ICF Syndrome

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder in which DNA hypomethylation of pericentromeric heterochromatin causes antibody deficiency, characteristic facial features and developmental delay.

Pathophysiology. Biallelic variants in DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3) or HELLS (ICF4) reduce DNA methylation of satellite repeats on chromosomes 1, 9 and 16. Centromeres become unstable in lymphocytes, and B cell differentiation into antibody secreting cells fails.

Onset is in infancy or early childhood. It is very rare, and consanguinity is common.

Without treatment, recurrent infection, malabsorption and malignancy limit survival.

• Recurrent respiratory and gastrointestinal infection from infancy: pneumonia, otitis media, chronic diarrhoea
• Failure to thrive and short stature
• Facial features: hypertelorism, epicanthic folds, flat nasal bridge, low set ears, macroglossia
• Developmental delay and intellectual disability (more in ICF2)
• Opportunistic infection in those with T cell involvement: Pneumocystis, candidiasis, mycobacteria
• Autoimmune cytopenias
• Lymphoma and other malignancy in some

• Immunoglobulins: low or absent IgG, IgA and IgM, with poor vaccine responses, and normal or near normal B cell numbers on flow cytometry.
• Lymphocyte subsets: variable T cell lymphopenia, and low memory B cells.
• Cytogenetics on phytohaemagglutinin stimulated lymphocytes: juxtacentromeric instability of chromosomes 1, 9 and 16, with multibranched chromosomes (the diagnostic finding).
• Genetic testing of DNMT3B, ZBTB24, CDCA7 and HELLS.
• Infection workup and full blood count for cytopenias.
• Growth, development and hearing assessments.

Differential diagnosis.

• Common variable immunodeficiency
• X-linked agammaglobulinaemia
• Other chromosomal instability syndromes (ataxia telangiectasia, Nijmegen breakage syndrome, Bloom syndrome)
• Combined immunodeficiencies with dysmorphism
• Secondary hypogammaglobulinaemia
• DiGeorge syndrome

• Immunoglobulin replacement for life: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Slow the infusion after a reaction; for anaphylaxis give adrenaline 0.01 mg/kg intramuscularly (maximum 0.5 mg).
• Antibiotic prophylaxis: azithromycin 10 mg/kg orally three times weekly in children (maximum 500 mg), 500 mg in adults, after ECG shows QTc under 450 ms.
• Pneumocystis prophylaxis with T cell lymphopenia: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Treat infections early by culture and PCR, with longer courses, and treat chronic diarrhoea by stool pathogens.
• Nutrition: dietitian support, high energy feeds, and enteral support if growth falters.
• Autoimmune cytopenia: prednisolone 1 mg/kg orally daily (maximum 60 mg) with taper over 4 to 8 weeks.
• Haematopoietic stem cell transplantation corrects the immune defect and is considered for severe or T cell deficient disease. It does not correct facial or developmental features.
• Developmental and educational support, and cancer surveillance with prompt biopsy of new nodes.
• Vaccines: inactivated only; avoid live vaccines with T cell deficiency.

Special groups.

• Families with a known variant: genetic counselling, since each pregnancy has a 1 in 4 risk, and prenatal testing.

Monitoring. Trough IgG every 3 to 6 months. Lymphocyte subsets and full blood count every 6 months. Growth, weight and development at each visit.

Referral and escalation. Refer to paediatric immunology and genetics. Urgent for sepsis, opportunistic infection, cytopenia or lymphadenopathy.