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Warts, hypogammaglobulinemia, infections, and myelokathexis

MedGen UID:
96875
•Concept ID:
C0472817
•
Disease or Syndrome
Synonym: WHIM syndrome
SNOMED CT: WHIM - Warts, hypogammaglobulinemia, infections and myelokathexis (234571003); Warts, hypogammaglobulinemia, infections, and myelokathexis (234571003)
 
Monarch Initiative: MONDO:0023880
OMIM®: 193670
OMIM® Phenotypic series: PS193670

Definition

An autosomal dominant immunodeficiency syndrome caused by mutation(s) in the CXCR4 gene, encoding C-X-C chemokine receptor type 4. It is characterized by neutropenia, hypogammaglobulinemia, extensive human papillomavirus (HPV) infection, and myelokathexis. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVWarts, hypogammaglobulinemia, infections, and myelokathexis
Follow this link to review classifications for Warts, hypogammaglobulinemia, infections, and myelokathexis in Orphanet.

Professional guidelines

PubMed

Can we identify WHIM in infancy? Opportunities with the public newborn screening process.
Yilmaz M, Potts DE, Geier C, Walter JE
Am J Med Genet C Semin Med Genet 2022 Jun;190(2):215-221. Epub 2022 Oct 9 doi: 10.1002/ajmg.c.32002. PMID: 36210583
WHIM syndrome: Immunopathogenesis, treatment and cure strategies.
McDermott DH, Murphy PM
Immunol Rev 2019 Jan;287(1):91-102. doi: 10.1111/imr.12719. PMID: 30565238
The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia.
Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Patterson CJ, Tsakmaklis N, Kanan S, Rodig S, Castillo JJ, Treon SP
Leukemia 2015 Jan;29(1):169-76. Epub 2014 Jun 10 doi: 10.1038/leu.2014.187. PMID: 24912431

Recent clinical studies

Etiology

Mesenchymal Stem/Stromal Cells Overexpressing CXCR4(R334X) Revealed Enhanced Migration: A Lesson Learned from the Pathogenesis of WHIM Syndrome.
Bidkhori HR, Bahrami AR, Farshchian M, Heirani-Tabasi A, Mirahmadi M, Hasanzadeh H, Ahmadiankia N, Faridhosseini R, Dastpak M, Shabgah AG, Matin MM
Cell Transplant 2021 Jan-Dec;30:9636897211054498. doi: 10.1177/09636897211054498. PMID: 34807749Free PMC Article
Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome.
Dale DC, Firkin F, Bolyard AA, Kelley M, Makaryan V, Gorelick KJ, Ebrahim T, Garg V, Tang W, Jiang H, Skerlj R, Beaussant Cohen S
Blood 2020 Dec 24;136(26):2994-3003. doi: 10.1182/blood.2020007197. PMID: 32870250Free PMC Article
Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies.
Dotta L, Notarangelo LD, Moratto D, Kumar R, Porta F, Soresina A, Lougaris V, Plebani A, Smith CIE, Norlin AC, Gòmez Raccio AC, Bubanska E, Bertolini P, Amendola G, Visentini M, Fiorilli M, Venuti A, Badolato R
J Allergy Clin Immunol Pract 2019 May-Jun;7(5):1568-1577. Epub 2019 Feb 2 doi: 10.1016/j.jaip.2019.01.045. PMID: 30716504
How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.
Badolato R, Donadieu J; WHIM Research Group
Blood 2017 Dec 7;130(23):2491-2498. Epub 2017 Oct 24 doi: 10.1182/blood-2017-02-708552. PMID: 29066537
Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.
Badolato R, Dotta L, Tassone L, Amendola G, Porta F, Locatelli F, Notarangelo LD, Bertrand Y, Bachelerie F, Donadieu J
J Pediatr 2012 Oct;161(4):763-5. Epub 2012 Jun 27 doi: 10.1016/j.jpeds.2012.05.058. PMID: 22748845Free PMC Article

Diagnosis

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, 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, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, 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 KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, Walter JE
J Clin Immunol 2022 Nov;42(8):1748-1765. Epub 2022 Aug 10 doi: 10.1007/s10875-022-01312-7. PMID: 35947323Free PMC Article
WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure.
Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM
J Clin Immunol 2019 Aug;39(6):532-556. Epub 2019 Jul 16 doi: 10.1007/s10875-019-00665-w. PMID: 31313072Free PMC Article
Adaptive Immunodeficiency in WHIM Syndrome.
Majumdar S, Murphy PM
Int J Mol Sci 2018 Dec 20;20(1) doi: 10.3390/ijms20010003. PMID: 30577453Free PMC Article
How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.
Badolato R, Donadieu J; WHIM Research Group
Blood 2017 Dec 7;130(23):2491-2498. Epub 2017 Oct 24 doi: 10.1182/blood-2017-02-708552. PMID: 29066537
Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome.
Dotta L, Tassone L, Badolato R
Curr Mol Med 2011 Jun;11(4):317-25. doi: 10.2174/156652411795677963. PMID: 21506920

