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At a glance

Syndrome characterized by immune deficiency associated with recurrent infections and facial dysmorphism. The dysmorphic facial features are variable and include a broad flat nasal bridge, hypertelorism, and epicanthic folds. The presence of micrognathia and macroglossia is a significant consideration in anesthesia. Other features include mental retardation and neurologic defects in about one-third and one-fifth of the patients, respectively. Slow cognitive and motor development as well as psychomotor impairment such as ataxic gait and muscular hypotonia.

Synonym

ICF Syndrome.

History

Immunodeficiency, Centromeric instability, and Facial Anomalies Syndrome was given the acronym ICF in 1988.

Incidence

Approximately 50 cases have been described.

Genetic inheritance

Autosomal recessive. It is a rare autosomal recessive disease described in about 50 patients worldwide since it was first described in the 1970. The patients come mostly from Europe. However, ICF patients show diverse ethnicity, including European, Turkish, Japanese, and African American. Consanguinity may have been involved rather than a familial tendency. Recently, a sharp increase in the number of diagnosed, nonfamilial cases in Europe and Japan suggest that this medical condition may be underdiagnosed especially in the United States, where only a few cases have been reported.

Pathophysiology

The immune defect is variable. Patients tend to have a reduction in at least two immunoglobulin classes. Immunodeficiency may be the result of an acquired viral infection in genetically predisposed individuals. Chromosomal abnormalities are multiple and affect the heterochromatic regions of chromosomes 1, 9, and 16. Chromosome 2 is occasionally affected. Chromosomal abnormalities consist of despiralization, chromosome and chromatid breaks, and pairing and interchanges between homologous and nonhomologous chromosomes. Chromosomal abnormalities are generally found only in peripheral blood lymphocytes. Low numbers of T lymphocytes and natural killer (NK) cells are noted. ICF Syndrome is caused by mutations of the DNA methyltransferase 3B (DNMT3B) gene, which has been mapped to 20q11.2.

Diagnosis

Based on the findings of severe immunodeficiency with recurrent infections, associated with a high frequency of pericentromeric decondensations and rearrangements in chromosome 1 and 16 upon karyotype analysis of blood samples. Additional clinical signs include short stature and peculiar facies. Laboratory examinations show reduced serum concentrations of immunoglobulin (Ig) A, IgG, IgE, T lymphocytes, and NK cells, whereas serum levels of IgM are increased. The diagnosis is usually made in infancy.

Clinical aspects

Patients have short stature, failure to thrive, and suffer from mental retardation. The disease affects the head and neck (hypertelorism, epicanthic folds, low-set ears, flat nasal bridge, micrognathia, macroglossia with protrusion of the tongue), gastrointestinal tract (diarrhea, malabsorption), and immune system (recurrent and prolonged respiratory tract infections, resulting in chronic bronchitis and bronchiectases; maxillary sinusitis, otitis media, cutaneous infections). Most patients die of infections (pulmonary and/or ...

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