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Growth Hormone Deficiency in Pseudohypoparathyroidism Type 1a: Another Manifestation of Multihormone Resistance

Department of Pediatrics, Division of Endocrinology (E.L.G.-L., J.L.C., M.A.L.); the Ilyssa Center for Molecular Endocrinology (E.L.G.-L., J.L.C., S.M.J.d.B., M.A.L.); the McKusick-Nathans Institute for Genetic Medicine (J.G., M.A.L.); and the Department of Medicine, Division of Endocrinology (S.M.J.d.B., M.A.L.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Address correspondence and request for reprints to: Emily L. Germain-Lee, M.D., Park 211, Division of Pediatric Endocrinology, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287. E-mail: egermain{at}jhmi.edu.

Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the -chain of G_s, and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G_s transcripts in specific tissues. Recent evidence has shown that G_s transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.

This work was supported by grants from the Genentech Center for Clinical Research and Education (to E.L.G.-L.), United States Public Health Service Grant R01 DK56178 (to M.A.L.), Supplement PA-99106 to RO1 DK56178 (to E.L.G.-L.), Human Growth Foundation (to E.L.G.-L.), and National Institutes of Health/National Center for Research Resources Grant M01 RR00052 (to the Johns Hopkins University School of Medicine General Clinical Research Center).

Abbreviations: AHO, Albright hereditary osteodystrophy; AUC, area under the curve; BMI, body mass index; CV, coefficient of variation; DEXA, dual energy x-ray absorptiometry; H/W, hand and wrist; IFGBP, IGF binding protein; MRI, magnetic resonance image; PHP, pseudohypoparathyroidism; pseudoPHP, pseudopseudohypoparathyroidism; r, Pearson correlation coefficient; SDS, SD score.

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