Clinical characteristics.

Warsaw syndrome is characterized by the clinical triad of severe congenital microcephaly, growth restriction, and sensorineural hearing loss due to cochlear hypoplasia. Intellectual disability is typically in the mild-to-moderate range. Severe speech delay is common. Gross and fine motor milestones are usually attained at the usual time, although a few individuals have mild delays. Additional common features include skeletal anomalies and cardiovascular anomalies. Abnormal skin pigmentation and genitourinary malformations have also been reported. Some individuals have had increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane and mitomycin C.

Diagnosis/testing.

The diagnosis of Warsaw syndrome is established in a proband by identification of biallelic pathogenic variants in DDX11 on molecular genetic testing.

Management.

Treatment of manifestations: Supplementary formula and/or gastrostomy tube as needed to optimize nutrition. Treatments for hearing loss include hearing aids, cochlear implantation, auditory brain stem implant; establishing system of communication and hearing habilitation that may include sign language, auditory therapy, speech therapy; educational programs designed for individuals with hearing impairment. Treatment of cardiac anomalies per cardiologist; treatment of genitourinary anomalies per nephrologist and/or urologist; early intervention and psychological evaluations; physical, occupational, and speech therapies.

Surveillance: Monitor growth, speech development, and educational needs with each visit; there is no consensus regarding tumor screening.

Genetic counseling.

Warsaw syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the DDX11 pathogenic variants in the family are known.

Suggestive Findings

Warsaw syndrome should be suspected in individuals with a triad of characteristic findings:

• Congenital severe microcephaly
• Prenatal and postnatal growth restriction
• Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)

Additional clinical, imaging, and laboratory findings include the following.

Clinical findings

• Intellectual disability and developmental delay
• Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
• Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
• Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
• Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)

Imaging findings. Cochlear anomalies on temporal bone imaging (e.g., cochlear hypoplasia)

Laboratory findings

• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
  Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
• Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (Figure 1)
• In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.

Figure 1.

C-banding of metaphase chromosomes in two individuals with Warsaw syndrome. Short arrows show chromosome morphology suggestive of PCD; long arrows show chromosomes with PCS. A. Representative metaphase from untreated (0 dose) culture

Establishing the Diagnosis

The diagnosis of Warsaw syndrome is established in a proband with biallelic pathogenic (or likely pathogenic) variants in DDX11 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic DDX11 variants of uncertain significance (or of one known DDX11 pathogenic variant and one DDX11 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Warsaw syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Warsaw syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Warsaw syndrome presents with a clinical triad of severe microcephaly, growth restriction, and hearing loss. Other anomalies have also been described. Fourteen children (8 female, 6 male) have been reported to date.

Microcephaly has a prenatal onset and is reported in all affected individuals. Congenital microcephaly can range from -3.3 to -10 SD for age and sex. Postnatal head growth velocity is slower than average for age and sex. However, there are no reports of a substantial decrease in head growth velocity in childhood.

Prenatal and postnatal growth deficiency. All 14 reported individuals to date had intrauterine growth deficiency with birth weight and height below the third percentile. Postnatal growth deficiency was also reported in all individuals; two individuals had weights between the 50th and 75th percentile later in childhood after they were started on gastric tube feedings [Bailey et al 2015, Alkhunaizi et al 2018].

Congenital sensorineural hearing loss is usually severe; the result of bilateral hypoplasia of the cochlea and the cochlear nerve. Children with Warsaw syndrome usually present early with a failed newborn hearing screen or severe speech disability that is comparable to the degree of sensorineural hearing loss. Expressive language is consistently affected due to the hearing loss; receptive language is also involved but to a lesser degree. Sign language can be learned; however, due to the intellectual disability, this is also limited in some individuals along with receptive language.

Intellectual disability and developmental delay range from mild to moderate and tend to be stable. Behavioral issues such as mild ADHD and aggression were reported in two individuals [Bailey et al 2015, Alkhunaizi et al 2018]; however, affected children usually have good interpersonal skills. Gross and fine motor milestones are usually attained at the usual time although a few individuals have mild delays.

Cardiovascular anomalies are reported in 42% (5/12). These include patent ductus arteriosus (1), small atrial septal defect with large patent ductus arteriosus (1), ventricular septal defect (2), and tetralogy of Fallot (1).

Additional structural brain abnormalities. In addition to cochlear hypoplasia, one individual presented with posterior labyrinthine anomaly with persistent lateral semicircular canal anlage [Alkhunaizi et al 2018]. Two individuals had focal poor sulcation pattern; focal lissencephaly was reported in one of these individuals [Alkhunaizi et al 2018].

Radial ray anomalies include proximal insertion of thumbs, shortened first metacarpals, small radii, and short thumbs.

Manifestations reported in single individuals

• Limb anomalies include fifth finger clinodactyly, brachydactyly, small fibula, talipes equino varus, partial syndactyly of toes 2/3, and overlapping toes.
• Abnormal skin pigmentation includes café au lait macules, cutis marmorata, hypo- or hyperpigmentation, and livedo reticularis with telangiectasia.
• Genitourinary malformations include hypoplastic scrotum, cryptorchidism, hypospadias, and multicystic kidneys.
• Other findings include early menarche in two sisters [Eppley et al 2017] and seizure disorder in one individual [Alkhunaizi et al 2018].

Malignancy. DDX11 is essential for genome maintenance and may act as a tumor suppressor [Parish et al 2006]. The possibility of an increased risk of malignancy in obligate heterozygotes (parents) was raised by van der Lelij et al [2010]; the current authors reported a family that included a mother of the proband with lymphoma and another heterozygous relative with endometrial adenocarcinoma. None of the five affected individuals nor their parents reported by Alkhunaizi et al [2018] had cancer. Therefore, the risk of malignancy in individuals with Warsaw syndrome or heterozygous individuals is not clear.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Nomenclature

Warsaw breakage syndrome was named for the city of origin of the first reported individual and the elevated level of chromosome breakage similar to Fanconi anemia reported in some affected individuals [van der Lelij et al 2010].

The observation of inconsistent increased level of chromosome breakage in individuals with this disorder led the current authors to suggest changing the name of the condition to Warsaw syndrome [Alkhunaizi et al 2018].

Prevalence

Warsaw syndrome is rare, with 14 individuals reported to date [van der Lelij et al 2010, Capo-Chichi et al 2013, Bailey et al 2015, Eppley et al 2017, Alkhunaizi et al 2018, Bottega et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Warsaw syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Warsaw syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one DDX11 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless the reproductive partner of an affected individual also has Warsaw syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in DDX11.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DDX11 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the DDX11 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the DDX11 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 6 June 2019 (sw) Review posted live
• 20 November 2018 (ea, dc) Original submission

Literature Cited

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