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Duane Syndrome

Synonyms: Duane Retraction Syndrome; Stilling-Turk-Duane Syndrome; Duane Anomaly, Isolated. Includes: Duane Retraction Syndrome 2

, MSc, , MD, PhD, and , MD.

Author Information
, MSc
Research Specialist II, Children's Hospital Boston
Department of Neurology, Harvard Medical School
Boston, Massachusetts
Howard Hughes Medical Institute
Chevy Chase, Maryland
, MD, PhD
Ophthalmologist-in-Chief, Children's Hospital Boston
Professor of Ophthalmology, Harvard Medical School
Boston, Massachusetts
, MD
Department of Neurology
Children's Hospital Boston
Professor of Neurology and Ophthalmology, Harvard Medical School
Boston, Massachusetts
Howard Hughes Medical Institute
Chevy Chase, Maryland

Initial Posting: ; Last Update: July 5, 2012.

Summary

Disease characteristics. Duane syndrome is a strabismus syndrome characterized by congenital non-progressive horizontal ophthalmoplegia (inability to move the eyes) primarily affecting the abducens nucleus and nerve and its innervated extraocular muscle, the lateral rectus muscle. At birth, affected infants 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. Most individuals with Duane syndrome have strabismus in primary gaze but can use a compensatory head position to align the eyes, and thus can preserve single binocular vision and avoid diplopia. Individuals with Duane syndrome who lack binocular vision are at risk for amblyopia. Approximately 70% of individuals with Duane syndrome have isolated Duane syndrome; i.e., they do not have other detected congenital anomalies.

Diagnosis/testing. The diagnosis of Duane syndrome is based on clinical findings. CHN1 is the only gene in which mutations are known to cause familial isolated Duane syndrome. Sequence analysis of CHN1 has to date detected missense mutations in ten probands and affected family members. Mutations in CHN1 have not been found to be a common cause of simplex Duane retraction syndrome.

Management. Treatment of manifestations: Spectacles or contact lenses for refractive error; occlusion or penalization of the better-seeing eye for treatment of amblyopia; prism glasses, usually in older individuals with mild involvement, to improve the compensatory head position; extraocular muscle surgery to correct or improve compensatory head posture, improve alignment in primary gaze position, improve upshoot or downshoot.

Prevention of secondary complications: Specialist examination early in life to detect refractive errors to prevent amblyopia and avoid compounding the motility problem; 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: Ophthalmologic visits every three to six months during the first years of life to prevent, detect, and treat amblyopia; annual or biannual eye examinations when no longer at risk for amblyopia (after age 7-12 years depending on binocular vision status).

Evaluation of relatives at risk: Eye examination within the first year of life so that early diagnosis and treatment can prevent secondary complications.

Genetic counseling. Most individuals with isolated Duane syndrome are simplex cases (i.e., a single occurrence in a family) of unknown cause. Isolated Duane syndrome resulting from a heterozygous mutation in CHN1 is inherited in an autosomal dominant manner with incomplete penetrance. A proband with isolated Duane syndrome may have inherited the disease-causing mutation or have a de novo mutation. Each child of an individual with Duane syndrome resulting from a CHN1 mutation has a 50% chance of inheriting the condition. Prenatal diagnosis is possible for pregnancies at increased risk for isolated Duane syndrome if the mutation has been identified in an affected family member.

Diagnosis

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 mutations are known to cause CHN1-related familial isolated Duane syndrome.

Clinical testing

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CHN1Sequence analysisSequence variants 4, 5Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Miyake et al [2008], Murillo-Correa et al [2009], Miyake et al [2010], Volk et al [2010], Chan et al [2011], Miyake et al [2011]

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.

Clinical Description

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. Individuals with Duane syndrome and Marcus Gunn jaw-winking phenomenon have been reported, lending support to the idea that the two syndromes are primarily neurogenic in origin [Isenberg & Blechman 1983, Oltmanns & Khuddus 2010].

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 individuals 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]. Decreased superior oblique muscle volume has also been observed, supporting trochlear nerve hypoplasia [Miyake et al 2011]. 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, trochlear, 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, Chan et al 2011].

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 proposed renaming of Duane syndrome as the "co-contractive retraction syndrome" (CCRS, types 1-3) [Hertle 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.

Differential Diagnosis

See Duane Retraction Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Duane syndrome with associated congenital anomalies. Approximately 30% of individuals with Duane syndrome have other congenital anomalies, particularly of the ear, kidney, heart, upper limbs, and skeleton. These associated anomalies are typically reported in simplex cases, but also occur together with Duane syndrome as familial malformation or genetic syndromes.

