Identification of the genes reponsible for syndromes of inherited neoplasia frequently provides insight into critical pathways governing cellular growth, proliferation and signalling. Approximately 5% of primary hyperparathyroidism (HPT) is familial in nature. Although cases of familial isolated hyperparathyroidism (FIH) constitute a significant fraction of this group, the causes FIH have not been systematically addressed in any large series. The few previous studies of kindreds with FIH did not evaluate for the hyperparathyroidism-jaw tumor syndrome (HPT-JT), and did not exclude occult multiple endocrine neoplasia type 1 (MEN1) and occult familial hypocalciuric hypercalcemia (FHH) with full clinical and biochemical evaluations. Thirty-six kindreds with apparently isolated hyperparathyroidism were evaluated with clinical, biochemical and gene mutational tests designed to recognize MEN1, HPT-JT, and FHH. There was an unexpectedly high or low frequency of each of those 3 known syndromes among 36 provisionally-diagnosed FIH kindreds. None of the 36 kindreds had MEN1. This finding refuted earlier suggestions that occult MEN1 was likely to be the commonest cause of the FIH phenotype. Three kindreds among the 36 had HPT-JT. Parathyroid cancer is common in the HPT-JT syndrome, and was present in 5 of 14 affected members (36%). Five of the 36 kindreds had likely inactivating mutation in the calcium-sensing receptor gene (CASR) and some other features similar to those in FHH. However, among the 5 families with a CASR mutation, 3 probands were hypercalciuric, and the 2 other kindreds contained hypercalcemic members with kidney stones. This indicates that atypical cases with FHH-like disorders remain at risk for unsuccessful parathyroidectomy and demonstrate a high yield and practical benefit for CASR mutation testing. Twenty-eight FIH kindreds showed no clear syndromic features. The spectrum of manifestations in these 28 FIH kindreds included some non-parathyroid tumors. No tumor association was consistent or distinctive enough to define a new clinical category. It is expected that selected families from the FIH subgroup will ultimately be reclassified among the 3 syndromic groups. The future ability to perform mutation testing for HPT-JT should clarify whether any of the remaining 28 FIH families have HPT due to currently unrecognized causes. To this end the Metabolic Diseases Branch is participating in an international collaborative effort to identify the gene responsible for HPT-JT on the long arm of chromosome 1 using a positional candidate approach.
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