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

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6 Scopus citations


Context: Germline loss-of-function CDKN1B gene variants cause the autosomal dominantsyndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitaryneuroendocrine tumors are a well-known component of the syndrome, only 2 cases of Cushing'sdisease (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 theirfunctional 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/orgermline copy number variant (CNV) analysis (n = 194). Sixty cases were previously unpublished.Variant segregation was investigated in the patients' families, and putative pathogenic variantswere functionally characterized.Results: Five variants of interest were found in 1 patient each: 1 truncating (p.Q107Rfs*12) and4 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 apparentlysporadically. Aside from colon adenocarcinoma in 1 carrier, no additional neoplasms weredetected in the probands or their families. In vitro assays demonstrated protein instability anddisruption 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% ofthe patients screened. Our finding that germline CDKN1B loss-of-function may present asapparently sporadic, isolated pediatric CD has important implications for clinical screening andgenetic counselling.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Issue number6
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
Financial Support: This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health. F.C. was the recipient of a master’s degree fellowship from the French Endocrine Society and Novartis Pharma laboratories.

Publisher Copyright:
© 2020 Endocrine Society. All rights reserved.


  • ACTH
  • CDKN1B
  • Cushing's disease
  • MEN4
  • Pituitary neuroendocrine tumor
  • corticotropinoma

PubMed: MeSH publication types

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


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