Pseudohypoparathyroidism 

Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by hypocalcemia, hyperphosphatemia, increased serum concentration of parathyroid hormone (PTH), and insensitivity to the biologic activity of PTH. (See Pathophysiology, Presentation, and Workup.)

Several variants of PHP have been identified. The molecular defects in the gene (GNAS1) encoding the alpha subunit of the stimulatory G protein (Gsa) contribute to at least 3 different forms of the disease: PHP type 1a, PHP type 1b, and pseudopseudohypoparathyroidism (pseudo-PHP).^[1] PHP type 1a is the best understood form of the disease. (See Etiology.)

In 1942, Fuller Albright first introduced the term pseudohypoparathyroidism to describe patients who presented with PTH-resistant hypocalcemia and hyperphosphatemia along with an unusual constellation of developmental and skeletal defects, collectively termed Albright hereditary osteodystrophy (AHO). These features included short stature, rounded face, shortened fourth metacarpals and other bones of the hands and feet (see the image below), obesity, dental hypoplasia, and soft-tissue calcifications/ossifications. In addition, administration of PTH failed to produce the expected phosphaturia or to stimulate renal production of cyclic adenosine monophosphate (cAMP). (See Presentation and Workup.)

Epidemiology

In 1998, a nationwide epidemiologic survey of PHP was conducted in Japan based on hospital visits in 1997; the period prevalence was 3.4 cases per 1 million people.^[2] No information is available regarding the prevalence of PHP in the rest of the world.

PHP occurs approximately twice as frequently in females as in males. Patients' ages range from infancy to senescence.

Patient education

For patient education information, see the Osteoporosis Center.

Testotoxicosis

Testotoxicosis with PHP type 1a can occur. Gonadotropin-independent sexual precocity has been reported in 2 boys who presented in infancy with classic PHP type 1a. Usually, patients with PHP type 1a show resistance to luteinizing hormone, which could lead to primary testicular insufficiency. The paradoxical presentation of testotoxicosis in these boys resulted from an identical point mutation in the GNAS1 gene, which caused both a loss and gain of Gsa function.

PHP type 1a, characterized by a loss of Gsa function, is caused by thermal inactivation of the mutant protein at body temperature. Testotoxicosis indicates an organ-specific gain of Gsa function, resulting from the expression of the mutant protein. The lower temperature of the testes protects the mutant protein from thermal inactivation.

Growth plate defects

A study by Sanchez et al found that an imprinting defect in GNAS may lead to growth plate defects in patients with PHP type 1b, including brachydactyly and Madelung deformity. This suggests that GNAS signaling has a more extensive role in chondrocyte maturation than was previously believed.^[3]

As previously discussed, several variants of PHP have been identified, with PHP type 1a being the best understood form of the disease. The molecular defects in the gene (GNAS1) encoding the alpha subunit of the stimulatory G protein (Gsa) contribute to at least 3 different forms of the disease: PHP type 1a, PHP type 1b, and pseudopseudohypoparathyroidism (pseudo-PHP).^[1] All patients are heterozygous, with 1 normal Gsa allele; the mutant allele leads to production of inactive Gsa or to small amounts of active Gsa.

PHP type 1a

Several other peptide hormones, including thyroid-stimulating hormone (thyrotropin), antidiuretic hormone, gonadotropins, glucagons, adrenocorticotropin, and growth hormone–releasing hormone, use the alpha subunit of stimulatory G protein to enhance cAMP production. Patients with PHP type 1a can present with resistance to the effects of any of these hormones, although in most patients, responses to corticotropin and glucagon are clinically unaffected.

The dominant pattern of inheritance of PHP type 1a has been attributed to haploinsufficiency of GNAS1, meaning that the protein produced by a single normal Gsa allele cannot support normal function, although it may suffice for survival. The single normal Gsa allele preserves the responses to hormones such as corticotropin and glucagon. The haploinsufficiency of the GNAS1 gene is tissue specific, which may explain the selective resistance to hormones and the characteristic habitus of patients with PHP type 1a.

Pseudo-PHP

In the same family, some patients with a defective GNAS1 gene have resistance to PTH, whereas others share with them the habitus of AHO but are not resistant to PTH. The latter group are said to have pseudo-PHP.

Davies et al reported an analysis of pedigrees of families that included patients with PHP and pseudo-PHP, suggesting that patients who inherit the defective gene from the father have pseudo-PHP because the mutant gene is not expressed and the product of a single maternally inherited GNAS1 gene preserves normal responses to PTH and thyrotropin.^[4] However, the occurrence of AHO in patients with pseudo-PHP indicates that 1 GNAS1 gene is not sufficient in all tissues.

PHP type 1b

Patients with PHP type 1b have a genetically and biochemically distinct disorder. Patients with PHP type 1b lack features of AHO, have normal expression of Gsa protein in accessible tissues, and manifest hormonal resistance limited to PTH target tissues. PTH resistance may be limited to the kidney, with PTH responsiveness preserved in the bone, as evidenced by the hyperparathyroid skeletal lesions observed in these patients.

PHP type 1b is inherited as an autosomal dominant trait, but mutations have not been found in the PTH gene or PTH receptor genes. In a study that involved 4 kindreds with affected members, Juppner et al reported that the unknown gene was paternally imprinted. The investigators mapped the gene to a small region of band 20q13.3, very near the GNAS1 gene.^[5]

The severity of PHP type 1b can vary considerably from one patient to another; even within a single kindred, the different affected members may experience considerable variations in the severity of the disorder. Members of the affected family who share the same haplotype in band 20q13.3 have been reported to be clinically asymptomatic and to have serum calcium levels within the reference range.

Current data suggest that a molecular defect in the GNAS1 gene may also be responsible for at least some forms of PHP type 1b. A mutant promoter or enhancer region of the GNAS1 gene that has lost the ability to support expression of Gsa in the kidney but not in other tissues may be responsible for the renal resistance to PTH.

Interestingly, a 2001 publication by Wu et al reported identification of a novel mutation in the carboxyl terminus of the GNAS1 gene in 3 patients with PHP type 1b and their clinically unaffected mother and maternal grandfather.^[6] The absence of PTH resistance in the mother and maternal grandfather who carried the same mutation was consistent with current models of paternal imprinting^[7] of the GNAS1 gene.

PHP type 1c and type 2

Two other variants of PHP, PHP type 1c and PHP type 2, are much less characterized than are the other forms of PHP. Patients with PHP type 1c do not have a detectable defect in Gsa protein despite having clinical and laboratory findings similar to those observed in patients with PHP type 1a.

Patients with PHP type 2 show no skeletal or developmental defects, similar to patients with PHP type 1b. Unlike patients with type 1b, however, they also demonstrate a normal urinary cAMP response.