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

Annette Grüters-Kieslich; Monica Reyes; Amita Sharma; Cem Demirci; Terry J. DeClue; Erwin Lankes; Dov Tiosano; Dirk Schnabel; Harald Jüppner


J Clin Endocrinol Metab. 2017;102(8):2670-2677. 

In This Article

Abstract and Introduction


Context: Early-onset obesity, characteristic for disorders affecting the leptin–melanocortin pathway, is also observed in pseudohypopara-thyroidism type 1A (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory Gprotein 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 gainswere 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.


Early-onset obesity in the first year of life characterizes patients with rare monogenic defects of the leptin–melanocortin pathway or genetically defined hypothalamic syndromes, some of which can now be treated with leptin or a novel melanocortin agonist.[1,2] Pseudohypoparathyroidism types 1A and 1B (PHP1A and PHP1B, respectively) are rare diseaseswith an estimated prevalence of 1:100,000 to 1:150,000 according to the few available epidemiological studies.[3,4] PHP1A, which is caused by maternal heterozygous mutations involving those GNAS exons that encode the α-subunit of the stimulatory G protein (Gsα), is usually diagnosed because patients have features of Albright hereditary osteodystrophy (AHO; i.e., developmental delay, short stature, subcutaneous ossifications, round face, brachydactyly, seizures, and mild hypothyroidism).[5] In addition, a family history positive for either PHP1A or pseudopseudohypoparathyroidism can help establish the diagnosis, although symptoms related to hypocalcemia rarely provide initial evidence for the disease.[6] However, as noted by Fuller Albright in 1942,[7] excessive weight gain in the first year of life frequently occurs in children affected by PHP1A. It was, therefore, speculated that the metabolic phenotype in PHP1A could be explained by impaired Gsα-dependent signaling of neurotransmitters such as norepinephrine in sympathetic neurons, leading to a reduction of energy expenditure.[8,9] However, this hypothesis has not been substantiated beyond the initial observations.[10]

In rodent models of PHP1A [i.e., mice with global ablation of maternal Gnas exons 1 or 2[11,12] or with a maternal mutation in Gnas exon 6 (V159E)[13–15]], central effects on energy metabolism, rather than an increase in food intake, have been documented. Moreover, impaired Gsα-dependent signaling at the melanocortin 4 receptor (MC4R) in the dorsomedial nucleus of the hypothalamus was recently found to be important for regulating energy expenditure and for enhancing brown adipose tissue metabolism but not for promoting food intake,[16] which may involveGαq/Gα11 signaling.[17]

In proximal renal tubules, the thyroid, the pituitary, parts of the central nervous system, and, possibly, other tissues, Gsα transcription from paternal GNAS is reduced through unknown mechanisms.[16,18] Because of silenced Gsα expression from this parental allele, maternal loss-of-function mutations involving GNAS exons 1 to 13 are thought to be sufficient to cause resistance to hormones that mediate their actions through different Gsα-coupled receptors. However, the reduction of paternal Gsα expression appears to be variable, because elevations of parathyroid hormone (PTH) and thyroid-stimulating hormone (TSH) develop over time in patients affected by PHP1A orPHP1B[18,19] and in amurinemodel of PHP1A.[18] Consistent with variable silencing of paternal Gsα expression in different murine tissues,[18,20,21] some studies have provided evidence for reduced energy expenditure in patients with PHP1A;[8,22] however, others have attributed the obesity in such patients to hyperphagia.[23,24] From these findings, it is conceivable that impaired signal transduction occurs at hypothalamic MC4R and/or melanocortin 3 receptor in a subset of patients with PHP1A,[23–25] which could lead to an increase in food intake similar to that observed in patients with MC4R or POMC mutations.[26] In addition, growth hormone deficiency (caused by growth hormone-releasing hormone resistance)[27,28] and mild-to-moderate hypothyroidism (caused by TSH resistance) are likely to contribute to the development of obesity in PHP1A.[29,30] Thus, multiple independent mechanisms with potentially variable, age-dependent factors could contribute to obesity in PHP1A.

PHP1B is an imprinting disorder caused by maternally inherited deletions involving either STX16 or GNAS that lead to complete methylation changes at one or several differentially methylated regions of the GNAS locus.[5,31,32] Gain-of-methylation at exon NESP (neuroendocrine secretory protein 55) and loss-of-methylation at exons AS, XL, and A/B of the maternal GNAS allele has also been observed in sporadic PHP1B cases, which account for most of this disease variant. The cause of the sporadic PHP1B variant is unknown, except for a small number of cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).[33] Patients affected by PHP1B rarely present with characteristic AHO stigmata, and symptomatic hypocalcemia typically occurs after the first decade of life. Until recently, it has been assumed that impaired Gsα signaling occurs only at the PTH receptor, thus leading in PHP1B to clinical symptoms related to abnormal mineral ion homeostasis. However, TSH levels can be elevated in newborns or infants,[34] hyperthyrotropinemia can precede the diagnosis of PHP1B by >1 decade.[35] In addition, accelerated chondrocyte differentiation leads to shortenedmetacarpals and/or tarsals suggesting that the actions of PTH-related protein in the growth plate are reduced, not only in patients affected by PHP1A but also in some patients with PHP1B.[31,36–38] In a few patients, imprinting abnormalities have been observed at several different genetic loci,[39–41] which can lead to PHP1B combined with Beckwith-Wiedemann syndrome (BWS).[42] In the latter patients, BWS was believed to be the main cause for the development of obesity early in life; however, it is conceivable that impaired Gsα signaling was a contributing factor.

Only a few recent case reports have reported childhood obesity as a noticeable finding in patients with PHP1B.[42,43] Although this could have been a coincidental finding, it is conceivable that early-onset weight gain associated with hyperphagia is an underappreciated sign of PHP1B. In the absence of additional AHOfeatures, even PHP1A might not be considered in the differential diagnosis of obesity early in life. In the present retrospective study, we analyzed the cases of several children who were initially followed clinically, in some cases for many years, because of obesity during infancy and hyperphagia. We furthermore screened a cohort of 24 obese patients for GNAS methylation changes and compared the findings to those observed in several childrenwith a diagnosis of PHP1A. Although early-onset obesity can be a sign of either PHP variant, the prevalence of PHP1B (or PHP1A) among obese patients remains to be determined. However, both disorders should be considered when exploring the cause of pediatric, and possibly, adult obesity.