Pseudohypoparathyroidism

Jüppner, Harald; Baştepe, Murat

doi:10.1002/9781118453926.ch73

Cited by 2 publications

(5 citation statements)

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“…The imprinted GNAS gene consists of 13 exons that encode the signaling protein Gsα, a ubiquitous signaling protein mediating the actions of many hormones via generation of the second messenger cAMP. Even if Gsα is biallelically expressed in the majority of tissues, maternal Gsα expression is silenced in tissues with maternal imprinting [22] namely the proximal renal tubules, thyroid, gonads and pituitary somatotrophs [13,23]. This tissue-specific imprinting leads to a parent of origin mutation effect: Maternal transmission of the mutations involves the development of AHO and multi-hormone resistance (namely, PHP1A and 1C), whereas paternal transmission is exclusively associated to the phenotypic features of AHO, without any hormone resistance (namely, PPHP and progressive osseous heteroplasia (POH)) [3,24].…”

Section: Geneticsmentioning

confidence: 99%

“…PHP1B is caused by loss of imprinting at GNAS locus, affecting either GNAS A/B: TSS-DMR exclusively or in combination with any of the other three differentially methylated regions (DMRs) (GNAS-NESP: TSS-DMR, GNAS-AS1: TSS-DMR or GNAS-XL: Ex1-DMR) [3,9]. In most cases of PHP1B these methylation alterations occur sporadically without any underlying genetic defect, but some cases are related to heterozygous deletions within STX16 or NESP/AS that imply the loss of methylation at GNAS A/B: TSS-DMR alone or at the four DMRs [3,13,23]. Genetic defects at GNAS, observed in patients with PHP 1A are associated with a generalized deficiency or reduction in activity of Gsα [7,25], whereas a slightly diminished activity has been observed in patients with PHP 1B [26].…”

Section: Geneticsmentioning

confidence: 99%

“…The genetic defects underlying PHP occurs at the GNAS locus on chromosome 20q13.2-q13.3, where the genes encoding Gsα, XLαs and NESP55 lie, as well as two non-translated transcripts called A/B and GNAS-AS1 (GNAS complex locus, Antisense Transcript 1) [13]. PTH, along with other select hormones, act through these G proteins coupled receptors whose signal transduction pathways is mediated by the alpha subunit of the stimulatory G protein (Gsα).…”

Section: Introductionmentioning

confidence: 99%

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Pseudohypoparathyroidism-Literature Update 2018

Sinnott¹

2018

Ann Endocrinol Metab

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Pseudohypoparathyroidism (PHP) is a rare heterogenous group of disorders characterized by end-organ resistance to PTH, specifically at the proximal renal tubule. The term PHP encompasses PHP 1A, PHP 1B, PHP 1C, PHP 2 and pseudopseudohypoparathyroidism (PPHP). The two most common subtypes are PHP 1A and PHP 1B, PHP 1A, PHP 1C and PPHP have the Albrights hereditary osteodystrophy (AHO) phenotype, in addition to end-organ resistance to PTH in the two former subtypes. Recently, the European Pseudohypoparathyroidism (EuroPHP) network have proposed a novel classification of PHP which encompasses all disorders of the PTH receptor and its signaling pathway, known as inactivating PTH/PTH-related protein signaling disorders (iPPSD) [1][2][3][4][5][6].PHP is caused by molecular alterations within the GNAS locus. The GNAS gene encodes an alpha subunit of the stimulatory G protein (Gsα) that mediates the actions of PTH and other hormones including TSH and gonadotropins. It is a defect in these stimulatory G-protein coupled receptors, that results in end-organ resistance to parathyroid hormone and select other hormones. Mutations of the GNAS gene are associated with iPPSD2 (PHP 1A, PHP 1C, PPHP, progressive osseous heteroplasia (POH)) whereas methylation defects are identified at the GNAS locus and associated with iPPSD3 (PHP 1B, including autosomal dominant-PHP 1B and sporadic-PHP 1B). This year, the first international consensus statement on the diagnosis and management of pseudohypoparathyroidism was published and is informative to physicians with limited experience treating these rare disorders. It is important to establish a diagnosis to enable appropriate medical treatment of the endocrine complications and provide accurate genetic and prenatal counselling of individuals and their first-degree relatives.

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Section: Geneticsmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pseudohypoparathyroidism-Literature Update 2018

Sinnott¹

2018

Ann Endocrinol Metab

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“…In pseudohypoparathyroidism type 1b, the kidneys are resistant to PTH, and mild resistance to thyrotropin is possible; however, evidence of Albright’s hereditary osteodystrophy is absent in most cases. 6 Pseudohypoparathyroidism type 1c is similar to type 1a, with the exception that receptor-independent cAMP production remains intact in vitro. 7 There are probably several variants of pseudohypoparathyroidism type 2.…”

Section: Differential Diagnosismentioning

confidence: 99%

“…In one of these variants, the urinary phosphorus level does not increase appropriately in response to PTH infusion, but the cAMP level does; Albright’s hereditary osteodystrophy is absent. 6 …”

Section: Differential Diagnosismentioning

confidence: 99%