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Familial Isolated Hyperparathyroidism Maps to the Hyperparathyroidism-Jaw Tumor Locus in 1q21-q32 in a Subset of Families¹

Department of Molecular Medicine (B.T.T., F.F., F.K.W., C.L.), Department of Pathology (A.H., L.G.), Department of Surgery (K.S., L-O.F.), Karolinska Hospital, Stockholm, S-17176 Sweden; Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, 2065 Australia; Department of Clinical Genetics (S.K.), Oulu University Hospital, Oulu, 90220 Finland; Department of Internal Medicine (E.K-H.), Seinäjoki Central Hospital, Seinäjoki, 60220 Finland; Department of Surgery (J.N.), Huddinge Hospital, S-14186 Sweden

Address correspondence and requests for reprints to: Bin Tean Teh M.D., Ph.D., Department of Molecular Medicine, Endocrine Tumor Unit, CMM L8:01, Karolinska Hospital, S-171 76 Stockholm, Sweden; E-mail: Bin.Teh{at}cmm.ki.se

Approximately 70 families with familial isolated hyperparathyroidism (FIHP) have been reported. Whether it is a separate entity or a variant of multiple endocrine neoplasia type 1 (MEN1 at 11q13) or hyperparathyroidism-jaw tumor (HPT-JT or HRPT2 at 1q21-32) syndrome is not known. We describe here 3 unreported families with familial primary hyperparathyroidism and evaluate their clinical, pathological, and genetic profiles. Biochemical and radiological screenings for MEN1 were negative for all families. In 2 families with a total of 10 affected cases and 3 female obligate carriers, there is no evidence of jaw or renal lesions despite careful radiological investigations. In both families the disease was linked to the 1q21-q32 region with the maximum logarithm of the odds (lod) scores of 3.10 and 3.43 for markers D1S222 and D1S249 respectively, at recombination fraction of 0. In 1 family 2 types of parathyroid pathology were found: 3 of chief cell type and 1 of oxyphil/oncocytic cell type. Two chief cell tumors and 1 oxyphil tumor were found to have loss of heterozygosity (LOH) involving loss of the wild-type alleles for chromosome 1q markers. In the third family, with 4 affected siblings, a parathyroid carcinoma and 2 cases of polycystic kidney disease were found. The parathyroid carcinoma also showed loss of heterozygosity in the 1q region. In conclusion, we found that the hyperparathyroidism traits in a subset of FIHP families are linked to the 1q21-32 markers in the HRPT2 region. We describe the spectrum of parathyroid disease in 1q-linked families involving 3 different types of pathology and demonstrate for the first time loss of wild-type alleles in these parathyroid tumors. Taken together, the results suggest that some of the FIHP are a variant of HPT-JT and that the gene involved is a tumor suppressor gene. .

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