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Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome

2005; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2005.08.040

1097-6825

Michael Tarzi, Michael Jenner, Keith Hattotuwa, Asma Faruqi, George A. Díaz, Hilary Longhurst,

Immune Response and Inflammation

The term WHIM syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus–related genital dysplasia. The term WHIM syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus–related genital dysplasia. After an episode of lobar pneumonia caused by Streptococcus pneumoniae with confirmed bacteremia, a 52-year-old white British woman was referred to the Outpatient Unit of the Department of Clinical Immunology at St Bartholomew's Hospital, London. She had a history of intractable human papilloma virus (HPV)–related dysplasia, having first presented at the age of 33 years with vulval dysplasia and grade III cervical intraepithelial neoplasia. Over a period of several years, severe multifocal dysplasia was managed by vulvectomy and total abdominal hysterectomy, together with bowel resection and formation of a stoma for grade III anal intraepithelial neoplasia. A selection of histopathological sections is presented in Fig 1. Further questioning revealed a significant infection history. She reported frequent bouts of respiratory sepsis from an early age, which generally responded fully to oral antibiotics with no significant respiratory symptoms between exacerbations. During infancy, she presented with extensive cellulitis of the right leg, requiring urgent hospital admission for intravenous antibiotics and, ultimately, surgical debridement. At the age of 10 years, she developed warts affecting both hands; these proved refractory to treatment, but eventually went into spontaneous remission after a period of several months. At age 21 years, neutropenia was identified before a routine dilatation and curettage. Extensive investigation including a bone marrow aspirate and trephine was inconclusive. The etiology of her neutropenia remained unclear, and she was subsequently lost to hematology follow-up. More recently, she had been troubled by severe, recurrent perioral herpes simplex virus (HSV) infection, as well as a single episode of unidermatomal thoracic zoster. She was born at term by spontaneous vaginal delivery, with no problems in the neonatal period. There was no history of opportunistic or mycobacterial infections, and childhood infections ran a benign course without apparent complications. She had tolerated vaccination with smallpox and BCG with no adverse sequelae. There was no other relevant past medical history, and apart from hormone replacement therapy, she was not taking any regular medication. Her parents, a single sibling, and her 2 children have remained free of significant infections, warts, and Pap smear abnormalities, and with the exception of one of her offspring who has not been tested, all immediate family members have normal blood films. She has never smoked cigarettes and drinks minimal alcohol. Physical examination was unremarkable, with no clinical evidence of bronchiectasis and no palpable lymph nodes. A blood film revealed lymphopenia and neutropenia, with further investigation demonstrating the latter to be noncyclical and in the severe to moderate range (absolute neutrophil count between 0.1 and 0.8 × 109/ L). The results of routine immunological tests are summarized in Table I. Analysis of lymphocyte surface markers revealed severe panlymphopenia, with a CD4 count of just 69 × 106/L (normal range, 455-1320/L); however, lymphocyte proliferation assessed by thymidine incorporation after stimulation with recall antigens was satisfactory. Further investigation demonstrated IgG at the lower end of the normal range, with mild deficiency of IgA and IgM. Baseline antibody titers specific to Haemophilus influenzae and S pneumoniae were nonprotective, and after immunization, she mounted a poor specific antibody response to H influenzae and no response to S pneumoniae. Serum electrophoresis