Albright Hereditary Osteodystrophy, Pseudohypoparathyroidism, and Other <i>GNAS</i>-Associated Syndromes

Louise C. Wilson

in Genetics of Obesity Syndromes

Published on behalf of Oxford University Press

Published in print July 2009 | ISBN: 9780195300161
Published online October 2012 | e-ISBN: 9780199975198 | DOI:

Series: Oxford Monographs on Medical Genetics

Albright Hereditary Osteodystrophy, Pseudohypoparathyroidism, and Other GNAS-Associated Syndromes

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Albright hereditary osteodystrophy (AHO) is a complex, variable disorder that may present initially to the endocrinologist, developmental pediatrician, clinical geneticist, or orthopedic surgeon. As well as representing a monogenic cause of syndromic obesity, it is providing fascinating insights into genomic imprinting, regulation of calcium metabolism, and skeletal development.

The terms PPHP and AHO are not interchangeable. The latter describes a constellation of physical features including round face, short adult stature, obesity, brachydactyly, and ectopic ossifications. The former means end-organ resistance to parathyroid hormone (PTH) and is subclassified into types Ia, Ib, Ic, and II. Pseudohypoparathyroidism may occur with or without associated AHO. The term PPHP is now reserved for individuals with AHO who have normal end-organ responses to PTH. Both the PHP type Ia and PPHP forms of AHO result from inactivating mutations in one allele of the GNAS1 gene on chromosome 20q13.3, associated with a 50% reduction in bioactivity of the Gsα protein which it encodes. The Gsα protein is an essential component of the signal-transduction pathway between all cell membrane receptors which cause activation of intracellular adenylyl cyclase when stimulated, including the PTH receptor. The gene is subject to tissue-specific genomic imprinting. Patients with mutations on their maternally derived allele are likely to have associated PHP Ia, whereas mutations on the paternal allele are usually associated with PPHP. It is now clear that GNAS1 is just one product of a complex gene with multiple alternative first exons, known as the “GNAS imprinted gene cluster”. The upstream exons are intimately involved in the tissuespecific imprinting of GNAS1. Isolated PTH resistance (PHP Ib) can result from mutations within the GNAS1 gene but is more commonly caused by epigenetic imprinting abnormalities affecting the upstream exon Exon 1A.

Chapter.  14633 words.  Illustrated.

Subjects: Clinical Genetics ; Endocrinology and Diabetes

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