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. 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

Annette Grüters-Kieslich  1   2 , Monica Reyes  1 , Amita Sharma  3 , Cem Demirci  4 , Terry J DeClue  5 , Erwin Lankes  2   6 , Dov Tiosano  7 , Dirk Schnabel  2   6 , Harald Jüppner  1   3
Affiliations

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

Annette Grüters-Kieslich et al. J Clin Endocrinol Metab. .

Abstract

Context: 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.

Objectives: 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.

Results: 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.

Conclusions: 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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Figures

Figure 1.
Figure 1.
Early-onset obesity in PHP1A and PHP1B. Individual body mass index z scores and mean values (horizontal lines) at different ages of children affected by (left) PHP1A (n = 5) and (right) PHP1B (n = 7; Student t test with Welch correction: no significant differences between both groups). Note that most patients were monitored at their respective clinics several times within each age bracket; thus, several independent measurements were obtained.
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References

    1. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–884. - PubMed
    1. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375(3):240–246. - PubMed
    1. Nakamura Y, Matsumoto T, Tamakoshi A, Kawamura T, Seino Y, Kasuga M, Yanagawa H, Ohno Y. Prevalence of idiopathic hypoparathyroidism and pseudohypoparathyroidism in Japan. J Epidemiol. 2000;10(1):29–33. - PubMed
    1. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism—epidemiology, mortality and risk of complications. Clin Endocrinol (Oxf). 2016;84(6):904–911. - PubMed
    1. Bastepe M, Jüppner H. Pseudohypoparathyroidism, Albright’s hereditary osteodystrophy, and progressive osseous heteroplasia: disorders caused by inactivating GNAS mutations In: DeGroot LJ, Jameson JL, eds. Endocrinology. 7th ed. Philadelphia, PA: WB Saunders; 2016:1147–1159.

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