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

Publication ,  Journal Article
Geier, CB; Ellison, M; Cruz, R; Pawar, S; Leiss-Piller, A; Zmajkovicova, K; McNulty, SM; Yilmaz, M; Evans, MO; Gordon, S; Ujhazi, B; Wiest, I ...
Published in: J Clin Immunol
November 2022

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.

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Published In

J Clin Immunol

DOI

EISSN

1573-2592

Publication Date

November 2022

Volume

42

Issue

8

Start / End Page

1748 / 1765

Location

Netherlands

Related Subject Headings

  • Warts
  • Receptors, CXCR4
  • Neutropenia
  • Lymphopenia
  • Immunology
  • Immunologic Deficiency Syndromes
  • Humans
  • Disease Progression
  • Agammaglobulinemia
  • 3204 Immunology
 

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Geier, C. B., Ellison, M., Cruz, R., Pawar, S., Leiss-Piller, A., Zmajkovicova, K., … Walter, J. E. (2022). Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients. J Clin Immunol, 42(8), 1748–1765. https://doi.org/10.1007/s10875-022-01312-7
Geier, Christoph B., Maryssa Ellison, Rachel Cruz, Sumit Pawar, Alexander Leiss-Piller, Katarina Zmajkovicova, Shannon M. McNulty, et al. “Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.J Clin Immunol 42, no. 8 (November 2022): 1748–65. https://doi.org/10.1007/s10875-022-01312-7.
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, et al. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients. J Clin Immunol. 2022 Nov;42(8):1748–65.
Geier, Christoph B., et al. “Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.J Clin Immunol, vol. 42, no. 8, Nov. 2022, pp. 1748–65. Pubmed, doi:10.1007/s10875-022-01312-7.
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO, Gordon S, Ujhazi B, Wiest I, Abolhassani H, Aghamohammadi A, Barmettler S, Bhar S, Bondarenko A, Bolyard AA, Buchbinder D, Cada M, Cavieres M, Connelly JA, Dale DC, Deordieva E, Dorsey MJ, Drysdale SB, Ehl S, Elfeky R, Fioredda F, Firkin F, Förster-Waldl E, Geng B, Goda V, Gonzalez-Granado L, Grunebaum E, Grzesk E, Henrickson SE, Hilfanova A, Hiwatari M, Imai C, Ip W, Jyonouchi S, Kanegane H, Kawahara Y, Khojah AM, Kim VH-D, Kojić M, Kołtan S, Krivan G, Langguth D, Lau Y-L, Leung D, Miano M, Mersyanova I, Mousallem T, Muskat M, Naoum FA, Noronha SA, Ouederni M, Ozono S, Richmond GW, Sakovich I, Salzer U, Schuetz C, Seeborg FO, Sharapova SO, Sockel K, Volokha A, von Bonin M, Warnatz K, Wegehaupt O, Weinberg GA, Wong K-J, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong M-S, Shcherbina A, Walter JE. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients. J Clin Immunol. 2022 Nov;42(8):1748–1765.
Journal cover image

Published In

J Clin Immunol

DOI

EISSN

1573-2592

Publication Date

November 2022

Volume

42

Issue

8

Start / End Page

1748 / 1765

Location

Netherlands

Related Subject Headings

  • Warts
  • Receptors, CXCR4
  • Neutropenia
  • Lymphopenia
  • Immunology
  • Immunologic Deficiency Syndromes
  • Humans
  • Disease Progression
  • Agammaglobulinemia
  • 3204 Immunology