Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype

Area of Science:

• Genetics
• Endocrinology
• Oncology

Background:

• Germline loss-of-function CDKN1B gene variants are associated with Multiple Endocrine Neoplasia type 4 (MEN4).
• Pituitary neuroendocrine tumors are a known feature of MEN4, but Cushing's disease (CD) is rarely reported in this context.

Purpose of the Study:

• To investigate the prevalence and functional impact of CDKN1B gene defects in a cohort of Cushing's disease patients.
• To determine if germline CDKN1B variants contribute to apparently sporadic cases of pediatric CD.

Main Methods:

• Screening of 211 Cushing's disease patients using germline whole-exome sequencing (WES), Sanger sequencing, and copy number variant (CNV) analysis.
• Functional characterization of identified CDKN1B variants through in vitro assays to assess protein stability and domain function.
• Segregation analysis within families of patients carrying CDKN1B variants.

Main Results:

• Five patients (2.6%) with CD were found to have germline CDKN1B variants (1 truncating, 4 non-truncating).
• Identified variants affected the CDKN1B protein's scatter domain, leading to instability and disruption.
• Patients presented early with apparently sporadic CD, with one case also developing colon adenocarcinoma.

Conclusions:

• Germline CDKN1B loss-of-function variants can present as isolated, sporadic pediatric Cushing's disease.
• This finding has significant implications for clinical genetic screening and counseling in patients with CD.
• Further investigation into CDKN1B variants is warranted for a comprehensive understanding of CD pathogenesis.