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ICF syndrome

(MIM.242860)

Sunday 19 March 2006

Definition: Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections.

About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1).

Loci

- ICF1
- ICF2 syndrome

  • germline mutations of ZBTB24 in ICF2 syndrome (ZBTB24)
  • The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences.
  • ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions.
  • ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage.

Synopsis

- height Below the third percentile
- weight Below the third percentile
- head circumference below the third percentile
- failure to thrive
- sinusitis
- flat face
- epicanthal folds
- hypertelorism
- low set ears
- flat nasal bridge
- small upturned nose
-  micrognathia
- tongue protrusion
- macroglossia
- chronic bronchitis
- bronchiectasis
- pneumonia
- diarrhea
- malabsorption
- variable mental retardation ranging from severe neurodegeneration to mild mental retardation

LABORATORY

- Reduced number of T cells
- Reduced number of natural killer cells
- Reduced IgA
- Increased IgM
- Centromeric instability of chromosomes 1, 9 and 16 with increased somatic recombination and formation of multibranched configurations

Etiology

- germline mutations of DNMT3 in ICF syndrome

References

- Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. de Greef JC, Wang J, Balog J, den Dunnen JT, Frants RR, Straasheijm KR, Aytekin C, van der Burg M, Duprez L, Ferster A, Gennery AR, Gimelli G, Reisli I, Schuetz C, Schulz A, Smeets DF, Sznajer Y, Wijmenga C, van Eggermond MC, van Ostaijen-Ten Dam MM, Lankester AC, van Tol MJ, van den Elsen PJ, Weemaes CM, van der Maarel SM. Am J Hum Genet. 2011 Jun 10;88(6):796-804. PMID: 21596365