Random Dermatology MCQ - WHIM syndrome

A 10-year-old girl has a lifelong history of recurrent sinopulmonary bacterial infections, extensive treatment-resistant cutaneous warts, and severe hypogammaglobulinemia requiring regular intravenous immunoglobulin (IVIG) infusions. Her most recent complete blood count reveals profound leukopenia with an absolute neutrophil count of 200/µL. The triad of clinical findings suggests a specific syndrome. What is the most likely genetic defect and the mechanism of the characteristic leukopenia?

A. Mutation in the BTK gene causing B-cell maturation arrest; leukopenia from bone marrow failure.
B. Gain-of-function mutation in the CXCR4 gene causing hyperresponsiveness to its ligand CXCL12; defective release of mature leukocytes from the bone marrow.
C. Mutation in the WAS gene causing cytoskeletal defects in hematopoietic cells; leukopenia from accelerated apoptosis.
D. Mutation in the NADPH oxidase complex; leukopenia due to chronic infections.
E. Mutation in the ADA gene causing toxic metabolite accumulation; leukopenia from lymphotoxicity.

Correct Answer: B. Gain-of-function mutation in the CXCR4 gene causing hyperresponsiveness to its ligand CXCL12; defective release of mature leukocytes from the bone marrow.

Answer and Explanation

The correct answer is B. This question describes the classic tetrad of WHIM syndrome: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The key clues are the severe, recalcitrant human papillomavirus (HPV) warts, recurrent bacterial infections, low immunoglobulins, and the profound neutropenia (a component of leukopenia). The term "myelokathexis" refers to the bone marrow showing an excess of mature, apoptotic neutrophils trapped within the marrow. This is caused by gain-of-function mutations in the CXCR4 gene, which encodes a chemokine receptor. The mutant receptor is hyperresponsive to its ligand, CXCL12 (SDF-1), leading to excessive retention and failed egress of neutrophils (and other leukocytes) from the bone marrow into the peripheral blood.

Why the Other Options are Incorrect:

• A. Mutation in the BTK gene: This causes X-linked agammaglobulinemia (Bruton's disease), characterized by profound hypogammaglobulinemia and bacterial infections from an early age, but not warts or myelokathexis. Patients have very low B-cells, but neutrophil counts are typically normal.

• C. Mutation in the WAS gene: This causes Wiskott-Aldrich syndrome, characterized by the triad of eczema, thrombocytopenia (with small platelets), and recurrent infections. It can include warts, but the hallmark is microthrombocytopenia, not isolated severe neutropenia/myelokathexis.

• D. Mutation in the NADPH oxidase complex: This causes chronic granulomatous disease (CGD), characterized by recurrent infections with catalase-positive organisms and granuloma formation, not warts or myelokathexis. Neutrophil count is normal or elevated.

• E. Mutation in the ADA gene: This causes severe combined immunodeficiency (SCID), presenting in infancy with life-threatening opportunistic infections and profound lymphopenia, not the specific tetrad of WHIM.

Additional High-Yield Information for Exams:

• Pathogenesis: The CXCR4 gain-of-function mutation leads to constitutive or exaggerated signaling. CXCL12/CXCR4 interaction is crucial for hematopoietic stem cell retention in the bone marrow niche. In WHIM, this retention signal is too strong, trapping mature neutrophils, B-cells, and other leukocytes in the marrow ("myelokathexis" = marrow holding). This explains both the peripheral cytopenias and the marrow hypercellularity.

• Clinical Features:

  • Infections: Recurrent pyogenic infections (pneumonia, otitis, sinusitis) due to neutropenia and hypogammaglobulinemia.

  • Warts: Severe, widespread, recalcitrant cutaneous and mucosal HPV warts, including oncogenic HPV types, leading to a high risk of HPV-related squamous cell carcinomas.

  • Hematologic: Chronic severe neutropenia is the rule. Lymphopenia and monocytopenia are also common.

• Differential Diagnosis: The combination of severe warts and neutropenia should strongly suggest WHIM. Other conditions with warts and immunodeficiency include GATA2 deficiency (MonoMAC syndrome) and everted WHIM syndrome (due to G6PC3 mutations), but these have distinct genetic bases and features.

• Associated Conditions & Prognosis:

  • HPV-related Cancer: Patients have a high risk of developing squamous cell carcinomas from oncogenic HPV types (cervical, vulvar, anal, head/neck).

  • Prognosis: Variable. Morbidity is high from chronic infections and warts. Mortality can result from invasive infections or HPV-related malignancies.

• Management & Rationale:

  • Rationale: Treatment aims to increase peripheral neutrophil counts, prevent infections, and manage HPV complications.

  • First-line Medical Therapy: Granulocyte colony-stimulating factor (G-CSF, filgrastim) is used to mobilize neutrophils from the bone marrow, improving neutrophil counts and reducing infection frequency.

  • Immunoglobulin Replacement: IVIG or subcutaneous IG for hypogammaglobulinemia.

  • Targeted Therapy: CXCR4 antagonists (e.g., plerixafor/mozobil) are a rational and effective targeted therapy, blocking the hyperactive receptor and promoting leukocyte egress from the bone marrow.

  • Cancer Surveillance: Regular and aggressive screening for HPV-related malignancies (gynecologic, dermatologic, ENT exams) is mandatory. Aggressive treatment of pre-malignant lesions.

  • Wart Management: Aggressive topical (imiquimod, cidofovir) or surgical therapies, but they are often refractory.