Phase 2 of Growth Hormone for Treatment of Albright Hereditary Osteodystrophy

Principal Investigator: Emily Germain-Lee

Sponsored by the Food and Drug Administration -- 5R01FD003409-02.

Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in the gene encoding the chain of 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 pseudopseudohypoparathyroidism (PPHP).

We hypothesized that PHP1a patients are resistant to growth hormone releasing hormone and found that 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 Gas in chondrocytes in PHP1 and PPHP causes premature chondrocyte differentiation which could be the etiology.

Based on the promising results with our GH trial in GH-deficient PHP1a patients, our 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 PHP1 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.