Immunodeficiency, Centromeric Region Instability, and Facial Anomalies Syndrome (ICF) in a Boy with Variable Clinical and Immunological Presentations
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare primary immunodeficiency disorder characterized by recurrent infections and low immunoglobulin levels due to variable combined immunodeficiency, and centromeric region instability, and facial dysmorphism.
We describe a 12-year-old boy with recurrent respiratory tract infections, facial anomalies, scoliosis, and psychomotor retardation. He had recurrent pneumonia with low serum IgG and IgM levels during infancy and preschool age. Later at the age of 10, he developed recurrent ear infections. An IgA and IgM deficiency was found accompanied by a normal B-cell and T-cell count as well as an impaired candida-induced T-cell proliferation. Further evaluations revealed a missense mutation in the DNMT3B gene on chromosome 20. Chromosomal analysis showed a sunburst multi-radial feature on chromosome 1, which is a hallmark of ICF syndrome.
The genetic mutation and chromosomal abnormality along with clinical findings are compatible with the diagnosis of ICF syndrome. To the best of our knowledge, this is the first time that scoliosis is observed in an ICF patient.
The additional variable clinical symptoms in the case were the presence of spastic gait as well as hypogammaglobulinemia with immunoglobulin isotype switch at different ages.
2. Gossling KL, Schipp C, Fischer U, Babor F, Koch G, Schuster FR, et al. Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome. Front Immunol. 2017;8:773.
3. Sathasivam S, Selvakumaran A, Jones QC, Wathen CG. Immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome diagnosed in an adult who is now a long-term survivor. BMJ Case Rep. 2013;2013.
4. Ehrlich M, Sanchez C, Shao C, Nishiyama R, Kehrl J, Kuick R, et al. ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity. 2008;41(4):253-71.
5. Ehrlich M, Jackson K, Weemaes C. Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphanet J Rare Dis. 2006;1:2.
6. Wang HD, Hou QF, Guo QN, Li T, Wu D, Zhang XP, et al. DNA methylation study of fetus genome through a genome-wide analysis. BMC Med Genomics. 2014;7:18.
7. Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, et al. DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet. 2008;17(5):690-709.
8. Hagleitner MM, Lankester A, Maraschio P, Hulten M, Fryns JP, Schuetz C, et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet. 2008;45(2):93-9.
9. Ben GRB, Abdelkrim O. Ziadi, S. DNMT3B (DNA (cytosine-5-)-methyltransferase 3 beta). 2013;17(2).
10. Solomon O, Kunik V, Simon A, Kol N, Barel O, Lev A, et al. G23D: Online tool for mapping and visualization of genomic variants on 3D protein structures. BMC Genomics. 2016;17:681.
11. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247-57.
12. Nitta H, Unoki M, Ichiyanagi K, Kosho T, Shigemura T, Takahashi H, et al. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. J Hum Genet. 2013;58(7):455-60.
13. Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, et al. Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort. J Allergy Clin Immunol Pract. 2019;7(3):864-78.e9.
14. Gartler SM, Hansen RS. ICF syndrome cells as a model system for studying X chromosome inactivation. Cytogenet Genome Res. 2002;99(1-4):25-9.
15. Kamae C, Imai K, Kato T, et al. Clinical and Immunological Characterization of ICF Syndrome in Japan. J Clin Immunol. 2018;38(8):927-937.
16. Kellner ES, Rathbun PA, Marshall GS, et al. The Value of Chromosome Analysis to Interrogate Variants in DNMT3B Causing Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome Type I (ICF1). J Clin Immunol. 2019;39(8):857-859.
17. Weemaes CM, van Tol MJ, Wang J, van Ostaijen-ten Dam MM, van Eggermond MC, Thijssen PE, et al. Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects. Eur J Hum Genet. 2013;21(11):1219-25.
18. Sterlin D, Velasco G, Moshous D, Touzot F, Mahlaoui N, Fischer A, et al. Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey. J Clin Immunol. 2016;36(2):149-59.
19. Sogkas G, Dubrowinskaja N, Bergmann AK, Lentes J, Ripperger T, Fedchenko M, et al. Progressive Immunodeficiency with Gradual Depletion of B and CD4(+) T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2). Diseases. 2019;7(2).
20. Rechavi E, Lev A, Eyal E, Barel O, Kol N, Barhom SF, et al. A Novel Mutation in a Critical Region for the Methyl Donor Binding in DNMT3B Causes Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome (ICF). J Clin Immunol. 2016;36(8):801-9.
|Issue||Vol 20 No 2 (2021)|
|Chromosomal instability DNA methyltransferase 3B Immunodeficiency Scoliosis|
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