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

Fanny Chasseloup; Nathan Pankratz; John Lane; Fabio R Faucz; Margaret F Keil; Prashant Chittiboina; Denise M Kay; Tara Hussein Tayeb; Constantine A Stratakis; James L Mills; Laura C Hernández-Ramírez

doi:10.1210/clinem/dgaa160

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

J Clin Endocrinol Metab. 2020 Jun 1;105(6):1983-2005. doi: 10.1210/clinem/dgaa160.

Authors

Affiliations

¹ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.
² Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Institut Cochin, INSERM U1016 CNRS 8104 Paris Descartes University, Paris, France.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota.
⁴ Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland.
⁵ Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York.
⁶ College of Medicine, Sulaimani University, Sulaimani, Kurdistan, Iraq.
⁷ Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
⁸ Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

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.

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 Sixty cases were previously unpublished.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.

Trial registration: ClinicalTrials.gov NCT00001595.

Keywords: ACTH; CDKN1B; Cushing’s disease; MEN4; corticotropinoma; pituitary neuroendocrine tumor.

Published by Oxford University Press on behalf of the Endocrine Society 2020.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Biomarkers / analysis*
Child
Cushing Syndrome / etiology*
Cushing Syndrome / pathology
Cyclin-Dependent Kinase Inhibitor p27 / genetics*
DNA Copy Number Variations*
Female
Follow-Up Studies
Germ-Line Mutation*
Humans
Male
Multiple Endocrine Neoplasia / complications*
Multiple Endocrine Neoplasia / genetics
Multiple Endocrine Neoplasia / pathology
Phenotype
Prognosis
Young Adult

Substances

Biomarkers
CDKN1B protein, human
Cyclin-Dependent Kinase Inhibitor p27

Supplementary concepts

Multiple Endocrine Neoplasia, Type IV

Associated data

ClinicalTrials.gov/NCT00001595