did not demonstrate paraproteinemia, and the urine was free of Bence-Jones proteins. Pulmonary function tests and plain chest radiography were unremarkable.Table ISummary of routine laboratory resultsImmunoglobulin level (g/L)IgG6.7 (5.5-16.5)IgA0.37 (0.80-4.00)IgM0.38 (0.40-2.00)Cells × 106/LCD3115 (918-2033)CD469 (455-1320)CD842 (140-906)CD197 (42-461)CD5621 (41-339)Preimmunization (mg/L)Postimmunization (mg/L)Minimum protective level (mg/L)Haemophilus 0.15Pneumococcus1011>30Unstimulated (counts per minute)Stimulated (counts per minute)Phytohemagglutinin22545678Purified protein derivative of Mycobacterium tuberculosis40532565 Open table in a new tab This patient's repeated respiratory sepsis raises the possibility of humoral immune deficiency, whereas a cellular component is suggested by intractable HPV-related dysplasia as well as zoster and recurrent HSV infection. The lifelong infection history indicates a primary immunodeficiency disorder. The history, clinical examination, and basic investigations (pulmonary function tests and plain radiography) are not suggestive of significant chronic respiratory disease, although definitive imaging by high-resolution computerized tomography was not performed initially given the possibility of immunodeficiency associated with an underlying DNA repair defect. Another aspect of her presentation is severe neutropenia, although notably (with the exception of cellulitis) the range of infections she has had are not particularly suggestive of neutropenic sepsis, and there was some evidence that in the past she had mounted a neutrophilia while unwell. The serum immunoglobulin levels are not markedly reduced, but the history together with poor vaccine response is supportive of significant humoral immunodeficiency. CD40 deficiency1Lougaris V. Bodolato R. Ferrari S. Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular and immunological features.Immunol Rev. 2005; 203: 48-66Crossref PubMed Scopus (135) Google Scholar (hyperimmunoglobulin syndrome type 3, autosomal-recessive) is characterized by combined immunodeficiency and neutropenia, but is excluded by the immunoglobulin profile and relatively benign clinical course. Common variable immunodeficiency2Conley M.E. Notarangelo L.D. Etzioni A. Diagnostic criteria for primary immunodeficiencies.Clin Immunol. 1999; 93: 190-197Crossref PubMed Scopus (892) Google Scholar is associated with predominantly humoral immunodeficiency, although in some cases, a degree of cellular immunodeficiency may coexist. Cytopenias, often autoimmune in nature, are not uncommon in common variable immunodeficiency. However, low IgG is characteristic of the condition. Certain DNA repair defect syndromes3Gennery A.R. Cant A.J. Jeggo P.A. Immunodeficiency associated with DNA repair defects.Clin Exp Immunol. 2000; 121: 1-7Crossref PubMed Scopus (53) Google Scholar may lead to a range of cellular and humoral immune deficiencies, sometimes associated with sensitivity to ionizing radiation. However, the condition that best fits her phenotype is warts, hypogammaglobulinemia, bacterial infections, and myelokathexis syndrome (WHIMS), a rare form of congenital neutropenia characterized by bacterial infections and marked susceptibility to HPV infection. A bone marrow aspirate was performed to investigate further the possibility of WHIMS. The erythroid and megakaryocytic lineages were normal and granulocytes and their precursors plentiful. However, there was vacuolation of mature neutrophils, polymorph nuclear hypersegmentation, and thin strands connecting the lobes, supporting the diagnosis (Fig 2). With informed consent, a blood sample was drawn for isolation of DNA from peripheral leukocytes by using the Puregene kit (Gentra, Minneapolis, Minn). A PCR-RFLP assay was used to screen for the presence of the recurrent 1000C→T mutation as described.4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar Primer sequences are available on request. The genomic sequence including the R334 codon was contained in a 126-bp PCR amplicon that was subsequently digested