Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive primary immunodeficiency caused by mutations in the DNMT3B, ZBTB24, CDCA7, or HELLS genes. It is characterized by a predominant humoral immune deficiency, centromeric instability involving chromosomes 1, 9, and 16, and variable facial dysmorphism. Patients typically present with severe and recurrent infections beginning in early childhood, which may be life-threatening.
We report the case of a 5-year-old girl born to first-degree consanguineous parents, hospitalized since infancy for recurrent severe infections. She developed bilateral bullous pneumonia due to Escherichia coli, Pneumocystis jirovecii pneumonia, disseminated Bacillus Calmette-Guerin (BCG) infection with pulmonary and bone involvement, candidemia caused by Candida tropicalis, and cytomegalovirus infection complicated by macrophage activation syndrome and hepatic involvement. Her clinical course was marked by psychomotor delay, persistent axial hypotonia, and failure to thrive. No obvious facial dysmorphism was noted. Hematological evaluation revealed chronic neutropenia and normocytic normochromic aregenerative anemia without evidence of bone marrow failure. Immunological assessment showed hypogammaglobulinemia, decreased natural killer cells, a preserved proliferative response to phytohemagglutinin, reduced response to anti-CD3 stimulation, and absent tuberculin reactivity. Genetic analysis confirmed ICF type 1 syndrome with a homozygous DNMT3B mutation. The patient is receiving regular intravenous immunoglobulin replacement and antimicrobial prophylaxis and is a candidate for allogeneic hematopoietic stem cell transplantation.
ICF syndrome should be suspected in infants with severe early-onset infections associated with hypogammaglobulinemia and unexplained cytopenias, even in the absence of evident facial dysmorphism. Early diagnosis is crucial to optimize supportive management and evaluate eligibility for curative hematopoietic stem cell transplantation.
