Warsaw Syndrome
Summary
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 as per cardiologist; treatment of genitourinary anomalies as 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.
Diagnosis
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 individualsNote: (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.
syndrome.">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 variants in DDX11 by molecular genetic testing (see Table 1).
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Warsaw syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of DDX11 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: Analysis of DDX11 is complicated by the presence of at least 16 highly homologous pseudogenes (e.g., DDX11L1, DDX11L2).
- A multigene panel that includes DDX11 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of Warsaw syndrome, some panels for microcephaly and/or hearing loss may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of Warsaw syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing or genome sequencing are most commonly used.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of Warsaw syndrome.
Note: Analysis of DDX11 is complicated by the presence of at least 16 highly homologous pseudogenes (e.g., DDX11L1, DDX11L2). Sequence for all exons of the gene may not be obtained by genomic testing.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Warsaw Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| DDX11 | Sequence analysis 3 | 14/14 individuals 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown, none reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
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]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
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 standard deviations below the mean for age and gender. Postnatal head growth velocity is slower than average for age and gender. 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].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Warsaw Syndrome
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/Warsaw syndrome | Distinguishing from Warsaw syndrome | |||
| Fanconi anemia | 21 genes 1 | AR AD XL |
| Progressive bone marrow failure w/pancytopenia |
| Nijmegen breakage syndrome | NBN | AR |
|
|
| Roberts syndrome | ESCO2 | AR | Cytogenetic findings of PCS | Bilateral symmetric tetraphocomelia or hypomelia |
| Microcephalic osteodysplastic primordial dwarfism type II (OMIM 210720) | PCNT | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PCS = premature chromatid separation; XL = X-linked
- 1.
BRCA2, BRIP1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, ERCC4, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC
- 2.
Increased chromosome breakage on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC)
Management
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.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Warsaw Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Assessment of growth parameters | To identify those w/failure to thrive |
| ENT | ENT referral & audiologic evaluation incl temporal bone imaging | |
| Cardiovascular | Cardiology evaluation w/echocardiogram | To evaluate for congenital cardiac anomalies |
| Genitourinary | Examination for genitourinary anomalies & renal ultrasound examination | |
| Other | Assessment of speech development & intellectual abilities | Particularly important in toddlers & school-age children |
| Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Warsaw Syndrome
| Manifestation/ Concern | Treatment |
|---|---|
| Poor weight gain / Failure to thrive |
|
| Hearing loss |
|
| Cardiac anomalies | Treatment as per cardiologist |
| Genitourinary anomalies | Treatment as per nephrologist &/or urologist |
| Developmental delay | Provide:
|
- 1.
Freeman & Sennaroglu [2018]
Surveillance
Table 5.
Recommended Surveillance for Individuals with Warsaw Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Constitutional | Monitor growth incl height, weight, head circumference, & body mass index | With each visit |
| Misc/Other | Monitor speech development & educational needs | With each visit |
| Malignancy | No consensus for tumor screening 1 | NA |
- 1.
Although van der Lelij et al [2010] suggested an increased incidence of malignancies in first-degree relatives of individuals with Warsaw syndrome, to date no affected individuals have developed malignancies and most reported families do not have an increased incidence of malignancies. Thus, it is not known if Warsaw syndrome is associated with an increased incidence of malignancy and if surveillance for malignancies should be recommended.
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.