Cutaneous manifestations of WHIM syndrome

Abstract

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare immunodeficiency caused by gain-of-function mutations in the chemokine receptor CXCR4. While human papillomavirus (HPV) skin infection (warts) is the dermatological hallmark of the disease, individuals with WHIM have high rates of other skin manifestations that may aid early diagnosis and management. This study was a retrospective review of medical records from a United States National Institutes of Health natural history cohort of patients with WHIM syndrome seen between 2005 and 2024, including a cross-sectional analysis of cutaneous manifestations and CXCR4 variants. The cohort compromised 45 patients with genetically confirmed WHIM syndrome, 16 men and 29 women, with a mean age of 33.3 years (range, 0-69 years) and mean age at diagnosis of 20.4 years (range, 0-59 years). The cohort exhibited a range of skin manifestations which included cutaneous infections with HPV in 34 (76%) patients, bacteria in 32 (71%) patients, other viruses in 27 (60%) patients, and fungi in 25 (56%) patients. Inflammatory conditions included six (13%) patients with seborrheic dermatitis, five (11%) with contact dermatitis, four (9%) with psoriasis, three (7%) with nummular eczema, and 13 (29%) with other eczematous dermatitis. Despite the young median age, seven (16%) patients had skin cancer. All seven patients had CXCR4 truncation mutations, while those with a missense mutation (E343K) generally had fewer skin manifestations. Our study found that WHIM syndrome is associated with diverse infectious, inflammatory, and neoplastic skin conditions beyond HPV skin infection.

Keywords: genetic disease; health; inborn; infectious; population characteristics; primary immunodeficiency syndromes; skin diseases.

FIGURE 1

Cutaneous manifestations of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome. Graphical representation of the cutaneous manifestations observed in 45 patients with WHIM Syndrome at the National Institutes of Health, as detailed in Table S4. The x‐axis displays the type of cutaneous manifestations, and the y‐axis displays the percentage of patients affected. Each category (skin infection, skin cancer, chronic inflammatory skin conditions, inflammatory skin findings, and other skin findings) is color‐coded according to the legend.

FIGURE 2

Cumulative incidence of first reported non‐human papillomavirus (HPV) and HPV skin infection. Age at reported onset for first documented non‐HPV and HPV skin infections were collected to calculate the cumulative incidence. Forty individuals had non‐HPV skin infection (mean age at onset 13.4 years, median age 9.0 years). Thirty‐four individuals had HPV skin infection in the cohort (mean onset 10.7 years, median 7.8 years). Sixteen of 40 patients (40%) with non‐HPV skin infection and eight of 34 patients (24%) with HPV skin infection had a first onset at 5 years or under. Twenty‐two of 40 patients (55%) with non‐HPV skin infection and 20 of 34 patients (59%) with HPV skin infection had a first onset before the age of 10 years.