Pseuohypoparathyroidism, together with Albright hereditary osteodystrophy (AHO), are rare, disabling disorders
These disorders encompass heterogeneous features such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones, primarily parathyroid hormone
The main subtypes of pseuohypoparathyroidism are caused by mutations and/or methylation defects within the imprinted GNAS cluster, whose main transcript encodes the α subunit of the stimulatory G protein
The clinical and molecular overlap between these different but related disorders represents a challenge for endocrinologists for making a differential diagnosis and providing genetic counseling
Moreover, this challenge highlights the need for different classification models and alters our understanding of the mechanisms through which defects in the cAMP signalling cascade cause AHO-related disorders
Pseudohypoparathyroidism exemplifies an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of the cAMP signalling pathway, rather than of the parathyroid hormone (PTH) receptor itself. Despite the first description of this disorder dating back to 1942, later findings have unveiled complex epigenetic alterations in addition to classic mutations in GNAS underpining the molecular basis of the main subtypes of pseudohypoparathyroidism. Moreover, mutations in PRKAR1A and PDE4D, which encode proteins crucial for Gsα–cAMP-mediated signalling, have been found in patients with acrodysostosis. As acrodysostosis, a disease characterized by skeletal malformations and endocrine disturbances, shares clinical and molecular characteristics with pseudohypoparathyroidism, making a differential diagnosis and providing genetic counselling to patients and families is a challenge for endocrinologists. Accumulating data on the genetic and clinical aspects of this group of diseases highlight the limitation of the current classification system and prompt the need for a new definition as well as for new diagnostic and/or therapeutic algorithms. This Review discusses both the current understanding and future challenges for the clinical and molecular diagnosis, classification and treatment of pseudohypoparathyroidism.
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The authors acknowledge funding support from the Italian Ministry of Health (GR-2009-1608394 to G.M.) and the Ricerca Corrente Funds of Fondazione IRCCS Ca Granda Policlinico, Milan. The authors are Members of the EuroPHP and of the EUCID.net (COST action BM1208 on imprinting disorders; www.imprinting-disorders.eu).
The authors declare no competing financial interests.
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Mantovani, G., Spada, A. & Elli, F. Pseudohypoparathyroidism and Gsα–cAMP-linked disorders: current view and open issues. Nat Rev Endocrinol 12, 347–356 (2016). https://doi.org/10.1038/nrendo.2016.52
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