Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with familial isolated hyperparathyroidism.

Objectives: Familial hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2A), hyperparathyroidism-jaw tumour (HPT-JT) syndrome and familial isolated hyperparathyroidism (FIHP). It is unclear whether the latter is a distinct genetic entity or a variant of MEN1 or HPT-JT, where, because of reduced penetrance, only primary hyperparathyroidism (PHPT) is present. In the present study, we describe two unrelated Italian kindreds with FIHP, in which the clinical, histopathological and genetic analyses of the MEN1 gene and HPRT2 locus at 1q21-32 suggest that both might be a variant of MEN1 and HPT-JT syndromes.
Patients and Design: We studied 16 members, aged 14-50 years, of two unrelated kindreds with FIHP. Genomic DNA was isolated from peripheral blood leucocytes in all family members, and from parathyroid tissue in those who underwent parathyroidectomy.
Measurements: Ionized calcium and PTH were measured in all family members. The nine coding exons and 16 splice junctions of the MEN1 gene from constitutional DNA were amplified by the polymerase chain reaction (PCR) and sequenced. Parathyroid glands were obtained from five subjects. Allelic deletions (loss of heterozygosity, LOH) of chromosomes 11q13 and 1q21-q32 were assessed using PYGM and D11S449, and D1S215, D1S222, D1S428, D1S412, D1S413 and D1S477, respectively. Forward primers were conjugated with 5' fluorescent dye. PCR products were analysed using an ABI PRISM 310 sequencer.
Results: Five members of family 1 and three of family 2 had PHPT. A heterozygous deletion of 1 bp of the MEN1 gene in exon 10 (1785delA) was found in affected members of family 1. No MEN1 gene mutation was found in any member of family 2. LOH at 11q13 was observed in family 1 tumours, but not in those from family 2. Studies at 1q21-32 showed LOH in two family 2 tumours, whereas a retained heterozygosity was found in the remaining member. No LOH at 1q21-32 was found in family 1 tumours. The pathology of family 1 showed chief cell hyperplasia with a diffuse-nodular pattern of growth. Cut surface showed no cystic structures. Typical parathyroid adenoma was diagnosed in one member of family 2 and atypical adenoma in the remaining two. These tumours showed cystic structures.
Conclusions: In conclusion, we describe two unrelated kindreds with FIHP which, on the basis of histopathological and genetic studies, could be labelled as variants of the MEN1 and HPT-JT syndromes, respectively. Therefore, an extensive analysis of the genes involved in these diseases should be performed in families with familial isolated hyperparathyroidism to identify the subset linked to the MEN1 gene or to the HPRT2 locus.