Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Gαs in the development of human obesity

Context: Obesity is a prominent feature of Albright hereditary osteodystrophy ( AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatoryGprotein alpha- subunit G alpha s. Because G alpha s is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [ pseudohypoparathyroidism type 1a ( PHP1a)], whereas paternal inheritance leads to AHO alone [ pseudopseudohypoparathyroidism ( pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions. Setting: This observational study was conducted at the General Clinical Research Center, 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 were studied. Main Outcome Measures: Main outcome measures were weight and height SD score ( SDS), body mass index ( BMI) percentiles, and BMI z- scores. Results: Patients with PHP1a had significantly greater mean weight SDS, BMI percentages, and BMI z- scores compared with patients with pseudoPHP. These differences in BMI were secondary to adipose content based on dual energy x-ray absorptiometry analysis. The mean BMI z- score +/- SEM for PHP1a was 2.31 +/- 0.18 compared with 0.65 +/- 0.31 in pseudoPHP ( P = 0.000032). Twenty- five of 40 ( 62.5%) patients with PHP1a had mean BMI z- scores greater than two SDS 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 G alpha s in the development of human obesity.