Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

Background: Immunodeficiency, centromeric instability and facial
dysmorphism (ICF syndrome) is a rare autosomal recessive disease
characterised by facial dysmorphism, immunoglobulin deficiency and
branching of chromosomes 1, 9 and 16 after PHA stimulation of
lymphocytes. Hypomethylation of DNA of a small fraction of the
genome is an unusual feature of ICF patients which is explained by
mutations in the DNA methyltransferase gene DNMT3B in some, but not
all, ICF patients. Objective: To obtain a comprehensive description
of the clinical features of this syndrome as well as genotype–
phenotype correlations in ICF patients. Methods: Data on ICF
patients were obtained by literature search and additional
information by means of questionnaires to corresponding authors.
Results and conclusions: 45 patients all with proven centromeric
instability were included in this study. Facial dysmorphism was
found to be a common characteristic (n=41/42), especially
epicanthic folds, hypertelorism, flat nasal bridge and low set
ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all
patients (n=39/44). Opportunistic infections were seen in several
patients, pointing to a T cell dysfunction. Haematological
malignancy was documented in two patients. Life expectancy of ICF
patients is poor, especially those with severe infections in
infancy or chronic gastrointestinal problems and failure to thrive.
Early diagnosis of ICF is important since early introduction of
immunoglobulin supplementation can improve the course of the
disease. Allogeneic stem cell transplantation should be considered
as a therapeutic option in patients with severe infections or
failure to thrive. Only 19 of 34 patients showed mutations in
DNMT3B, suggesting genetic heterogeneity. No genotype–phenotype
correlation was found between patients with and without DNMT3B
mutations.