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Key Points

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  • Disease summary:

    • Pseudohypoparathyroidism is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH).

    • This spectrum of disorders includes pseudohypoparathyroidism type Ia (PHP-Ia), pseudopseudohypoparathyroidism (PPHP), pseudohypoparathyroidism type Ib (PHP-Ib), pseudohypoparathyroidism type Ic (PHP-Ic), and progressive osseous heteroplasia (POH).

    • The lack of responsiveness to parathyroid hormone results in low serum calcium, high serum phosphate, and inappropriately high serum parathyroid hormone.

    • PTH resistance, the most clinically evident abnormality, usually develops over the first years of life, with hyperphosphatemia and elevated PTH generally preceding hypocalcemia. Renal function is conserved through life and so seems to be bone mineral density (BMD).

    • Individuals with Albright hereditary osteodystrophy (AHO) have short stature, characteristically shortened fourth and fifth metacarpals, rounded face, ectopic ossifications, and often mild mental retardation.

  • Hereditary basis:

    • PHP-Ia is caused by inactivating mutations in Gs gene and is inherited in an autosomal dominant manner. Patients inheriting the disease from the mother display all signs of AHO together with multihormone resistance, while patients inheriting the disease from the father have AHO with no evidence of resistance to hormone action (PPHP).

    • In PHP-Ib the defect is often sporadic but it may occasionally present as familial, with an autosomal dominant pattern of transmission (AD-PHP-Ib). Both sporadic and familial PHP-Ib are now known to be associated with disturbed imprinting at the GNAS locus.

    • POH is an autosomal dominant disorder caused by inactivating GNAS mutations of paternal inheritance.

  • Differential diagnosis:

    • PHP type I is classically differentiated according to the presence (PHP-Ia and PHP-Ic) or absence (PHP-Ib) of AHO (Table 66-1).

    • In PHP-Ia and Ic patients resistance to hormones is not limited to PTH, but often includes thyroid-stimulating hormone (TSH), gonadotropins, and growth hormone-releasing hormone (GHRH), and patients may develop resistance to these different hormones with a variable severity and variable time course. Patients with PHP-Ia have been shown to have a partial deficiency (about 50%) of Gs activity due to a reduction in mRNA and protein, whereas this defect is absent in patients with PHP-Ic.

    • Patients showing the physical features of AHO without any evidence of PTH resistance are described as affected by PPHP. PPHP may be present either in kindreds in which PHP is present or as an isolated defect (AHO-like syndrome).

    • The molecular defect causing POH is the same as that causing PPHP. However, the observation that POH patients do not usually present with AHO, suggests that POH may be an extreme end of the spectrum of the AHO features seen in PPHP.

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Table Graphic Jump Location
Table 66–1Genetic Differential Diagnosis

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