  • SALL4-related disorders. The SALL4-related syndromes include Okihiro syndrome, Duane-radial ray syndrome, acro-renal-ocular syndrome, and IVIC syndrome. These overlapping syndromes are characterized by unilateral or bilateral Duane syndrome and radial ray malformations that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). Deafness, renal anomalies, and imperforate anus can be co-inherited. Inheritance is autosomal dominant. Heterozygous SALL4 mutations are associated with most familial cases of these syndromes [Al-Baradie et al 2002, Kohlhase et al 2002, Kohlhase et al 2003, Kohlhase et al 2005, Paradisi & Arias 2007]. Individuals with simplex isolated Duane syndrome have not been found to harbor mutations in SALL4 [Wabbels et al 2004]. However, some members of families segregating a SALL4-related disorder have been found to harbor a SALL4 mutation and to manifest isolated Duane syndrome (without hand or other anomalies) [Al-Baradie et al 2002].
  • SALL1-related disorders. Townes-Brocks syndrome (TBS) has been found to result from mutations in SALL1 [Kohlhase et al 1998]. This rare disorder is characterized by renal, anal, limb, and ear anomalies and is an autosomal dominantly inherited malformation syndrome. More recently SALL1 mutations have been reported in three individuals with TBS and Duane syndrome [Botzenhart et al 2007, Barry & Reddy 2008, van den Akker et al 2009]. Additional ophthalmic findings in these individuals included coloboma, ptosis, epibulbar dermoid, and crocodile tears. There is overlap between TBS and Okihiro syndrome.
  • HOXA1-related syndromes. The HOXA1-related syndromes include the overlapping Bosley-Salih-Alorainy syndrome (BSAS, OMIM 601536) [Tischfield et al 2005] and Athabaskan brain stem dysgenesis syndrome (ABDS) [Holve et al 2003]. They are characterized by Duane syndrome type 3 or horizontal gaze palsy and, in most individuals, bilateral sensorineural hearing loss caused by an absent cochlea and rudimentary inner-ear development. Subsets of individuals manifest intellectual disability, autism, moderate-to-severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, and skull and craniofacial abnormalities.

    These disorders result from truncating mutations in HOXA1 [Tischfield et al 2005]. Inheritance is autosomal recessive. Individuals with simplex isolated Duane syndrome have not been found to harbor mutations in HOXA1 [Tischfield et al 2006].
  • Wildervanck syndrome (cervicooculoacoustic syndrome, OMIM 314600) is characterized by Duane syndrome, deafness, and Klippel-Feil anomaly (fused cervical vertebrae). The perceptive deafness results from a bony malformation of the inner ear. Most Wildervanck syndrome is sporadic and limited to females.
  • Goldenhar syndrome (hemifacial microsomia, oculoauriculovertebral spectrum, OMIM 164210) is characterized by craniofacial, ocular, cardiac, vertebral, and central nervous system defects, consistent with maldevelopment of the first and second branchial arches. Duane syndrome can be associated with this disorder [Tillman et al 2002, Caca et al 2006]. The majority of cases are sporadic, but there are a few reports of both autosomal dominant and recessive inheritance (see Craniofacial Microsomia Overview).

Chromosome disorders

  • Chromosome 8. Several individuals with Duane syndrome have been reported to have chromosome 8 anomalies: anomalies of the 8q13 DURS1 locus (OMIM 126800); mosaic trisomy 8 [2 separate reports]; deletion 8q13-q21.2; a de novo reciprocal balanced translocation consisting of t(6:8)(q26;q13) disrupting the gene for carboxypeptidase (CPAH); and a microduplication of 8q12. Two reports suggest that abnormal dosage of CHD7 may be causative of the resultant phenotype on 8q12. Individuals described in these case reports manifest Duane syndrome with various associated congenital abnormalities including other cranial nerve deficits, facial dysmorphisms, intellectual disabilities, and cardiac defects.
  • Other chromosome aberrations associated with Duane syndrome have been reported to involve 2q13, 4q27-31, 6p25, 10q24.2q26.3, 20q13.12 and 22pter-q11. Duane syndrome has been described in one individual with 48,XXYY syndrome and another with atypical Silver-Russell syndrome, Duane syndrome and maternal uniparental disomy of chromosome 7.

Individuals with Duane syndrome and associated congenital defects should be evaluated further for possible underlying chromosomal rearrangements.

Ocular congenital cranial dysinnervation disorders. The term congenital cranial dysinnervation disorders (CCDDs) refers to disorders of innervation of cranial musculature [Gutowski et al 2003]. The ocular CCDDs are also included in the category of complex or incomitant strabismus, in which the degree of misalignment of the eyes varies with the direction of gaze.

