ESPE Abstracts

Introduction: Pediatric obesity is an important public health problem. Exogenous obesity represents most cases; in some children, obesity is attributable to endocrine or genetic disorders. Genetic etiology should be considered in children with dysmorphic features, global developmental delay, early onset severe obesity (before 5 years), hyperphagia or severe obesity family history. Regardless of the etiology, treatment must begin with long-term lifestyle changes. Nevertheless, specific genetic causes may require additional treatment strategies.

Case report: The authors describe a 15y.o. female adolescent, referred to the Pediatric Endocrinology department at age of 10 due obesity and high stature. Personal history of late pre-term delivery, birth weight and length appropriate for gestational age; normal psychomotor development. No family history of overweight; mid-parental target height of 165.5cm (z-score +0.36). History of abnormal weight and height gain from 1y.o.: weight significantly greater than the 97^th percentile from 15 months and height greater than the 97^th percentile from 3 years of age. Excluded hyperphagia and other symptoms. Physical examination showed signs of Cushing syndrome, 86.9kg (z-score +5.26), 160.1cm (z-score +3.35), BMI of 33.9 kg/m² (z-score +3.95) and Tanner M3P4. The first laboratory tests revealed high insulin-like growth factor (IGF-1) levels, reduced leptin levels, marked hyperinsulinism and bone age 2.5 years advanced. The oral glucose tolerance test did not show complete suppression of somatotropin levels. The MRI revealed an enlarged adenohypophysis. Subsequent evaluations showed IGF-1 normalization, variable leptin levels and persisting marked hyperinsulinism. Serial neuroimaging exams were similar to the initial one. Because of maintained excessive ponderal gain, an obesity genetic testing panel was performed. Mutations in three genes were identified: melanocortin-4 receptor (MC4R) in heterozygosity; ghrelin (GHRL) in heterozygosity; and aquaporin 7 (AQP7) in homozygosity. The MC4R gene variant was identified in the father (no overweight).

Comments: The authors present a case of early onset severe non-syndromic obesity with mutations in three distinct genes. The MC4R mutations have been described as the main cause of genetic obesity. However, the detected variant does not explain per si this child obesity. Whereas GHRL and AP7 mutations have been described as obesity risk factors, they cannot individually explain the observed condition. The authors suggest a possible synergistic effect of all three mutations as the underlying cause of this severe obesity. In vitro functional or animal studies may explain the pathogenicity of these mutations. Concluding, it is mandatory to always consider a genetic etiology in children with early onset severe obesity.