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

Melanie M. Hagleitner(Radboud University Nijmegen), Arjan C. Lankester(Leiden University), P Maraschio(University of Pavia), Maj Hultén(University of Warwick), J. P. Fryns, Catharina Schuetz(University Hospital Ulm), Giorgio Gimelli(Istituto Nazionale di Fisica Nucleare, Galileo Galilei Institute for Theoretical Physics), E. Graham Davies(Great Ormond Street Hospital), A Gennery(North Tyneside General Hospital), B. H. Belohradsky(University Children's Hospital Tübingen), Ronald de Groot(Radboud University Nijmegen), E.J.A. Gerritsen, Teresa Mattina(University of Catania), P. J. Howard(University of Liverpool), Anders Fasth(University of Gothenburg), İsmail Reisli(Selçuk University), Dieter Furthner, Mary Slatter(North Tyneside General Hospital), A J Cant(North Tyneside General Hospital), G Cazzola(Cystic Fibrosis Research Foundation), P J van Dijken(Elisabeth-TweeSteden Ziekenhuis), Marcel van Deuren(Radboud University Nijmegen), Jessica C. de Greef(Leiden University), Silvère M. van der Maarel(Leiden University), Corry M.R. Weemaes(Radboud University Nijmegen)
Journal of Medical Genetics
September 24, 2007
10.1136/jmg.2007.053397
Cited by 217

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.

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