with BstUI. The expected products of 104 and 22 bp (not visualized) from wild-type amplicons and 126 bp (undigested) in the case of the 1000C→T mutation were resolved on 2% agarose gels (Fig 3). To validate that the mutation detected by the RFLP assay did indeed encode the 19-residue R334X truncation, sequence analysis of genomic DNA was performed. The patient was confirmed to be heterozygous for the 1000C→T mutation, confirming the molecular diagnosis. A high-resolution computerized tomography scan of the thorax subsequently confirmed the presence of mild bronchiectasis. WHIMS derives its name from the clinical features of warts, hypogammaglobulinemia, bacterial infections, and myelokathexis, although it is clear from the 30 or so cases appearing in the literature that the phenotype is heterogeneous.5Diaz G.A. CXCR4 mutations in WHIM syndrome: a misguided immune system?.Immunol Rev. 2005; 203: 235-243Crossref PubMed Scopus (71) Google Scholar, 6Gorlin R.J. Gelb B. Diaz G.A. Lofsness K.G. Pittelkow M.R. Fenyk Jr., J.R. WHIM syndrome, an autosomal dominant disorder: clinical, haematological and molecular studies.Am J Med Genet. 2000; 91: 368-376Crossref PubMed Scopus (164) Google Scholar Zuelzer7Zuelzer W.W. "Myelokathexis"—a new form of chronic granulocytopenia: report of a case.N Engl J Med. 1964; 270: 699-704Crossref PubMed Scopus (135) Google Scholar and Krill et al8Krill Jr., C.E. Smith H.D. Mauer A.M. Chronic idiopathic granulocytopenia.N Engl J Med. 1964; 270: 973-979Crossref PubMed Scopus (59) Google Scholar are credited with the first descriptions of WHIMS in 1964, independently reporting a 10-year-old girl with congenital neutropenia and recurrent infections. Zuelzer7Zuelzer W.W. "Myelokathexis"—a new form of chronic granulocytopenia: report of a case.N Engl J Med. 1964; 270: 699-704Crossref PubMed Scopus (135) Google Scholar noted the characteristic bone marrow abnormalities, which he astutely ascribed to a failure of polymorph mobilization, leading him to coin the phrase "myelokathexis" to describe the morphology (kathexis meaning retention). Around a third of reported WHIMS cases are sporadic, whereas the majority of pedigrees are consistent with autosomal-dominant inheritance. Patients typically present in infancy with recurrent pyogenic infections, particularly of the respiratory tract, with periodontitis, cellulitis, and meningitis also described. Infections generally respond well to antibiotics and run a relatively benign course; only a single case of sepsis-related mortality appears in the literature,8Krill Jr., C.E. Smith H.D. Mauer A.M. Chronic idiopathic granulocytopenia.N Engl J Med. 1964; 270: 973-979Crossref PubMed Scopus (59) Google Scholar although structural lung damage related to recurrent infection may occur. HPV-related disease is a major feature, typically manifested as treatment-refractory cutaneous warts, with multiple, common HPV serotypes contributing; however, as observed in our patient, cutaneous verrucosis may be minimal or even absent. HPV infection may also be manifested as genital dysplasia, with at least 2 other reported patients requiring local resection.9Wetzler M. Talpaz M. Kellagher M.J. Gutterman J.U. Kurzrook R. Myelokathexis: normalisation of neutrophil counts and morphology by GM-CSF.JAMA. 1992; 267: 2179-2180Crossref PubMed Google Scholar, 10Weston B. Axtell R.A. Todd R.F. Vincent M. Balazovich V.J. Suchard S.J. et al.Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis.J Pediatr. 1991; 118: 229-234Abstract Full Text PDF PubMed Scopus (45) Google Scholar Neutropenia, usually in the moderate to severe range, is a ubiquitous finding, whereas assays of neutrophil migration, opsonization, and phagocytosis generally demonstrate normal function. The bone marrow findings are of myeloid hypercellularity and polymorph abnormalities, with cytoplasmic vacuolation and thin strands connecting hypersegmented, pyknotic nuclei. Despite severe neutropenia, patients with WHIMS do not appear to be at risk of overwhelming neutropenic sepsis, presumably because functional neutrophils are released from the bone marrow during stress; indeed, granulocyte colony stimulating factor (G-CSF) has been demonstrated to correct neutropenia and normalize the bone marrow in WHIMS.9Wetzler M. Talpaz M. Kellagher M.J. Gutterman J.U. Kurzrook R. Myelokathexis: normalisation of neutrophil counts and morphology by GM-CSF.JAMA. 1992; 267: 2179-2180Crossref PubMed Google Scholar, 10Weston B. Axtell R.A. Todd R.F. Vincent M. Balazovich V.J. Suchard S.J. et al.Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis.J Pediatr. 1991; 118: 229-234Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 11Beynon D.W.G. Lopes A. Daras B. Monaghan J.M. Radical vulvectomy and groin node dissection in a patient with chronic neutropenia—maintenance of leucocyte count using granulocyte colony-stimulating factor.Int J Gynecol Cancer. 1993; 3: 405-407Crossref PubMed Scopus (2) Google Scholar, 12Wetzler M. Talpaz M. Kleimerman E.S. King A. Huh Y.O. Gutterman J.U. et al.A new familial immunodeficiency disorder characterised by severe neutropenia, a defective bone marrow release mechanism, and hypogammaglobulinemia.Am J Med. 1990; 89: 663-672Abstract Full Text PDF PubMed Scopus (98) Google Scholar The frequency and extent of lymphoid abnormalities appears to be very variable, with reports of B and T cytopenias as well as poor T-cell function. However, despite lymphopenia in a large proportion of patients, there are no reports of opportunistic or mycobacterial infections, and childhood infections such as rubella run a benign course. Although forming part of the acronym, immunoglobulin levels appear to be very variable, ranging from normality to moderate IgG deficiency. Normal vaccine responses are documented, but antibody titers may not be well maintained. Clinical improvement with immunoglobulin replacement therapy is described.12Wetzler M. Talpaz M. Kleimerman E.S. King A. Huh Y.O. Gutterman J.U. et al.A new familial immunodeficiency disorder characterised by severe neutropenia, a defective bone marrow release mechanism, and hypogammaglobulinemia.Am J Med. 1990; 89: 663-672Abstract Full Text PDF PubMed Scopus (98) Google Scholar Genetic studies in affected families recently associated WHIMS with heterozygous, autosomal-dominant truncating mutations in the gene encoding the chemokine receptor CXCR4,4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar with expression of the mutant gene product confirmed at both mRNA and protein level.4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar, 13Gulino A.V. WHIM syndrome: a genetic disorder of leukocyte trafficking.Curr Opin Allergy Clin Immunol. 2003; 3: 443-450Crossref PubMed Scopus (57) Google Scholar, 14Balabanian K. Lagane B. Pablos J.L. Laurent L. Planchenault T. Verola O. et al.WHIM syndromes with different genetic abnormalities are accounted for by impaired CXCR4 desensitisation to CXCL12.Blood. 2005; 105: 2249-2257Crossref PubMed Scopus (239) Google Scholar A widely expressed G protein–coupled receptor, CXCR4 is composed of an extracellular amino-terminal domain, linked by 7 transmembrane spanning regions to a 45–amino acid intracellular carboxy-terminal domain. The sole cognate ligand, CXCL12, is abundantly expressed in bone marrow stroma and lymphoid organs. CXCR4-CXCL12 interactions are implicated in organogenesis15Zou Y.R. Kottmann A.H. Kuroda M. Taniuchi I. Littman D.R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development.Nature. 1998; 393: 595-599Crossref PubMed Scopus (2113) Google Scholar, 16Tachibana K. Hirota S. Iizasa H. Yoshida H. Kawabata K. Kataoka Y. et al.The chemokine receptor CXCR4 is essential for vascularisation of the gastrointestinal tract.Nature. 1998; 393: 591-594Crossref PubMed Scopus (1315) Google Scholar and both myelopoiesis and lymphopoiesis in utero,17Ansel K.M. Cyster J.G. Chemokines in lymphopoiesis and lymphoid organ development.Curr Opin Immunol. 2001; 13: 172-179Crossref PubMed Scopus (162) Google Scholar whereas the pathway in adult life is critical for the bone marrow homing of hematopoietic cells.17Ansel K.M. Cyster J.G. Chemokines in lymphopoiesis and lymphoid organ development.Curr Opin Immunol. 