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

Abstract

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.

Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract

“…Immunodeficiencycentromeric instability facial anomalies has also been reported to include congenital malformations, including CAKUT. 18 Patient B268 presented with isolated CAKUT and was found to harbor a previously reported truncating mutation in the gene HPSE2. 19 This gene is responsible for urofacial syndrome.…”

Cardiovascular abnormalities in primary immunodeficiency diseases

“…However, with age, some patients exhibit T-cell lymphopenia and reduced proliferation of T cells following ex vivo stimulation. Few patients also develop neutropenia in the second decade of life (Weemaes et al 2013). …”

“…The majority of ICF patients have delayed walking and speech, and some may suffer from intellectual disabilities. Diagnosis of ICF can be established by demonstrating excess deletions and peri-centromeric breaks of chromosomes 1, 9, and 16 in metaphases of stimulated peripheral blood lymphocytes (Weemaes et al 2013).…”

“…HSCT was performed in few patients because of severe infections or myelodysplasia with some success (Weemaes et al 2013). …”

“…Pathogenesis: Hypomethylation of various genes, including those important for immune and neurological development, as well as satellite DNA located in the pericentromeric regions of chromosomes 1, 9, and 16 may lead to the diverse clinical and laboratory features (Weemaes et al 2013). …”