Angiosarcoma in a patient with immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome

Brand, Michiel van den; Flucke, Uta; Bult, Peter; Weemaes, C.M.R.; Deuren, Marcel van

doi:10.1002/ajmg.a.33831

Cited by 18 publications

(8 citation statements)

References 14 publications

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“…Opportunistic infections (Candida albicans, Pneumocystis jiroveci) were found in some patients within all groups (Table 2). Malignancy Angiosarcoma has been described in one ICF1 patient 14 and ICF1 patient 42 suffered from an acute lymphoblastic leukemia. Hodgkin lymphoma was described in ICF2 patient 37.…”

Section: Infectionsmentioning

confidence: 99%

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

et al. 2013

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Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B-and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.

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Section: Infectionsmentioning

confidence: 99%

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

et al. 2013

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“…The hypomethylation of germ line genes and centromeric repeats constitute molecular signatures of the ICF syndrome and cancer ( Figure 2 ) but it is unclear how hypomethylation at these sites create a favorable context for disease. Despite the clear similarities between the molecular signatures of the ICF syndrome and cancer, malignancies have been reported in very few cases in ICF patients [ 117 , 132 ]. In ICF patient cells, in which cell checkpoints appear to be normal [ 133 ], it is probable that epigenetic defects alone are not sufficient to drive tumorigenesis.…”

Section: Consequences Of Hypomethylation At Dnmt3b Targets For Dismentioning

confidence: 99%

Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases

Walton

Francastel

Velasco

2014

Biology

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The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.

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“…Developmental delay and intellectual disability are often seen in affected patients [Ehrlich et al, 2006]. Hematological diseases and malignancies including macrophage activation syndrome, myelodysplastic syndrome, Hodgkin lymphoma, adrenocortical adenoma, and angiosarcoma have been reported in some affected patients [Andre et al, 2004; Schuetz et al, 2007; Hagleitner et al, 2008; van den Brand et al, 2011]. Life expectancy of ICF patients is significantly reduced because of severe immunodeficiency leading to recurrent, severe and often fatal respiratory and gastrointestinal infections.…”

Section: Introductionmentioning

confidence: 99%

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst

Cerbone

Wang

Maarel

et al. 2012

American J of Med Genetics Pt A

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The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agammaglobulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases.

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Angiosarcoma in a patient with immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome

Cited by 18 publications

References 14 publications

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst

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