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.

Update on the current management of persistent and recurrent primary hyperparathyroidism after parathyroidectomy

“…However, CDC73 mutations can be an early developmental event from PA to PC[ 42 ]. Germline mutations in CDKIs (the CDKN1B gene and CDKN2C g ene) should be included in the genetic testing of patients with pHPT[ 43 ].…”

Genetics of hereditary forms of primary hyperparathyroidism

“…A recent case series and comprehensive literature review of MEN4 reported a total of 32 unique CDKN1B variants associated with MEN4 (with six located in the 5′UTR) from 22 studies [ 13 ]. Since then, a further two unique CDKN1B variants have been reported in association with familial PHPT [ 14 ]. The overall prevalence of PHPT in the entire cohort was ~ 42%, with 53.2% diagnosed with PTHP by the age of 60 years [ 13 ].…”

“…e HPT-JT CDC73 1q31.2 Parafibromin a ? f PHPT, ossifying fibromas of the jaw 95% PHPT primary hyperparathyroidism (PHPT), PNET pancreatic neuroendocrine tumor, MTC medullary thyroid carcinoma, PA pituitary adenoma a Loss of function b Gain of function c Overall, 76 cases have been reported [ 13 , 14 ] d Germline MAX mutations and pheochromocytomas in association with other endocrine tumors have been reported in 11 cases (PHPT, pituitary adenoma, and PNETs) [ 15 – 22 ] e PHPT has been reported in four cases in patients with MEN5 f CDC73 mutations are reported to account for ~ 12% of patients with hereditary PHPT [ 23 , 24 ] * There are three classical types of MEN2 syndrome, as follows: MEN2A (now referred to as MEN2), MEN2B (now referred to as MEN3) which is characterized by the occurrence of aggressive MTC, and pheochromocytoma in association with a Marfinoid habitus, mucosal neuromas, medullated corneal nerve fibers, and intestinal ganglioneuromas; and familial MTC, in which MTC is the sole manifestation. MEN2 has also been reported to be associated with cutaneous lichen sclerosis and Hirschsprung’s disease

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Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort

“…MEN2A is caused by activating variants in the proto-oncogene RET and typically presents as medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumours (20-30%) with a lower penetrance ( 9 ). Patients with MEN4 express MEN1-like milder phenotypes due to CDKN1B germline variants and, less frequently, other non-endocrine neoplasms such as breast cancer, prostate cancer, colon cancer, papillary thyroid carcinoma, angiomyolipoma, and meningioma, although only approximately 100 cases have been reported to date ( 10 , 11 ). Variants in other cyclin-dependent kinase inhibitors ( CDKIs ), such as CDKN1A , CDKN2B , and CDKN2C , have been described in patients with the MEN1 phenotype or suspected FHPT, despite limited data ( 11 , 12 ).…”

“…Patients with MEN4 express MEN1-like milder phenotypes due to CDKN1B germline variants and, less frequently, other non-endocrine neoplasms such as breast cancer, prostate cancer, colon cancer, papillary thyroid carcinoma, angiomyolipoma, and meningioma, although only approximately 100 cases have been reported to date ( 10 , 11 ). Variants in other cyclin-dependent kinase inhibitors ( CDKIs ), such as CDKN1A , CDKN2B , and CDKN2C , have been described in patients with the MEN1 phenotype or suspected FHPT, despite limited data ( 11 , 12 ). Recently, germline variants of the MAX tumour suppressor gene have been associated with a new entity, MEN5.…”