ICF syndrome

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