Pseudohypoparathyroidism and Growth

Abstract

Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). There are two main subtypes of PHP, named as PHP types Ia and Ib and caused by genetic alterations within upstream of the GNAS locus. Heterozygous inactivating mutations within alpha subunit of the stimulatory G protein (Gsα) encoding GNAS exons are found in patients with PHP-Ia. These patients often present with additional hormonal resistance and show characteristic physical features that are totally called as Albright’s hereditary osteodystrophy (AHO). AHO is characterized by short stature, brachydactyly, obesity, skull facial deformities (round face, short neck, flat wide nose, and teeth hypoplasia), short limbs due to brachydactyly or short metacarpal bones, subcutaneous calsinosis, and, in some cases, mental or developmental abnormalities. These features are also present in pseudopseudohypoparathyroidism (PPHP); however, patients affected by this disorder show the same features except hormone resistance. Maternal inheritance of a mutation leads to PHP-Ia with AHO plus hormone resistance, while paternal inheritance of the same mutation leads to PPHP with AHO only. PHP-Ib patients present predominantly with renal PTH resistance and do not show any features of AHO. The proposed mechanism of both the familial autosomal dominant form of PHP-Ib and the sporadic form of PHP-Ib is the distribution of long-range imprinting control elements of GNAS locus, with consequent decreased Gsα transcription in the proximal renal tubules and PTH resistance. It is widely known that patients with PHP-Ia and PPHP have short stature. The effects of Gsα -inactivating mutations on skeletal growth are likely to involve a number of factors. One effect will be intrinsic to the growth plate, because Gsα couples to PTH/PTH-related polypeptide (PTHrP) receptor to adenylate cyclase and cyclic adenosine monophosphate production, controlling the proliferation and differentiation of chondrocytes. Another explanation is that many patients with PHP-Ia have insufficient growth hormone (GH) and exhibit a partial resistance to growth hormone-releasing hormone (GHRH). This condition could have an additive effect on the growth defects, which are mediated by blunted signaling from the PTH/PTHrP receptor owing to Gsα deficiency. In contrast with what is observed in PHP-Ia, patients with PHP-Ib display normal responsiveness to GHRH and normal IGF-I levels. These data provide new information on this rare disease and emphasize the clinical heterogeneity of genetic defects within the GNAS locus.