Hagleitner, M.M.; Lankester, A.; Maraschio, P.; Hultén, M.; Fryns, J.P.; Schuetz, C.; Gimelli, G.; Davies, E.G.; Gennery, A.; Belohradsky, Bernd H.; de Groot, R.; Gerritsen, E.J.A.; Mattina, T.; Howard, P.J.; Fasth, A.; Reisli, I.; Furthner, D.; Slatter, M.A.; Cant, A.J.; Cazzola, G.; van Dijken, P.J.; van Deuren, M.; de Greef, J.C.; van der Maarel, S.M.; Weemaes, C.M.R.
Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).
In: Journal of Medical Genetics, Vol. 45: pp. 93-99
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.