Studies of Hormone Action in Patients with Altered G-protein-coupled Signal Transduction

Principal Investigator: Emily Germain-Lee

Includes Substudies Entitled: "Study of Growth Hormone Secretion in Patients with Pseudohypoparathyroidism Type 1a (R01 FD002568)" and "Phase 2 Growth Hormone for Treatment of Albright Hereditary Osteodystrophy (R01 FD003409)"

Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in GNAS, the gene encoding the alpha 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 (e.g., PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism type 1a (PHP 1a). Patients who inherit mutations from the paternal allele have the phenotype alone without hormonal resistance, a variant termed pseudopseudohypoparathyroidism (PPHP). Because the alpha chain of Gs is imprinted in the pituitary, we hypothesized that PHP1a patients are resistant to growth hormone releasing hormone (GHRH) and in a pilot study found approximately two-thirds of these patients to be growth hormone (GH) deficient (Germain-Lee et al., 2003). Further data obtained during FDA OPD grant (R01 FD002568) have confirmed this prevalence in a larger patient population, thus providing a possible explanation for the short stature and obesity. We are currently conducting a GH treatment trial in GH deficient PHP1a patients. GH therapy has led to increased linear growth velocities, taller adult heights compared to historical controls, decreased body mass indices and % adiposity, improvements in lipid levels, increases in bone density, and improvements in sense of well-being 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 markedly advanced bone ages is also a cause. This occurs in all patients with PHP1a including those who are GH sufficient, as well as in patients with PPHP. In vitro and mouse studies have implicated that haploinsufficiency of the alpha chain of Gs in chondrocytes in both PHP1a and PPHP causes premature chondrocyte differentiation which could be the etiology of this early epiphyseal closure. Because of the promising results with our GH trial in GH deficient PHP1a patients, we hypothesize that GH may also be of value in children with PHP1a who are GH sufficient as well as in children with PPHP by accelerating linear growth velocity maximally prior to the cessation of growth secondary to premature bone fusion. If GH treatment does indeed result in taller final adult heights in GH sufficient PHP1a and PPHP children, this could lead to an FDA-approved indication for GH treatment for all children with AHO (PHP1a and PPHP), not only the GH deficient PHP1a children and adults, thereby eliminating the need for GH testing in children with AHO. In addition, FDA-approval would lead to better awareness of the role of GH in improving the quality of life in children with this disorder. Finally, our studies have the potential to change the standard of care in these patients and may reveal other benefits of GH treatment in GH sufficient AHO children, as well as help define the role of GH in the etiology of the short stature and obesity.

The primary specific aims of the growth hormone sub-studies are:

1) To conduct a GH treatment trial in GH deficient PHP1a children to determine whether this leads to an increase in their linear growth velocities prior to premature epiphyseal fusion such that their final adult heights are greater than historical control heights as well as greater than heights of GH deficient PHP1a adults examined within this overall study (PHP1a adults have been and continue to be tested within this study for GH status; see secondary specific aims) [R01 FD002568]

2) To conduct a GH treatment trial in GH sufficient PHP1a children in attempt to increase their linear growth velocities prior to premature epiphyseal fusion such that their final adult heights are greater than historical control heights as well as greater than heights of GH sufficient PHP1a adults examined within this overall study [R01 FD003409]

3) To conduct a GH treatment trial in children with PPHP who, by definition, are GH sufficient to see whether the above effect can also be achieved in this patient population who are also at risk for premature bone fusion (PPHP adults have been and continue to be tested for GH status within this study; see secondary specific aims) [R01 FD003409]

4) To obtain FDA approval for GH use in Albright hereditary osteodystrophy (if the results from the above aims reveal a positive response) to include all children with AHO (GH deficient PHP1a, GH sufficient PHP1a, and PPHP children) thereby eliminating the need for GH testing in children with AHO.

5) To evaluate the effects of GH in GH deficient PHP1a adults. GH use in PHP1a adults would be restricted to those who are GH deficient, and adults would still need testing.

The secondary specific aims of this sub-study are:

1) To examine a large group of adult PHP1a patients who are GH deficient versus those who are GH sufficient or those with PPHP (who by definition are GH sufficient) in order to determine the role of GH deficiency compared to premature bone fusion on final adult height. (Preliminary results demonstrate that GH deficient patients are shorter than those who are GH sufficient as described above)

2) To examine patients with PHP1a who are GH deficient versus those with PHP1a who are GH sufficient and those with PPHP in order to determine the role of GH treatment on weight and lipid parameters, and also bone density in PHP1a patients.