Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies

J Allergy Clin Immunol Pract. May-Jun 2019;7(5):1568-1577. doi: 10.1016/j.jaip.2019.01.045. Epub 2019 Feb 2.

Abstract

Background: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results.

Objective: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management.

Methods: Data were collected from an international cohort of 18 patients with CXCR4 mutations.

Results: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively.

Conclusions: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

Keywords: B lymphopenia; Congenital neutropenia; Human papilloma virus; Hypogammaglobulinemia; Lung disease; Myelokathexis; Panleukopenia; Tumors; WHIM syndrome; Warts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Adolescent
  • Adult
  • Age of Onset
  • Anti-Bacterial Agents / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • Anus Neoplasms / etiology
  • Anus Neoplasms / therapy
  • Anus Neoplasms / virology
  • Bronchiectasis / physiopathology*
  • Child
  • Child, Preschool
  • Chronic Disease
  • Codon, Nonsense
  • Cohort Studies
  • Cryosurgery
  • Delayed Diagnosis
  • Disease Progression
  • Female
  • Frameshift Mutation
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Heart Defects, Congenital
  • Humans
  • Imiquimod / therapeutic use
  • Infant
  • Infant, Newborn
  • Keratolytic Agents / therapeutic use
  • Limb Deformities, Congenital
  • Lung Diseases / physiopathology
  • Lymphopenia / physiopathology
  • Male
  • Middle Aged
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / physiopathology*
  • Pneumonia / physiopathology*
  • Primary Immunodeficiency Diseases / genetics
  • Primary Immunodeficiency Diseases / immunology
  • Primary Immunodeficiency Diseases / physiopathology*
  • Primary Immunodeficiency Diseases / therapy
  • Receptors, CXCR4 / genetics
  • Retinoids / therapeutic use
  • Salicylic Acid / therapeutic use
  • Uterine Cervical Neoplasms / etiology
  • Uterine Cervical Neoplasms / therapy
  • Uterine Cervical Neoplasms / virology
  • Warts / genetics
  • Warts / immunology
  • Warts / physiopathology*
  • Warts / therapy
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • CXCR4 protein, human
  • Codon, Nonsense
  • Keratolytic Agents
  • Receptors, CXCR4
  • Retinoids
  • Granulocyte Colony-Stimulating Factor
  • Salicylic Acid
  • Imiquimod

Supplementary concepts

  • Heart defects limb shortening
  • WHIM syndrome