CONTEXT: Germline loss-of-function CDKN1B gene variants cause the autosomal dominant syndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitary neuroendocrine tumors are a well-known component of the syndrome, only 2 cases of Cushing's disease (CD) have so far been described in this setting. AIM: To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects. PATIENTS: We screened 211 CD patients (94.3% pediatric) by germline whole-exome sequencing (WES) only (n = 157), germline and tumor WES (n = 27), Sanger sequencing (n = 6), and/or germline copy number variant (CNV) analysis (n = 194). Sixty cases were previously unpublished. Variant segregation was investigated in the patients' families, and putative pathogenic variants were functionally characterized. RESULTS: Five variants of interest were found in 1 patient each: 1 truncating (p.Q107Rfs*12) and 4 nontruncating variants, including 3 missense changes affecting the CDKN1B protein scatter domain (p.I119T, p.E126Q, and p.D136G) and one 5' untranslated region (UTR) deletion (c.-29_-26delAGAG). No CNVs were found. All cases presented early (10.5 ± 1.3 years) and apparently sporadically. Aside from colon adenocarcinoma in 1 carrier, no additional neoplasms were detected in the probands or their families. In vitro assays demonstrated protein instability and disruption of the scatter domain of CDKN1B for all variants tested. CONCLUSIONS: Five patients with CD and germline CDKN1B variants of uncertain significance (n = 2) or pathogenic/likely pathogenic (n = 3) were identified, accounting for 2.6% of the patients screened. Our finding that germline CDKN1B loss-of-function may present as apparently sporadic, isolated pediatric CD has important implications for clinical screening and genetic counselling.

• Keywords
• ACTH, CDKN1B, Cushing’s disease, MEN4, corticotropinoma, pituitary neuroendocrine tumor,
• MeSH
• Biomarkers analysis   MeSH
• Cushing Syndrome etiology   pathology   MeSH
• Child MeSH
• Adult MeSH
• Phenotype MeSH
• Cyclin-Dependent Kinase Inhibitor p27 genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Multiple Endocrine Neoplasia complications   genetics   pathology   MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• DNA Copy Number Variations * MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Biomarkers MeSH
• CDKN1B protein, human MeSH Browser
• Cyclin-Dependent Kinase Inhibitor p27 MeSH

Microsomal epoxide hydrolase (EPHX1) is an evolutionarily highly conserved biotransformation enzyme for converting epoxides to diols. Notably, the enzyme is able to either detoxify or bioactivate a wide range of substrates. Mutations and polymorphic variants in the EPHX1 gene have been associated with susceptibility to several human diseases including cancer. This review summarizes the key knowledge concerning EPHX1 gene and protein structure, expression pattern and regulation, and substrate specificity. The relevance of EPHX1 for human pathology is especially discussed.

• Keywords
• Disease, EPHX1, Function, Gene, Genotype, Structure,
• MeSH
• Liver Diseases, Alcoholic genetics   metabolism   MeSH
• Epoxide Hydrolases genetics   metabolism   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Humans MeSH
• Mutation * MeSH
• Neoplasms genetics   metabolism   MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Risk Factors MeSH
• Substrate Specificity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• EPHX1 protein, human MeSH Browser
• Epoxide Hydrolases MeSH