Germline CDKN1B variant type and site are associated with phenotype in MEN4

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene – CDKN1B, encodes for the cell...

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Veröffentlicht in:Endocrine-related cancer 2023-01, Vol.30 (1), p.1
Hauptverfasser: Halperin, Reut, Arnon, Liat, Nasirov, Sapir, Friedensohn, Limor, Gershinsky, Michal, Telerman, Alona, Friedman, Eitan, Bernstein-Molho, Rinat, Tirosh, Amit
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Sprache:eng
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Zusammenfassung:Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene – CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype–phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94–96 were associated with higher risk for PHPT (P 
ISSN:1351-0088
1479-6821
DOI:10.1530/ERC-22-0174