Duane syndrome is the most common of the ocular CCDDs. Other ocular CCDDs include the following:

  • Congenital fibrosis of the extraocular muscles (CFEOM) (OMIM 135700, 602078, 600638, 609428, 609384) refers to at least seven genetically defined syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, and Tukel syndrome. CFEOM is characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) that is restrictive and includes some limitation of vertical gaze. It often but does not have to include ptosis (droopy eyelids). It typically results from aberrant development of all or part of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpebrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, facial weakness, and/or a progressive axonal peripheral neuropathy (a form of Charcot-Marie-Tooth disease). Individuals with CFEOM3C also have intellectual disability and facial dysmorphism reminiscent of Albright hereditary osteodystrophy-like syndrome. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands.
  • Moebius syndrome (MBS) (OMIM 157900) is characterized by sixth and seventh nerve palsies, resulting in abduction defect and facial weakness. The vast majority of individuals with Moebius syndrome are simplex cases (i.e., single occurrence in a family) and many are associated with additional developmental defects of lower cranial nerves and distal extremities.
  • Hereditary congenital facial paresis (HCFP) (OMIM 601471) is characterized by the isolated dysfunction of cranial nerve VII. It may be confused with Moebius syndrome if it is coincidentally accompanied by strabismus.
  • Horizontal gaze palsy with progressive scoliosis (HGPPS) (OMIM 607313) is characterized by congenital horizontal gaze palsy (no horizontal eye movements) accompanied by progressive scoliosis. HGPPS is inherited in an autosomal recessive manner and is caused by mutations in ROBO3 [Jen et al 2004]. Compound heterozygous ROBO3 mutations have also been identified in children of non-consanguineous parents [Chan et al 2006]. Neuroimaging and neurophysiology studies of individuals with HGPPS found that the axons that make up the major motor and sensory pathways for communication between the brain and the spinal cord fail to cross the midline in the hindbrain [Jen et al 2004, Bosley et al 2005].

Complex and common forms of strabismus that could be confused with Duane syndrome:

  • Common strabismus. In common or comitant strabismus, the misalignment of the eyes is equal regardless of the direction of gaze. Common strabismus includes esotropia, exotropia, dissociated vertical deviation, microstrabismus, and monofixation syndrome.
  • Sixth nerve palsy is characterized by impaired abduction of the affected eye in the absence of globe retraction and narrowing of the palpebral fissure. Sixth nerve palsy may be accompanied by esotropia. Sixth nerve palsies are typically acquired; however, congenital and/or inherited cases are rare but have been reported.
  • Crossed fixation. The signs of Duane syndrome may be difficult to detect in an infant with large-angle esotropia. In such infants, the right eye is used for left gaze and the left eye is used for right gaze. As a result, the child may appear to have an abduction limitation when in fact abduction is found to be full when tested monocularly.
  • Congenital ocular motor apraxia is a rare disorder of horizontal gaze in which affected individuals are unable to generate horizontal saccades. Horizontal tracking requires head movement, but the head must be thrust past the object of regard in order to overcome the intact doll's head response. Vertical saccades are preserved.
  • Brown syndrome ('superior oblique tendon sheath syndrome') is characterized by the inability to elevate the adducted eye actively or passively. Forced duction testing is positive for tightness of the superior oblique muscle. The downshoot seen in Duane syndrome can mimic Brown syndrome. Most congenital Brown syndrome is simplex (i.e., single occurrence in a family) and believed to result from anomalies of the tendon or the trochlear apparatus. Rare familial cases have been reported [Iannaccone et al 2002].
  • Congenital esotropia and exotropia refer to eye conditions in which the eye(s) are either crossed or deviating outwards. There is evidence of both genetic and environmental components to these disorders.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 and Marcus Gunn jaw wink.
  • Optional forced duction testing and/or force generation testing in cooperative individuals
  • Photographic documentation to identify changes in the condition and for future review
  • If surgery is planned: Consider brain and orbital 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

The following may be considered:

  • Hearing evaluation
  • Medical genetics consultation if there is a family history of Duane syndrome, dysmorphic features and/or congenital anomalies in the proband, or if a mutation is found in CHN1

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

Note: Surgery does not generally improve abduction of the affected eye, though transposition procedures may provide partial improvement in some cases.

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. Both the superior and inferior rectus muscles may be transposed, or alternatively the superior rectus muscle alone may be transposed in combination with a medial rectus muscle recession. 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 affected individual fixates with the uninvolved eye, and the contralateral lateral rectus if the affected individual fixates with the involved eye. If upshoot or downshoot occurs in adduction, consider recession of the lateral rectus muscle, possibly with Y-splitting.

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

Evaluation of Relatives at Risk

Duane syndrome can often be diagnosed by clinical findings within the first year 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 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, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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.

