
Homocysteine ----------------------------------- < 1.76 mg/L (< 13 umol/L) Islet-cell antibody assay ---------------- 0 Juvenile Diabetes Foundation units
ß-Human chorionic gonadotropin (b-hCG) ---------------------------------- Luteinizing hormone (LH) -------------- 1.0-9.0 mlU/mL (1.0-9.0 IU/L) (male);
<3.0 mIU/mL (<3.0 IU/L) nonpregnant female); <1.0 mIU/mL (<1.0 IU/L) (prepuberty, female);
>25 mIU/mL (>25 IU/L) indicates a positive pregnancy test 1.0-18.0 mIU/mL (1.0-18.0 IU/L) (follicular, female);
20.0-80.0 mIU/mL (20.0-80.0 IU/L) (midcycle, female);
ß-Hydroxybutyrate ----------------------------- <3.0 mg/dL (<300 µmol/L)
0.5-18.0 mIU/mL. (0.5-18.0 IU/L) (luteal, female);
17-Hydroxypregnenolone ------------ 29-189 ng/dL (0.87-5.69 nmol/L)
>30 mIU/mL (>30 IU/L) (postmenopausal, female)
17a-Hydroxyprogesterone---<220 ng/dL (<6.67 nmol/L) (adult male);
Metanephrines (plasma fractionated)
<80 ng/dL (<2.42 nmol/L) (follicular, female);
Metanephrine ----------------------------------------------<57 pg/mL (<289 pmol/L)
<285 ng/dL (<8.64 nmol/L) (Iuteal, female);
Normetanephrine--------------------------------------- <148 pg/mL (<808 pmol/L)
<51 ng/dL (1.55 nmol/L) postmenopausal, female)
75-g oral glucose tolerance test -- 60-100 mg/dL (3.3-5.6 mmol/L) (fasting)
25-Hydroxyvitamin D -- < 10 ng/mL (<25.0 nmol/L) (Severe deficiency);
Blood glucose values ---------<200 mg/dL (<11.1 mmol/L) (1 hour);
10-24 ng/mL (25.0-59.9 nmol/L) (mild to moderate deficiency);
<140 mg/dL (<7.8 mmol/L) (2 hour)
25-80 ng/mL (62.4-199.7 nmol/L) (optimum levels);
Between 140-200 mg/dL (7.8-11.1 mmol/L) is considered
>80 ng/mL (>199.7 nmol/L) toxicity possible)
impaired glucose tolerance or prediabetes. Greater than
inhibin B ---------------------------------------- 15-300 pg/mL (15-300 ng/L)
200 mg/dL (11.1 mmol/L) is a sign of diabetes mellitus.
Insulinlike growth factor 1 (IGF-1)
50-g oral glucose tolerance test for gestational diabetes ------------------------
Patient Age Female Male
<140 mg/dL (<7.8 mmol/L) (1 hour)
18 years 162-541 ng/mL 170-640 ng/mL
100-g oral glucose tolerance test for gestational diabetes ----------------------
(21.2-70.9 nmol/L) (22.3-83.8 nmol/L)
<95 mg/dL (<5.3 mmol/L) (fasting);
19 years 138-442 ng/mL 147-527 ng/mL
<180 mg/dL (<10.0 mmol/L) (1 hour);
(18.1-57.9 nmol/L) (19.3-69.0 nmol/L)
<155 mg/dL (<8.6 mmol/L) (2 hour);
20 years 122-384 ng/mL 132-457 ng/mL
<140 mg/dL (<7.8 mmol/L) (3 hour)
(16.0-50.3 nmol/L) (17.3-59.9 nmol/L)
Osteocalcin -----------------------------------------9.0-42.0 ng/mL (9.0-42.0 pg/L)
21-25 years 116-341 ng/mL 116-341 ng/mL
Parathyroid hormone, intact (PTH)------------------ 10-65 pg/mL (10-65 ng/L)
(15.2-44.7 nmol/L) (15.2-44.7 nmol/L)
Parathyroid hormone-related protein (PTHrP) 14-27 pg/mL (14-27 ng/L)
98
Progesterone --------------------------------- <1.2 ng/mL (<3.8 nmol/L) (male); Creatinine ----------------------- 0.7-1.3 mg/dL (61.9-114.9 µmol/L) (male);
<1.0 ng/mL (s3.2 nmol/L) (follicular, female); 0.6-1.1 mg/dL (58.0-97.2 µmol/L) (female)
2.0-20.0 ng/mL (6.4-63.6 nmol/L) (luteal, female); Ferritin-------------------------------------- 15-200 ng/mL (33.7-449.4 pmol/L)
<1.1 ng/mL (<3.5 nmol/L) (postmenopausal, female); Folate ------------------------------------------------------>4.0 ng/mL (24.0 pg/L)
