Body Mass Index Differences in Pseudohypoparathyroidism Type 1a versus Pseudopseudohypoparathyroidism May Implicate Paternal Imprinting of G{alpha}s in the Development of Human Obesity. [J Clin Endocrinol Metab] Journal article

Context: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations which disrupt the stimulatory G protein alpha-subunit Galphas. Because Galphas is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)] while paternal inheritance leads to AHO alone [pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions.
Setting: GCRC at Johns Hopkins University School of Medicine; National Institutes of Health.
Patients: Fifty-three patients with AHO, 40 with PHP1a and 13 with pseudoPHP, and two with progressive osseous heteroplasia (POH).
Interventions: Observational. Main Outcome Measures: Weight and height SDS; BMI percentiles and z-scores.
Results: PHP1a patients had significantly greater mean weight SDS, BMI %, and BMI z- scores compared to patients with pseudoPHP. These differences in BMI were secondary to adipose content based on DEXA analysis. The mean BMI z-score +/- SEM for PHP1a was 2.31 +/- 0.18 compared to 0.65 +/- 0.31 in pseudoPHP(P=0.000032). Twenty-five out of 40 (62.5%) PHP1a patients had mean BMI z-scores greater than two standard deviations above the mean, whereas no patients with pseudoPHP had BMI z-scores in this range.
Conclusions: Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galphas in the development of human obesity.

J Clin Endocrinol Metab