Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

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Abstract
Background A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism–jaw tumour syndrome (HPT‐JT). Aim/patients and methods We investigated the involvement of the HRPT2, MEN1 and CASR genes in 11 provisional FIHP families and two HPT‐JT families. Results Germline mutations of HRPT2 were found in two of the 11 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 518–521del and 62–66del, respectively. In a patient with HPT‐JT, a de novo germline mutation of 39delC was detected. Novel somatic HRPT2 mutations of 70–73del and 95–102del were found in two of five parathyroid tumours in a family with a 518–521del mutation. Biallelic inactivation of HRPT2 by a combination of germline and somatic mutation was confirmed in the parathyroid tumours. The finding that two families diagnosed with FIHP carried HRPT2 mutations suggests that they have occult HPT‐JT. In the remaining 10 families, one family had a missense MEN1 mutation. No mutations of CASR were detected. Conclusion Our results confirm the need to test for HRPT2 in FIHP families, especially those with parathyroid carcinomas, atypical adenomas or adenomas with cystic change.