Duane Syndrome

Clinical characteristics.

Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly results from failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle; globe retraction occurs as a result of abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Many individuals with Duane syndrome have strabismus in primary gaze but can use a compensatory head turn to align the eyes, and thus can preserve binocular vision and avoid diplopia. Individuals with Duane syndrome who lack binocular vision are at risk for amblyopia. The majority of affected individuals with Duane syndrome have isolated Duane syndrome (i.e., they do not have other detected congenital anomalies). Other individuals with Duane syndrome fall into well-defined syndromic diagnoses. However, many individuals with Duane syndrome have non-ocular findings that do not fit a known syndrome; these individuals are included as part of the discussion of nonsyndromic Duane syndrome.

Diagnosis/testing.

The diagnosis of Duane syndrome is usually made by an ophthalmologist based on clinical findings. More than 98% of individuals with isolated Duane syndrome and no family history lack an identified genetic etiology. Molecular genetic testing for a pathogenic variant in CHN1, MAFB, or SALL4 is most appropriate for those with a positive family history of isolated Duane syndrome (although de novo pathogenic variants in these genes have been detected in some simplex cases) and for those with clinical ocular findings designated as type I or type III Duane 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 address alignment in primary gaze, compensatory head posture, and upshoot or downshoot.

Prevention of secondary complications: Amblyopia therapy to prevent vision loss in the less preferred eye; extraocular muscle surgery to prevent loss of binocular vision in individuals who abandon the compensatory head posture and allow strabismus to become manifest, and to prevent neck muscle problems in those with large compensatory head postures.

Surveillance: Ophthalmologic visits every three to six months during the first years of life to prevent, detect, and treat amblyopia; annual or biannual examinations once the presence of binocular vision and reduced risk for amblyopia is confirmed, and in all individuals older than age seven to 12; no surveillance in adulthood beyond public health guidelines.

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.

The majority of individuals with isolated Duane syndrome represent simplex cases (i.e., a single occurrence in a family), with a positive family history apparent for only approximately 10% of affected individuals. Duane syndrome resulting from a CHN1, MAFB, or SALL4 pathogenic variant is inherited in an autosomal dominant manner. Most individuals with isolated CHN1-, MAFB-, or SALL4-related Duane syndrome have the disorder as the result of a pathogenic variant inherited from an affected parent. Each child of an individual with Duane syndrome resulting from an identified pathogenic variant has a 50% chance of inheriting the variant. Prenatal and preimplantation genetic testing are possible once the causative pathogenic variant has been identified in an affected family member.

Suggestive Findings

Duane syndrome, a congenital, non-progressive eye movement disorder, should be suspected in individuals who present with the following features:

• Congenital limited horizontal eye movement with impairment of abduction and/or adduction
• Globe retraction (co-contraction) accompanied by narrowing of the palpebral fissure (i.e., reduced distance between the upper and lower eyelids) on adduction.

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

Establishing the Diagnosis

Clinical findings. The diagnosis of Duane syndrome is established in a proband typically by an ophthalmologist with detection of the specific clinical findings of limited abduction and/or adduction in association with globe retraction on adduction. Individuals can usually be categorized within the three types detailed below, though there may be some overlap among these categories.

Molecular genetic testing (see Table 2) is most appropriate for those individuals with:

• A positive family history of Duane syndrome.
  • After finding a CHN1 pathogenic variant in seven of 20 families with Duane syndrome, Miyake et al [2010] screened 140 individuals with Duane syndrome with a negative family history and failed to identify a CHN1 pathogenic variant in any individual. Of note, a suspected disease-causing CHN1 variant was identified in an affected individual lacking a positive family history [Biler et al 2017], but such reports are rare.
  • Park et al [2016] studied 401 individuals with Duane syndrome and found a pathogenic variant in MAFB in four probands. Three of the probands had a positive family history; in the fourth the pathogenic variant was de novo. Also, in one of the familial pedigrees, the de novo nature of the pathogenic variant was determined for the original proband, who had unaffected parents.
  • Due to variable expressivity, individuals with a SALL4 pathogenic variant may present with apparently isolated Duane syndrome themselves [Al-Baradie et al 2002, Yang et al 2013], though they may have a positive family history of syndromic Duane syndrome.
• Bilateral Duane syndrome. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [Engle et al 2007, Gutowski & Chilton 2015].
• Duane syndrome type I or type III or a combination of those types. Duane syndrome type II has not been observed in those with a positive family history or in individuals with pathogenic variants in the identified genes, suggesting a distinct etiology [Engle et al 2007, Gutowski & Chilton 2015].

