Molecular genetics in familial primary hyperparathyroidism: A study from Northern India

Purpose Familial primary hyperparathyroidism (FPHPT) accounts for about 10% of cases, owing to germline mutations in specific genes. The genetic profile of FPHPT has not been studied in our population. This is most likely the first study in our region to examine the genetic profile to search for any other PHPT-related tumours in these patients. Methods This prospective cross-sectional study was conducted in the Department of Endocrinology SKIMS from February 2021 to February 2023, in which 103 patients diagnosed with PHPT were taken. A customised gene panel (CDC 73, MEN 1/2A/4 mutation) using next-generation sequencing (NGS)was performed in 39 patients with strong suspicious of FPHT based on age < 35 years, multiglandular disease, cystic parathyroid adenoma (PA), parathyroid carcinoma (PC), suspicious of MEN 1/2A/4 syndrome. We tried to compare the clinical characteristics of individuals with those of positive and negative genetic tests. Results Germline variants were observed in 11/39 (28.2%). 7(17.9%) patients tested positive for MEN 1 mutation while 4(10.2%) patients tested positive for CDC 73 mutation; however, no one tested positive for MEN 2A/4 mutation. 4 patients with MENI syndrome had c.1366-2A > G p? while as 1 had c.247_250del CTGT(p.Ile85SerfsTer33), 1 had c.1763C > T (p.S588L), 1 had c.415 C > T(p.H139Y). Out of 7 who tested positive for MEN 1 mutation, 2 patients had microprolactinomas, 2 had multi-glandular disease, 1 had recurrent disease, 1 had persistent disease, 1 had gastric neuroendocrine tumour. In contrast, out of 4 who tested positive for CDC 73 mutation, 2 had familial PHPT, 1 had multiple uterine fibroids, and 1 had bilateral renal cysts. In the case of patients with CDC 73 mutations, 1 patient had codon 222 CGA (Arg) > TGA, 1 had c.415C > T at codon 139 (R139X), 1 had c.687_688dellAG (p.Arg229Serfs37), other had c76delA (p.Ile26SerfsX11). These were all reported mutations. Age, greater serum calcium, higher ALP and more skeletal involvement were statistically significant characteristics of those who tested positive for the mutation. Conclusion The observed prevalence of genetic variants in our population was remarkably higher than in other populations. Recognition of predisposing germline mutations can have significant implications in patient management, such as preventing PC in HPT-JT and optimizing the approach to parathyroidectomy in MEN 1. So, we strongly recommend genetic screening in PHPT patients with high-risk features.