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Pseudohypoparathyroidism and Growth

  • S. Semiz
  • F. Duzcan
Chapter

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 (G) 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 G 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 G -inactivating mutations on skeletal growth are likely to involve a number of factors. One effect will be intrinsic to the growth plate, because G 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 G 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.

Keywords

Growth Hormone Growth Plate Growth Hormone Deficiency Adult Height Hormone Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AD-PHP-Ib

Autosomal dominant pseudohypoparathyroidism type 1b

AHO

Albright’s hereditary osteodystrophy

Ca

Calcium

cAMP

cyclic Adenosine monophosphate

DMR

Differentially methylated region

GH

Growth hormone

GHRH

Growth hormone-releasing hormone

GNAS

Alpha subunit of the stimulatory G protein (G)

NESP

Neuroendocrine secretory protein

P

Phosphate

PHP

Pseudohypoparathyroidism

PHP-Ia

Pseudohypoparathyroidism type 1a

PPHP

Pseudopseudohypoparathyroidism

PTH

Parathyroid hormone

PTHrP

PTH/PTH-related polypeptide

TSH

Thyroid stimulating hormone

XLαs

Extra-large variant of Gsα

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Pediatric Endocrinology, Department of PediatricsSchool of Medicine, Pamukkale UniversityDenizliTurkey
  2. 2.Department of Medical GeneticsSchool of Medicine, Pamukkale UniversityDenizliTurkey

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