ICF4 Syndrome: From Genetic Diagnosis to Therapeutic Approaches

Introduction ICF syndrome (immunodeficiency, centromeric instability, and facial dysmorphism) is a rare genetic disorder characterized by variable combined immunodeficiency and facial anomalies. The ICF4 subtype, associated with HELLS gene mutations, remains poorly described in the literature. We report an illustrative case highlighting the clinical aspects of this syndrome. Case Report The patient, the first child of consanguineous parents (second-degree cousins), was born at 39 weeks with facial dysmorphism and growth retardation. During the neonatal period, a congenital cytomegalovirus (CMV) infection was confirmed by a highly positive urinary PCR without detectable visceral involvement, necessitating a 21-day course of ganciclovir treatment. At 4 months, the patient experienced a gastric perforation, leading to peritonitis caused by a non-groupable Streptococcus, necessitating surgical intervention. The hospitalization was complicated by severe nosocomial infections, including sepsis with secondary pulmonary involvement. At 8 months, he was admitted to the hospital with severe proctitis, chronic mucoid diarrhea, moderate malnutrition, and delayed growth. Laboratory tests revealed hypogammaglobulinemia with low levels of IgG, IgA, and IgM. Then, the child developed hepatosplenomegaly, anicteric cholestasis with hepatic cytolysis, and persistent neutropenia. Immunological assessments indicated a severe atypical, combined immunodeficiency, characterized by reduced levels of CD3, CD4, CD8, NK, and B lymphocytes. The NBT test and CD95 expression were within normal ranges, whereas the lymphoblastic transformation response to tuberculin was weak. Genetic testing revealed the diagnosis of ICF4 syndrome. The patient is on regular immunoglobulin infusion with antibiotic, antifungal, and antiviral prophylaxis, showing good progress, adequate weight gain, and no recurrence of severe infectious episodes. Conclusion ICF4 syndrome is a rare immunodeficiency disorder with severe clinical manifestations, often requiring hematopoietic stem cell transplantation (HSCT) as a curative option. Advancing genetic research in rare disorders like ICF4 syndrome will enhance early diagnosis, optimize treatment strategies, and improve long-term prognosis.