ICF syndrome

The autosomal recessive inherited ICF syndrome (immunodeficiency-centromere instability-facial anomalies syndrome) is a very rare autosomal recessive inherited immunodeficiency syndrome with associated skeletal dysplasias (mainly facial dysplasias) caused by mutation in the DNMT3B gene.

Immunodeficiency syndrome has been described in about 50 patients worldwide to date.

Mutations in the DNMT3B gene. By an as yet unclear mechanism, DNMT3B deficiency, the cause of ICF syndrome, interferes with lymphogenesis (at a stage after the class switch) or with lymphocyte activation.

Clinical signs are recurrent infections, usually in early childhood. Immunodeficiency is often associated with developmental delay, facial abnormalities with hypertelorism, flat nasal bridge, epicanthal folds, a protruding tongue, and mild micrognathia.

Serum levels of IgG, IgM, IgE, and/or IgA are decreased, but other types of immunoglobulin deficiency are possible.

Almost always, treatment consists of regular (and usually intravenous) infusions of immunoglobulins. More recently, bone marrow transplants have also been attempted.

Chromosome instability occurs when mutations are present in genes that code for DNA repair proteins. Due to these mutations, incomplete repair of mutations occurs and thus, among other things, chromosome breaks.

Haas (1990) pointed out 8 reports of variable immunodeficiencies associated with instability of the centromeric regions of chromosomes 1, 9, and 16. The children suffered from severe variable immunodeficiency, mild developmental delay, and facial abnormalities with hypertelorism, a flat nasal bridge, epicanthal folds, a protruding tongue, and mild micrognathia. The severity of the disorder is indicated by the fact that 3 children died at the ages of 14, 12.5, and 2.5 years. They had the absence or severe reduction of at least 2 immunoglobulin classes with or without impaired cell-mediated immunity. Although no cytogenetically documented familial cases were reported, a genetic predisposition was suspected by retrospective recognition of similar symptoms in deceased siblings of two of the patients (Tiepolo et al., 1979; Valkova et al., 1987).

Fasth et al. (1990) observed instability of the centromeric region of chromosome 1 and multiple branched configurations formed by the short and long arms in a pair of siblings with facial dysmorphism, mental retardation, and recurrent infections. The parents, who were first cousins, had no chromosomal abnormalities. A combined immunodeficiency characterized by a lack of immunoglobulin production, a low number of T cells, and the absence of cells with NK markers (natural killer cells) was found.

1. Brown DC et al (1995) ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome. Hum. Genet 96: 411-416.
2. Fasth A et al. (1990) Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings: a recessively inherited entity? Acta Paediat Scand 79: 605-612.
3. Haas OA etal. (1990) Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon? Hum Genet 85: 244-246.
4. Jin B 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 Molec Genet 17: 690-709.
5. Tiepolo L et al (1979) Multibranched chromosomes 1, 9 and 16 in a patient with combined IgA and IgE deficiency. Hum Genet 51: 127-137.
6. Valkova G et al (1987) Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome. Clin Genet 31: 119-124.