[Alon]

566 Pseudohypoparathyroidism (Albright Hereditary Osteodystrophy)
In contrast to the situation in hypoparathyroidism, in pseudohypoparathyroidism (PHP), 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.
Type IA.
This type 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 . This coupling factor is required for PTH bound to cell surface receptors to activate cyclic adenosine monophosphate (AMP). Heterogeneous mutations of the Gsα gene have been documented; the gene is located on chromosome 20q13.2. Deficiency of the Gsα 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 due to 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 2nd metacarpal is involved least often. As a result, the index finger may occasionally be longer than the middle finger. Likewise, the 2nd 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 frequently have calcium deposits and metaplastic bone formation subcutaneously. Moderate degrees of mental retardation, calcification of the basal ganglia, and lenticular cataracts are common in patients who are diagnosed late.
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Some members of affected kindreds may have the usual anatomic stigmata of PHP, but serum levels of calcium and phosphorus are normal despite reduced Gsα activity; however, PTH levels may be slightly elevated. Such patients have been labeled as having pseudopseudohypoparathyroidism. Transition from normocalcemia to hypocalcemia often occurs with increasing age of the patient. These phenotypically similar but metabolically dissimilar patients may occur in the same family and have the same mutations of Gsα protein. It is not known what other factors cause clinically overt hypocalcemia in some affected patients and not in others. There is some evidence to suggest that the Gsα 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.
In addition to resistance to PTH, resistance to other G protein-coupled receptors for thyroid-stimulating hormone (TSH), gonadotropins, and glucagon may 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 detected 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 cyclic AMP secondary to a deficiency of Gsα, but it is not clear why resistance to other G protein-dependent hormones (e.g., 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 cyclic AMP after intravenous infusion of the synthetic 1-34 fragment of human PTH (teriparatide acetate), but this compound is no longer commercially available in the United States. Definitive diagnosis is established by demonstration of the mutated G protein.
TYPE IA WITH PRECOCIOUS PUBERTY.
Two boys have been reported with both type IA PHP and gonadotropin-independent precocious puberty (see Chapter 556.6). 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.
Type IB.
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 cyclic AMP 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.
Type II.
This type of pseudohypoparathyroidism has been detected in only a few patients and differs from type I in that the urinary excretion of cyclic AMP is elevated both in the basal state and after stimulation with PTH, but phosphaturia does not increase. Phenotypically, patients are normal and hypocalcemia is present. The defect appears to be distal to cyclic AMP because it is normally activated, but the cell is unable to respond to the signal.

Printed from: Nelson Textbook of Pediatrics (on 24 April 2006)