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

Abstract

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.

Keywords: Cyclin dependent kinase inhibitors; Multiple endocrine neoplasia type 1; Multiple endocrine neoplasia type 4; Parathyroid; Primary hyperparathyroidism.

Fig. 1

Immunostaining with p27/kip1 of parathyroid adenomas from cases 1 (a) and 2 (b). Absence of nuclear expression in adenoma cells. × 400

Fig. 2

Pedigreeandtumors of probands (withconfirmatedmutation) andtheirrelatives. a Case 1, variant c.280_281delinsG, p.(Pro94Alafs*25) CDKN1B; b case 2, variant c.169C > T, p.(Gln57*) CDKN1B; c case 3, variant c.319 T > G, p.(Leu107Val) CDKN2C. Generation number is indicated with roman numerals. Arrows indicate index case; circle, female; square, male; double line below descent line, no offspring; empty symbol, unaffected family member; slashed symbol, deceased; + , mutation positive; −, mutation negative; ?, no mutation test performed; filled upper right quadrant, PHPT; filled upper rightspot, history of nephrolithiasis, renal colics or hypercalcemia; filled upper left quadrant, pituitary adenoma; filled lower right quadrant, neuroendocrine tumor; filled lower left quadrant, tumor unspecified

Fig. 3

Genome-wide DNA study of loss of heterozygosity (LOH) and copy number variation (CNV) in case 3. CNV track shows a gain of chromosome 1 and B-allele frequency (BAF) track shows uniparental disomy of whole chromosome 1