Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome)

Background: Immunodeficiency, centromeric instabilityand facial dysmorphism (ICF syndrome) is a rareautosomal recessive disease characterised by facialdysmorphism, immunoglobulin deficiency and branchingof chromosomes 1, 9 and 16 after PHA stimulation oflymphocytes. Hypomethylation of DNA of a small fractionof the genome is an unusual feature of ICF patients whichis explained by mutations in the DNA methyltransferasegene DNMT3B in some, but not all, ICF patients.Objective: To obtain a comprehensive description of theclinical features of this syndrome as well as genotype–phenotype correlations in ICF patients.Methods: Data on ICF patients were obtained byliterature search and additional information by means ofquestionnaires to corresponding authors.Results and conclusions: 45 patients all with provencentromeric instability were included in this study. Facialdysmorphism was found to be a common characteristic(n=41/42), especially epicanthic folds, hypertelorism,flat nasal bridge and low set ears. Hypo- or agammaglobulinaemiawas demonstrated in nearly all patients(n=39/44). Opportunistic infections were seen in severalpatients, pointing to a T cell dysfunction. Haematologicalmalignancy was documented in two patients. Lifeexpectancy of ICF patients is poor, especially those withsevere infections in infancy or chronic gastrointestinalproblems and failure to thrive. Early diagnosis of ICF isimportant since early introduction of immunoglobulinsupplementation can improve the course of the disease.Allogeneic stem cell transplantation should be consideredas a therapeutic option in patients with severe infectionsor failure to thrive. Only 19 of 34 patients showedmutations in DNMT3B, suggesting genetic heterogeneity.No genotype–phenotype correlation was found betweenpatients with and without DNMT3B mutations.