Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry

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.

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

“…12,13 Both treatments have been used in WHIM patients; however, no studies have documented clinical efficacy, and they are nonspecific, expensive, difficult to administer, and of questionable efficacy in controlling infections and warts. 4,14 In contrast, the small molecule plerixafor (also known as Mozobil and AMD3100), which is approved by the US Food and Drug Administration (FDA) for mobilizing hematopoietic stem cells from bone marrow to blood for transplantation in cancer, 15,16 is a highly specific antagonist of both wild-type and WHIM variants of CXCR4 and can rapidly mobilize all major subsets of mature leukocytes to blood in both healthy donors and patients with WHIM syndrome. Specifically, in two phase 1 clinical trials lasting 1 to 2 weeks in patients with WHIM syndrome, plerixafor was able to safely and rapidly increase absolute lymphocyte, monocyte, and neutrophil counts in the peripheral blood in a dose-dependent manner, including at the lowest dose tested, 0.02 mg/kg per day by subcutaneous administration, which is 8% of the FDA-approved dose for stem cell mobilization (0.24 mg/kg per day).…”

La chimiokine CXCL12 et son récepteur CXCR4 dans le contrôle des infections par les papillomavirus humains

“…L'infection, à l'origine productive et asymptomatique, se transforme séquentiellement en une lésion bénigne, puis précancéreuse (dysplasie) ou cancéreuse (néoplasie) (Figure 1). Les génotypes HPV infectant l'épithé-lium cervical ne développeraient leur potentiel oncogène que dans certaines populations cellulaires de la jonction située entre l'exocol 2 et l'endocol [4], également le cas moins étudié du WHIM 3 , un syndrome d'immunodéficience très rare, dont un des signes cardinaux est une susceptibilité sélective aux infections par les HPV, se révélant dans plus de 70 % des cas par le développement de verrues cutanées étendues et de papillomes ano-génitaux qui évoluent en cancers [6]. 3 Le syndrome WHIM (Warts -hypogammaglobulinemiainfections -myelokathexis) est un déficit immunitaire autosomique dominant congénital principalement caractérisé par une lymphopénie, une neutropénie et une myélokathexie (présence anormalement élevée de neutrophiles matures dans la moelle osseuse) associées à une susceptibilité aux infections par les papillomavirus humains.…”

“…Cette entéropathie est moins fréquente que l'AMV, avec une incidence estimée à 1/200 000 en Europe. La DEI est histologiquement définie par un épithélium dysplasique caractéristique, prenant de façon hétérogène un aspect pseudostratifié où les entérocytes s'accumulent sous forme de houppettes ou « tufts » [6], qui touchent jusqu'à 70 % des villosités à un stade avancé [6]. …”

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome

“…In the presented case 1, tetralogy of Fallot was the first manifestation. This association was reported in 10% of WHIM syndrome patients, 8,14,15 suggesting that the diagnostic assessment of infants with congenital heart defect should include a full blood count to screen for neutropenia ( Table 1). Lack of neutropenia in at least 3 or more complete blood counts in the absence of acute or recent infection rules out the hypothesis of WHIM syndrome.…”

“…The CXCR4 intracellular tail mediates its negative regulation through G-protein-coupled receptor kinase (GRK)-mediated phosphorylation and b-arrestin-mediated internalization 2,3,14,17 (Table 2). Consequently, the mutated receptor displays an impaired ligand-dependent downregulation and prolonged responses of CXCR4 mutants to CXCL12 (ie, gain of function causing an excessive accumulation of mature neutrophils, lymphocytes, and monocytes in the bone marrow and accounting for the symptoms of the disease 3,5,6,18,19 ).…”