Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients with ICF2 have been reported in the literature. Here we present 3 siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G), including two twin sisters.
Mutation in ZBTB24 in living patient was detected with whole exome sequencing. Genetic alterations in ZBTB24 were validated by Sanger sequencing. All previously ICF2 patients have been identified through a search in pubmed. Their phenotypes and immunological data have been documented and summarized.
We identified three siblings, including two dizygotic twin sisters with ICF2. One patient had mycobacterial infection and bronchial malformation, which are for the first time associated with ICF2. All patients displayed a gradual reduction in their IgG, B-cell and CD4+ T cell counts, suggesting a progressive course of immunodeficiency in ICF2. Despite their common genetic background, including the same causative mutation in ZBTB24, clinical heterogeneity (recurrent infections Vs. no significant infection record) and evident differences in immunological profiles (e.g. normal IgG levels Vs. severe hypogammaglobulinemia) among these patients suggest the pathogenic relevance of epigenetic modification in this monogenic immunodeficiency disorder.
Considering the high mortality rate of ICF2, previous reports on severe complications, such as opportunistic infections, lymphomas and EBV-induced hemophagocytic lymphohystiosis as well as the here presented evidence on a progressive impairment of the immune system, we suggest early consideration of HSCT in all ICF2 patients.