Pseudohypoparathyroidism Clinical Trial
Official title:
Evaluation of rhGH Replacement Therapy in Patients With Pseudohypoparathyroidism Type Ia (PHP Ia)
We have recently demonstrated resistance to GHRH leading to GH deficiency in patients with Pseudohypoparathyroidism type Ia (Mantovani et al., J Clin Endocrinol Metab, 2003. 88: 4070-4074). The purpose of this study is to evaluate the effect of at least 1-year GH replacement in these patients. In particular, we will focus our attention on growth velocity in children affected with this disease.
Albright’s Hereditary Osteodystrophy is a rare autosomal dominant disease characterized by a
constellation of physical features including short stature, central obesity, round face,
brachydactyly, subcutaneous calcifications and mental retardation. In the same family, it
may present associated to end organ resistance to the action of different hormones,
primarily PTH, TSH and gonadotropins and in this case it is named PHP type Ia, or on the
contrary we may find it as an isolated defect and this is the case of PPHP.
In about 80% of affected families, heterozygous loss of function mutations in the Gs alpha
gene are detected. It is of interest mutations inherited from the mother always lead to the
complete form of the disorder, that is PHP; on the contrary when the same mutations are
inherited from the father, patients show the physical abnormalities of Albright’s
Osteodystrophy, without any evidence of hormone resistance. This pattern of inheritance is
consistent with a tissue-specific paternal imprinting of the Gs alpha gene. Imprinting is an
epigenetic phenomenon by which one of the 2 alleles undergoes partial or total loss of
expression; in the case of the Gs alpha gene one would expect that only the paternal allele
should be lost in specific endocrine tissues, such as the kidney, the thyroid and the gonad,
which are the target organs resistant to hormone action in PHP Ia. Indeed, our group
demonstrated that in specific human endocrine tissues also Gs alpha transcription mainly
derives from the maternal allele (Mantovani et al., J Clin Endocrinol Metab, 2002. 87:
4736-4740). In particular a predominant maternal origin of transcription was found in
thyroid and gonad and these data are consistent with the clinical finding of TSH and
gonadotropin resistance present in patients affected with PHP. Interestingly, we observed a
predominance of the maternal allele also in the pituitary gland, an organ which is not
classically included among the target organs resistant to hormone action in PHP Ia.
Following this observation, we have recently demonstrated resistance to GHRH leading to GH
deficiency in most of our patients with PHP Ia (Mantovani et al., J Clin Endocrinol Metab,
2003. 88: 4070-4074). The purpose of this study is to evaluate the effect of at least 1-year
GH replacement in these patients. In particular, we will focus our attention on growth
velocity in children affected with this disease.
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Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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