What are the other Names for this Condition? (Also known as/Symptoms)

• DRRS (Duane-Radial Ray Syndrome)
• Duane Anomaly with Radial Ray Abnormalities and Deafness
• Okihiro Syndrome

What is Duane-Radial Ray Syndrome? (Definition/Background Information)

• Duane-Radial Ray Syndrome (DRRS) is an extremely rare genetic disorder; very few families with DRRS have been described in the scientific literature. The syndrome is caused by mutation(s) in the SALL4 gene
• The SALL family of genes code for transcription factors that bind DNA at specific locations to regulate gene expression for fetal growth. A mutation in SALL4 leads to lack of specific transcription factors. This results in signs and symptoms, such as abnormal eye and bone development, during the fetal stage
• Duane-Radial Ray Syndrome is inherited in an autosomal dominant manner, in which a single copy of the defective gene in each cell of an individual is sufficient to cause disorder. Thus, having a family history of the disorder is a major risk factor for its development
• The disorder may affect one or both sides of the body. The symptoms may include a long, weak or absent thumb, fused vertebrae, clubfeet, vision and hearing impairment, and kidney abnormalities, among others. Progressive loss of hearing, extremely poor vision, and progressive kidney malfunction are some potential complications that could arise from Duane-Radial Ray Syndrome
• Duane-Radial Ray Syndrome is diagnosed with the help of a physical examination, symptom assessment, family medical history evaluation, imaging studies to check for bone and organ abnormalities, and blood and urine tests. It may be confirmed by genetic molecular testing
• The treatment options for DRRS are tailored to each affected individual’s symptoms. The treatments often include the use of vision and hearing aids, corrective surgery, and medication. The prognosis of Duane-Radial Ray Syndrome depends upon the severity of the signs and symptoms. However, currently, no specific data on prognosis is available owing to the very few reported cases

Who gets Duane-Radial Ray Syndrome? (Age and Sex Distribution)

• Duane-Radial Ray Syndrome is reported to be a very rare genetic disorder. The exact prevalence of the disorder is not known
• Both genders are susceptible to developing DRRS
• Very few affected families have been reported globally, but no racial and ethnic group preference is observed

What are the Risk Factors for Duane-Radial Ray Syndrome? (Predisposing Factors)

• Duane-Radial Ray Syndrome is a genetic disorder. In cases where the disorder is inherited (i.e., does not develop spontaneously/randomly), a family history of the condition is a major risk factor for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Duane-Radial Ray Syndrome? (Etiology)

• Duane-Radial Ray Syndrome is caused by mutation(s) in the SALL4 gene, belonging to the SALL family of genes
• Under normal circumstances, the SALL genes code for proteins that are known as transcription factors
  • Transcription factors bind to specific regions in the DNA and regulate gene expression
  • The transcription factors coded by SALL family of genes are essential for the formation of fetal tissues and organs
  • Although the specific role of SALL4 is not known, it is believed by the scientific community that the gene codes for transcription factors that regulate the development of the eyes, heart, and limb bones
• When SALL4 gene is mutated, specific transcription factors are rendered dysfunctional, possibly leading to the characteristic symptoms observed in the affected individuals
• Duane-Radial Ray Syndrome is inherited in an autosomal dominant manner. In this type of inheritance, a single defective copy of the gene in all cells of the body is sufficient to cause disorder. An affected individual inherits the gene mutation from an affected parent
• In some cases, the disorder can occur with no family history of the condition. In such cases, new and spontaneous mutations in SALL4 gene are considered to be responsible for its development

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Duane-Radial Ray Syndrome?

The signs and symptoms of Duane-Radial Ray Syndrome can affect one or both sides of the body (i.e., unilateral or bilateral) and may include the following:

• Thumb related:
  • Absence of thumb
  • Underdevelopment of tissues at the base of thumb
  • Abnormally long thumb that looks like a finger
  • Weakness of thumb resulting in inability to move thumb away from the palm, or touch other fingers of the same hand
• Underdeveloped bones in the forearm (radius and ulna)
• Absence of forearm
• Clubfeet (inward- and upward- turned feet)
• Extra fingers and/or toes; fused fingers and/or toes
• Fused vertebrae
• Distinctive facial features; unusual head turns
• Malformed ears (unusually shaped); hearing impairment
• Eye and vision abnormalities that include:
  • Misaligned eyes
  • Poor vision
  • Erratic eye movements, owing to lack of control of muscles that control the movements. Both outward and inward movements may be restricted or the eyeballs may roll back into the sockets (retraction). These erratic movements are collectively termed “Duane anomaly”
• Abnormalities in the structure and function of the kidneys
  • Reduced kidney size
  • Kidneys fused to form a horseshoe shape
  • Abnormally-rotated kidneys
  • Backflow of urine from the ureter to the kidneys (vesicoureteral reflux)
• Abnormalities in the structure and function of the heart

How is Duane-Radial Ray Syndrome Diagnosed?

An accurate diagnosis of Duane-Radial Ray Syndrome may be made through:

• A thorough physical examination and an assessment of the signs and symptoms
• An evaluation of family medical history
• Vision and hearing tests
• Imaging studies to assess bone malformations and to check for structural defects in the heart and kidneys
• Urine analysis and blood tests to ascertain the function of kidneys
• Genetic molecular testing to check for mutation(s) in the SALL4 gene, for confirmation of diagnosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Duane-Radial Ray Syndrome?

The potential complications of Duane-Radial Ray Syndrome include:

• Progressive kidney malfunction
• Severe heart abnormalities
• Complete hearing loss
• Extremely poor vision
• Reduced quality of life

How is Duane-Radial Ray Syndrome Treated?

There is no cure available for Duane-Radial Ray Syndrome. The treatment options are tailored for each affected individual to alleviate discomfort from various symptoms of the disorder. The treatments offered may include:

• Use of lenses to correct poor vision
• Surgery for misaligned eyes
• Hearing aids to improve hearing
• Surgery to improve abnormal head turns
• Surgery for bone deformities
• Medication and/or surgery to correct kidney abnormalities
• Surgery for heart defects

How can Duane-Radial Ray Syndrome be Prevented?

Currently, there are no specific methods or guidelines to prevent Duane-Radial Ray Syndrome, since it is a genetic condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Duane-Radial Ray Syndrome
• Regular medical screening at periodic intervals with tests, and physical examinations are necessary to monitor progression of disorder

What is the Prognosis of Duane-Radial Ray Syndrome? (Outcome/Resolutions)

• Duane-Radial Ray Syndrome is a very rare disorder with very few affected families reported in the scientific literature. There is scarcity of data regarding the prognosis of this disorder
• However, individuals with milder signs and symptoms have better prognosis than those with more severe conditions

Additional and Relevant Useful Information for Duane-Radial Ray Syndrome:

• Acro-renal-ocular syndrome:
  • Acro-renal-ocular syndrome is characterized by Duane anomaly and other eye abnormalities, radial ray malformations, and kidney defects. Both conditions can be caused by mutations in the same gene
  • Based on these similarities, researchers are investigating whether Duane-Radial Ray Syndrome and acro-renal-ocular syndrome are separate disorders or part of a single syndrome with many possible signs and symptoms
• Duane syndrome can be co-inherited with radial anomalies in an autosomal dominant fashion. In affected individuals, radial dysplasia ranges from hypoplasia of the thenar eminence to absence of the radial bone or forearm
• The features of Duane-Radial Ray Syndrome also overlap with those of a condition called Holt-Oram syndrome. However, these two disorders are caused by mutations in different genes