title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
abstract: 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.
authors.affiliation: AP-HP, Registre Français des Neutropénies Chroniques Sévères, Centre de Référence des Déficits Immunitaires Héréditaires, Service d'Hémato-Oncologie Pédiatrique Hôpital Trousseau, 26 avenue du Dr Netter, 75012 Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beaussant Cohen
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Plouvier
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Rohrlich
authors.forename: Gerard
authors.initials: G
authors.lastname: Daltroff
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plantier
authors.forename: Alain
authors.initials: A
authors.lastname: Dupuy
authors.forename: Delphine
authors.initials: D
authors.lastname: Kerob
authors.forename: Blandine
authors.initials: B
authors.lastname: Beaupain
authors.forename: Pierre
authors.initials: P
authors.lastname: Bordigoni
authors.forename: Fanny
authors.initials: F
authors.lastname: Fouyssac
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Gilles
authors.initials: G
authors.lastname: Devouassoux
authors.forename: Jean François
authors.initials: JF
authors.lastname: Nicolas
authors.forename: Philippe
authors.initials: P
authors.lastname: Bensaid
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Christine Bellanne
authors.initials: CB
authors.lastname: Chantelot
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
authors.forename: Jean
authors.initials: J
authors.lastname: Donadieu
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001424:Bacterial Infections / Q000209:etiology / Q000517:prevention & control; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D007223:Infant; D008297:Male; D010375:Pedigree; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics; D012042:Registries; D014860:Warts / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4