WHIM syndrome is caused by mutations leading to a gain of function in C-X-C chemokine receptor type 4 (CXCR4), a type of G-protein-coupled receptor in leukocytes. The resulting truncated protein lacks residues normally involved in negative feedback control of the chemokine-signaling pathway. Consequently, in WHIM syndrome, affected cells including leukocytes exhibit enhanced and sustained response to chemokines.
WHIM syndrome is extremely rare, with fewer than 100 cases reported worldwide since 1964, and has an estimated prevalence of 0.23 cases per million births. The age of onset and clinical features vary from patient to patient. WHIM syndrome patients have increased susceptibility to human papillomavirus (HPV) and classically present with numerous warts over the trunk, hands, and feet. They typically have condyloma acuminata in the genital and anal region, and female patients are at increased risk for cervical carcinoma and severe dysplasia.
Patients also typically have an early childhood history of recurrent bacterial infections, such as cellulitis, urinary tract infection, thrombophlebitis, osteomyelitis, omphalitis, sinusitis, and pneumonia. Typical causal organisms include encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, and Proteus mirabilis. Cases with severe bronchiectasis with chronic Pseudomonas aeruginosa and Burkhoderia cepacia have also been recorded.
Hematological findings include panlymphopenia and hypogammaglobulinemia. Most patients exhibit B-cell lymphopenia and neutropenia, and many also have deficits in T lymphocytes. In contrast, there is marked hyperplasia of the bone marrow. Here, apoptotic mature myeloid cells (myelokathexis) including neutrophils are found in increased numbers. The prevailing theory is that it is the failure of the myeloid cells to leave the bone marrow due to the aberrant CXCR4-based chemokine response that leads to the lower neutrophil count in the peripheral blood and not a defect in production. Therefore, this syndrome differs from other congenital neutropenias in that stimulating factors such as granulocyte-colony stimulating factor (G-CSF) and glucocorticoids induce a quick neutrophil release.
D81.9 – Combined immunodeficiency, unspecified
234571003 – Warts, hypogammaglobulinemia, infections, and myelokathexis
Differential Diagnosis & Pitfalls
- Glycogen storage disease type 1 (G6PC deficiency) – Associated with infections and neutropenia.
- Kostmann syndrome – Autosomal recessive disorder characterized by severe neutropenia and increased susceptibility to infection.
- Barth syndrome – X-linked recessive disease characterized by neutropenia, dilated cardiomyopathy, and skeletal myopathy.
- Shwachman-Diamond syndrome – Autosomal recessive condition characterized by pancreatic insufficiency, neutropenia, and bone marrow abnormalities.
- GATA2 haploinsufficiency syndrome – Autosomal dominant syndrome characterized by panleukopenia and recurrent mycobacterial infections.
- Cyclic neutropenia
- Chronic neutropenia
- Tree man syndrome – A distinct genetic disorder of defective T-cell immunity to α-HPV2 resulting in multiple recalcitrant warts that develop into giant cutaneous horns.