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Hagleitner, M.M.; Lankester, A.; Maraschio, P.; Hultén, M.; Fryns, J.P.; Schuetz, C.; Gimelli, G.; Davies, E.G.; Gennery, A.; Belohradsky, Bernd H.; de Groot, R.; Gerritsen, E.J.A.; Mattina, T.; Howard, P.J.; Fasth, A.; Reisli, I.; Furthner, D.; Slatter, M.A.; Cant, A.J.; Cazzola, G.; van Dijken, P.J.; van Deuren, M.; de Greef, J.C.; van der Maarel, S.M.; Weemaes, C.M.R. (2008): Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). In: Journal of Medical Genetics, Vol. 45: S. 93-99
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Abstract

Background: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. Objective: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype– phenotype correlations in ICF patients. Methods: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. Results and conclusions: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n=41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n=39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype–phenotype correlation was found between patients with and without DNMT3B mutations.