2001; 13: 172-179Crossref PubMed Scopus (162) Google Scholar Disease-causing mutations identified thus far all truncate between 10 and 19 residues from the receptor cytoplasmic tail. The 19-residue truncation present in our patient and about 70% of characterized patients with WHIMS to date4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar, 14Balabanian K. Lagane B. Pablos J.L. Laurent L. Planchenault T. Verola O. et al.WHIM syndromes with different genetic abnormalities are accounted for by impaired CXCR4 desensitisation to CXCL12.Blood. 2005; 105: 2249-2257Crossref PubMed Scopus (239) Google Scholar is of particular interest, because Hernandez et al4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar reported an unaffected germline mosaic patient who transmitted the mutation to affected offspring, strongly supporting an association between CXCR4 truncation in affected tissues and the expression of the WHIM phenotype. The identification of CXCR4 mutations in patients with WHIMS raises intriguing questions about the pathogenesis of this rare disease (see reviews5Diaz G.A. CXCR4 mutations in WHIM syndrome: a misguided immune system?.Immunol Rev. 2005; 203: 235-243Crossref PubMed Scopus (71) Google Scholar, 18Gulino A.V. Moratto D. Sozzani S. Cavadini P. Otero K. Tassone L. et al.Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis syndrome (WHIM) syndrome.Blood. 2004; 104: 444-452Crossref PubMed Scopus (144) Google Scholar). Cells transfected with truncated CXCR4 receptors display increased CXCL12-induced calcium flux and inositol triphosphate formation, suggesting that the truncated receptor is functionally enhanced.19Signoret N. Rosenkilde M.M. Klasse P.J. Schwartz T.W. Malim M.H. Hoxie J.A. Marsh M. Differential regulation of CXCR4 and CCR5 endocytosis.J Cell Sci. 1998; 111: 2819-2830Crossref PubMed Google Scholar, 20Haribabu B. Richardson R.M. Fisher I. Sozzani S. Peiper S.C. Horuk R. et al.Regulation of human chemokine receptors CXCR4: role of phosphorylation in desensitisation and internalisation.J Biol Chem. 1997; 272: 28726-28731Crossref PubMed Scopus (243) Google Scholar Of note, the distal portion of the cytoplasmic tail of the CXCR4 receptor, in which disease-causing mutations cluster, is a target for G protein-coupled receptor (GPCR)-specific kinases involved in signaling downregulation. The truncated CXCR4 may be less amenable to phosphorylation by GPCR-specific kinases, leading to diminished β-arrestin binding and impaired downregulation of activation. An attractive model for WHIMS therefore envisages the myelokathexis phenotype as arising directly from functional enhancement of CXCL12-dependent signaling via CXCR4, preventing the normal release of neutrophils from the marrow. This model would also explain the dominant nature of the truncated CXCR4 receptor mutation. There is indeed some experimental evidence supporting this hypothesis, the most convincing of which relates to the effect of mutations on chemotaxis. In experiments with primary mutant T cells and neutrophils18Gulino A.V. Moratto D. Sozzani S. Cavadini P. Otero K. Tassone L. et al.Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis syndrome (WHIM) syndrome.Blood. 2004; 104: 444-452Crossref PubMed Scopus (144) Google Scholar as well as mutant lymphoblastoid transfects (Diaz GA, Unpublished data, July 2002), chemotaxis down a CXCL12 gradient was enhanced compared with wild-type cells, with a right shift in the dose-response curve. However, other data are conflicting: although calcium flux was increased in CXCL12-stimulated mutant lymphoblastoid B cells,4Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinject J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (534) Google Scholar calcium flux in mutant primary T cells did not differ from that in controls.18Gulino A.V. Moratto D. Sozzani S. Cavadini P. Otero K. Tassone L. et al.Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis syndrome (WHIM) syndrome.Blood. 