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Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2020 Jun 01; Vol. 105 (6). - Publication Year :
- 2020
-
Abstract
- 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.<br />Aim: To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects.<br />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 Sixty cases were previously unpublished.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.<br />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&#95;-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.<br />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.<br /> (Published by Oxford University Press on behalf of the Endocrine Society 2020.)
- Subjects :
- Adolescent
Adult
Child
Cushing Syndrome pathology
Female
Follow-Up Studies
Humans
Male
Multiple Endocrine Neoplasia genetics
Multiple Endocrine Neoplasia pathology
Phenotype
Prognosis
Young Adult
Biomarkers analysis
Cushing Syndrome etiology
Cyclin-Dependent Kinase Inhibitor p27 genetics
DNA Copy Number Variations
Germ-Line Mutation
Multiple Endocrine Neoplasia complications
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7197
- Volume :
- 105
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 32232325
- Full Text :
- https://doi.org/10.1210/clinem/dgaa160