Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases

Abstract

Context The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment. Objective To expand current knowledge of the MEN4 phenotype including assessment of penetrance. Design This is a case report and a brief review of previously published MEN4 cases. Patients We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene. Main Outcome/Result The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors. Conclusion Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.

Clinical and Molecular Genetics of Primary Hyperparathyroidism

“…The characterization of CDKN1B as a susceptibility gene for the development of primary parathyroid tumors is supported by recent evidence [68,71,72]. Thus CDKN1B is a valid candidate for which germline mutation may provide an etiology for some cases of familial HPT, including kindreds with MEN1-like features but negative for germline MEN1 mutation.…”

“…Since the original report by Pellegata and co-workers [59], several groups have investigated a role for CDKN1B mutation in parathyroid neoplasia. Apart from the demonstration of HPT linked to CDKN1B mutation in monozygotic twins [62], none of the studies of CDKN1B mutation-positive kindreds expressing MEN1-like tumors but lacking MEN1 germline mutation, and thus characterized by the MEN4 designation, had identified kindreds that include more than one genetically unique member with HPT proven to segregate with germline CDKN1B mutation [59,[62][63][64][65][66][67][68][69][70], until a recent report by Frederiksen et al [71]. The latter study described a large Danish family in which HPT occurred in 13 carriers of a germline frameshift CDKN1B mutation spanning two generations [71].…”

Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas

“…Expression of p27 is also regulated by menin suggesting that mechanisms of tumorogenesis of MEN1 and 4 may be interconnected [51]. To date, 42 cases with 17 different mutations have been reported, the majority of them being missense, but also frameshift and nonsense mutations [48,52]. They generally lead to faster p27 degradation, reduced binding to interacting partners and decreased nuclear translocation of p27 [51].…”

Hereditary Pituitary Tumor Syndromes: Genetic and Clinical Aspects

“…Until 2019, only 29 MEN4 cases were reported 34 . Very recently, Frederiksen et al described a large Danish family with 13 cases of multiple endocrine tumors, none of which harbored any abnormalities in menin, that segregated with a pathogenic CDKN1B variant (c.121_122delTT, p.Leu41Asnfs*83) 43 . A comprehensive phenotype of MEN4 patients is not yet established due to the small number of patients identified so far.…”