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Case Study Obesity
MC4R Mutation in Early-onset Severe
Correlation Shweta Birla, 1 Deepak Khandelwal, 2 Arundhati Sharma, 1 and Rajesh Khadgawat 3
1. Laboratory of Cytomolecular Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India; 2. Department of Diabetes
and Endocrinology, Maharaja Agrasen Hospital, Punjabi Bagh, New Delhi, India; 3. Department of Endocrinology and Metabolism, All India Institute of
Medical Sciences, New Delhi, India
M elanocortin-4 receptor (MC4R; OMIM#155541) encodes a 332-amino acids protein possessing typical G-protein-coupled receptors'
(GPCRs) structural design having three intact and functional domains, mutations which lead to the most recurrent type of monogenic
obesity. Methods: We report here a case of a 5-year-old boy from Iraq who presented to the clinic for evaluation of progressive weight
gain since he was 6 months of age. There were no symptoms of hypothalamic dysfunction except increase in appetite. His height was 120 cm
(97th centile of the Centers for Disease Control and Prevention [CDC] growth chart, mid parental height was 50th centile), weight was 57 kg (>97th
centile on CDC chart) and body mass index was 39.6 kg/m 2 (>97th centile on CDC chart). A monogenic cause of obesity was strongly suspected
in view of early onset severe childhood obesity. Results: Mutation screening of MC4R revealed a homozygous isoleucine by arginie at codon 69
(I69R) mutation in the patient, while his father was heterozygous for this mutation. Conclusion: We describe a monogenic form of obesity with
characteristic presentation due to I69R MC4R mutation inherited as an autosomal recessive condition. The finding is different from previous
reports which have documented this mutation to be inherited in a dominant manner. The findings of the present study reiterate the complex
nature of obesity with possible involvement of modifier genes and/or genetic heterogeneity in its causation.
Keywords Monogenic obesity, melanocortin-4 receptor
(MC4R) , hypothalamic obesity, childhood
onset obesity, mutation, screening
Disclosure: Shweta Birla, Deepak Khandelwal,
Arundhati Sharma, and Rajesh Khadgawat have
nothing to declare in relation to this article. No funding
was received in the publication of this article.
Compliance with Ethics: All procedures were followed
in accordance with the responsible committee on human
experimentation and with the Helsinki Declaration of 1975
and subsequent revisions, and informed consent was
received from the patient involved in this case study.
Authorship: All named authors meet the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, take responsibility
for the integrity of the work as a whole, and have given
final approval to the version to be published. Shweta
Birla and Deepak Khandelwal contributed equally.
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any noncommercial use, distribution,
adaptation, and reproduction provided the original
author(s) and source are given appropriate credit.
Received: August 18, 2017
Accepted: October 16, 2017
Citation: US Endocrinology, 2017;13(2):69–71
Corresponding Author: Arundhati Sharma, Department
of Anatomy, All India Institute of Medical Sciences,
New Delhi, India. E: firstname.lastname@example.org
TOU CH MED ICA L MEDIA
Obesity is a complex and multifactorial condition caused by various behavioral and environmental
factors, socioeconomic background, and genetic susceptibility. The leptin-melanocortin system has
a well-established role in energy homeostasis and deficiencies of the vital molecules of the pathway
due to defects in the genes encoding those results into a monogenic form of obesity. 1
The most recurrent type of monogenic obesity is caused by mutations in the gene that codes for
the melanocortin-4 receptor (MC4R). Expressed primarily in neurons, MC4R is a G protein-coupled
receptor and is known to mediate the anorexigenic effects of leptin, reducing food intake and
increasing energy expenditure. It responds to α-melanocyte-stimulating hormone (α-MSH) an agonist
leading to initiation of receptor activity and restraining food intake, whereas sensitizing with an
antagonist agouti-related peptide (AgRP) has the reverse effect. 2 We report here a case of severe
early-onset childhood obesity due to homozygous I69R MC4R mutation.
Materials and methods
A 5-year-old boy from Iraq presented to the clinic for evaluation of progressive weight gain since
the age of 6 months (Figure 1A). He was a product of consanguineous marriage and his perinatal
history was unremarkable. Developmental milestones were appropriate for his age and there
were no symptoms suggestive of neuro-developmental abnormalities. There were no symptoms
of hypothalamic dysfunction, except increase in appetite, and no family history of morbid obesity
except for type 2 diabetes (T2D) in one of his maternal uncles. His father’s height and weight was
171 cm and 82 kg, respectively. His mother’s height and weight was 165 cm and 60 kg, respectively.
His height was 120 cm (97th centile of the Centers for Disease Control and Prevention [CDC] growth
chart, midparental height 50th centile), weight was 57 kg (>97th centile on CDC chart), and body
mass index (BMI) was 39.6 kg/m 2 (>97th centile on CDC chart). Blood pressure was 80/52 mmHg
(right arm in sitting position). On examination he was prepubertal and had acanthosis over the
neck and axillary region. Hemogram, renal function test, and serum electrolytes were within
the normal range. Liver function test showed evidence of transaminitis (Table 1). Tests were negative
for hepatitis B surface antigen (HBsA) and anti-hepatitis C virus (HCV) antibodies. Ultrasonography