Molecular genetic testing approaches can include concurrent or serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Concurrent single-gene testing. Sequence analysis of CHN1, MAFB, and SALL4 is performed first, and followed by gene-targeted deletion/duplication analysis of MAFB and SALL4 if no pathogenic variant is found.

Note: (1) If serial gene analysis is to be performed for isolated Duane syndrome, sequence analysis CHN1 is performed first, followed by sequence analysis of MAFB and gene-targeted deletion/duplication analysis if no pathogenic variant is found. The exception to this would be if there was evidence of hearing loss in addition to Duane syndrome, in which case MAFB followed by CHN1 would be more appropriate. If the causative variant is not identified, SALL4 sequencing and gene-targeted deletion/duplication analysis should be considered. (2) Since CHN1-related disease occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for CHN1 intragenic deletions or duplication is unlikely to identify a disease-causing variant.

• A multigene panel that includes CHN1, MAFB, SALL4, 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. (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.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing (which does not require the clinician to determine which gene[s] are likely involved) may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  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.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: The testing recommendations in this section are for individuals with Duane syndrome, either isolated or with one or more non-ocular anomalies that do not constitute an established or recognizable syndrome. If an individual presents with Duane syndrome plus significant anomalies that suggest the possibility of a chromosome abnormality, testing with chromosome microarray analysis (CMA) can be considered.

Clinical Description

Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly is due to failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle, with globe retraction occurring due to abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Affected individuals may also have upshoot or downshoot of the affected eye on attempted adduction. For reasons yet to be determined, the left side is more commonly affected; this is supported by the authors' internal data showing that the left side is affected in 70% of unilateral cases [Gutowski & Chilton 2015; Kekunnaya et al 2012; Authors, unpublished observation].

Duane syndrome is often reported as more common in females than in males, particularly in unilateral and simplex cases [Kekunnaya et al 2012, Graeber et al 2013, Kekunnaya & Negalur 2017]. Internal data reveal that 56% of individuals with unilateral Duane syndrome are female and 51% of simplex cases are female [Authors, unpublished observation].

Restriction in vertical movement of the eyes may also be found in some individuals with Duane syndrome, depending on the associated gene (see Genotype-Phenotype Correlations).

Strabismus is the 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 I and exotropia in Duane syndrome type II.

• Although esotropia is more common in most studies, a recent report found that nearly a third of individuals with Duane syndrome seen at a tertiary care center in south India had exotropia [Bhate et al 2017].
• While movement of the affected eye is impaired, when the contralateral eye is able to move freely, it allows individuals with strabismus in primary gaze to use 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 early in life, the vision loss from amblyopia is irreversible.

Visual acuity is good except in those individuals with amblyopia.

Other dysinnervation phenomena may occur in individuals with Duane syndrome. These include:

• Infraduction of the affected eye in attempted lateral gaze; this occurs in the majority of cases [Rhiu et al 2018.] The phenomenon is more likely to be observed in more severely affected individuals.
• Marcus Gunn jaw-winking phenomenon (upper eyelid movement/fluttering each time the jaw opens and closes) [Isenberg & Blechman 1983, Oltmanns & Khuddus 2010, Gupta et al 2014].
• An exaggerated oculo-auricular phenomenon (coactivation of external ear muscles during lateral gaze) [Gilbert & Hunter 2017].
• Crocodile tears (tearing with chewing due to aberrant facial salivary fibers innervating the lacrimal gland) [Gutowski & Chilton 2015].

Neuroimaging. Orbital and brain stem MRI of affected members of two pedigrees with CHN1 pathogenic variants did not visualize the abducens nerve in most affected individuals and revealed structurally abnormal lateral rectus muscles in some. The oculomotor and optic nerves were also small [Demer et al 2007]. Decreased superior oblique muscle volume has also been observed on MRI in individuals with CHN1 pathogenic variants, supporting trochlear nerve hypoplasia [Miyake et al 2011].

