Familial isolated primary hyperparathyroidism in a large Georgian-Jewish kindred: Genetic studies

Familial hyperparathyroidism occurs in the context of multiple endocrine neoplasia type 1, 2A (MEN1, MEN2A), and hyperparathyroidism-jaw tumor syndrome (HPT-JT or HRPT2). When no additional phenotypic features can be demonstrated the term familial isolated hyperparathyroidism (FIHP) is used. FIHT is genetically heterogeneous, with mutations in and/or linkage to several genes and loci previously shown in different families: MEN1, calcium-sensing receptor gene (CaSR), and the HPRT2 locus. We describe a three-generation Jewish kindred of Russian-Georgian origin with autosomal dominant inheritance of primary hyperparathyroidism (HPT). Five of 13 members had hyperparathyroidism and nephrolithiasis, and in one individual four hyperplastic parathyroid glands were resected. No phenotypic features suggestive of MEN1, MEN2 or HPT-JT were detected in any affected member. Mutational analysis of the coding regions of the MEN1 and CaSR genes as well as the predominant MEN2A mutations in the RET protooncogene, and linkage analyses with markers located at 11q13 (MEN1), 1q25-q31 (HRPT2) and 3q13.3-q21 (CaSR) were performed. No mutations were detected in the MEN1, CaSR and the relevant regions of the RET protooncogene in affected members. In addition, analysis performed with polymorphic markers close to MEN1, HRPT2 and CaSR excluded these loci in this family. We conclude that in this family, a yet unidentified gene is responsible for FIHP.