AUTOSOMAL-DOMINANT PRIMARY HYPERPARATHYROIDISM AND JAW TUMOR SYNDROME-ASSOCIATED WITH RENAL HAMARTOMAS AND CYSTIC KIDNEY-DISEASE - LINKAGE TO 1Q21-Q32 AND LOSS OF THE WILD-TYPE ALLELE IN RENAL HAMARTOMAS

Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autos omal dominant disease (OMIM 145001) that has recently been mapped to c hromosomal region 1q21-q32 (HRPT2). Here we report two families with H PT-JT syndrome in which adult renal hamartomas or cystic kidney diseas e were prominent associated features, possibly representing a new phen otypic variant of the HPT-JT syndrome. In the first family, renal lesi ons were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second fa mily, ST was found in three of the five affected individuals and two a ffected members also exhibited polycystic kidney disease. The possibil ity of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resul ting in predominantly male-affected cases was evident in the two famil ies. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds wa s linked to five markers in the 1q21-q32 region (logarithm-of-odds sco res: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was exclud ed. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from >60 t o similar to 34 centimorgans. Loss of heterozygosity was studied in se ven renal hamartomas from two affected individuals in the first family , as well as in a jaw tumor and a parathyroid tumor from the second fa mily. All renal hamartomas showed loss of heterozygosity at the 1q21-q 32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor su ppressor gene in this region.