Endocrine Abstracts

Introduction: Familial and hereditary forms of primary hyperparathyroidism (PHPT) represent a small minority of all patients with PHPT (5 – 10%). The surgical approach is different in such cases than in sporadic PHPT. Hereditary PHPT may be syndromic (multiple endocrine neoplasia: MEN – type 1, 2A or 4 and others) or nonsyndromic (familial isolated PHPT). The aim of the study was to identify and describe hereditary and familial forms of PHPT in patients referred to parathyroid surgery in our centre at University Hospital Motol Prague.

Patients and Methods: 370 patients underwent parathyroidectomy for PHPT from January 2020 until December 2021. Familial PHPT was defined as the occurrence of PHPT at least in two first-degree relatives. Genetic testing was recommended in patients I) with familial PHPT, II) with PHPT onset ≤ 40 years of age, III) with recurrent disease, IV) with clinical presentation of MEN1 (PHPT and/or pituitary adenoma and/or gastroenteropancreatic neuroendocrine tumor). A total of 45 patients (33 female, 14 male) underwent genetic testing. The median age of PHPT diagnosis was 36 (range 15 - 62). 6 patients who were recommended for genetic testing did not participate. Genetic analysis was performed by next-generation sequencing of DNA obtained from peripheral blood. We sequenced the all exons and UTR regions of these genes: AIP, AIRE, AP2S1, CaSR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GATA3, GCM1, GCM2, GNA11, MEN1, PTH, RET, STX16.

Results: We identified 11 different germline causal mutations in the MEN1 gene in 12 patients (2 patients were siblings): NM_130799.2:p.Pro32Arg; Asp70ProfsTer51; Ile85SerfsTer33; Asp123 MetfsTer31; Gln209Ter; Gln258Ter; Thr210SerfsTer13; Gln450His; Trp471Ter, c.1049+1G >C (change in mRNA restriction) and the loss of the entire MEN1 allele in one patients. Moreover we found a mutation in RET gene: NM_020975.4:p.Cys611Tyr. A variant of uncertain significance was identified in 5 patients.

Conclusion: Hereditary and familial forms of PHPT were found in 16 (4%) of all patients who underwent parathyroidectomy for PHPT in our centre. There may exist undiagnosed hereditary PHPT among those who have not been genetically tested. Germline mutations were detected in 13 patients (12 in MEN 1, 1 in RET – MEN 2A). Familial PHPT without detected germline mutation was found in 3 patients. 2 of them had variant of uncertain significance and further familial segregation study will be provided. Supported by Ministry of Health Czech Republic - DRO (Institute of Endocrinology - EÚ, 00023761)