WHIM Syndrome

WHIM syndrome (warts, hypogammaglobulinaemia, infections, myelokathexis) is a combined immunodeficiency from gain-of-function variants in CXCR4, usually inherited as autosomal dominant. Chronic neutropenia with marrow retention of mature neutrophils is its hallmark.

Pathophysiology. C-terminal truncation of CXCR4 blocks receptor desensitisation, so neutrophils and lymphocytes stay in the bone marrow in response to its ligand CXCL12. Blood neutrophils and lymphocytes fall, while the marrow is cellular with mature, hypersegmented neutrophils.

It is very rare. Onset is in infancy to early childhood, with wide variation in severity.

Persistent HPV infection leads to extensive warts and a lifelong risk of HPV-related cancers of the cervix, vulva, anus and oropharynx.

• Recurrent otitis media, sinusitis, pneumonia and bronchiectasis, and skin infection (cellulitis)
• Severe, multifocal or recalcitrant warts, and genital warts, in the second decade or earlier
• Gingivitis, mouth ulcers and periodontal disease
• Neutropenia (blood neutrophils usually 0.1 to 0.5 x 109/L) and lymphopenia, which may fall further during infection
• Congenital cardiac malformations, such as tetralogy of Fallot, in some

• Full blood count with differential, repeated: neutropenia and lymphopenia.
• Bone marrow aspirate: hypercellular marrow with mature neutrophils showing hypersegmented nuclei and cytoplasmic vacuoles.
• Immunoglobulins, B and T cell subsets: low IgG (variable IgA and IgM), low B cells, and lymphopenia.
• Genetic testing of CXCR4 (heterozygous truncating variants).
• Specific antibody responses to tetanus and pneumococcal vaccines.
• HPV testing, cervical cytology and colposcopy, and anal cytology, from adolescence.
• Chest imaging and CT for bronchiectasis; echocardiography for congenital heart disease.

Differential diagnosis.

• Severe congenital neutropenia (ELANE and other gene defects)
• Cyclic neutropenia
• Shwachman-Diamond syndrome
• GATA2 deficiency
• Common variable immunodeficiency
• Epidermodysplasia verruciformis and other HPV susceptibility disorders
• Autoimmune neutropenia

• CXCR4 antagonist therapy: mavorixafor 400 mg orally once daily on an empty stomach in patients aged 12 years and over weighing at least 50 kg. It raises blood neutrophils and lymphocytes. Check liver enzymes and avoid strong CYP3A4 or P-glycoprotein interactions. Plerixafor is used off label in specialist centres.
• Granulocyte colony stimulating factor: filgrastim 1 to 5 microgram/kg subcutaneously daily or on alternate days, titrated to keep blood neutrophils at 1.0 x 109/L or more. Monitor spleen size and bone pain.
• Immunoglobulin replacement when IgG is low and infections occur: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, adjusted to a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Premedicate after a reaction with paracetamol 15 mg/kg orally (maximum 1 g).
• Antibiotic prophylaxis: co-trimoxazole 480 mg orally once daily in adults (children trimethoprim 5 mg/kg daily in two divided doses on 3 days each week) when neutropenia is persistent and infections frequent.
• Febrile neutropenia: an emergency. Give piperacillin with tazobactam 4.5 g intravenously every 6 hours in adults after blood cultures, with dose adjusted to renal function.
• HPV disease: 9-valent HPV vaccine (non-live) from age 9 years. Treat warts with cryotherapy or imiquimod 5% cream three times weekly at night for up to 16 weeks. Lifelong cervical, anal and oropharyngeal screening.
• Dental care every 6 months, with antiseptic mouthwash for gingivitis.
• Haematopoietic stem cell transplantation for severe, treatment refractory disease.

Special groups.

• Women: begin cervical screening early, with colposcopy at any abnormal result.
• Children: weight based dosing for all drugs, and check growth.

Monitoring. Full blood count every 3 to 6 months. Trough IgG every 3 to 6 months on replacement. Liver enzymes at baseline and every 3 months on mavorixafor. Annual HPV-related cancer screening. Echocardiogram once.

Referral and escalation. Refer to immunology and haematology. Urgent for fever with neutropenia, sepsis, and any suspicious HPV lesion.