{"doi":"10.1210/clinem/dgaa160","title":"Germline <i>CDKN1B</i> Loss-of-Function Variants Cause Pediatric Cushing’s Disease With or Without an MEN4 Phenotype","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 Sixty cases were previously unpublished.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.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2020,"id":67289,"datarank":1.3610078375107004,"base_score":3.8712010109078907,"endowment":3.8712010109078907,"self_citation_contribution":0.5806801516361837,"citation_network_contribution":0.7803276858745167,"self_endowment_contribution":0.5806801516361837,"citer_contribution":0.7803276858745167,"corpus_percentile":null,"corpus_rank":null,"citation_count":47,"citer_count":43,"citers_with_citation_signal":32,"citers_with_endowment":32,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT00001595"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":40739,"name":"Nathan Pankratz","orcid":"0000-0001-5958-693X","position":1,"is_corresponding":false},{"id":256102,"name":"John Lane","orcid":"0000-0002-3582-5825","position":2,"is_corresponding":false},{"id":356392,"name":"Fábio R. Faucz","orcid":"0000-0001-7959-9842","position":3,"is_corresponding":false},{"id":356393,"name":"Margaret F. Keil","orcid":"0000-0001-5077-2218","position":4,"is_corresponding":false},{"id":356394,"name":"Prashant Chittiboina","orcid":"0000-0001-9349-4756","position":5,"is_corresponding":false},{"id":356395,"name":"Denise M. Kay","orcid":"0000-0002-9928-2698","position":6,"is_corresponding":false},{"id":88727,"name":"Tara Hussein Tayeb","orcid":"0000-0002-0687-7335","position":7,"is_corresponding":false},{"id":287856,"name":"Constantine A. Stratakis","orcid":"0000-0002-4058-5520","position":8,"is_corresponding":false},{"id":308451,"name":"James L. Mills","orcid":"0000-0003-4496-332X","position":9,"is_corresponding":false},{"id":356396,"name":"Laura C. Hernández‐Ramírez","orcid":"0000-0002-6599-6406","position":10,"is_corresponding":false},{"id":356391,"name":"Fanny Chasseloup","orcid":"0000-0002-2228-9437","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T21:15:12.020735Z","pmid":"32232325","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}