Clinical Diagnosis

Duane syndrome, a congenital, non-progressive eye movement disorder, is characterized by the following:

• Congenital limitation of abduction and/or adduction

• Globe retraction (co-contraction) on adduction

• Palpebral fissure (i.e., the separation between the upper and lower eyelids) narrowing on adduction.

Note: Adduction is movement of the globe toward the midline (the nose); abduction is movement of the globe away from the midline (toward the ear).

Isolated Duane syndrome. Most individuals with Duane syndrome have isolated Duane syndrome, i.e., they do not have other detected congenital anomalies. The vast majority of individuals with isolated Duane syndrome are simplex cases (i.e., single occurrence in a family). This GeneReview focuses on isolated Duane syndrome. (See Differential Diagnosis for a discussion of Duane syndrome with associated congenital anomalies.)

Duane syndrome can be clinically subdivided into three types:

Type 1 (~75%-80% of all Duane syndrome) is characterized by the following:

• Absent to markedly restricted abduction

• Normal to mildly restricted adduction

• Retraction of the globe and narrowing of the palpebral fissure on adduction

• Upshoot and downshoot of affected globe on attempted adduction

• Esotropia in primary gaze (variably present)

• Head turn toward involved side (variably present)

• Unilateral or bilateral involvement

Type 2 (~5%-10% of all Duane syndrome) is characterized by the following:

• Absent to markedly restricted adduction

• Normal to mildly restricted abduction

• Retraction of the globe and narrowing of the palpebral fissure (the separation between the upper and lower eyelids) on adduction

• Upshoot and downshoot of affected globe on attempted adduction (variably present)

• Exotropia in primary gaze (variably present)

• Head turn toward uninvolved side (variably present)

• Unilateral or bilateral involvement

Type 3 (~10%-20% of all Duane syndrome) is characterized by the following:

• Absent to markedly restricted abduction

• Absent to markedly restricted adduction

• Retraction of the globe and narrowing of the palpebral fissure on attempted adduction

• Upshoot and downshoot of affected globe on attempted adduction (more common than in types 1 or 2)

• Esotropia or exotropia in primary gaze (variably present)

• Head turn toward involved side (variably present)

• Unilateral or bilateral involvement

Molecular Genetic Testing

Gene. CHN1 is by definition the only gene in which mutation causes CHN1-related familial isolated Duane syndrome.

Clinical testing

• Sequence analysis. Heterozygous missense mutations affecting non-conservative and conservative amino acid substitutions were identified by direct sequencing of the 13 exons of CHN1 in pedigrees segregating Duane syndrome as an isolated, autosomal dominant trait [Miyake et al 2008, Murillo-Correa et al 2009, Miyake et al 2010].

Table 1. Summary of Molecular Genetic Testing Used in Duane Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
CHN1	Sequence analysis	Sequence variants 2	Unknown	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis of Duane syndrome is established by clinical findings.

• Molecular genetic testing of CHN1 is recommended in familial cases only.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those described in this GeneReview are known to be associated with mutations in CHN1.

Natural History

Duane syndrome is a strabismus syndrome characterized by congenital non-progressive horizontal ophthalmoplegia (inability to move the eyes) without ptosis (droopy eyelids) primarily affecting the abducens nucleus and nerve and its innervated extraocular muscle, the lateral rectus muscle. At birth, affected individuals have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction). In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. The left side is more commonly affected in most studies.

The female-to-male ratio for simplex cases is 3:2.

Restriction in vertical movement of the eyes may also be found in association with mutations in CHN1.

Strabismus, the deviation of the position of one eye relative to the other, results in misalignment of the line of sight of the two eyes. Many individuals with Duane syndrome have strabismus in primary gaze; esotropia is more common in Duane syndrome type 1 and exotropia in Duane syndrome type 2. The impaired movement of one eye with respect to the other allows individuals with strabismus in primary gaze to utilize a compensatory head turn in order to align the eyes, thus avoiding diplopia and preserving single binocular vision.

Amblyopia occurs in approximately 10% of individuals with Duane syndrome; these persons are typically a subset of those with Duane syndrome who lack binocular vision. The amblyopia in Duane syndrome responds to standard therapy if detected early; if not treated promptly, the vision loss from amblyopia is irreversible.

Visual acuity is good except in those individuals with amblyopia.

Marcus Gunn jaw-winking phenomenon. An individual with Duane syndrome and Marcus Gunn jaw-winking phenomenon has been reported, lending support to the idea that the two syndromes are primarily neurogenic in origin.

Pathophysiology. It is generally believed that Duane syndrome results from maldevelopment of motor neurons in the abducens nucleus and aberrant innervation of the lateral rectus muscle. Early studies of Duane syndrome reported fibrosis of the lateral rectus or medial rectus muscles, and suggested a primary myopathic etiology for this disorder. Subsequently, several postmortem examinations of patients with simplex Duane syndrome revealed absence of the abducens motor neurons and ipsilateral cranial nerve VI, and partial innervation of the lateral rectus muscle(s) by branches from the oculomotor nerve. Electromyography revealed simultaneous activation of the medial and lateral rectus muscles, supporting co-contraction of these two horizontal muscles as the cause of the globe retraction.

Neuroimaging. Magnetic resonance imaging (MRI) in simplex cases has verified the absence of cranial nerve VI.

Orbital and brain stem MRI of affected members of two pedigrees with a CHN1 mutation did not visualize the abducens nerve in most affected individuals and revealed structurally abnormal lateral rectus muscles. The oculomotor and optic nerves were also small [Demer et al 2007]. This leads to the suggestion that Duane syndrome resulting from mutations in CHN1 represents a congenital cranial dysinnervation disorder that results from errors in abducens and oculomotor axon pathfinding.

