Pseudohypoparathyroidism

PHP is a heterogeneous group of disorders characterized by hormone resistance—the hallmark of which is PTH resistance. Typically, these patients present with hypocalcemia and hyperphosphatemia that is due to impaired target tissue responsiveness to PTH rather than PTH deficiency. Two genetically distinct forms of PHP type 1 have been described. The more common variant, termed PHP type la, is an autosomal dominant disorder with resistance to multiple hormones (PTH, thyroid-stimulating hormone, luteinizing hormone, gonadotropin hormone-releasing hormone) and a constellation of developmental defects termed Albright's hereditary osteodystrophy (AHO). These defects include short stature, obesity, round facies, brachymetacarpia, subcutaneous ossification, and mental deficiency,5 Patients with PHP type la have mutations in maternal GNAS1 alleles that abrogate expression or activity of Gs, the heterotrimeric G protein that couples receptors to activation of adenylyl cyclase.6 Identical mutations in paternal alleles are associated with AHO and normal hormone responsiveness, a variant termed pseudo-pseudohypoparathyroidism (PPHP).7

PHP type lb is a less common and clinically distinct variant of PHP that has also been linked to the GNAS1 locus.8-9 Subjects with PHP lb lack features of AHO, show renal resistance to PTH as the only manifestation of hormone resistance, and have normal Gsa activity in tissue. PHP lb arises as a result of an imprinting defect that affects expression of GNAS1 in the proximal renal tubule and is the basis for this disorder. Specifically, patients with PHP lb have paternal-specific patterns of cytosine methylation within differentially methylated regions of maternally inherited GNAS1 alleles.10 The specific genetic mutation(s) that accounts for this methylation defect is unknown.

Biochemically, PHP la and lb lead to functional hypoparathyroidism. Laboratory evaluation reveals hypocalcemia, hyperphosphatemia, and elevated levels of PTH (Table 59-2). In addition, individuals with PHP la may also manifest biochemical evidence of hypothyroidism, gonadotropin resistance, and growth hormone deficiency. In contrast, individuals with PPHP do not exhibit hormone resistance and have normal calcium, phosphorus, and PTH levels. Confirmation of the diagnosis of PHP la or lb can be accomplished by monitoring urinary cyclic adenosine monophosphate and phosphate excretion following infusion of PTH.11 Although a reliable diagnosis of PHP la may be made on clinical grounds, the molecular genetic diagnosis of PHP la requires identification of heterozygous inactivating mutations in GNAS1. This genetic test is now available at several centers. There is currently no commercially available genetic test for PHP lb.

The basic principles associated with the treatment of PHP are similar to those for postoperative hypoparathyroidism, with the mode of treatment being dictated by the severity of the hypocalcemia, the rapidity of development of the hypocalcemia, and the presence of signs and symptoms of hypocalcemia. Intravenous infusion of calcium is required in patients with acute hypocalcemic crises. Long-term maintenance therapy consists of oral administration of calcium and vitamin D.

TABLE 59-2. Classification of Pseudohypoparathyroidism

Disorder

Calcium

Phosphorus

PTH

Other Hormone Resistance

AHO

Erythrocyte G„a Levels

Genetic Defect

PHP type la

Low

High

High

TSH, LH, Gn-RH

Yes

50% reduced

Haploinsufficiency of

GNAS1 maternal allele

PPHP

Normal

Normal

Normal

None

Yes

50% reduced

Haploinsufficiency of

GNAS1 paternal allele

PHP type lb

Low

High

High

None

No

Normal

GNAS1 imprinting defect

TSH = thyroid-stimulating hormone; LH = luteinizing hormone; Gn-RH = gonadotropin-releasing hormone; PHP = pseudohypoparathyroidism; PPHP = pseudo-pseudohypoparathyroidism; AHO = Albright's hereditary osteodystrophy.

TSH = thyroid-stimulating hormone; LH = luteinizing hormone; Gn-RH = gonadotropin-releasing hormone; PHP = pseudohypoparathyroidism; PPHP = pseudo-pseudohypoparathyroidism; AHO = Albright's hereditary osteodystrophy.

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