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Chromosome abnormalities in ICF syndrome. (A) Multibranched configuration of two chromosomes 16 (16ppqqqq). (B) Multibranched chromosome (lpqq) and association of two chromosomes 16. (C) Multibranched chromosome 1 (lpqq) with a chromosome 16 associated or interchanged (QFQ banding).
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We describe a new familial case of ICF syndrome (immunodeficiency, centromeric instability, facial anomalies) in a woman of 29 years and in her brother of 30 years. The proband showed mental retardation, facial anomalies, recurrent respiratory infections, combined deficit of IgM and IgE immunoglobulin classes, and paracentromeric heterochromatin in...
Citations
... Facial abnormalities are also one of the clinical manifestations of ICF patients, including hyperopia, flat nasal bridge, internal pleats and low ear [25], and a few ICF patients have other congenital defects such as cleft palate and phalanx [26]. ICF patients often have delayed mental movements, and most of them suffer from mental and neurological deficits [27,28], including cognitive developmental delay, poor motor skills, and psychomotor disorders [29]. Some patients have congenital anomalies, such as skin pigmentation, scleral telangiectasia, etc. [30]. ...
Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disorder, which is characteristic of a severe impairment of immunity. In the genetic aspect, ICF is featured with mutations primarily located in the specific genes (DNMT3B for ICF1, ZBTB24 for ICF2, CDCA7 for ICF3, and HELLS for ICF4). The subtelomeric region is defined as 500 kb at the terminal of each autosomal arm. And subtelomeric DNA fragments can partially regulate key biological activities, including chromosome movement and localization in the nucleus. In this review, we updated and summarized gene mutations in ICF based on the previous review. In addition, we focused on the correlation between subtelomeric DNA methylation and ICF. The relationship between subtelomeric methylation and telomere length in ICF was also summarized.
... He was only diagnosed with it following the same diagnosis in his sister (who did have many features of ICF syndrome) which prompted investigations in the rest of her family. 11 Cerbone et al 12 also describe a patient with ICF syndrome with subclinical immunodeficiency (low IgM) and suggest that ICF syndrome could be more common than previously thought. ...
We describe a 42-year-old British man of Indo-Caribbean origin with immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome. Most patients with ICF syndrome die of infection at a young age, usually in the first or second decade of life. The patient was born 3.5 weeks premature to non-consanguineous parents. He had a mild bird-like face abnormality, but had no other congenital malformations, cognitive impairment or developmental delays. He had recurrent ear and chest infections during childhood and developed bronchiectasis. Investigations revealed IgG, IgA and IgM deficiencies with a normal lymphocyte count and normal T cell proliferation to in vitro mitogenic stimulation. Following several unsuccessful attempts to make a diagnosis during childhood, a recent chromosomal analysis showed centromeric region instability of chromosomes 1 and 16, diagnosing ICF syndrome. The patient receives immunoglobulin replacement for hypogammaglobulinameia and has chest physiotherapy and antibiotics for bronchiectasis. Recently, he developed liver cirrhosis of unknown cause.
... The dysmorphic facial features of ICF are variable, usually mild [50,53], and frequent [ 10]. The typical facial features areab road flatn asal bridge, hypertelorism (very widely spaced eyes), epicanthic folds andl ow-set ears. ...
... Lessf requentb ut still often associated with the syndrome are micrognathia (small jaw) andm acroglossia (protrusion or enlargemento f the tongue) [6,28,53 -56].F ailuret ot hrive and low birth weight are observed in about half of the patients [10]. Mental retardation and neurologic defects have been seeni na bout one-thirdo ft he patients [10,50,53,57]. Otherc ongenitala bnormalitiesi n ICF are highly variable being observed in one or a few patients. ...
The immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) is the only disease known to result from a mutated DNA methyltransferase gene, namely, DNMT3B. Characteristic of this recessive disease are decreases in serum immunoglobulins despite the presence of B cells and, in the juxtacentromeric heterochromatin of chromosomes 1 and 16, chromatin decondensation, distinctive rearrangements, and satellite DNA hypomethylation. Although DNMT3B is involved in specific associations with histone deacetylases, HP1, other DNMTs, chromatin remodelling proteins, condensin, and other nuclear proteins, it is probably the partial loss of catalytic activity that is responsible for the disease. In microarray experiments and real-time RT-PCR assays, we observed significant differences in RNA levels from ICF vs. control lymphoblasts for pro- and anti-apoptotic genes (BCL2L10, CASP1, and PTPN13); nitrous oxide, carbon monoxide, NF-kappaB, and TNFalpha signalling pathway genes (PRKCH, GUCY1A3, GUCY1B3, MAPK13; HMOX1, and MAP4K4); and transcription control genes (NR2F2 and SMARCA2). This gene dysregulation could contribute to the immunodeficiency and other symptoms of ICF and might result from the limited losses of DNA methylation although ICF-related promoter hypomethylation was not observed for six of the above examined genes. We propose that hypomethylation of satellite 2 at 1qh and 16qh might provoke this dysregulation gene expression by trans effects from altered sequestration of transcription factors, changes in nuclear architecture, or expression of noncoding RNAs.
