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 correlation in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed literature review on published and unpublished data from previously reported MEN4/CDKN1B cases.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), for PitAd - 16.2% and NET - 23.2% (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<0.001) and PitAd (p=0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.
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