Warsaw Breakage Syndrome

A number sign (#) is used with this entry because of evidence that Warsaw breakage syndrome (WABS) is caused by homozygous or compound heterozygous mutation in the DDX11 gene (601150) on chromosome 12p11.

Clinical Features

Van der Lelij et al. (2010) described a 14-year-old boy with severe pre- and postnatal growth retardation, microcephaly, facial dysmorphism (small and elongated face, narrow bifrontal diameter, jugular hypoplasia, bilateral epicanthal folds, relatively large mouth, and cup-shaped ears), high-arched palate, coloboma of the right optic disc, deafness, ventricular septal defect, bilateral clinodactyly of the fifth fingers, syndactyly of the second and third toes, abnormal skin pigmentation, increased chromosomal breakage induced by mitomycin C, and premature chromatid separation. Immunoblot analysis of protein products from candidate genes with a role in sister chromatid exchange revealed barely detectable levels of the DDX11 protein in lymphoblasts and fibroblasts from the patient. Van der Lelij et al. (2010) designated the disorder Warsaw breakage syndrome.

Capo-Chichi et al. (2013) reported 3 sibs from a consanguineous Lebanese family with Warsaw breakage syndrome. The female proband was examined at 20 months of age and was found to be hypotonic, with severe intellectual disability, small and receding forehead, short nose, small nares, short neck, clinodactyly of the fifth fingers, and a single palmar crease on both hands. She had no abnormalities on abdominal ultrasonography or echocardiography. CT of the brain showed small, rounded cochlea without visible cochlear turns or spirals, and bilateral sensorineural deafness was diagnosed by auditory evoked potential. Her brother also had severe intellectual disability, sensorineural deafness, and similar dysmorphic features, as well as prominent cheeks, flat philtrum, microretrognathism, and strabismus. Echocardiogram showed tetralogy of Fallot, and he died at age 4 years of heart failure. A younger sister also had severe intellectual disability, sensorineural deafness, and the same dysmorphic features as her sibs, but no cardiac malformation.

Alkhunaizi et al. (2018) reported 5 additional unrelated patients with Warsaw breakage syndrome and reviewed clinical data on 7 previously reported WABS patients. Severe microcephaly with prenatal onset was identified in all patients, and severe pre- and postnatal growth restriction was observed in 11 of 11 patients. All 12 patients had sensorineural hearing loss, with 10 of 10 having cochlear hypoplasia or functional abnormalities; 1 patient had a posterior labyrinthine anomaly. In all 4 patients who had brain imaging, abnormalities were identified. Some patients had other structural anomalies, including cardiac defects (5/12), recurrent infections (4/9), and skin pigmentation changes (6/12). Craniofacial features included a depressed nasal bridge with a broad nasal tip and overhanging columella. Elevated induced chromosome breakage was observed in 6 of 8 reported patients. Cohesin defects (premature chromatid separation and premature centromere division) were consistent in most metaphases among the patients examined. Alkhunaizi et al. (2018) suggested renaming the condition 'Warsaw syndrome' since chromosome breakage is variable and not a diagnostic feature. They proposed a clinical triad of severe microcephaly, hearing loss with cochlear anomalies, and intrauterine growth restriction as the minimal criteria for WABS. Alkhunaizi et al. (2018) noted that the possibility of increased cancer risk in heterozygous carriers of DDX11 mutations had been raised. None of their patients or carrier parents had cancer, and the authors suggested that a larger cohort is needed to determine whether heterozygosity for DDX11 mutations predisposes to cancer.

Molecular Genetics

In a 14.5-year-old boy with Warsaw breakage syndrome, van der Lelij et al. (2010) identified compound heterozygosity for mutations in the DDX11 gene: a splice site mutation (601150.0001) on the maternal allele and a 3-bp deletion (601150.0002) on the paternal allele. The patient had not developed any malignancies, but his mother and grandmother, both carriers of the splice site mutation, had developed Hodgkin lymphoma and adenocarcinoma of the endometrium, respectively. Van der Lelij et al. (2010) suggested that the DDX11 gene may function as a tumor suppressor.

In 2 sisters with Warsaw breakage syndrome from a consanguineous Lebanese family, Capo-Chichi et al. (2013) performed whole-exome SNP genotyping and identified 10 candidate regions of homozygosity. Exome capture, read mapping, variant calling, and annotation, followed by Sanger sequencing of the unaffected parents, confirmed that only 1 variant, a missense mutation in the DDX11 gene (R263Q; 601150.0003), was heterozygous in the parents and homozygous in the affected sibs.

By whole-exome sequencing, Alkhunaizi et al. (2018) identified 5 patients with Warsaw breakage syndrome who had novel homozygous or compound heterozygous mutations in the DDX11 gene (see, e.g., R378P, 601150.0004 and V859G, 601150.0005). All of the mutations, which were confirmed by Sanger sequencing, segregated with the phenotype in the families, which were of Italian/Croatian, Pakistani, Saudi, and Egyptian descent. The V859G variant appeared to be a Saudi founder mutation.