Pseudohypoparathyroidism

The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity. Since PHP-related phenotypes are overlapping and other non GNAS-dependent disorders mimicking AHO, such as acrodysostosis, have been genetically characterized, the term PHP is today considered obsolete and better referred to the more comprehensive "inactivating PTH/PTHrP signaling disorder (iPPSD)" as proposed in a recent classification. This broad term include all the congenital rare disorders due to impaired PTH/PTHrP cAMP pathway. Genetic and epigenetic analyses, although not necessary for diagnosis made on the basis of major and minor criteria according to clinical and biochemical signs, will let to differentiate among the different forms for proper therapeutic planning, counseling and follow-up.