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 be 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Human Genome Research Institute (NHGRI)
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Prevent Blindness America
    211 West Wacker Drive
    Suite 1700
    Chicago IL 60606
    Phone: 800-331-2020 (toll-free)
    Email: info@preventblindness.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Duane Syndrome: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
DURS1Unknown8q13Unknown
DURS2CHN12q31​.1N-chimaerinCHN1 homepage - Mendelian genesCHN1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Duane Syndrome (View All in OMIM)

118423CHIMERIN 1; CHN1
126800DUANE RETRACTION SYNDROME 1; DURS1
604356DUANE RETRACTION SYNDROME 2; DURS2

Normal allelic variants. Alternatively spliced transcript variants encoding different isoforms have been described for this gene (see Table A, Gene Symbol). The longest CHN1 transcript variant (NM_001822.5) has 13 exons.

Pathogenic allelic variants. Ten different heterozygous missense changes have been identified in CHN1 [Miyake et al 2008, Chan et al 2011, Miyake et al 2011]. All ten nucleotide substitutions cosegregated with the affected haplotypes. None were present in online single nucleotide databases or on 788 control chromosomes. Six of the ten resulted in non-conservative amino acid substitutions. All were predicted to alter amino acids that are conserved in CHN1 orthologs of eight different species. Recently Miyake et al [2011] described the mutation NM_001822.5:c.443A>T; NP_001813.1:p.Tyr148Phe which expands the phenotypic spectrum of hyperactivating CHN1 mutations.

Normal gene product. There are multiple N-chimaerin isoforms. N-chimaerin has three domains: an N-terminal SH2 domain, a C-terminal RhoGAP domain, and a central C1 domain similar to protein kinase C. No mutations have been identified in the N-terminal SH2 domain. The longest isoform NP_001813.1 has 459 amino acid residues.

Abnormal gene product. All identified mutations act as gain-of-function mutations that increase N-chimaerin (α2-chimerin RacGAP) activity in vitro. Several mutations appear to enhance N-chimaerin translocation to the cell membrane or enhance its ability to self-associate. To test the hypothesis that N-chimaerin overactivity results in aberrant axon development in vivo, a chick in ovo system was used to overexpress wildtype and mutant alpha-2-chimerin in the embryonic ocular motor nucleus [Miyake et al 2008]. In the majority (71%-87%) of embryos overexpressing wildtype or mutant constructs, the oculomotor nerve stalled and its axons terminated prematurely adjacent to the dorsal rectus muscle. It is possible with the p.Tyr148Phe amino acid substitution reported by Miyake et al [2011] that the variable phenotype is a result of both hyperactivation of α2-chimerin and interaction of its SH2 of Rac-GAP domains with other proteins.

References

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Suggested Reading

  1. Amouroux C, Vincent M, Blanchet P, Puechberty J, Schneider A, Chaze AM, Girard M, Tournaire M, Jorgensen C, Morin D, Sarda P, Lefort G, Geneviève D. Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay. Eur J Hum Genet. 2012;20:580–3. [PMC free article: PMC3330221] [PubMed: 22258531]
  2. Bayrakli F, Bilguvar K, Ceyhan D, Ercan-Sencicek AG, Cankaya T, Bayrakli S, Guney I, Mane SM, State MW, Gunel M. Heterozygous 5p13.3-13.2 deletion in a patient with type I Chiari malformation and bilateral Duane retraction syndrome. Clin Genet. 2010;77:499–502. [PubMed: 20447154]
  3. Bedoyan JK, Lesperance MM, Ackley T, Iyer RK, Innis JW, Misra VK. A complex 6p25 rearrangement in a child with multiple epiphyseal dysplasia. Am J Med Genet A. 2011;155A:154–63. [PubMed: 21204225]
  4. Chew CK, Foster P, Hurst JA, Salmon JF. Duane's retraction syndrome associated with chromosome 4q27-31 segment deletion. Am J Ophthalmol. 1995;119:807–9. [PubMed: 7785704]
  5. 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]
  6. Mehendale RA, Dagi LR, Wu C, Ledoux D, Johnston S, Hunter DG. Superior rectus transposition and medial rectus recession for Duane syndrome and sixth nerve palsy. Arch Ophthalmol. 2012;130:195–201. [PMC free article: PMC3753366] [PubMed: 22332212]
  7. Smith SB, Traboulsi EI. Duane syndrome in the setting of chromosomal duplications. Am J Ophthalmol. 2010;150:932–8. [PubMed: 20933218]
  8. Stark Z, Ryan MM, Bruno DL, Burgess T, Savarirayan R. Atypical Silver-Russell phenotype resulting from maternal uniparental disomy of chromosome 7. Am J Med Genet A. 2010;152A:2342–5. [PubMed: 20684011]
  9. Weis A, Bialer MG, Kodsi S. Duane syndrome in association with 48,XXYY karyotype. J AAPOS. 2011;15:295–6. [PubMed: 21680214]

Chapter Notes

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

  • 5 July 2012 (me) Comprehensive update posted live
  • 18 February 2010 (me) Comprehensive update posted live
  • 25 May 2007 (me) Review posted to live Web site
  • 23 February 2007 (ee) Original submission
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