Glucose ----------------------------------------- 70-99 mg/dL (3.9-5.5 mmol/L)
>10.0 ng/mL (>31.8 nmol/L) (evidence of ovulatory adequacy)
y-Giutamyltransferase ----------------------------2-30 U/L (0.03-0.50 µkat/L)
Proinsulin -----------------------------------26.5-176.4 pg/mL (3.0-20.0 pmol/L)
Iron ----------------------------------- 50-150 µg/dL (9.0-26.8 µmol/L) (male);
Prolactin --------------------------------- 4-23 ng/mL (0.17-1.00 nmol/L) (male);
35-145 µg/dL (6.3-26.0 µmol/L) (female)
4-30 ng/mL (0.17-1.30 nmol/L) (nonlactating female); Lactate dehydrogenase ----------------------- 100-200 U/L (1.7-3.3 µkat/L)
10-200 ng/mL (0.43-8.70 nmol/L) (lactating female) Lactic acid ----------------------------------- 5.4-20.7 mg/dL (0.6-2.3 mmol/L)
Prostate-specific antigen----------------<2.0 ng/mL (<2.0 ug/L) (<40 years); Lipase ---------------------------~----------------- 10-73 U/L (0.17-1.22 µkat/L)
<2.8 ng/mL (<2.8 µg/L) (<50 years); Magnesium ----------------------------------- 1.5-2.3 mg/dL (0.6-0.9 mmol/L)
<3.8 ng/mL (<3.8 µg/L) (<60 years); Osmolality ----------------------------275-295 mOsm/kg (275-295 mmol/kg)
<5.3 ng/mL (<5.3 µg/L) (<70 years); Phosphorus -----~-----------------------------2.3-4.7 mg/dL (0.7-1.5 mmol/L)
Potassium -------------------------------------3.5-5.0 mEq/L (3.5-5.0 mmol/L)
<7.0 ng/mL (<7.0 µg/L) (<79 years);
Prothrombin time-------------------------------------------------------- 8.3-10.8 s
<7.2 ng/mL (<7.2 µg/L) (>80 years)
Serum urea nitrogen -------------------------- 8-23 mg/dL (2.9-8.2 mmoi/L)
Renin activity, plasma, sodium replete, ambulatory -- 0.6-4.3 ng/mL per h
Sodium ------------------------------------- 136-142 mEq/L (136-142 mmol/L)
Renin, direct concentration -------------------- 30-40 pg/mL (0.7-1.0 pmol/L) Transferrin saturation --------------------------------------------------- 14%-50%
Sex hormone-binding globulin------- 1.1-6.7 µg/mL (10-60 nmol/L) (male); Troponin | ------------------------------------------------- <0.6 ng/mL (<0.6 µg/L)
2.2-14.6 µg/mL (20-130 nmol/L) (female) Tryptase ------------------------------------------------< 11.5 ng/mL (<11.5 µg/L)
a-Subunit of pituitary glycoprotein hormones-------<1.2 ng/mL (<1.2 µg/L) Uric acid -----------------------------------3.5-7.0 mg/dL (208.2-416.4 µmol/L)
Testosterone (bioavailable)------------------0.8-4.0 ng/dl. (0.03-0.14 nmol/L) Urine
(20-50 years, female on oral estrogen); Albumin ------------------------ 30-300 µg/mg creat (3.4-33.9 µg/mol creat)
Albumin-to-creatinine ratio ------------------------------------- <30 mg/g creat
0.8-10.0 ng/dL (0.03-0.35 nmol/L)
Aldosterone -------------------------------------3-20 µg/24 h (8.3-55.4 nmol/d)
(20-50 years, female not on oral estrogen);
(should be <12 µg/24 h [<33.2 nmol/d] with oral sodium loading—
83.0-257.0 ng/dL (2.88-8.92 nmol/L) (male 20-29 years);
confirmed with 24-hour urinary sodium >200 mEq)
72.0-235.0 ng/dL (2.50-8.15 nmol/L) (male 30-39 years);
Calcium ------------------------------------ 100-300 mg/24 h (2.5-7.5 mmol/d)
61.0-213.0 ng/dL (2.12-7.39 nmol/L) (male 40-49 years); Catecholamine fractionation
50.0-190.0 ng/dL (1.74-6.59 nmol/L) (male 50-59 years): Normotensive normal ranges:
40.0-168.0 ng/dL. (1.39-5.83 nmol/L) (male 60-69 years) Dopamine -------------------------- <700 µg/24 h (<4567 nmol/d)