Genotype-Phenotype Correlations

The incidence of bilateral involvement and vertical movement abnormalities in CHN1 mutation-positive individuals with Duane syndrome is higher than that found in CHN1 mutation-negative individuals with Duane syndrome who are simplex cases (i.e., a single occurrence in a family) [Chung et al 2000, Demer et al 2007, Engle et al 2007, Miyake et al 2008].

Penetrance

Duane syndrome pedigrees that have a CHN1 mutation may have reduced penetrance [Engle et al 2007, Miyake et al 2008].

Nomenclature

Historically, Duane syndrome was initially proposed to be myogenic in origin. Electromyography (EMG) of the EOMs, postmortem examinations, and MRI, however, now support a neurogenic etiology [Demer et al 2007]. This has led to the renaming of Duane syndrome as the "co-contractive retraction syndrome" (CCRS, types 1-3) [Hertle et al 2002] and classifying it as one of the ocular congenital cranial dysinnervation disorders (CCDD) [Gutowski et al 2003, Engle 2006].

Duane syndrome is named for the ophthalmologist Alexander Duane (1858-1926).

Prevalence

Duane syndrome accounts for 1%-5% of all cases of strabismus.

Isolated Duane syndrome in familial and simplex cases has been identified worldwide. The prevalence of Duane syndrome is estimated to be 1:1000 in the general population.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Duane syndrome, the following evaluations are recommended:

• Family history

• Ophthalmologic examination

  • Determination of primary gaze position, head position with eyes in primary position, and horizontal and vertical gaze restrictions

  • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the sine qua non of Duane syndrome. Other features sometimes observed include up- and downshoot on attempted adduction, Marcus Gunn jaw wink.

• Optional forced duction testing

• Photographic documentation for future comparison

• If surgery is planned: MRI to determine brain stem and orbital anatomy (muscles and nerves)

• General physical examination. Because of association with systemic anomalies, affected children should have a complete physical examination.

• If surgery is performed, forced duction testing to confirm tightness of the horizontal rectus muscles

Treatment of Manifestations

Nonsurgical treatment of ophthalmologic findings

• Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.

• Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.

• Prism glasses may improve the compensatory head position in mild cases. They are more likely to be tolerated by older persons.

• Correction of hypermetropic refractive error in children may reduce the angle of strabismus and thus decrease the angle of head turn.

Surgical treatment of ophthalmologic findings (extraocular muscle surgery)

• To correct or improve compensatory head posture

• To improve alignment in primary gaze position

• To improve upshoot or downshoot

Principles of surgical approach

• Type 1 and type 3. If head turn is present, consider recession of the medial rectus muscle or horizontal transposition of the vertical rectus muscles. Vertical rectus muscle transposition may be augmented, either with posterior augmentation sutures on the transposed muscles, or with botulinum toxin injections into the medial rectus muscle. If up and/or downshoot occurs in adduction, or if globe retraction is severe and creates a deformity, consider recession of both the medial and lateral rectus muscles. Y-splitting of the lateral rectus muscle may decrease the amount of recession required.

• Type 2. If head turn is present, consider recession of the ipsilateral lateral rectus muscle if the patient fixates with the uninvolved eye, and the contralateral lateral rectus if the patient fixates with the involved eye. If upshoot or downshoot occurs in adduction, consider recession of both the medial and lateral rectus muscles.

Prevention of Secondary Complications

The following are appropriate:

• Amblyopia therapy to prevent vision loss in the less preferred eye

• Surgery to prevent loss of binocular vision in individuals who abandon the compensatory head posture and allow strabismus to become manifest

Surveillance

Surveillance is important for prevention of amblyopia, and to treat amblyopia if it occurs.

• Routine ophthalmologic visits every three to six months during the first years of life

• Annual or biannual examinations in affected individuals older than age seven to 12 years who have good binocular vision and thus are no longer at risk for amblyopia

Testing of Relatives at Risk

Duane syndrome can often be diagnosed by clinical findings within the first months of life; early diagnosis can result in early treatment and thus, prevention of secondary complications.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Most individuals with Duane syndrome represent simplex cases (i.e., single occurrence in a family).

Isolated Duane syndrome caused by mutations in CHN1 is inherited in an autosomal dominant manner with incomplete penetrance.

Risk to Family Members — Autosomal Dominant Inheritance (Isolated Duane Syndrome)

Parents of a proband

• Some individuals diagnosed with isolated Duane syndrome have an affected parent.

• It is possible that a proband with Duane syndrome may have the disorder as the result of a new gene mutation in CHN1.

• Recommendations for the evaluation of parents of a proband with isolated Duane syndrome include ophthalmologic examinations. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

• Although some individuals diagnosed with isolated Duane syndrome have an affected parent, the family history may appear to be negative because of reduced penetrance in this disorder.

Sibs of a proband

• The risk to sibs of a proband with isolated Duane syndrome depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to each sib is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but cannot be accurately determined.

Offspring of a proband. Each child of an individual with Duane syndrome and a CHN1 mutation has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as isolated Duane syndrome are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purposes of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Suggested Reading

1. Evans JC, Frayling TM, Ellard S, Gutowski NJ. Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31. Hum Genet. 2000;106:636–8. [PubMed: 10942112]

Author Notes

Children’s Hospital Boston
Intellectual and Developmental Disabilities Research Center (IDDRC) Web site

Department of Neurology, Howard Hughes Medical Institute
Engle Laboratory Web site

Revision History

• 18 February 2010 (me) Comprehensive update posted live

• 25 May 2007 (me) Review posted to live Web site

• 23 February 2007 (ee) Original submission