Pseudopseudohypoparathyroidism

Pseudopseudohypoparathyroidism (pseudo-PHP) is a disease characterized by a constellation of clinical features collectively termed Albright hereditary osteodystrophy (AHO; see this term) but no evidence of resistance to parathyroid hormone (PTH), which is seen in other forms of pseudohypoparathyroidism (PHP; see this term).

Epidemiology

Prevalence is unknown but series of patients usually include one patient with pseudo-PHP for every two patients with PHP 1a (see this term).

Clinical description

Due to the absence of hormone resistance, the age at diagnosis varies from birth to late adulthood. Patients display various features of AHO including short stature which develops over time, absence of pubertal growth spurt (mean final height is between -2 and -3 SD), rounded face, brachydactyly, absence of widening of the lumbar spine, and ectopic ossifications of soft-tissues, which may develop spontaneously or after trauma. The spectrum of the ectopic ossifications ranges from absent to extensive and may generate severe pain. Patients with extensive ectopic ossifications may also be considered as having progressive osseous heteroplasia (POH; see this term). Cognitive impairment is present in only 10% of the patients. Unlike in PHP 1a, obesity is not constant and, when present, is only moderate.

Etiology

The disease is caused by paternally inherited heterozygous molecular defects in the GNAS gene (20q13) encoding the alpha sub-unit of the stimulatory G protein (Gs alpha), which results in a reduction in the expression/activity of Gs alpha. In families in which PHP 1a and pseudo-PHP co-exist, mutations in the gene can be detected in all affected members.

Diagnostic methods

Diagnosis is based on the presence of features of AHO and the exclusion of other forms of PHP (by measuring serum calcium, phosphate and PTH). X-rays show typical shortening of the fourth metacarpal and advanced bone age. All metacarpals and metatarsals may be affected. Molecular genetic testing identifying a mutation in the GNAS gene confirms diagnosis.

Differential diagnosis

The differential diagnosis includes PHP 1a, PHP 1c and 2q37 microdeletion syndrome (see these terms).

Antenatal diagnosis

Antenatal diagnosis is possible when a disease causing mutation in the family is known.

Genetic counseling

Transmission is autosomal dominant with parental imprinting. Pseudo-PHP most frequently occurs in relatives of patients with PHP 1a, but may present in families without PHP as an isolated defect. Paternal inheritance of the mutation is responsible for pseudo-PHP. Genetic counseling is possible.

Management and treatment

There are no specific treatments for the various manifestations of AHO, although subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.

Prognosis

Pseudo-PHP is not life threatening but quality of life can be affected in those with severe ectopic ossification.