Magnetic resonance imaging (MRI) in simplex cases (without a pathogenic variant identified in any known gene) has verified the absence or severe hypoplasia of the abducens nerve, often with normal appearance of the lateral rectus muscle [Demer et al 2006].

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 [Yüksel et al 2010]. Early studies of Duane syndrome reported fibrosis of the lateral rectus or medial rectus muscles, and suggested a primary myopathic etiology for this disorder [Matteucci 1946]. 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 [Hotchkiss et al 1980, Miller et al 1982]. 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 [Scott & Wong 1972].

The decreased superior oblique muscle volume observed on MRI, supporting trochlear nerve hypoplasia, leads to the suggestion that Duane syndrome resulting from pathogenic variants in CHN1 represents a congenital cranial dysinnervation disorder that results from errors not only in abducens, but also trochlear and oculomotor axon pathfinding [Miyake et al 2011].

Animal models of both CHN1 and MAFB pathogenic variants support a neurogenic cause of Duane syndrome. In CHN1-related mouse models, axons of the abducens nerve stall, then retract and die, and the lateral rectus is subsequently innervated by branches from the oculomotor nerve [Nugent et al 2017]. In Mafb-knockout mice, the abducens nucleus does not form, and the lateral rectus muscle is innervated by branches from the oculomotor nerve [Park et al 2016].

Other Anomalies

Most affected individuals with Duane syndrome have isolated Duane syndrome without other congenital anomalies. Published estimates of individuals with other systemic findings range from lows of under 10% [Kekunnaya et al 2012] to just over 50% [Marshman et al 2000]. Far fewer individuals have a constellation of anomalies that falls within recognizable syndromic patterns which are often inherited in an autosomal dominant pattern. In the authors' cohort, approximately 30% of all individuals with a diagnosis of Duane syndrome have non-ocular systemic findings. When individuals who fall within the spectrum of SALL-4 related disorders are removed, 25% of individuals have syndromic findings [Authors, unpublished data].

From the authors' unpublished data, 26.7% of individuals with Duane syndrome who do not have a pathogenic variant in any of the currently known associated genes have non-ocular findings, ranging from minor anomalies such as preauricular tags to more severe conditions such as Hirschsprung disease.

Genotype-Phenotype Correlations

CHN1. Individuals with pathogenic variants in CHN1 are more likely to have bilateral involvement, vertical movement abnormalities beyond the upshoot and downshoot often seen in Duane syndrome, and a positive family history when compared to individuals with Duane syndrome who do not have a CHN1 pathogenic variant [Chung et al 2000, Demer et al 2007, Engle et al 2007, Miyake et al 2008, Miyake et al 2011].

MAFB. Individuals with pathogenic variants in MAFB are more likely to have bilateral Duane syndrome and may have mild-to-severe sensorineural hearing loss in addition to the Duane syndrome. Hearing loss was documented in one of four reported pedigrees of otherwise isolated Duane syndrome, and confirmed in three of four individuals in that family [Park et al 2016].

SALL4. Individuals thus far reported with isolated Duane syndrome associated with SALL4 pathogenic variants have family members with Duane-radial ray syndrome [Al-Baradie et al 2002, Yang et al 2013]. The eye condition tends to be bilateral rather than unilateral in individuals with SALL4 variants [Kohlhase et al 2005].

Penetrance

Families with Duane syndrome in whom a CHN1 pathogenic variant has been identified may have reduced penetrance [Engle et al 2007, Miyake et al 2008, Chan et al 2011].

There has been no evidence of reduced penetrance in the limited number of families with isolated Duane syndrome identified with MAFB or SALL4 pathogenic variants [Yang et al 2013, Park et al 2016]

Nomenclature

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

Historically, Duane syndrome was initially proposed to be myogenic in origin. Electromyography of the extraocular muscles, postmortem examinations, and MRI, however, now support a neurogenic etiology [Demer et al 2007]. This is also supported by developmental studies of mouse models [Nugent et al 2017] and has led to the proposed renaming of Duane syndrome as the "co-contractive retraction syndrome" (types 1-3) [Hertle 2002] and classification as one of the congenital cranial dysinnervation disorders [Gutowski et al 2003, Engle 2006].

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 at between 1:1000 and 1:10,000 in the general population [Yüksel et al 2010, Gutowski & Chilton 2015]