WHIM syndrome, an autosomal dominant disorder: Clinical, hematological, and molecular studies

Abstract

The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The latter refers to the retention of white cells in the marrow, which becomes hypercellular. We have found approximately 20 examples of WHIM syndrome in the literature under various designations; the first examples are Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and hypercellular bone marrow represent defective release of marrow cells into the peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in form. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasm suggest apoptosis. Fever or other stress increases the release of neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia). Patients have numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. We report on a kindred of 6 affected individuals in 3 generations with autosomal dominant WHIM syndrome. The sex ratio among reported patients and in our kindred is 17 female to 8 male. Because there had been no male-to-male transmssion, search of the entire X-chromosome including the pseudoautosomal area was carried out and no linkage was found. Recently, the propositus has had an unaffected daughter, confirming our finding that the gene is not X-linked. A genome-wide search is being carried out.

WHIM syndrome: A defect in CXCR4 signaling

“…Interestingly, these genetic studies have also identified phenocopies with the same clinical features but without mutation of CXCR4, suggesting that mutations in as yet uncharacterized downstream regulators of the receptor may be involved in a proportion of cases. and pre-malignant dysplastic changes, necessitating surgical resection of involved tissue [6,10]. Unfortunately for patients with extensive HPV infection, the papillomas are refractory to treatment with standard ablation and immunomodulatory therapies.…”

Genetic Syndromes with Evidence of Immune Deficiency

“…A three-generation pedigree was described with neutropenia, hypogammaglobulinemia, and warts. 265 A mutation in the gene encoding chemokine, CXC motif, receptor-4, CXCR4, is associated with the disease (see Chapter 35). 266 …”

Genetic Insights into Congenital Neutropenia

“…First described by Zuelzer in a sporadic case [65], myelokathexis was subsequently found to occur as an autosomal dominant trait in association with hypogammaglobulinemia and dermal/genital papilloma virus infections [66]. Severe infections are rare since neutrophils can be adequately released to the periphery in case of infections.…”