ESPE Abstracts (2016) 86 RFC13.7

Early Onset Obesity and Hyperphagia Associated with Defects in the GNAS Gene

Marta Garcíaa, Nuria Espinosab, Julio Guerrero-Fernándezc, Luis Salamancac, Ana Moráisd, Ricardo Graciac, Intza Garin Elkoroe, Isabel González Casadoc, Guiomar Pérez de Nanclarese & José C. Morenoa

aThyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain; bPaediatrics Department, Vega Baja Hospital, Orihuela, Alicante, Spain; cPaediatric Endocrinology Department, La Paz University Hospital, Madrid, Spain; dPaediatric Nutrition Unit, La Paz University Hospital, Madrid, Spain; eEpigenetic Molecular Laboratory, Research Unit, OSI Araba University Hospital, Vitoria-Gasteiz, Spain

Background: Imprinted genes are known to regulate fetal growth and a ‘parental conflict’ model predicts that paternally and maternally expressed imprinted genes promote and inhibit fetal growth, respectively. GNAS is a complex imprinted locus with multiple oppositely imprinted gene products. Maternal, but not paternal, G(s)alpha mutations lead to obesity in pseudohypoparathyroidism type IA (PHPIA). However, the disorder rarely causes severe obesity in infancy as predominant clinical feature.

Objective and hypotheses: To investigate the genetic basis of severe early hyperphagic obesity in childhood with clinical suspicion of obesogenic or macrosomic syndromes.

Method: Clinical, hormonal and metabolic characterization of 3 pediatric patients with infantile obesity with clinical suspicion of MOMO and Prader-Willi syndromes. Chronological characterization of the phenotype, including nutritional behavior and energy expenditure. Investigation of the GNAS gene by Sanger sequencing.

Results: Three children (2 males), 11 months to 5 years of age, were diagnosed with severe obesity (weight> 99th centile) at 9–18 months of age. At birth, none was obese or large for gestational age (weight <83th centile and height <54th centile). They developed hyperphagia with excessive caloric intake for age, which was restricted as part of clinical handling. One patient presented decreased resting energy expenditure (REE) at indirect calorimetry. At diagnosis, all patients presented asymptomatic hyperthyrotropinemia, hyperparathyroidism with hypocalcemia and hyperphosphatemia. Other features were psychomotor retardation (3/3), overgrowth (1/3), macrocephaly (1/3) and cryptorchidism (2/2). Three missense heterozygous mutations in GNAS (p.M222T, p.D224H, p.R232H) were identified.

Conclusion: Early-onset obesity with hyperphagia can be a prominent presenting feature of PHPIA, which should be considered in the differential diagnosis for monogenic childhood obesity. This type of obesity is postnatal and develops progressively, and its pathophysiology may include both low energy expenditure and excessive food intake through hyperphagia.