家族性副甲状腺機能亢進症として診断された家系における HRPT2 遺伝子の解析

Familial isolated hyperparathyroidism (FIHP) has an estimated frequency of approximately 1% among all cases of primary hyperparathyroidism. FIHP is an autosomal dominant disorder that can result from incomplete expression of a syndromic form of multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), familial hypocalciuric hypercalcaemia (FHH), hyperparathyroidism-jaw tumor (HPT-JT) syndrome or from still unrecognized causes.
　HPT-JT is predisposed to parathyroid tumors, fibro-osseous lesions of the mandible and maxilla, and renal cysts. Interestingly, it is associated with a high incidence of parathyroid carcinoma in contrast to sporadic and other familial forms of primary hyperparathyroidism. The gene whose inactivation is directly associated with the pathogenesis of HPT-JT syndrome has been identified as the tumor suppressor gene HRPT2. In addition, somatic mutations of HRPT2 have been frequently found in patients with sporadic parathyroid carcinoma.
　We investigated the involvement of the HRPT2, MEN1 and calcium sensing receptor (CASR) genes in 10 provisional FIHP families and two HPT-JT families. Germline mutations of HRPT2 were found in two of the 10 FIHP families and one of the two HPT-JT families. One FIHP family with parathyroid carcinoma and atypical adenomas and another FIHP family with cystic parathyroid adenoma had novel frameshift mutations of c.518-521del and c.62-66del, respectively. In a patient with HPT-JT, a de novo germline mutation of c.39delC was detected. Novel somatic HRPT2 mutations of c.70-73del and c.95-102del were found in two of five parathyroid tumors in a family with a c.518-521del mutation. Biallelic inactivation of HRPT2 by a combination of germline and somatic mutation was confirmed in the parathyroid tumors. The finding that two families diagnosed with FIHP carried HRPT2 mutations suggests that they have occult HPT-JT.
　In conclusion, genetic analysis is important for diagnosing HPT-JT.