Bone mineral density in pseudohypoparathyroidism type 1a.

CONTEXT: The biochemical hallmark of pseudohypoparathyroidism type 1a (PHP1a) is resistance to PTH, but based on tissue-specific imprinting of GNAS, PTH resistance may be limited to the renal cortex. Some studies have shown that bone is responsive to PTH, suggesting that PHP1a patients with chronically elevated PTH levels may have low bone mineral density (BMD). SETTING: This observational study was conducted at the Institute of Clinical and Translational Research, Johns Hopkins Medical Institutions. SUBJECTS: Twenty-two children and adults with PHP1a were studied. MAIN OUTCOME MEASURE: The main outcome measure was BMD Z-score at the lumbar spine (LS), total hip, femoral neck, and total body using dual-energy x-ray absorptiometry, relative to height, weight, and pubertal status. RESULTS: The mean (+/-SD) Z-score for height was 0.77 +/- 1.66 and 1.85 +/- 1.15 for BMI. The BMD Z-score at each of the four sites studied was as follows: LS, 0.29 +/- 1.08; total hip, 0.27 +/- 1.24; femoral neck, 0.02 +/- 1.26; and total body, 0.98 +/- 1.50. Only two subjects (9%) had BMD Z-scores less than -2, and each had additional risk factors for low BMD. BMD in total body and LS spine corrected for height-for-age Z-score was significantly greater than normal. There was no correlation between PTH level and BMD Z-score or between body mass index and BMD Z-score. CONCLUSIONS: Despite secondary hyperparathyroidism, region-specific BMD is not reduced in patients with PHP1a, and total body BMD is significantly greater than normal.

Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) 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 stimulatory G protein alpha-subunit Galpha(s). Because Galpha(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 Galpha(s) in the development of human obesity.

Gender role across development in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

This study evaluated the degree of femininity and masculinity at different developmental stages in a group of adult women, some of whom were exposed to elevated prenatal adrenal androgens as a result of congenital adrenal hyperplasia (CAH) due to 21 hydroxylase (21-OH) deficiency. Women who had presented to the Johns Hopkins Hospital Pediatric Endocrine Clinic for treatment of CAH due to 21-OH deficiency were included. The control group consisted of sisters of CAH participants and women referred for evaluation of polycystic ovary syndrome. Study participants were given a questionnaire asking them to indicate their degree of masculinity and femininity during childhood, adolescence, and adulthood. In addition, participants were asked questions related to their play behavior during childhood, including playmate preferences, toy preferences, and admiration of male or female characters during fantasy play. Across participant groups, self-reported femininity decreased in a dose response manner, according to prenatal androgen exposure. For all groups, femininity increased through developmental stages. Women with salt-losing CAH remained less feminine than controls into adulthood. Conversely, self-reported masculinity increased in a dose-response manner, according to prenatal androgen exposure, across participant groups. Women with CAH showed a decrease in masculinity across developmental stages, such that by adulthood, there were no significant differences in masculinity between controls and the women with CAH. Women with salt-losing CAH were more likely to recall preferences for boy playmates, male-typical toys, and admiration for male characters during childhood than other study participants. Our data support the effect of both prenatal androgen exposure and socialization on gender role behavior in adult women with CAH due to 21-OH deficiency.