Abstract
Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term “inactivating PTH/PTHrP signaling disorders (iPPSD)” was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.
Highlights
In 1942, Fuller Albright described pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, and not many years passed since he realized the complexity of the disease and recognized the existence of different subtypes
In addition to the best known PHP type 1A (PHP1A) patients, characterized by increased PTH serum levels, hypocalcemia and hyperphosphatemia and a constellation of clinical abnormalities collectively named as Albright Hereditary Osteodystrophy (AHO), other patients displayed the presence of physical features of AHO without resistance to the action of PTH and the condition was termed
The study of the parental transmission of the disease showed that the maternal transmission resulted in the full phenotype with AHO and hormone resistance, while the paternal inheritance was associated with AHO alone or to progressive osseous heteroplasia (POH), a clinical condition defined by the presence of progressive ectopic ossifications [11–22]
Summary
In 1942, Fuller Albright described pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, and not many years passed since he realized the complexity of the disease and recognized the existence of different subtypes. The diagnosis should be based on clinical and biochemical characteristics, which will vary depending on the age of the patient and, in some cases, on the family history Both the new classification proposal [56] and the Consensus Statement agree that the 3 major criteria are resistance to PTH (rPTH), ectopic ossifications (EO) and brachydactyly (BR), that maybe variably combined in a given patient and associated with other supporting signs and symptoms such as growth impairment (either intrauterine or post-natal), specific face characteristics, obesity, additional hormone resistances, cognitive impairment, mineralization defects such as enamel hypoplasia, delayed tooth eruption or tooth ankylosis, oligodontia or hypodontia, advanced skeletal maturation. Recent evidence described patients who were clinically diagnosed with PHP1A or PPHP and who turned out to carry PRKAR1A or PDE4D mutations [87–89], pointing out the limits of the current, rigid nomenclature
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