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

MM Hagleitner ¹, A Lankester ², P Maraschio ³, M Hultén ⁴, JP Fryns ⁵, C Schuetz ⁶, G Gimelli ⁷, EG Davies ⁸, A Gennery ⁹, BH Belohradsky ¹⁰, R de Groot ¹¹, EJA Gerritsen ¹², T Mattina ¹³, PJ Howard ¹⁴, A Fasth ¹⁵, I Reisli ¹⁶, D Furthner ¹⁷, MA Slatter ¹⁸, AJ Cant ¹⁸, G Cazzola ¹⁹, PJ van Dijken ²⁰, M van Deuren ²¹, JC de Greef ²², SM van der Maarel ²² and CMR Weemaes ^23*

¹ Dept. Paediatric Immunology, Radboud University Nijmegen Medical Centre, Netherlands
² Dept. Pediatrics, Leiden University Medical Centre, Netherlands
³ Dept. di Patologia Umana ed Ereditaria, Biologica Generale e Genetica Medica, Università di P, Italy
⁴ Dept. of Biological Sciences, University of Warwick, Coventry, United Kingdom
⁵ Centre of Human genetics, University Hospital Gasthuisberg, Leuven, Belgium
⁶ Dept. Pediatrics,University Hospital Ulm, Germany
⁷ Laboratorio di Citogenetica, Instituto G. Galini, Genova, Italy
⁸ Dept. Immunology, Great Ormond Street Hospital, London, United Kingdom
⁹ Dept. Pediatric Immunology, Newcastle General Hospital, United Kingdom
¹⁰ Dept. Infectious Diseases and immunology, University Childrens Hospital Munich, Germany
¹¹ Dept. of Paediatric Immunology, Radboud University Nijmegen Medical Centre, Netherlands
¹² Dept of Paediatrics, Oosterschelde Hospital, Goes, Netherlands
¹³ Dipartimento di Pediatrica, Genetica Medica University of Catania, Italy
¹⁴ Merseyside & Cheshire Regional Genetics Laboratory Liverpool Womens's Hospital, United Kingdom
¹⁵ Dept of Paediatrics, The Sahlgrenska Academy Goeteborg, Sweden
¹⁶ Dept of Pediatric Immunology and Allergy, Selcuk University, Turkey
¹⁷ Landesfrauen- & Kinderklinik Linz, Austria
¹⁸ Paediatric Immunology Dept, New Castle General Hospital, United Kingdom
¹⁹ Centro Fibrosi Cistica, Verona, Italy
²⁰ Dept of Paediatrics, Elisabeth Hospital Tilburg, Netherlands
²¹ Dept of Internal Medicine, Radboud University Nijmegen Medical Centre, Netherlands
²² Dept of Human Genetics, Leiden University Medical Centre, Netherlands
²³ Dept of Paediatric Immunology, Radboud University Nijmegen Medical Centre, Netherlands

^* To whom correspondence should be addressed. E-mail: c.weemaes{at}cukz.umcn.nl.

Accepted 13 September 2007

Abstract

Background: ICF is a rare autosomal recessive disease characterized 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 a 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 of ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. Results and conclusions: Forty-five 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 agammaglobulinemia was demonstrated in nearly all patients (N=39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Hematological 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.

Keywords: Genotype/Phenotype, Hypomethylation, ICF syndrome, Immunodeficiency

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