Familial occurrence of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome

Abstract

Introduction:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder with an autosomal-dominant pattern of inheritance and low fatality rate but significant lifelong morbidity.Materials and Methods:A 27-year-old mother of two children has been suffering from severe neutropenia and recurrent infections with the diagnosis of sporadic WHIM syndrome established by sequencing the CXCR4 gene and the finding of a heterozygous 1000 C→T nonsense mutation in the second CXCR4 exon. The first child was an apparently healthy boy delivered at full term. Umbilical cord blood cells were obtained for genetic analysis. Peripheral blood cells were also analyzed at 8 months of life. Both analyses revealed the same mutation as that of his mother. The child was in a good condition, manifesting neutropenia without infections until 11 months of life. He subsequently developed pneumonia requiring a more aggressive treatment. After that, the regular substitution of immunoglobulins (IVIGs) and G-CSF has been preventing serious infections. Six months ago the second boy was delivered who also demonstrated neutropenia without severe infections. Genetic studies using cord blood and also peripheral blood cells in the fourth month showed an identical mutation of the CXCR4 gene as in his mother. Moreover, the mother and her first son demonstrated monocytopenia.Results:The results indicate that genetic defects connected with WHIM syndrome may influence not only the granulocyte, but also the monocytic lineage. Moreover, a perinatal diagnosis of WHIM syndrome made by sequencing the CXCR4 gene should be performed in cases where either parent is known to be affected with this disease.Conclusions:This would facilitate an earlier detection of the deficiency in children, thereby allowing a more comprehensive follow-up and administration of appropriate therapy.

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

“…9,21 The sequestration site for other leukocyte subsets mobilized by plerixafor in WHIM patients is not directly addressed by our study, nor has it been defined in healthy subjects receiving the drug. Monocytopenia in WHIM syndrome has only recently been recognized, 24 and our results suggest that both classic and inflammatory monocyte numbers in the circulation are controlled by CXCR4. It is unknown whether monocytopenia causes any of the phenotypes in the syndrome, although monocytes are known to play a significant role in controlling infection, particularly by intracellular pathogens.…”

Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome

“…This highlights the problem of a perinatal diagnosis in cases where either parent is known to be affected with the syndrome. Genetic analysis can be performed by obtaining umbilical cord blood cells, subsequently confirmed with peripheral's one [29]. There appear to be patients manifesting clinical features of WHIM in whom mutations of CXCR4 cannot be found [22]: in these cases a presumptive diagnosis should be given in order to proceed with the clinical and therapeutical management.…”

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

“…Of the approximately 90 cases of WHIM syndrome reported to date, 3 had Tetralogy of Fallot (ToF), a rare congenital heart defect found in only ∼3/10,000 live births in the general population [33]. Other developmental abnormalities include double aortic arch [7], ventricular septal defect with pulmonary atresia [30], skeletal malformations [34,35], and angioma [36]. Both lymphoid follicular hyperplasia [1] and hypoplasia [25] have been described in the only two descriptions of lymph node histology from WHIM patients in the literature.…”