BACKGROUND: 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. 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.
OBJECTIVE: This study aims to describe the natural history of WS based on a 
French cohort of 8 patients.
METHODS: We have reviewed the clinical, biological and immunological features of 
patients with WS enrolled into the French Severe Chronic Neutropenia Registry.
RESULTS: We 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.
CONCLUSIONS: Continuous 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.