Abstract
BackgroundWHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.ObjectiveThis study aims to describe the natural history of WS based on a French cohort of 8 patients.MethodsWe have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.ResultsWe identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient’s death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.ConclusionsContinuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.
Highlights
WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the Chemokine receptor type 4 (CXCR4) chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis
In 1964, Zuelzer reported an exceptional congenital neutropenia associated with hyperplasia of mature neutrophils in the bone marrow (BM) – myelokathexis [1]
Leukocytes from the minority of patients who carry a wild-type (WT) CXCR4 gene presented a similar pattern of aberrant Chemokine ligand 12 (CXCL12)/CXCR4 responses [4,7,8,9] consistent with a role for these dysfunctions in the WS hematological defects [10]
Summary
WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. Leukocytes from the minority of patients who carry a wild-type (WT) CXCR4 gene presented a similar pattern of aberrant CXCL12/CXCR4 responses [4,7,8,9] consistent with a role for these dysfunctions in the WS hematological defects [10] In support of this assumption, a new knock-in mouse strain that harbors a WS-associated heterozygous mutation of the CXCR4 gene exhibits striking parallels to the major immunological features of WS (i.e. panleukopenia) and is considered as a valuable model of the human syndrome [11]
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