Hereditary Primary Hyperparathyroidism

Key Points

· Hereditary forms of primary hyperparathyroidism (PHPT) account for up to 10% of cases of PHPT and include several multiple tumor syndromes or the occurrence of PHPT as an isolated endocrinopathy.

· Multiple tumor syndromes associated with hereditary PHPT include multiple endocrineneoplasia (MEN) type 1 (MEN1), MEN type 2A, MEN type 4, and the hyperparathyroidism–jaw tumor (HPT-JT) syndrome, each inherited in an autosomal dominant manner.

· Familial isolated hyperparathyroidism (FIHP) describes the familial occurrence of PHPT without the additional manifestations associated with hereditary PHPT syndromes. In a majority of FIHP kindreds, the genetic basis of the disorder is undefined, although 15% to 20% of families harbor activating mutations in theGCM2gene.

· Kindreds manifesting apparent FIHP, but harboring pathogenic variants inMEN1orCDC73genes, should usually be diagnosed and managed in accordance with the associated PHPT syndrome (ie, MEN1 and HPT-JT, respectively).

· It is important to distinguish PHPT from FHH, which has a similar biochemical phenotype to PHPT but is characterized by hypocalciuria. Three forms of FHH are recognized, resulting from pathogenic variants in CASR(FHH1),GNA11(FHH2), andAP2S1(FHH3).

· Genetic testing should be offered to patients in whom hereditary PHPT or FHH is suspected to improve clinical management and to identify other family members who maybe at risk of disease.