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Case Study Obesity MC4R Mutation in Early-onset Severe Childhood Obesity—Genotype–phenotype 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: arundhatisharma1@gmail.com 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 Case presentation 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 69