Daniel A. Doyle
In contrast to the situation in hypoparathyroidism, in pseudohypoparathyroidism (PHP, also known as Albright hereditary osteodystrophy) the parathyroid glands are normal or hyperplastic and they can synthesize and secrete parathyroid hormone (PTH). Serum levels of immunoreactive PTH are elevated even when the patient is hypocalcemic and may be elevated when the patient is normocalcemic. Neither endogenous nor administered PTH raises the serum levels of calcium or lowers the levels of phosphorus. The genetic defects in the hormone receptor adenylate cyclase system are classified into various types depending on the phenotypic and biochemical findings (Table 590.1 ).
Table 590.1
Clinical, Biochemical, and Genetic Features of Hypoparathyroid and Pseudohypoparathyroid Disorders
| HYPOPARATHYROIDISM | PSEUDOHYPOPARATHYROIDISM | |||||
|---|---|---|---|---|---|---|
| PHP 1a | PPHP | PHP 1b | PHP 1c | PHP 2 | ||
| AHO manifestations | No | Yes | Yes | No | Yes | No |
| Serum calcium | ↓ | ↓ | N | ↓ | ↓ | ↓ |
| Serum PO4 | ↑ | ↑ | N | ↑ | ↑ | ↑ |
| Serum PTH | ↓ | ↑ | N | ↑ | ↑ | ↑ |
| Response to PTH: | ||||||
| Urinary cAMP* (Chase-Aurbach test) | ↑ | ↓ | ↑ | ↓ | ↓ | ↑ |
| Urinary PO4 (Ellsworth-Howard test) | ↑ | ↓ | ↑ | ↓ | ↓ | ↓ |
| Gs α activity | N | ↓ | ↓ | N | N | N |
| Inheritance | AD, AR, X | AD | AD | AD | AD | Sporadic |
| Molecular defect | PTH, CaSR, GATA3, Gcm2, others | GNAS1 | GNAS1 | GNAS1 † | ?Adenyl cyclase | ?cAMP targets |
| Other hormonal resistance | No | Yes | No | No | Yes | No |
* Plasma cyclic adenosine monophosphate (cAMP) responses are similar to those of urinary cAMP.
† Involves deletions that are located upstream of GNAS1.
↓, decreased; ↑, increased; ?, presumed, but not proved; AD, autosomal dominant; AHO, Albright's hereditary osteodystrophy; AR, autosomal recessive; N, normal; PHP, pseudoparathyroidism; PPHP, pseudopseudoparathyroidism; PTH, parathyroid hormone; X, X-linked.
From Thakker RV: The parathyroid glands, hypercalcemia and hypocalcemia. In Goldman L, Schafer AI, editors: Goldman-Cecil medicine , ed 25. Philadelphia, 2016, Elsevier, Table 245-8.
Type Ia accounts for the majority of patients with PHP. Affected patients have a genetic defect of the α subunit of the stimulatory guanine nucleotide-binding protein (Gs α). This coupling factor is required for PTH bound to cell surface receptors to activate cyclic adenosine monophosphate (cAMP). Heterogeneous mutations of the Gs α gene have been documented; the gene is located on chromosome 20q13.2. Deficiency of the Gs α subunit is a generalized cellular defect and accounts for the association of other endocrine disorders with type Ia PHP. The defect is inherited as an autosomal dominant trait, and the paucity of father-to-son transmissions is thought to be a result of decreased fertility in males.
Tetany is often the presenting sign. Affected children have a short, stocky build and a round face. Brachydactyly with dimpling of the dorsum of the hand is usually present. The second metacarpal is involved least often. As a result, the index finger occasionally is longer than the middle finger. Likewise, the second metatarsal is only rarely affected. There may be other skeletal abnormalities such as short and wide phalanges, bowing, exostoses, and thickening of the calvaria. These patients often have calcium deposits and metaplastic bone formation subcutaneously. Moderate degrees of cognitive impairment, calcification of the basal ganglia, and lenticular cataracts are common in patients whose disease is diagnosed late.
Some members of affected kindreds may have the usual anatomic stigmata of PHP, but serum levels of calcium and phosphorus are normal despite reduced Gs α activity; however, PTH levels may be slightly elevated. Such patients have been labeled as having pseudopseudohypoparathyroidism or PHP1C . Transition from normocalcemia to hypocalcemia often occurs with increasing age of the patient. These phenotypically similar but metabolically dissimilar patients may be in the same family and have the same mutations of Gs α protein. It is not known what other factors cause clinically overt hypocalcemia in some affected patients and not in others. There is evidence that the Gs α mutation is paternally transmitted in pseudopseudohypoparathyroidism and maternally transmitted in patients with type Ia disease. The gene may be imprinted in a tissue-specific manner and have different methylation patterns .
In addition to resistance to PTH, resistance to other G-protein–coupled receptors for thyroid-stimulating hormone (TSH), gonadotropins, and glucagon can result in various metabolic effects. Clinical hypothyroidism is uncommon, but basal levels of TSH are elevated and thyrotropin-releasing hormone–stimulated TSH responses are exaggerated. Moderately decreased levels of thyroxine and increased levels of TSH have been demonstrated by newborn thyroid-screening programs, leading to the detection of type Ia PHP in infancy. In adults, gonadal dysfunction is common, as manifested by sexual immaturity, amenorrhea, oligomenorrhea, and infertility. Each of these abnormalities can be related to deficient synthesis of cAMP secondary to a deficiency of Gs α, but it is not clear why resistance to other G-protein–dependent hormones (corticotropin, vasopressin) is much less affected.
Serum levels of calcium are low, and those of phosphorus and alkaline phosphatase are elevated. Clinical diagnosis can be confirmed by demonstration of a markedly attenuated response in urinary phosphate and cAMP after intravenous infusion of the synthetic 1-34 fragment of human PTH (teriparatide acetate). Definitive diagnosis is established by demonstration of the mutated G protein.
Two boys have been reported with both type Ia PHP and gonadotropin-independent precocious puberty (see Chapter 578.7 ). They were found to have a temperature-sensitive mutation of the Gs protein. Thus, at normal body temperature (37°C), the Gs is degraded, resulting in PHP, but in the cooler temperature of the testes (33°C) the Gs mutation results in constitutive activation of the luteinizing hormone receptor and precocious puberty.
Affected patients have normal levels of G protein activity and a normal phenotypic appearance. These patients have tissue-specific resistance to PTH but not to other hormones. Serum levels of calcium, phosphorus, and immunoreactive PTH are the same as those in patients with type Ia PHP. These patients also show no rise in cAMP in response to exogenous administration of PTH. Bioactive PTH is not increased. The pathophysiology of the disorder in this group of patients is caused by paternal uniparental isodisomy of chromosome 20q and resulting GNAS1 methylation. This, along with the loss of the maternal GNAS1 gene, leads to PTH resistance in the proximal renal tubules, which leads to impaired mineral ion homeostasis.
Patients with acrodysostosis resemble those with PHP type Ia, but defects in the Gs α subunit are not present. Instead, in 1 subgroup of patients there is a defect in the gene encoding PRKAR1A , the cAMP-dependent regulatory subunit of protein kinase A that confers resistance to multiple hormones, including PTH. Another subgroup has a defect in a phosphodiesterase gene Pde4d . This subgroup also carries the phenotype of PHP type Ia but rarely exhibits the hormone resistance. Acroscyphodysplasia is a distinctive form of metaphyseal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho or cup deformity and is a phenotypic variation of PHP and acrodysostosis.