2004; 104: 444-452Crossref PubMed Scopus (144) Google Scholar Further studies are required to determine the functional effects of the relatively limited receptor truncations in WHIMS. Another critical question relates to the mechanisms underlying susceptibility to HPV infection in WHIMS, the severity of which is disproportionate to the degree of cellular immunodeficiency. It is notable that recent work identified CXCL12 expression in dermal biopsies from HPV-infected sites taken from patients with and without WHIM,14Balabanian K. Lagane B. Pablos J.L. Laurent L. Planchenault T. Verola O. et al.WHIM syndromes with different genetic abnormalities are accounted for by impaired CXCR4 desensitisation to CXCL12.Blood. 2005; 105: 2249-2257Crossref PubMed Scopus (239) Google Scholar whereas both keratinocytes and dendritic cells express CXCR4, raising the possibility that verrucosis in WHIM is yet another manifestation of disturbed cell trafficking. The final diagnosis is WHIMS. Therapy with G-CSF at a dose of 5 μg/kg (started before confirmation of the diagnosis) did not improve her clinical condition and had little apparent effect on neutrophil counts. Because of worsening recurrent respiratory sepsis, she was started on intravenous immunoglobulin replacement, which has virtually abolished respiratory infections and rapidly improved her overall well being. She has had no further attacks of zoster or HSV infection since starting prophylactic aciclovir. Her multifocal genital dysplasia is of major concern, and she remains under gynecological observation. With increasing awareness of this rare disease, a previously undiagnosed pool of WHIMS cases is likely to emerge, most probably with a consequent expansion of the clinical phenotype. Susceptibility to HSV infection has not been emphasized in previous reports but was mentioned to have affected a patient with WHIMS in a recent article by Balabanian et al14Balabanian K. Lagane B. Pablos J.L. Laurent L. Planchenault T. Verola O. et al.WHIM syndromes with different genetic abnormalities are accounted for by impaired CXCR4 desensitisation to CXCL12.Blood. 2005; 105: 2249-2257Crossref PubMed Scopus (239) Google Scholar; given the occurrence of zoster and HSV described here, 2 previous cases of EBV-associated lymphoma,21Imashuku S. Miyagawa A. Chiyonobu T. Ishida H. Yoshihara T. Teramura T. et al.Epstein-Barr virus-associated T-lymphoproliferative disease with hematophagic syndrome, followed by fatal intestinal B lymphoma in a young adult female with WHIM syndrome.Ann Hematol. 2002; 81: 470-473Crossref PubMed Scopus (52) Google Scholar, 22Chae K.M. Ertle J.O. Tharp M.D. B-cell lymphoma in a patient with WHIM syndrome.J Am Acad Dermatol. 2001; 44: 124-128Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and a case of Kaposi sarcoma5Diaz G.A. CXCR4 mutations in WHIM syndrome: a misguided immune system?.Immunol Rev. 2005; 203: 235-243Crossref PubMed Scopus (71) Google Scholar (note added in proof), it seems likely that patients with WHIMS are also susceptible to viruses of the herpes class. Rapid improvement in (although not necessarily normalization of) the absolute neutrophil count after G-CSF has been widely reported as characteristic of WHIMS. We did not escalate dosages beyond 5 μg/kg, and it is possible that she was inadequately treated; her clinical improvement with immunoglobulin replacement has obviated the requirement for G-CSF, but clinicians should be aware that standard doses of G-CSF may not be sufficient. Better understanding of the pathogenesis of WHIMS raises the possibility of therapy directed at correcting the functional enhancement of CXCL12-CXCR4–mediated signaling. Various agents have been developed to block CXCR4 and are an exciting possibility for future therapy. Suspect WHIMS in patients with neutropenia, pyogenic infections, and HPV infection, which may be manifested as warts and/or dysplasia. Bone marrow findings are helpful in establishing the diagnosis. WHIMS is effectively managed by G-CSF, antibiotic prophylaxis, and immunoglobulin replacement therapy where indicated.