Search

Purpose: CDKN1Bmutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). Methods: During genetic screening for familial hyperparathyroidism, three novel CDKIsgermline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. Results: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1Bin cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. Conclusion: Germline mutations in CDKIsshould be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.