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J Clin Endocrinol Metab. 2017 Aug 1;102(8):2670-2677. doi: 10.1210/jc.2017-00395.

Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes.

Author information

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
Department of Pediatric Endocrinology and Diabetes, Charité-Universitätsmedizin, Berlin 10117, Germany.
Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
Pediatric Endocrinology, Connecticut Children's Medical Center, University of Connecticut School of Medicine, Farmington, Connecticut 06030.
Pediatric Endocrine Associates, Tampa, Florida 33647.
Center for Chronically Sick Children, Charité-Universitätsmedizin, Berlin 10117, Germany.
Division of Pediatric Endocrinology, Meyer Children's Hospital, Rambam Health Care Campus, Haifa 31096, Israel.



Early-onset obesity, characteristic for disorders affecting the leptin-melanocortin pathway, is also observed in pseudohypoparathyroidism type 1A (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory G protein α-subunit (Gsα). Mutations and/or epigenetic abnormalities at the same genetic locus are also the cause of pseudohypoparathyroidism type 1B (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.


To further emphasize the overlapping features between both disorders, we report the cases of several children, initially brought to medical attention because of unexplained early-onset obesity, in whom PHP1B or PHP1A was eventually diagnosed.

Patients and Methods:

Search for GNAS methylation changes or mutations in cohorts of patients with early-onset obesity.


Severe obesity had been noted in five infants, with a later diagnosis of PHP1B due to STX16 deletions and/or abnormal GNAS methylation. These findings prompted analysis of 24 unselected obese patients, leading to the discovery of inherited STX16 deletions in 2 individuals. Similarly, impressive early weight gains were noted in five patients, who initially lacked additional Albright hereditary osteodystrophy features but in whom PHP1A due to GNAS mutations involving exons encoding Gsα was diagnosed.


Obesity during the first year of life can be the first clinical evidence for PHP1B, 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 of whether epigenetic GNAS analyses should be considered for unexplained obesity.

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