Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of ... Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients that is explained by mutations in the DNMT3B gene in some, but not all, ICF patients (Hagleitner et al., 2008). - Genetic Heterogeneity of Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome ICF2 (614069) is caused by mutation in the ZBTB24 gene (614064) on chromosome 6q21.
Variable immune deficiency in association with centromeric instability of chromosomes 1, 9, 16, and, rarely, 2, with an increased frequency of somatic recombination of the arms of these chromosomes and a marked tendency to formation of multibranched configurations, ... Variable immune deficiency in association with centromeric instability of chromosomes 1, 9, 16, and, rarely, 2, with an increased frequency of somatic recombination of the arms of these chromosomes and a marked tendency to formation of multibranched configurations, has been reported by Hulten (1978), Tiepolo et al. (1979), Fryns et al. (1981), Howard et al. (1985), and Valkova et al. (1987). Three males and 2 females have been reported. The parents are clinically and cytogenetically normal. In 2 of the 5 families, those reported by Tiepolo et al. (1979) and Valkova et al. (1987), sibs were affected. The most frequent symptoms of the syndrome are facial dysmorphism, mental retardation, recurrent and prolonged respiratory infections, infections of the skin and digestive system, and variable immune deficiency with a constant decrease of IgA. Maraschio et al. (1988) described ICF syndrome in a 4-year-old girl. From the age of 2 years she had suffered from recurrent pulmonary infections and from diarrhea in the summertime. The face was described as dysmorphic with hypertelorism, flat nasal bridge, low-set ears, and protrusion of the tongue. Maraschio et al. (1989) reported further clinical data on this child, who had severe chronic bronchitis with bronchiectasis, maxillary sinusitis, and otitis media. They demonstrated that, unlike lymphocytes, fibroblasts showed no major chromosomal anomalies. Turleau et al. (1989) reported a patient with ICF syndrome. Haas (1990) pointed to 8 reports of variable immunodeficiency associated with instability of the centromeric regions of chromosomes 1, 9, and 16. The children suffered from a serious variable immunodeficiency, mild developmental delay, and facial abnormalities with hypertelorism, a flat nasal bridge, epicanthal folds, protrusion of the tongue, and mild micrognathia. The severity of the disorder was indicated by the fact that 3 children died at ages 14, 12.5, and 2.5 years. They showed absence or severe reduction of at least 2 immunoglobulin classes with or without a defective cell-mediated immunity. Although no cytogenetically documented familial cases were reported, a genetic trait was suggested by the retrospective recognition of similar symptoms in deceased sibs of 2 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 multibranched configurations formed by the short and long arms in a brother and sister with facial dysmorphism, mental retardation, and recurrent infections. The parents, who were first cousins, showed no chromosomal abnormalities. A combined immunodeficiency characterized by a lack of immunoglobulin production, low numbers of T cells, and lack of cells with NK (natural killer) cell markers was found. Gimelli et al. (1993) reported ICF syndrome in a 29-year-old woman and her 30-year-old brother. The proband showed mental retardation, facial anomalies, recurrent respiratory infections, combined deficit of IgM and IgE immunoglobulin classes, and paracentromeric heterochromatin instability of chromosomes 1, 9, and 16. Smeets et al. (1994) reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. Brown et al. (1995) described a 25-month-old girl with ICF syndrome. The proband's grandfathers were twin brothers and her grandmothers were sisters. Assuming that the twin grandfathers were monozygotic, the parents were related to each as half sibs, giving a coefficient of relationship of one-fourth; but they were also related to each other as first cousins, giving an additional coefficient of relatedness of one-eighth and a total coefficient of three-eighths. In other words, the parents were related as something half way between half sibs and full sibs. Brown et al. (1995) reviewed the features of the 15 published ICF cases. All but 1 had facial anomalies, most often hypertelorism, flat nasal bridge, epicanthic folds, protrusion of the tongue, and micrognathia. Mental retardation was variable, from severe neurodegeneration to special educational needs without any delay in motor function. Their patient was typical in that speech development was delayed. Follow-up information was provided on the published cases. Franceschini et al. (1995) reported 2 new patients and reviewed the literature. They commented on the marked phenotypic variability in the 15 affected individuals reported to that time. Both of their patients were boys found to have hypogammaglobulinemia. Both of them were described as having bipartite nipples. One had shawl scrotum and the other had cryptorchidism and hypospadias. The photographs showed striking similarity of facies in the 2 boys. They showed abnormal mitotic configurations, involving chromosomes 1, 16, and to a lesser extent, 9. De Ravel et al. (2001) found reports of 32 cases of this rare disorder. They reported findings in a young patient who received appropriate early therapy, with a good outcome. The published photograph showed hypertelorism, low-set ears, and high forehead as facial features. Starting at the age of 7 months, gammaglobulin was periodically administered intravenously, with no serious infections occurring. Despite nasogastric feeding, malnutrition was a problem, requiring continuous gastrostomy feeding from 19 to 28 months of age. A verbal IQ of 104 and a performance IQ of 90 was observed at 4 years of age. Hagleitner et al. (2008) reviewed the clinical features of 45 patients with ICF syndrome. Facial dysmorphism, including epicanthic folds, hypertelorism, flat nasal bridge, and low-set ears, was commonly present. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (39 of 44), and opportunistic infections were seen in several patients, indicating T-cell dysfunction. However, there was phenotypic variability in that not all patients had obvious facial dysmorphism, and 39% had normal intelligence. Life expectancy was poor: 17 (40.5%) patients died at a mean age of 8 years, predominantly due to severe respiratory tract infections, sepsis, and failure to thrive.
Among 44 patients with a clinical diagnosis of ICF, Weemaes et al. (2013) found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified ... Among 44 patients with a clinical diagnosis of ICF, Weemaes et al. (2013) found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified in 8 patients. Although the phenotype was relatively homogeneous, systematic phenotypic evaluation showed that humoral immunodeficiency was generally more pronounced in ICF1 patients and that ICF2 patients had a significantly higher incidence of intellectual disability. Both T- and B-cell compartments were involved in ICF1 and ICF2. A few patients from both groups had congenital malformations including cardiac defects, cleft lip, clinodactyly, choanal stenosis, hip dislocation, and cerebral malformations.
Xu et al. (1999) demonstrated homozygous or compound heterozygous mutations in the DNMT3B gene (e.g., 602900.0001) in 5 unrelated ICF patients. All mutations affected residues invariant in DNMT3A (602769) and DNMT3B of mouse and human, and in an ... Xu et al. (1999) demonstrated homozygous or compound heterozygous mutations in the DNMT3B gene (e.g., 602900.0001) in 5 unrelated ICF patients. All mutations affected residues invariant in DNMT3A (602769) and DNMT3B of mouse and human, and in an uncategorized zebrafish Dnmt3 family member. Okano et al. (1999) identified compound heterozygous mutations in the DNMT3B gene in DNA from a lymphoblastoid cell line derived from an individual with ICF syndrome and her parents. One of the 2 mutations was de novo (not present in the parents), and neither was found in 100 normal alleles.