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J Med Genet 2008;45:93-99 doi:10.1136/jmg.2007.053397
  • Original article

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

  1. M M Hagleitner1,
  2. A Lankester2,
  3. P Maraschio3,
  4. M Hultén4,
  5. J P Fryns5,
  6. C Schuetz6,
  7. G Gimelli7,
  8. E G Davies8,
  9. A Gennery9,
  10. B H Belohradsky10,
  11. R de Groot1,
  12. E J A Gerritsen11,
  13. T Mattina12,
  14. P J Howard13,
  15. A Fasth14,
  16. I Reisli15,
  17. D Furthner16,
  18. M A Slatter9,
  19. A J Cant9,
  20. G Cazzola17,
  21. P J van Dijken18,
  22. M van Deuren19,
  23. J C de Greef20,
  24. S M van der Maarel20,
  25. C M R Weemaes1
  1. 1
    Department of Paediatric Immunology, Radboud University Nijmegen Medical Centre, The Netherlands
  2. 2
    Department of Paediatrics, Leiden University Medical Centre, The Netherlands
  3. 3
    Dipartimento di Patologia Umana ed Ereditaria, Biologica Generale e Genetica Medica, Universitè di Pavia, Italy
  4. 4
    Department of Biological Sciences, University of Warwick, Coventry, UK
  5. 5
    Centre of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
  6. 6
    University Hospital Ulm, Paediatrics, Germany
  7. 7
    Laboratorio di Citogenetia, Instituto G Galini, Genova, Italy
  8. 8
    Department of Immunology, Great Ormond Street Hospital, London, UK
  9. 9
    Paediatric Immunology Department, Newcastle General Hospital, Newcastle, UK
  10. 10
    Department of Infectious Diseases and Immunology, University Children’s Hospital Munich, Germany
  11. 11
    Department of Paediatrics, Oosterschelde Hospital, Goes, The Netherlands
  12. 12
    Dipartimento di Pediatrica, Genetica Medica University of Catania, Italy
  13. 13
    Merseyside & Cheshire Regional Genetics Laboratory Liverpool Women’s Hospital, Liverpool, UK
  14. 14
    Department of Paediatrics, The Sahlgrenska Academy Göteborg, Sweden
  15. 15
    Department of Pediatric Immunology and Allergy, Selcuk University, Turkey
  16. 16
    Landesfrauen- & Kinderklinik Linz, Austria
  17. 17
    Centro Fibrosi Cistica, Verona, Italy
  18. 18
    Department of Paediatrics, Elisabeth Hospital Tilburg, The Netherlands
  19. 19
    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands
  20. 20
    Department of Human Genetics, Leiden University Medical Centre, The Netherlands
  1. C M R Weemaes, Department of Pediatric Immunology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; c.weemaes{at}cukz.umcn.nl
  • Received 24 July 2007
  • Revised 12 September 2007
  • Accepted 13 September 2007
  • Published Online First 24 September 2007

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.

Footnotes

  • See end of article for authors' affiliations

  • Competing interests: None declared.

  • Ethics approval: Ethical approval was obtained for the publication of the data in this study.

  • Parental/guardian informed consent was obtained for publication of fig 1.

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