... The immunodeficiency, despite the presence of B cells almost always[31], results in severe recurrent infections, often seen in early childhood and usually as the presenting finding[32,33]. A review of the literature shows that almost all ICF patients have severe respiratory infections and more than half have recurrent gastrointestinal infections. ...
... The dysmorphic facial features are variable[31,34]and usually mild; moreover, several patients did not display them (unpub. data). ...
... Mental retardation and neurologic defects have been seen in about one-third and one-fifth of the patients, respectively[31,34,37], and include slow cognitive and motor development and psychomotor impairment (ataxic gait and muscle hypotonia)[3,8,31,41]. In one case, delayed psychomotor development changed into age-appropriate development at 36 months[35]. ...
The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation. Serum levels of IgG, IgM, IgE, and/or IgA are low, although the type of immunoglobulin deficiency is variable. Recurrent infections are the presenting symptom, usually in early childhood. ICF always involves limited hypomethylation of DNA and often arises from mutations in one of the DNA methyltransferase genes (DNMT3B). Much of this DNA hypomethylation is in 1qh, 9qh, and 16qh, regions that are the site of whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. By an unknown mechanism, the DNMT3B deficiency that causes ICF interferes with lymphogenesis (at a step after class switching) or lymphocyte activation. With the identification of DNMT3B as the affected gene in a majority of ICF patients, prenatal diagnosis of ICF is possible. However, given the variety of DNMT3B mutations, a first-degree affected relative should first have both alleles of this gene sequenced. Treatment almost always includes regular infusions of immunoglobulins, mostly intravenously. Recently, bone marrow transplantation has been tried.
... It might also explain why both ICF patients from the same sibship present very different phenotypes. 47 . Therefore, for an ICF patient with a given genotype, the size of the 1qh and 16qh heterochromatins, which corresponds to the amount of satellite DNA, 48 could influence the severity of the phenotype. ...
The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin. In order to investigate the effect of DNA hypomethylation on heterochromatin organization, we analyzed the in vivo distribution of HP1 proteins, essential components of heterochromatin, in three ICF patients. We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin. We found that SP100, SUMO-1 and other proteins from the promyelocytic leukemia nuclear bodies (NBs) form a large body that co-localizes with the HP1 signal. This is the first description of altered nuclear distribution of HP1 proteins in the constitutional ICF syndrome. Our results show that satellite DNA hypomethylation does not prevent HP1 proteins from associating with heterochromatin. They suggest that, at G2 phase, HP1 proteins are involved in the heterochromatin condensation and may therefore remain concentrated at these sites until the condensation is complete. They also indicate that proteins from the NB could play a role in this process. Finally, satellite DNA length polymorphism could affect the efficiency of heterochromatin condensation and thus contribute to the variability of the ICF phenotype.
... However, the natural history of ICF has not yet been fully established because of both the small number of cases and the wide phenotypic variability. In 1993, Gimelli et al. [3] described a new familial case of this syndrome in two sibs, a 29-year-old woman and a 30- year-old man. The sister showed typical paracentromeric heterochromatin instability and combined deficit of IgM and IgE immunoglobulin classes with recurrent respiratory infections, facial anomalies and mental retardation. ...
... A 35-year-old woman [3] was admitted to our Department in March 1995 for a first generalized tonic –clonic seizure. She reported episodes of peripheral facial palsy at ages 2, 20 and 35, and recurrent respiratory and gastrointestinal infections since the age of 4. Neurological examination , brain CT and MRI studies, and CSF findings indicated no abnormalities. ...
We report on a patient affected by ICF syndrome (immunodeficiency, centromeric instability of chromosomes 1, 9 and 16 and facial dysmorphism), who presented with slowing in mentation, mild right hemiparesis and focal motor seizures. MRI study of the brain suggested a diagnosis of progressive multifocal leukoencephalopathy (PML), which was confirmed by JC virus DNA detection on CSF by polymerase chain reaction (PCR). This is a unique case of adult infective neurological complication described in ICF Syndrome.
... ICF is a recessive disease with only two invariant aspects of its phenotype, namely, an otherwise inexplicable prolonged immunodeficiency affecting serum Ig levels with at least some B cells present and a peculiar array of related chromosome-specific cytogenetic anomalies detected by routine karyotype analysis of blood [3,5]. Immune problems in ICF patients are generally, but not always, severe. ...
