Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 2

A number sign (#) is used with this entry because immunodeficiency-centromeric instability-facial anomalies syndrome-2 (ICF2) is caused by homozygous or compound heterozygous mutation in the ZBTB24 gene (614064) on chromosome 6q21.

Description

Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disorder characterized by facial dysmorphism, immunoglobulin deficiency resulting in recurrent infections, and mental retardation. Laboratory studies of patient cells show hypomethylation of satellite regions of chromosomes 1, 9, and 16, as well as pericentromeric chromosomal instability in response to phytohemagglutinin stimulation (summary by de Greef et al., 2011).

For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (242860).

Clinical Features

De Greef et al. (2011) reported 7 patients from 6 families with agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds. Four of the patients also had motor delay. Five of the patients had previously been reported by Hagleitner et al. (2008). All had recurrent infections, sometimes leading to early death. While there were no apparent clinical differences between ICF1 and ICF2. cells from patients with ICF2 showed hypomethylation of the alpha-satellite repeat on chromosome 9.

Chouery et al. (2012) reported 3 Lebanese brothers with ICF2. The parents originated from the same village, but denied consanguinity. The boys showed delayed psychomotor development and recurrent respiratory infections from infancy. They had a round face, high-arched palate, small chin, retrognathism, and everted lower lip. Head circumferences were between the 5th and 15th percentiles, and height was below the 5th percentile. Karyotype analysis showed 30 to 40% cells with whole-arm deletions and pericentromeric breaks of chromosomes 1, 9, and 16; multibranched chromosomes containing 3 or more arms of 1, 9, and 16 joined in the vicinity of the centromere; and/or decondensation in the 1qh and 16qh regions. Methylation studies showed a lack of methylation of the alpha satellite in 2 patients, thus leading to the diagnosis. Laboratory studies showed decreased IgM and IgG; IgA was normal. Absolute and relative numbers of B and T cells were normal, but there was absence of memory B cells and a decrease in memory T cells.

Inheritance

The transmission pattern of ICF2 in the families reported by de Greef et al. (2011) was consistent with autosomal recessive inheritance. Five of 6 reported families were consanguineous.

Molecular Genetics

By homozygosity mapping of 5 patients with ICF2, born of consanguineous parents, followed by exome sequencing in 1 patient, de Greef et al. (2011) identified a homozygous truncating mutation in the ZBTB24 gene (R320X; 614064.0001). Homozygous mutations in the ZBTB24 gene were subsequently identified in 3 of the 4 remaining consanguineous families, as well as in an additional consanguineous family (see, e.g., S16X; 614064.0002 and R457X; 614064.0005). An affected sib pair of nonconsanguineous descent was compound heterozygous for ZBTB24 mutations (S278X; 614064.0003 and C408G; 614064.0004). Mutations in this gene were not identified in 4 remaining patients with a similar phenotype, indicating further genetic heterogeneity. All but 1 of the mutations created a premature stop codon, indicating that ICF2 is caused by ZBTB24 loss of function.

Chouery et al. (2012) identified a homozygous 2-bp deletion in the ZBTB24 gene (396delTA; 614064.0006) in 3 Lebanese brothers with ICF2. The molecular studies indicated a loss-of-function effect. The unaffected parents were heterozygous for the mutation, which was found by Sanger sequencing after no mutations were found in the DNMT3B gene.

Genotype/Phenotype Correlations

Among 44 patients with a clinical diagnosis of ICF, Weemaes et al. (2013) found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified in 8 patients. Although the phenotype was relatively homogeneous, systematic phenotypic evaluation showed that humoral immunodeficiency was generally more pronounced in ICF1 patients and ICF2 patients had a significantly higher incidence of intellectual disability. Both T- and B-cell compartments were involved in ICF1 and ICF2. A few patients from both groups had congenital malformations including cardiac defects, cleft lip, clinodactyly, choanal stenosis, hip dislocation, and cerebral malformations.