ICF syndrome (ORPHA:2268)
A rare autosomal recessive syndrome with combined immunodeficiency characterized by the clinical triad of immunodeficiency, centromeric instability and facial anomalies (abbreviated ICF syndrome). The immunodeficiency is with panhypogammaglobulinemia, and a lack of memory (CD19+CD27+) B cells in the peripheral blood, although B and T-cell counts are normal. Anomalies and rearrangements associated with DNA hypomethylation in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9, in mitogen-stimulated lymphocytes, is a hallmark of the syndrome. The typical facial anomalies include hypertelorism, low-set ears, epicanthus and macroglossia.
Epidemiology
ICF has been described in about 100 patients worldwide.
Clinical description
Recurrent infections are the presenting symptom, usually in early childhood. Autoimmune manifestations have been described. Other variable symptoms of this probably under-diagnosed syndrome include delayed developmental milestones with growth delay, failure to thrive, and global developmental delay, with various degrees of cognitive impairment.
Etiology
The syndrome is caused by homozygote or heterozygote mutations in the DNA methyltransferase 3B (DNMT3B; ICF1), the zinc finger and BTB domain containing 24 (ZBTB24; ICF2), the cell division cycle-associated 7 (CDCA7; ICF3), the helicase lymphoid specific (HELLS; ICF4) genes. More recently, variants in the ubiquitin like with PHD and ring finger domains 1 gene (UHRF1) have been associated with one ICF patient. Loss of DNA methylation at satellite repeats embedded in the juxta-centromeric heterochromatin in the 1qh, 9qh, and 16qh, regions is a hallmark of ICF patients and is associated with whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. DNA hypomethylation at centromeric satellite repeats (alpha-satellite), at subtelomeres and a set of unique genes are linked to the genotype of the patients.
Diagnostic methods
Diagnosis is suspected on clinical presentation, mostly on recurrent infections and immunologic abnormalities (very low memory B cells). Molecular investigations based on cytogenetic analysis and gene panel sequencing enable to confirm the diagnosis.
Differential diagnosis
The differential diagnosis includes other syndromic combined immunodeficiencies.
Antenatal diagnosis
Prenatal diagnosis is available for this disorder.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is proposed to family with ICF syndrome. At-risk couples (both individuals are carriers of a disease-causing mutation) have a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes regular infusions of immunoglobulins, mostly intravenously, and antibacterial prophylaxis. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for ICF patients.
Prognosis
HSCT can cure the immunodeficiency of patients with ICF syndrome. Very few cases have been reported (less than 10 cases) and only for patients with mutations in the DNMT3B gene (ICF1). Long-term follow-up studies are limited.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Pr Capucine PICARD  - Dr Guillaume VELASCO