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Article: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

TitleDisease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
Authors
Keywordsautoimmunity
CXCR4
lymphopenia
myelokathexis
neutropenia
warts
Issue Date10-Aug-2022
PublisherCell Press
Citation
Cell Reports Medicine, 2022, v. 42, n. 8, p. 1748-1765 How to Cite?
Abstract

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.


Persistent Identifierhttp://hdl.handle.net/10722/331795
ISSN
2023 Impact Factor: 11.7
2023 SCImago Journal Rankings: 4.276
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGeier, CB-
dc.contributor.authorEllison, M-
dc.contributor.authorCruz, R-
dc.contributor.authorPawar, S-
dc.contributor.authorLeiss-Piller, A-
dc.contributor.authorZmajkovicova, K-
dc.contributor.authorMcNulty, SM-
dc.contributor.authorYilmaz, M-
dc.contributor.authorEvans, MO-
dc.contributor.authorGordon, S-
dc.contributor.authorUjhazi, B-
dc.contributor.authorWiest, I-
dc.contributor.authorAbolhassani, H-
dc.contributor.authorAghamohammadi, A-
dc.contributor.authorBarmettler, S-
dc.contributor.authorBhar, S-
dc.contributor.authorBondarenko, A-
dc.contributor.authorBolyard, AA-
dc.contributor.authorBuchbinder, D-
dc.contributor.authorCada, M-
dc.contributor.authorCavieres, M-
dc.contributor.authorConnelly, JA-
dc.contributor.authorDale, DC-
dc.contributor.authorDeordieva, E-
dc.contributor.authorDorsey, MJ-
dc.contributor.authorDrysdale, SB-
dc.contributor.authorEhl, S-
dc.contributor.authorElfeky, R-
dc.contributor.authorFioredda, F-
dc.contributor.authorFirkin, F-
dc.contributor.authorForster-Waldl, E-
dc.contributor.authorGeng, B-
dc.contributor.authorGoda, V-
dc.contributor.authorGonzalez-Granado, L-
dc.contributor.authorGrunebaum, E-
dc.contributor.authorGrzesk, E-
dc.contributor.authorHenrickson, SE-
dc.contributor.authorHilfanova, A-
dc.contributor.authorHiwatari, M-
dc.contributor.authorImai, C-
dc.contributor.authorIp, W-
dc.contributor.authorJyonouchi, S-
dc.contributor.authorKanegane, H-
dc.contributor.authorKawahara, Y-
dc.contributor.authorKhojah, AM-
dc.contributor.authorKim, VHD-
dc.contributor.authorKojic, M-
dc.contributor.authorKoltan, S-
dc.contributor.authorKrivan, G-
dc.contributor.authorLangguth, D-
dc.contributor.authorLau, YL-
dc.contributor.authoret al-
dc.date.accessioned2023-09-21T06:58:59Z-
dc.date.available2023-09-21T06:58:59Z-
dc.date.issued2022-08-10-
dc.identifier.citationCell Reports Medicine, 2022, v. 42, n. 8, p. 1748-1765-
dc.identifier.issn2666-3791-
dc.identifier.urihttp://hdl.handle.net/10722/331795-
dc.description.abstract<p>Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.<br></p>-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofCell Reports Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectautoimmunity-
dc.subjectCXCR4-
dc.subjectlymphopenia-
dc.subjectmyelokathexis-
dc.subjectneutropenia-
dc.subjectwarts-
dc.titleDisease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1007/s10875-022-01312-7-
dc.identifier.scopuseid_2-s2.0-85137112242-
dc.identifier.volume42-
dc.identifier.issue8-
dc.identifier.spage1748-
dc.identifier.epage1765-
dc.identifier.eissn2666-3791-
dc.identifier.isiWOS:000838547000002-
dc.identifier.issnl2666-3791-

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