Therapy

Severe CD8+ T Lymphopenia in WHIM Syndrome Caused by Selective Sequestration in Primary Immune Organs.
Majumdar S, Pontejo SM, Jaiswal H, Gao JL, Salancy A, Stassenko E, Yamane H, McDermott DH, Balabanian K, Bachelerie F, Murphy PM
J Immunol 2023 Jun 15;210(12):1913-1924. doi: 10.4049/jimmunol.2200871. PMID: 37133343Free PMC Article
Plerixafor on a WHIM - Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome?
Merati N, Sivachandran S, Jfri A, Ben-Shoshan M, Vinh DC, Popradi G, Litvinov IV
Skin Therapy Lett 2022 Mar;27(2):1-5. PMID: 35385630
Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment.
Scala S
Clin Cancer Res 2015 Oct 1;21(19):4278-85. Epub 2015 Jul 21 doi: 10.1158/1078-0432.CCR-14-0914. PMID: 26199389
Inhibitors of CXC chemokine receptor type 4: putative therapeutic approaches in inflammatory diseases.
Hummel S, Van Aken H, Zarbock A
Curr Opin Hematol 2014 Jan;21(1):29-36. doi: 10.1097/MOH.0000000000000002. PMID: 24275689
Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.
Badolato R, Dotta L, Tassone L, Amendola G, Porta F, Locatelli F, Notarangelo LD, Bertrand Y, Bachelerie F, Donadieu J
J Pediatr 2012 Oct;161(4):763-5. Epub 2012 Jun 27 doi: 10.1016/j.jpeds.2012.05.058. PMID: 22748845Free PMC Article

Prognosis

Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome.
Laberko A, Deordieva E, Krivan G, Goda V, Bhar S, Kawahara Y, Rao K, Worth A, McDermott DH, Balashov D, Maschan A, Shcherbina A
J Clin Immunol 2022 Jan;42(1):171-182. Epub 2021 Oct 26 doi: 10.1007/s10875-021-01155-8. PMID: 34697698Free PMC Article
Plerixafor for the Treatment of WHIM Syndrome.
McDermott DH, Pastrana DV, Calvo KR, Pittaluga S, Velez D, Cho E, Liu Q, Trout HH 3rd, Neves JF, Gardner PJ, Bianchi DA, Blair EA, Landon EM, Silva SL, Buck CB, Murphy PM
N Engl J Med 2019 Jan 10;380(2):163-170. doi: 10.1056/NEJMoa1808575. PMID: 30625055Free PMC Article
C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma.
Roccaro AM, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, Aljawai Y, Sahin I, Kuhne M, Cardarelli P, Cohen L, San Miguel JF, Garcia-Sanz R, Ghobrial IM
Blood 2014 Jun 26;123(26):4120-31. Epub 2014 Apr 7 doi: 10.1182/blood-2014-03-564583. PMID: 24711662
Epstein-Barr virus-associated T-lymphoproliferative disease with hemophagocytic syndrome, followed by fatal intestinal B lymphoma in a young adult female with WHIM syndrome. Warts, hypogammaglobulinemia, infections, and myelokathexis.
Imashuku S, Miyagawa A, Chiyonobu T, Ishida H, Yoshihara T, Teramura T, Kuriyama K, Imamura T, Hibi S, Morimoto A, Todo S
Ann Hematol 2002 Aug;81(8):470-3. Epub 2002 Jul 20 doi: 10.1007/s00277-002-0489-9. PMID: 12224006

Clinical prediction guides

Vedolizumab for children with intestinal graft-versus-host disease: a case report and literature review.
Fukuta T, Muramatsu H, Yamashita D, Sajiki D, Maemura R, Tsumura Y, Yamamori A, Imaya M, Wakamatsu M, Nishikawa E, Narita K, Kataoka S, Taniguchi R, Narita A, Nishio N, Takahashi Y
Int J Hematol 2023 Sep;118(3):411-417. Epub 2023 Apr 19 doi: 10.1007/s12185-023-03590-2. PMID: 37074509
Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, 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, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, 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 KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, Walter JE
J Clin Immunol 2022 Nov;42(8):1748-1765. Epub 2022 Aug 10 doi: 10.1007/s10875-022-01312-7. PMID: 35947323Free PMC Article
Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.
Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR
Blood 2014 May 1;123(18):2791-6. Epub 2014 Feb 19 doi: 10.1182/blood-2014-01-550905. PMID: 24553177
Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.
Badolato R, Dotta L, Tassone L, Amendola G, Porta F, Locatelli F, Notarangelo LD, Bertrand Y, Bachelerie F, Donadieu J
J Pediatr 2012 Oct;161(4):763-5. Epub 2012 Jun 27 doi: 10.1016/j.jpeds.2012.05.058. PMID: 22748845Free PMC Article
WHIM syndrome: a defect in CXCR4 signaling.
Diaz GA, Gulino AV
Curr Allergy Asthma Rep 2005 Sep;5(5):350-5. doi: 10.1007/s11882-005-0005-0. PMID: 16091205

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