Testosterone (free) ---------------- 9.0-30.0 ng/dL (0.31-1.04 nmol/L) male): Epinephrine --------------------------- <35 µg/24 h (<191 nmol/d)
0.3-1.9 ng/dL (0.01-0.07 nmol/L) (female) Norepinephrine--------------------- <170 µg/24 h (<1005 nmol/d)
Testosterone (total) -------------- 300-900 ng/dL (10.4-31.2 nmol/L) (male); Cortisol--------------------------------------------- 4-50 µg/24 h (11-138 nmoi/d)
Cortisol following dexamethasone suppression test --------- <10 µ9/24 h
8-60 ng/dL (0.3-2.1 nmol/L) (female)
(<27.6 nmol/d) (low-dose: 2 day, 2 mg daily)
Vitamin B12 ---------------------------------------- 180-914 pg/mL (180-914 ng/L)
Creatinine ------------------------------ 1.0-2.0 g/24-h (8.8-17.7 mmol/d}
Chemistry Values Glomerular filtration rate (estimated) ---------- >60 mL/min per 1.73 m2
Alanine aminotransferase ----------------------- 10-40 U/L (0.17-0.67 µkat/L) 5-Hydroxyindole acetic acid -----------2-9 mg/24 h (10.5-47.1 µmol/d)
Albumin ----------------------------------------------------- 3.5-5.0 g/dL (35-50 g/L) lodine (random)-----------------------------------------------—------- >100 µg/L
Amylase -------------------------------------------- 26-102 U/L (0.43-1.70 µkat/L) 17-Ketosteroids -----------6.0-21.0 mg/24 h (20.8-72.9 µmol/d) (male);
Aspartate aminotransferase -------------------- 20-48 U/L (0.33-0.80 µkat/L) 4.0-17.0 mg/24 h (13.9-59.0 µmol/d) (female)
Metanephrine fractionation
Bicarbonate -----------------------------------------21-28 mEq/L (21-28 mmol/L)
Metanephrine -------------------------- <400 µg/24 h (<2028 nmol/d)
Bilirubin (total) -------------------------- 0.3-1.2 mg/dL (5.1-20.5 µmoi/L)
Normetanephrine --------------------- <900 µg/24 h (<4914 nmol/d)
Blood gases
Total metanephrine ----------------- <1000 µg/24 h (<5260 nmol/d)
Po,2 art erial blood ------------------------- 80-100 mm Hg (10.6-13.3 kPa) Osmolality ----------------------- 150-1150 mOsm/kg (150-1150 mmol/kg)
Pco2, arterial blood -----------------------------35-45 mm Hg (4.7-6.0 kPa) Oxalate --------------------------------------------<40 mg/24 h (<456 mmol/d)
Blood pH------------------------------------------------------------------------ 735-745 Phosphate ------------------------------- 0.9-1.3 g/24 h (29.1-42.0 mmoi/d)
Calcium ----------------------------------------- 8.2-10.2 mg/dL (2.1-2.6 mmol/L) Potassium ----------------------------------17-77 mEQ/24 h (17-77 mmol/d)
Calcium (ionized) --------------------------- 4.60-5.08 mg/dL (1.2-1.3 mmol/L) Sodium ------------------------------------- 40-217 mEq/24 h (40-217 mmol/d)
Uric acid ------------------------------------------- <800 mg/24 h (<4.7 mmol/d)
Carbon dioxide -------------------------------------22-28 mEq/L (22-28 mmol/L)
9
Saliva
CD4cel l count ------------------------------------- 500-1400/µL (0.5-1.4 x 10 /L)
Cortisol (salivary), midnight ---------------------- <0.13 µg/dL (<3.6 nmol/L
Chloride ------------------------------------------ 96-106 mEq/L (96-106 mmol/L) Semen
Creatine kinase -----------------------------------50-200 U/L (0.84-3.34 µkat/L) Semen analysis -------------------- > 20 million sperm/mL: >50% motility
99
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Pakistan Endocrine Society

