Warsaw Breakage Syndrome is an exceptionally rare inherited disorder affecting multiple body systems. First described based on a patient from Warsaw, the condition is defined by its impact on growth and cellular stability. It presents with physical and developmental challenges that appear before birth and continue throughout life, requiring careful diagnosis and management.
The Genetic Cause of Warsaw Breakage Syndrome
The cause of Warsaw Breakage Syndrome lies in mutations within the DDX11 gene. This gene provides instructions for producing the ChlR1 enzyme, a DNA helicase responsible for unwinding the DNA double helix. This unwinding process is necessary for DNA replication and repair. The ChlR1 enzyme plays a part in maintaining genetic stability by helping repair DNA damage and ensuring chromosomes are handled correctly during cell division.
Mutations in the DDX11 gene severely reduce or eliminate the ChlR1 enzyme’s activity. Without a functional enzyme, the cell’s ability to repair DNA is impaired, leading to an accumulation of damage. This damage can manifest as physical breaks in the chromosomes, which gives the syndrome its name.
This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two mutated copies of the DDX11 gene, one from each parent. Parents who carry one mutated gene are carriers and do not show signs of the condition. When two carriers have a child, there is a 25% chance with each pregnancy that the child will be affected by the syndrome.
Physical and Developmental Characteristics
The most consistent features are severe growth problems that begin before birth and continue after, resulting in short stature. This is accompanied by microcephaly, a condition where the head is significantly smaller than average for the person’s age and sex.
Individuals have a set of distinctive facial features, which contribute to a recognizable appearance associated with the condition. These can include:
- A small or narrow forehead
- A short nose with small nostrils
- Prominent cheeks
- A small lower jaw
- A high-arched palate
- Unusually shaped ears
Sensorineural hearing loss, caused by problems with the inner ear’s cochlea, is present from birth and can be severe. Developmental delays are also common, with intellectual disability ranging from mild to severe. While many individuals achieve motor milestones like sitting and walking on time, severe speech delays are a frequent challenge.
The underlying chromosomal instability increases the risk for certain health complications, including a higher predisposition to developing some types of cancer like leukemia. Other reported features can include skeletal anomalies, such as differences in fingers and toes, heart defects, and unusual skin pigmentation.
The Diagnostic Process
A diagnosis is often suspected when an individual presents with a triad of characteristic findings: severe microcephaly, significant prenatal and postnatal growth restriction, and sensorineural hearing loss from cochlear malformations. These primary indicators prompt further investigation.
To support a clinical suspicion, a chromosome breakage analysis may be performed. This test treats a sample of the patient’s cells, usually lymphocytes from a blood draw, with chemicals like diepoxybutane (DEB) or mitomycin C (MMC). In individuals with the syndrome, these chemicals induce a high level of chromosome breaks, demonstrating the characteristic cellular instability.
A definitive diagnosis requires molecular genetic testing to sequence the DDX11 gene. Identifying pathogenic mutations on both copies of the gene inherited from the parents confirms Warsaw Breakage Syndrome.
Management and Supportive Care
There is no cure for Warsaw Breakage Syndrome, so care focuses on managing symptoms and providing support to improve quality of life. A multidisciplinary team of specialists is required to address the various health challenges. This team includes:
- Pediatricians
- Geneticists
- Audiologists
- Cardiologists
- Various therapists
For significant growth issues, nutritional support like high-calorie formula or a gastrostomy tube can help optimize growth. Management for profound hearing loss includes hearing aids or cochlear implants to provide access to sound. Early intervention with auditory and speech therapy is also used to help communication development.
Physical, occupational, and speech therapies are mainstays of supportive care, helping individuals reach their maximum developmental potential. These therapies assist with motor skills, daily living activities, and speech delays. Regular psychological evaluations can also address learning or behavioral needs and provide support for the family.
Ongoing health surveillance includes regular monitoring of growth, development, and educational needs. Given the chromosomal instability, discussions with a cancer predisposition specialist may be recommended to determine if specific screenings are appropriate.