FAMILIAL ISOLATED HYPERPARATHYROIDISM - A DISTINCT GENETIC ENTITY WITH AN INCREASED RISK OF PARATHYROID CANCER

Familial isolated hyperparathyroidism (FIHP) is a rare heritable disor der characterized by hypercalcemia, inappropriately high PTH levels, a nd isolated parathyroid tumors with no evidence of hyperfunction of an y other endocrine tissues. To establish whether FIHP exists as a disti nct disease entity or represents a variant of any of the known multipl e endocrine neoplasia (MEN) syndromes, we tested 19 members of a large , well characterized family with FIHP in which the disease is transmit ted through 4 generations in an autosomal dominant fashion. Fourteen D NA markers at 10 polymorphic loci closely linked to the MEN1 locus on the long arm of chromosome 11 and 5 markers close to the MEN2A gene on chromosome 10 were tested using Southern blot analysis and polymerase chain reaction-based techniques. Additionally, two polymorphic marker s (Mir1 and Mir2) within the prepro-PTH gene on the short arm of chrom osome 11 were analyzed using denaturant gradient gel electrophoresis. Linkage was clearly excluded between FIHP and the MEN1 and MEN2A loci as well as to the PTH gene. Comparison of constitutional and tumor gen otypes showed that constitutional heterozygosity was retained for mark ers in the MEN1 and MEN2A regions as well as to the PTH gene in 4 tumo rs from 3 affected members. In 1 individual, a parathyroid carcinoma w as found after recurrence of hypercalcemia. We, therefore, propose tha t autosomal dominant FIHP can occur as a genetically and clinically di stinct entity with an increased risk of malignant transformation of pa rathyroid tumors.