ESPE Abstracts (2015) 84 P-2-200

ESPE2015 Poster Category 2 Adrenals (38 abstracts)

A Novel Mutation (c.delG209) in the Proopiomelanocortin Gene in a Child with Early-onset Obesity

Semra Cetinkaya a , Tulay Guran b , Erdal Kurnaz a , Meliksah Keskin a , Elif Sagsak a , Senay Savas Erdeve a , Federica Buonocore c & Zehra Aycan a,

aDr Sami Ulus Obstetrics and Gynecology, Clinics of Pediatric endocrinology, Children’s Health and Disease Training and Research Hospital, Ankara, Turkey; bMarmara University Faculty of Medicine, Clinics of Pediatric Endocrinology, Istanbul, Turkey; cGenetics and Genomic Medicine, UCL Institute of Child Health, University College London, London, UK; dYildirim Beyazit University, Faculty of Medicine, Clinics of Pediatric endocrinology, Ankara, Turkey

Background: Proopiomelanocortin (POMC) deficiency is characterized by early-onset obesity, adrenal failure, red hair and pale skin. The first genetic mutation in the POMC gene was demonstrated in 1998. This disorder is rare, but has increased our insight into the important role of the leptin-melanocortin pathway in energy balance. POMC deficiency causes obesity due to the inadequate production of alpha and beta MSH from POMC, which normally activate the melanocortin 3 receptor (MC3R) in the arcuate nucleus and the melanocortin 4 receptor (MC4R) in the paraventricular nucleus and antagonize the action of agouti-related peptide (AgRP). The hypocortisolism and hypopigmentation are due to inadequate stimulation of MC2R and MC1Rs by POMC-derived peptides in the adrenal gland and skin, respectively.

Case presentation: The patient presented at 2 months with cyanosis and convulsions after 4 h of fasting. Her blood sugar was 31 mg/dl. She was born to non-consanguineous healthy parents after an uneventful 39-week pregnancy with a birth weight of 3 000 g. Physical examination revealed a weight of 3 700 gr (<3rd percentile), height of 51 cm (<3rd percentile) and red hair. There was no clinical or laboratory evidence of infection and she was admitted for blood sugar monitoring. Blood glucose level was 20 mg/dl, insulin 0.11 μIU/ml, ACTH <5 pg/ml and cortisol <0.2 μg/dl. The peak cortisol response during standard dose ACTH stimulation test was 0.44 μg/dl. Hydrocortisone treatment was initiated for secondary adrenal failure. There was no hypoglycemia under treatment. At 12 months, the patient’s weight was 12 kg (1.99 SDS), height 76 cm (0.29 SDS) and the BMI 20.78 kg/m2 (2.21 SDS) while these values at 15 months were 14.7 kg (+2.5 SDS), 83 cm (+0.24 SDS), and 22.4 kg/m2 (+2.9 SDS) respectively. A novel homozygous c.delG209 mutation was found causing a frameshift at codon 69 (exon 4) of the POMC gene.

Conclusion: POMC gene mutations should be considered among the rare causes of hypoglycemia in newborns and early infancy. Rare causes of monogenic obesity will help to elucidate POMC-AgRP-MC3R-MC4R interactions, and crosstalk between hypothalamic and peripheral signals in the development of obesity.

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