Knowledge on rare diseases and orphan drugs

WHIM syndrome is extremely rare, with 65 cases reported worldwide to date. The incidence in France between 1990 and 2006 has been estimated at less than 1/ 4,000,000 births.

WHIM syndrome has a heterogeneous clinical picture. Onset usually occurs during early childhood with recurrent bacterial infections, including pharyngitis, sinusitis, otitis, meningitis and pneumonia, which respond well to antibiotics. The response to vaccination is poor; when measured by the titer of specific antibodies, a low response is initially observed followed by a rapid disappearance of specific antibodies. More than 80% of the patients develop, by the age of 30 years old, widespread HPV-induced warts that are often difficult to treat, generally starting on hands and feet. 25% develop anogenital condylomata acuminata which may progress to intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer. Tetralogy of Fallot has been reported in about 1/4 of cases.

WHIM syndrome is caused by heterozygous gain of function mutations in the CXCR4 gene (2q21) encoding a chemokine receptor expressed on mature leukocytes and involved in signal transduction pathways controlling bone marrow cell adhesion and homing, myelopoiesis and lymphopoiesis. Mutations result in prolonged activation of the receptor that leads to retention of neutrophils and other leukocytes in the bone marrow.

Diagnosis is based on the evaluation of clinical signs in addition to the following laboratory findings: cell blood counts usually showing (except in case of acute infection) neutropenia, lymphopenia, and monocytopenia resulting in severe panleukopenia, with normal hemoglobin levels and platelets; serum immunoglobulins G, A and M levels showing mild hypogammaglobulinemia in almost all cases; and bone marrow aspirates demonstrating myelokathexis. Genetic analysis of CXRC4 confirms diagnosis.

Differential diagnosis of diseases with myelokathexis include autosomal dominant severe congenital neutropenia, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, epidermodysplasia verruciformis, and monocytopenia with susceptibility to infections.

Prenatal testing by amniocentesis or chorionic villus sampling is possible in case of family history.

WHIM syndrome is usually transmitted as an autosomal dominant trait. Autosomal recessive or sporadic cases have also been described.

Current treatment is symptomatic. Immunoglobulin replacement therapy and prophylactic antibiotic treatment may prevent infections. Treatment with granulocyte-colony stimulating factor (GCSF) may also be used. Standard methods (cauterization, laser therapy) or more aggressive treatments (surgical removal, Interferon, cidofovir, imiquimod) appear mostly ineffective for the management of HPV induced lesions. A clinical trial using CXCR4 antagonist (Plerixafor) is currently ongoing in the USA, and soon in Europe. Case reports suggest that the HPV vaccine may limit the occurrence of HPV infection.

WHIM affected individuals may live well into adulthood. Major risk factors include intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer, and liver failure. By the age of 40, the cancer risk is of about 30%.

Last update: October 2014 - Expert reviewer(s): Dr Jean DONADIEU