Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in the gene encoding the a chain of stimulatory gene proteins (Gs). Among other abnormalities, it is associated with short stature and obesity. Because of tissue-specific imprinting, patients with GNAS mutations on maternally inherited alleles are resistant to multiple G protein-coupled hormones, a variant termed pseudohypoparathyroidism type 1a (PHP1a). Patients who inherit mutations from the paternal allele have a similar phenotype but without hormonal resistance, termed pseudopseudohypo- parathyroidism (PPHP). The investigators hypothesized that PHP1a patients are resistant to growth hormone releasing hormone and found that approximately two-thirds are growth hormone (GH) deficient. GH therapy has led to increased growth velocities, taller adult heights, decreased BMI and adiposity, and improvements in lipids, bone density, sense of well-being, and self-esteem without any significant side effects from GH use. However, GH deficiency is not the only cause of the short stature in PHP1a. Premature fusion of the epiphyses reflected in advanced bone ages is also a cause and occurs in patients with PHP1a who are GH-sufficient as well as in patients with PPHP. In vitro and mouse studies have implicated that haploinsufficiency of G protein in chondrocytes in PHP1a and PPHP causes premature chondrocyte differentiation which could be the etiology. Based on the promising results with the GH trial in GH- deficient PHP1a patients, the hypothesis is that GH may also be of value in children with PHP1a who are GH-sufficient as well as in children with PPHP by accelerating growth velocity maximally prior to the cessation of growth secondary to early bone fusion. This study will examine the effects of GH on growth velocity in prepubertal GH-sufficient children with PHP1a and PPHP. Preliminary data for safety and dosing of GH, as well as quality of life effects will be gathered. If the results are promising, these children will be followed to final height after completion of this proposed initial investigation. This ultimately could lead to a new FDA-approved indication for GH use in all children with AHO, thus eliminating the need for GH testing for these children. The overall goal is to improve the quality of life in these patients.

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Albright hereditary osteodystrophy (AHO) is a rare disorder associated with short stature. Growth hormone (GH) therapy improves the height and quality of life of AHO patients who are GH-deficient. I will examine the effects of GH on children with AHO who are GH-sufficient, with the hope that this could lead to an FDA-approved indication for GH in all children with AHO and ultimately improve quality of life.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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Lin, Maria H; Numbenjapon, Nawaporn; Germain-Lee, Emily L et al. (2015) Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy. J Pediatr Endocrinol Metab 28:911-8