Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

• Published in: Journal of endocrinological investigation 2023-04, Vol.46 (4), p.829-840
• Main Authors: Mazarico-Altisent, I., Capel, I., Baena, N., Bella-Cueto, M. R., Barcons, S., Guirao, X., Albert, L., Cano, A., Pareja, R., Caixàs, A., Rigla, M.
• Format: Article
• Language: English
• Subjects: Adenoma; Copy number; Cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-dependent kinase inhibitors; Cyclin-dependent kinases; DNA - genetics; DNA Copy Number Variations; Dysplasia; Endocrinology; Genetic analysis; Genetic screening; Genomes; Germ Cells - pathology; Germ-Line Mutation; Heterozygosity; Humans; Hyperparathyroidism; Hyperparathyroidism, Primary - diagnosis; Hyperparathyroidism, Primary - genetics; Hyperparathyroidism, Primary - pathology; Immunohistochemistry; Internal Medicine; Kinases; Loss of heterozygosity; Lymphocytes T; Medicine; Medicine & Public Health; Metabolic Diseases; Multiple endocrine neoplasia; Multiple Endocrine Neoplasia Type 1; Mutation; Neoplasms; Nucleotide sequence; Original; Original Article; Parathyroid; Phenotypes; Pituitary; Sequence analysis; Tumors; Uniparental disomy
• ISSN: 1720-8386; 0391-4097; 1720-8386
• DOI: 10.1007/s40618-022-01948-7

Purpose CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors ( CDKIs ) were found in some MEN1-like cases without the MEN1 mutation. 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 CDKIs germline 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 CDKN1B in 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 CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.