Pseudohypoparathyroidism (ORPHA:97593)
Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine disorders characterized by normal renal function and resistance to the action of parathyroid hormone (PTH), manifesting with hypocalcemia, hyperphosphatemia and elevated PTH levels and that includes the subtypes PHP type 1a (PHP-1a) , PHP type 1b (PHP-1b), PHP type 1c (PHP-1c), PHP type 2 (PHP-2) and pseudopseudohypoparathyroidism (PPHP) (see these terms).
Epidemiology
The exact prevalence is unknown. PHP occurs twice as frequently in females as in males. The estimated prevalence (of PHP-1a, 1b and PPHP) in Italy is 1/150,000. The estimated prevalence in Japan (of PHP-1a and 1b) is 1/295,000.
Clinical description
All forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms).Some forms of PHP may remain unnoticed if patients do not have hypocalcemia (or if hypocalcemia is misdiagnosed and treated as ''seizures'') and/or characteristic physical features, which include short stature, rounded face, short neck, centripetal obesity, brachydactyly and soft-tissue and calcifications/ossifications, and are collectively termed Albright hereditary osteodystrophy (AHO; see this term). AHO is observed in patients with PHP-1a, PHP-1c and PPHP but is absent in patients with PHP-1b and PHP-2. Intellectual disability is sometimes observed in patients with AHO features while it is almost always present in PHP-1A and PHP -1C. There have also been reports that olfaction is impaired in PHP-1a but not in PPHP or PHP-1b. Patients with PHP can also present with symptoms of resistance to hormones other than PTH including thyroid-stimulating hormone (TSH) (in PHP1a, PHP1c and sometimes PHP1b), gonadotropins (in PHP1a, PHP1c) and growth-hormone-releasing hormone (GHRH) (in PHP1a). Cataracts, dental problems and intracranial calcifications (bilateral striopallidodentate calcinosis; see this term) represent the long-term complications.
Etiology
PHP-1a, PPHP, and PHP-1b are all due to molecular defects in the same locus of the GNAS (20q13.2-q13.3) gene coding the alpha sub-unit of the stimulatory G protein. Patients inheriting PHP from the mother display all the signs of AHO with multi-hormone resistance, while patients inheriting the disease from the father have AHO without any resistance to hormone action (PPHP). This pattern of inheritance is consistent with a tissue-specific paternal imprinting of the gene causing the disease. Those with the autosomal dominant form of PHP-Ib display an isolated loss of methylationat exon A/B associated with a recurrent 3-kb deletion in the STX16 gene (20q13.32). To date, the genetic anomaly responsible for PHP2 and PHP1c has not yet been identified, although in a few PHP1c patients, GNAS heterozygous mutations have been detected. It has been hypothesized that in most cases, PHP2 may be an acquired defect secondary to vitamin D deficiency.
Genetic counseling
PHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.

                            Last update: 
                            October 2014


                            - Expert reviewer(s): 
                            Pr Giovanna MANTOVANI