Pakistan Endocrine Cases Collection (PECC) 2023

Dr. Mussarat Riaz Dr. Urooj Lal Rehman

Dr. Sidrah Lodhi Dr. Saima Askari

Dr. Erum Sohail Dr. Nadeem Naeem

Dr. Shaista Kanwal Dr. Tejhmal Rehman

Dr. Nasir Siddique

The Pakistan Endocrine Society is Pakistan’s eminent and active organization

Visit us at: www.pakendosociety.org

Request for permission of publication should be directed to the Endocrine Society

Dr. Ibrar Ahmed

Science of Endocrinology, encompass numerous physiological processes, which is

Endocrinology encompass clinical chalanges from delicate balance of insulin which

Therefore, whether you are an experienced endocrinologist looking to broaden your

Dr. S. Abbas Raza

Primary Hyperparathyroidism with Maxillary and

(National Institute of Diabetes and Endocrinology, DUHS, Karachi)

On examination: BP:109/63mmHg, Pulse:84/min, Height:149cm, Weight:49kg

Corrected serum calcium: 12.3mg/dl (8.6-10.2mg/dl)

¡ Ultrasound neck showed a well-defined homogenous lesion inferior to the right

¡ Parathyroid scintigraphy showed a functioning parathyroid adenoma over lower

A. Left maxillary swelling

Q: What is most likely diagnosis in this patient?

Answer: (a) Primary Hyperparathyroidism

Radiographic features described in hyperparathyroidism are mainly beacuse to bone

Brown tumors are one of the most pathognomonic features of primary

A Case of Charcot Neuro Arthropathy

Dr. Saima Askari

Dr. Musarrat Riaz

(Baqai Institute of Diabetology and Endocrinology, Karachi Pakistan)

Date Tests name Results Reference range

Hb: 12.2 g/dl 11.1-13.8 g/dl

5/10/22 Serum Electrolytes

Sodium: 140 mEq/L 136-145 mEq/L

5/10/22 Serum Creatinine: 0.73mg/dl 0.6-1.1mg/dl

5/10/22 HBA1C: 10.6%

5/10/22 TSH: 2.2mIU/ml 0.4-4.2mIU/ml

Q. Charcot joint in seen in all of the following conditions except:

The classical clinical presentation of an acute CN is a red/pink/dark (depending on skin

STAGES OF CHARCOT FOOT

Stage 0 Stage 1 Stage 2 Stage 3

Swelling Debris formation at Lessening of edema Further repair and

Resorption of bone Repair

3. Harris A, Violand M. Charcot neuropathic osteoarthropathy (Charcot joint). StatPearls [Internet]

Case of Immune Mediated Diabetes,

Dr. Erum Sohail Dr. Inshirah Rana

Dr. Fahmeeda Jan Dr. Tazeen Khalid

(Jinnah Postgraduate Medical Centre JPMC, Karachi)

How will you classify her according to recent classification?

Autoimmunity seems to be the first pathological factor in LADA. Although T1D is

A case of 46XX Congenital Adrenal Hyperplasia

Dr. Urooj Lal Rehman

(Jinnah Postgraduate Medical Centre JPMC, Karachi)

His hormonal Profile showed

Testosterone: 13.50 nmol/L (0.52-2.43)

Karyotype was 46XX

What is the next best step in the management of this patient?

The virilizing form of 21-hydroxylase CAH comprises of a whole spectrum of virilization in

(A) As the patient is fully androgenized, both phenotypically and biochemically,