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Familial Isolated Hyperparathyroidism Is Rarely Caused by Germline Mutation in HRPT2, the Gene for the Hyperparathyroidism-Jaw Tumor Syndrome

Metabolic Diseases Branch (W.F.S., S.K.A., S.J.M.), National Institute of Diabetes and Digestive and Kidney Diseases, and Cancer Genetics Branch (C.M.R., J.D.C.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; and Departments of Medicine, Physiology, and Human Genetics (G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada

Address all correspondence and requests for reprints to: Dr. William F. Simonds, Building 10, Room 8C-101, 10 Center Drive, MSC 1752, Bethesda, Maryland 20892-1752. E-mail: wfs{at}helix.nih.gov.

Familial isolated hyperparathyroidism (FIHP) can result occasionally from the incomplete expression of a syndromic form of familial hyperparathyroidism (HPT), specifically multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric hypercalcemia, or the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The cause of FIHP has not been identified in the majority of families. We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. All families had negative clinical testing for MEN1, hypocalciuric hypercalcemia, and HPT-JT and negative mutational screening of MEN1 and CASR, the gene for the calcium-sensing receptor. Thus, an extended effort was made to exclude each of the principal syndromic causes of FIHP. The families were characterized by young probands (42 ± 3 yr) and occasionally unusual parathyroid histology, including four families with one case of parathyroid cancer. We had speculated that there was a high frequency of occult mutation in HRPT2 among such carefully screened kindreds. This hypothesis became testable with the recent identification of that gene. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2 (679insAG); this mutation predicts premature truncation of its gene product, parafibromin, and thus its presumed inactivation. Even accounting for families with one of the three occult syndromes and false negative biochemical or DNA testing, these results indicate that an unexpectedly large fraction of FIHP has currently unrecognized causes.

This work was supported in part by grants (to G.N.H.) from the Canadian Institutes of Health Research (MT-9315) and The Kidney Foundation of Canada.

Abbreviations: CaSR, Calcium-sensing receptor; CASR, CaSR gene; FHH, familial hypocalciuric hypercalcemia; FIHP, familial isolated hyperparathyroidism; HPT, hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumor syndrome; HRPT2, the gene for HPT-JT; MEN1, multiple endocrine neoplasia type 1; MEN1, gene for MEN1; MEN2A, multiple endocrine neoplasia type 2A; MIM, Mendelian Inheritance in Man.

¹ The six-digit number is the entry number for the disorder in Mendelian Inheritance in Man (MIM) (67 ). The continuously updated online version (Online Mendelian Inheritance in Man) is accessible from the National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, through the World Wide Web (http://www. ncbi. nlm.nih.gov/omim/).

² The difference in the means of proband age of onset between HPT-JT and FIHP groups did not reach statistical significance with a q value of 2.9 in the Tukey-Kramer multiple comparisons test (q values greater than 3.9 are associated with P < 0.05).

³ A kindred with nonsyndromic familial isolated hyperparathyroidism has been reported with five affected members that lack mutations in the coding regions of MEN1, CASR, and RET and with exclusion of linkage to MEN1, CASR, and HRPT2 (68 ). The trait was not studied at other FHH loci (52 53 ).

⁴ Kindred 28,200 has eight known affected members in three generations (Table 1) (1 31 ); however, leukocyte DNA is available from only three surviving affected individuals precluding linkage analysis.

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