Journal of Clinical Immunology

, Volume 31, Issue 2, pp 245–252 | Cite as

ICF Syndrome in Saudi Arabia: Immunological, Cytogenetic and Molecular Analysis

  • Namik Kaya
  • Saleh Al-Muhsen
  • Bandar Al-Saud
  • Albandary Al-Bakheet
  • Dilek Colak
  • Abdulaziz Al-Ghonaium
  • Hasan Al-Dhekri
  • Hamoud Al-Mousa
  • Rand Arnaout
  • Mohammad Al-Owain
  • Mohammad Iqbal



Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disorder. In addition to the juxtacentromeric heterochromatic instability, the disease is characterized by variable reduction in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood as well as exhibit facial dysmorphism including hypertelorism, epicanthal folds, and low-set ears.

Subjects and Methods

A case series of five patients with ICF from a major immunodeficiency center in Saudi Arabia were included. Immunological and cytogenetic studies were performed for all the five patients. Molecular data was conducted on three patients.


All patients had variable hypogammaglobulinemia and characteristic centromeric instability of chromosomes 1, 16, and sometimes 9. One of the patients had pseudomonas meningitis. Pauciarticular arthritis was noted in one patient, a previously not reported finding in ICF, though it has been reported among patients with humoral immune defect. In addition, we identified a novel homozygous c.2506 G>A (p.V836M) mutation in DNMT3B in one of the three patients tested.


This report describes five patients with ICF Saudi Arabia for the first time. ICF should be suspected in children with facial dysmorphism who present with recurrent infections especially in highly inbred populations.


ICF syndrome centromeric instability DNMT3B pauciarticular arthritis 


Conflicts of interest



  1. 1.
    Brown DC, Grace E, Sumner AT, et al. ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome. Hum Genet. 1995;96:411–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Jeanpierre M, Turleau C, Aurias A, et al. An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum Mol Genet. 1993;2:731–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Xu GL, Bestor TH, Bourc'his D, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999;402:187–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Wijmenga C, van den Heuvel LP, Strengman E, et al. Localization of the ICF syndrome to chromosome 20 by homozygosity mapping. Am J Hum Genet. 1998;63:803–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Wijmenga C, Hansen RS, Gimelli G, et al. Genetic variation in ICF syndrome: evidence for genetic heterogeneity. Hum Mutat. 2000;16:509–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Ehrlich M, Sanchez C, Shao C, et al. ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity. 2008;41:253–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Seabright M. A rapid banding technique for human chromosomes. Lancet. 1971;2:971–2.PubMedCrossRefGoogle Scholar
  8. 8.
    Kuhn RM, Karolchik D, Zweig AS, et al. The UCSC genome browser database: update 2009. Nucleic Acids Res. 2009;37:D755–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Karolchik D, Hinrichs AS, Kent WJ. The UCSC Genome Browser. Curr Protoc Bioinformatics 2007: Chapter 1: Unit 1 4.Google Scholar
  10. 10.
    Hubbard TJ, Aken BL, Ayling S, et al. Ensembl 2009. Nucleic Acids Res. 2009;37:D690–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Sayers EW, Barrett T, Benson DA, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2009;37:D5–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Stenson PD, Ball E, Howells K, et al. Human gene mutation database: towards a comprehensive central mutation database. J Med Genet. 2008;45:124–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Thomas PD, Kejariwal A. Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proc Natl Acad Sci USA. 2004;101:15398–403.PubMedCrossRefGoogle Scholar
  14. 14.
    Thomas PD, Campbell MJ, Kejariwal A, et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 2003;13:2129–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Brunham LR, Singaraja RR, Pape TD, et al. Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene. PLoS Genet. 2005;1:e83.PubMedCrossRefGoogle Scholar
  16. 16.
    Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001;11:863–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Sunyaev S, Ramensky V, Koch I, et al. Prediction of deleterious human alleles. Hum Mol Genet. 2001;10:591–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Yue P, Melamud E, Moult J. SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinform. 2006;7:166.CrossRefGoogle Scholar
  20. 20.
    Larkin MA, Blackshields G, Brown NP, et al. Clustal W and Clustal X version 2.0. Bioinformatics. 2007;23:2947–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Ehrlich M, Jackson K, Weemaes C. Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphanet J Rare Dis. 2006;1:2.PubMedCrossRefGoogle Scholar
  22. 22.
    Hansel TT, Haeney MR, Thompson RA. Primary hypogammaglobulinaemia and arthritis. Br Med J (Clin Res Ed). 1987;295:174–5.CrossRefGoogle Scholar
  23. 23.
    Webster AD, Loewi G, Dourmashkin RD, et al. Polyarthritis in adults with hypogammaglobulinaemia and its rapid response to immunoglobulin treatment. Br Med J. 1976;1:1314–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Hagleitner MM, Lankester A, Maraschio P, et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet. 2008;45:93–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Hansen RS, Wijmenga C, Luo P, et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA. 1999;96:14412–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Jiang YL, Rigolet M, Bourc’his D, et al. DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat. 2005;25:56–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Shirohzu H, Kubota T, Kumazawa A, et al. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am J Med Genet. 2002;112:31–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Namik Kaya
    • 1
  • Saleh Al-Muhsen
    • 2
    • 3
    • 4
  • Bandar Al-Saud
    • 2
  • Albandary Al-Bakheet
    • 1
  • Dilek Colak
    • 5
  • Abdulaziz Al-Ghonaium
    • 2
  • Hasan Al-Dhekri
    • 2
  • Hamoud Al-Mousa
    • 2
  • Rand Arnaout
    • 2
  • Mohammad Al-Owain
    • 6
    • 7
  • Mohammad Iqbal
    • 8
  1. 1.Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  2. 2.Department of PediatricsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  3. 3.Prince Naif Center for Immunology ResearchKing Saud UniversityRiyadhSaudi Arabia
  4. 4.Department of Pediatrics, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  5. 5.Department of Biostatistics Epidemiology and Scientific ComputingKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  6. 6.Department of Medical GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  7. 7.College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
  8. 8.Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterUSA

Personalised recommendations