RF27 | LBSUN362 Germline CDKN1B Variants Type And Site Are Associated With Specific Phenotype In Multiple Endocrine Neoplasia 4

BACKGROUND: The latest of the multiple endocrine neoplasia (MEN) syndromes described is MEN4, caused by germline CDKN1B tumor suppressor gene mutation. The main clinical manifestations of MEN4 are primary hyperparathyroidism (PHPT), neuroendocrine tumors (NET) and pituitary adenomas (PitAd). CDKN1B codes for the nuclear protein p27, a key regulator of cell cycle. This protein is an intrinsically unstructured protein, that folds upon interacting a putative interactor. It is comprised of two major domains: a kinase inhibitory domain (CDKi) that binds to cyclins and cyclin dependent kinase (CDK), and a scatter domain. p27 acts by inhibiting complexes of cyclins and CDKs, thus preventing the transition between phases of the cell cycle. Less than sixty cases of MEN4 syndrome were described thus far, with clinical manifestations resembling in part to a late onset of MEN1. HYPOTHESIS: Specific alterations in p27 protein will result in distinct clinical phenotypes. METHODOLOGY CASE REPORT: We collected published and unpublished data on all currently known patients with MEN4 worldwide, including newly identified kindreds from our clinic, and performed a thorough genotype-phenotype analysis of the various MEN4 manifestations. Whole exome sequencing was performed, revealing a germline CDKN1B frameshift variant (p.Q107fs*12), that was further verified by Sanger sequencing. A detailed literature review, including requests of unpublished clinical data from past studies was undertaken. Based on the data we performed a time-dependent risk analysis for the three main manifestations of MEN4 by various genotype-related parameters: variant type (single-nucleotide variant vs. indels) and site (variant- and domain-specific analyses). Major results Of 73 cases, 53.4% developed PHPT, 28.8% had PitAD and 19.2% - NET. PitAd developed earlier (age, 34.4±21.4 years) compared with PHPT (50.6±13.9 years) and NET (52.9±13.9 years). The risk to develop PHPT, PitA and NET in patients with MEN4 were 53.4%, 23.2% and 16.2% by age 60 years, respectively.CDKN1B variants clustered in genetic locations, or "hotspots" (i.e., codon 41 frameshift: n=13, codon 107 frameshift: n=11, c.-29-(-26)AGAG deletion: n=4). Although founder effect is relevant, this finding is in contrast to MEN1 genotype. We then performed time-dependent risk analysis for developing clinical manifestation by each gene domain alteration (either point mutation or upstream indel). We found a higher risk to develop PHPT or PitAd with variants affecting codons 94-96 (Log-rank, p values 0.014 and 0.047, respectively), and trend towards higher risk for PHPT for Scatter domain variants (p=0.09). Moreover, indels were associated Conclusions: MEN4 genotype is distinct than MEN1, by the presence of hotspots, and genotype-phenotype association. Further, the risk for PHPT is lower than MEN1, with a lower penetrance, and older age at diagnosis. Presentation: Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.