Only one human disease that involves Mendelian inheritance of immunodeficiency and aberrant DNA methylation has been identified. This is a rare chromosome breakage disease called the immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF). Its diagnostic characteristics are agammaglobulinemia with B cells as well as DNA rearrangements targeted to the centromere-adjacent heterochromatic region (qh) of chromosomes 1, 16, and sometimes 9 in mitogen-stimulated lymphocytes. These rearrangement-prone regions show DNA hypomethylation in all examined ICF cell populations. This review summarizes our knowledge about the immunological symptoms of ICF; the nature of DNMT3B mutations in ICF patients; the phenotypes of DNA hypomethylation mutants in humans, mice, and Arabidopsis; the epigenetics of ICF; and ICF-specific RNA expression and cell-surface antigen expression in lymphoblastoid cell lines. Comparisons of ICF and control lymphoblastoid cell lines and ICF patients' symptoms suggest an involvement of DNA methylation in the late stages of lymphocyte maturation.
... Cultured peripheral lymphocytes always display numerous aberrations, whereas other tissues, such as cultured fibroblasts, EBV-transformed B cells, and bone marrow, show only a few aberrant cells, or none at all. If aberrations are present in these tissues, they are mostly of a much reduced complexity than those in lymphocytes (Howard et al. 1985;Maraschio et al. 1989;Turleau et al. 1989;Fasth et al. 1990;Gimelli et al. 1993). Nevertheless, in one case, ICF syndrome was reported to be diagnosed Tiepolo et al. 1979;3 Fryns et al. 1981;4 Howard et al. 1985;5 Valkova et al. 1987;6 Maraschio et al. 1988;7 Carpenter et al. 1988;8 Turleau et al. 1989;9, 10 Fasth et al. 1990;11 Bauld et al. 1991;12 Kieback et al. 1992; 13 present case; 14, 15 Gimelli et al. 1993 on cultured amniotic cells at 34 weeks of gestation (Fasth et al. 1990). ...
... If aberrations are present in these tissues, they are mostly of a much reduced complexity than those in lymphocytes (Howard et al. 1985;Maraschio et al. 1989;Turleau et al. 1989;Fasth et al. 1990;Gimelli et al. 1993). Nevertheless, in one case, ICF syndrome was reported to be diagnosed Tiepolo et al. 1979;3 Fryns et al. 1981;4 Howard et al. 1985;5 Valkova et al. 1987;6 Maraschio et al. 1988;7 Carpenter et al. 1988;8 Turleau et al. 1989;9, 10 Fasth et al. 1990;11 Bauld et al. 1991;12 Kieback et al. 1992; 13 present case; 14, 15 Gimelli et al. 1993 on cultured amniotic cells at 34 weeks of gestation (Fasth et al. 1990). In a second prenatal case of ICF syndrome, the diagnosis was made on a cultured blood sample of a 20-week-old fetus (Jeanpierre et al. 1993). ...
... Facial dysmorphisms have been reported in all but one patient with ICF syndrome (Gimelli et al. 1993); they are mostly mild and are characterized by epicanthic folds, hypertelorism, flat nasal bridge, macroglossia with protruding tongue, and mild micrognathia (Table 2). Various Table 2 Clinical findings in patients with ICF syndrome ($ reduced, r missing, w weeks, t term, other symbols as in Table 1 Table 1 neurological defects have been described in four patients (Tiepolo et al. 1979;Valkova et al. 1987;Carpenter et al. 1988;Gimelli et al. 1993). ...
Patients with ICF syndrome can be recognized by the presence of a variable immunodeficiency, instability of the pericentromeric heterochromatin of, in particular, chromosomes 1, 9, and 16 in cultured peripheral lymphocytes, and a number of facial anomalies. Recently, aberrations at the molecular level have been described, consisting of alterations in the methylation pattern of classical satellite DNA, in a number of patients. ICF syndrome is considered to be inherited in an autosomal recessive manner and may be rare, as only 14 patients have been described thus far. We present a new case, a boy with agammaglobulinemia, who was extensively studied by means of classical cytogenetics and fluorescent in situ hybridization. All patients previously reported in the literature are reviewed.
There is a growing recognition that many syndromes and metabolic disorders have a component of immune deficiency. The set of conditions detailed in this chapter all have dysmorphic features, developmental delay and are all due to altered chromatin, the structural aspect of DNA. Although some features are discordant, all the syndromes have a relatively high concordance for many features. In all, the humoral immune system is predominantly affected and the patients exhibit short stature, developmental delay, and dental defects with high frequency.
