ArticleThe Journal of clinical endocrinology and metabolism2020
Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype.
Article in The Journal of clinical endocrinology and metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 45 citations in OpenAlex.
- Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations.Nature reviews. Endocrinology · 2024Guideline
- [A combination of endogenous hypercortisolism and primary hyperparathyroidism: clinical and genetic characteristics].Problemy endokrinologii · 2026Observational
- Genetic testing in pituitary adenomas: a Pituitary Society International Consensus Statement.Nature reviews. Endocrinology · 2026Review
- The germline landscape of pituitary adenomas: established and emerging predisposition genes.The Journal of clinical endocrinology and metabolism · 2026Review
- MEN4 variant of unknown significance in two generations of patients presenting with Cushing disease.JCEM case reports · 2026Article
- A Brief Overview of Molecular Biology in Pituitary Adenomas with a Focus on Aggressive Lesions.International journal of molecular sciences · 2025Review
- Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia.Endocrinology and metabolism (Seoul, Korea) · 2025Review
- Childhood Multiple Endocrine Neoplasia (MEN) Syndromes: Genetics, Clinical Heterogeneity and Modifying Genes.Journal of clinical medicine · 2024Review
- Challenges in molecular diagnosis of multiple endocrine neoplasia.Frontiers in endocrinology · 2024Review
- Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.Journal of endocrinological investigation · 2023Article
- The Spectrum of Familial Pituitary Neuroendocrine Tumors.Endocrine pathology · 2023Review
- Multiple endocrine neoplasia type 4: a new member of the MEN family.Endocrine connections · 2023Article
- Gene Mutations in Cushing's Syndrome.Molecular syndromology · 2023Review
- Genetic drivers of Cushing's disease: Frequency and associated phenotypes.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Clinical Biology of the Pituitary Adenoma.Endocrine reviews · 2022Review
- Genetic and Epigenetic Pathogenesis of Acromegaly.Cancers · 2022Review
- MEN4, the MEN1 Mimicker: A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations.The Journal of clinical endocrinology and metabolism · 2022Article
- Genetic Basis of ACTH-Secreting Adenomas.International journal of molecular sciences · 2022Review
- Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management.Frontiers in endocrinology · 2022Review
- Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.Reviews in endocrine & metabolic disorders · 2021Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
contextGermline 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.
aimTo 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.
resultsFive 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.
conclusionsFive 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.
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