A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome

Familial primary hyperparathyroidism is the main feature of 2 familial endo crine neoplasia syndromes: multiple endocrine neoplasia type 1 (MEN 1) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The latter is a recently d escribed syndrome that has been associated with ossifying fibroma of the ja w and various types of renal lesions, including benign cysts, Wilms' tumor, and hamartomas. To further illustrate the natural history of this syndrome , we describe a large, previously unreported Dutch kindred in which 13 affe cted members presented with either parathyroid adenoma or carcinoma; in 5 a ffected individuals, cystic kidney disease was found. Additionally, pancrea tic adenocarcinoma, renal cortical adenoma, papillary renal cell carcinoma, testicular mixed germcell tumor with major seminoma component, and Hurthle cell thyroid adenoma were also identified. Linkage analysis of the family using MEN1-linked microsatellite markers and mutation analysis excluded the involvement of the MEN1 gene. Using markers from the HPT-JT region in 1q25 -31, cosegregation with the disease was found, with a maximum logarithm of odds score of 2.41 obtained for 6 markers using the most conservative calcu lation. Meiotic telomeric recombination between D1S413 and D1S477 was ident ified in 3 affected individuals, and when combined with previous reports, d elineated the HPT-JT region to 14 centimorgan. Combined comparative genomic hybridization and loss of heterozygosity data revealed complex genetic abn ormalities in the tumors, suggesting different possible genetic mechanisms for the disease. In conclusion, we report a family with hyperparathyroidism Linked to chromo some 1q, and exhibiting several types of renal and endocrine tumors that ha ve not been previously described.