EARLY-ONSET OBESITY: UNRECOGNIZED FIRST EVIDENCE FOR GNAS MUTATIONS AND METHYLATION CHANGES.

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EARLY-ONSET OBESITY: UNRECOGNIZED FIRST EVIDENCE FOR GNAS MUTATIONS AND METHYLATION CHANGES.

J Clin Endocrinol Metab. 2017 Apr 27;:

Authors: Grüters-Kieslich A, Reyes M, Sharma A, Demirci C, DeClue TJ, Lankes E, Tiosano D, Schnabel D, Jüppner H

Abstract
Context: Early-onset obesity, characteristic for disorders affecting the leptin-melanocortin pathway, is also observed in pseudohypoparathyroidism type Ia (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory G protein (Gsα). Mutations and/or epigenetic abnormalities at the same genetic locus are also the cause of pseudohypoparathyroidism type Ib (PHP1B). However, although equivalent biochemical and radiographic findings can be encountered in these related disorders caused by GNAS abnormalities they are considered distinct clinical entities.
Objectives: To further emphasize overlapping features between both disorders, we report several children, initially brought to medical attention because of unexplained early-onset obesity, who were eventually diagnosed with PHP1B or PHP1A.
Patients and Methods: Search for GNAS methylation changes or mutations in cohorts of patients with early-onset obesity.
Results: Severe obesity had been noted in five infants, later diagnosed with PHP1B due to STX16 deletions and/or abnormal GNAS methylation. These findings prompted analysis of twenty-four unselected obese patients leading to the discovery of inherited STX16 deletions in two individuals. Similarly impressive early weight gains were noted also in five patients, who initially lacked additional AHO features, but were subsequently diagnosed with PHP1A due to GNAS mutations involving exons encoding Gsα.
Conclusions: Obesity during the first year of life can be the first clinical evidence for PHP1B, thus expanding the spectrum of phenotypic overlap between PHP1A and PHP1B. Importantly, GNAS methylation abnormalities escape detection by targeted or genome-wide sequencing strategies raising the question whether epigenetic GNAS analyses should be considered for unexplained obesity.

PMID: 28453643 [PubMed - as supplied by publisher]

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