NORD is very grateful to N.J. Gutowski, MD, Consultant Neurologist and Senior Lecturer, Royal Devon and Exeter Hospital and Peninsula Medical School, UK, for assistance in the preparation of this report.
Synonyms of Duane syndrome
- DR syndrome
- Duane radial ray syndrome (DRRS)
- Duane's retraction syndrome
- eye retraction syndrome
- retraction syndrome
- Stilling-Turk-Duane syndrome
- Duane syndrome Type 2A, 2B, 2C
- Duane syndrome Type 3A, 3B, 3C
- Duane syndrome Type IA, 1B, 1C
Duane syndrome (DS) is an eye movement disorder present at birth (congenital) characterized by horizontal eye movement limitation [a limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction), or in both directions]. In addition, when the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases, when the eye attempts to look inward, it moves upward (upshoot) or downward (downshoot).
Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the subclassification of incomitant strabismus (misalignment of the eyes that varies with gaze directions) and subheading of what was previously termed extraocular fibrosis syndromes (conditions associated with fibrosis of the muscles that move the eyes), now termed Congenital Cranial Dysinnervation Disorders (CCDDs). The CCDDs are a group of congenital neuromuscular diseases resulting from developmental errors in innervation, the abnormalities involve one or more cranial nerves/nuclei with absence of normal innervation and/or secondary aberrant innervation. The group includes Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, Marcus Gunn Jaw winking, Möbius syndrome, Crocodile tears, horizontal gaze palsy and congenital facial palsy, but this is not an exhaustive list.
Duane syndrome has been subdivided clinically into three types: Type 1, Type 2, and Type 3.
The three types of Duane syndrome present as follows:
Duane syndrome Type 1: The ability to move the affected eye(s) outward toward the ear (abduction) is limited, but the ability to move the affected eye(s) inward toward the nose (adduction) is normal or nearly so. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when looking inward toward the nose (adduction). When looking outward toward the ear (abduction), the reverse occurs.
Duane syndrome Type 2: The ability to move the affected eye(s) inward toward the nose (adduction) is limited, whereas the ability to move the eye outward (abduction) is normal or only slightly limited. The eye opening (palpebral fissure) narrows and the eyeball retracts into the orbit when the affected eye(s) attempts to look inward toward the nose (adduction).
Duane syndrome Type 3: The ability to move the affected eye(s) both inward toward the nose (adduction) and outward toward the ear (abduction) is limited. The eye opening narrows and the eyeball retracts when the affected eye(s) attempts to look inward toward the nose (adduction).
Each of these three types has been further classified into three subgroups designated A, B, and C to describe the eyes when looking straight (in primary gaze). In subgroup A, the affected eye is turned inward toward the nose (esotropia). In subgroup B, the affected eye is turned outward toward the ear (exotropia), and in subgroup C, the eyes are in a straight primary position.
Different clinical types may be present within the same family, suggesting that the same genetic defect may produce a range of clinical presentations.
The most common clinical presentation is Type 1 DS (78 percent of cases) followed by Type 3 (15 percent) and Type 2 (7 percent). Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral). Approximately 80-90 percent of cases are unilateral. Of the unilateral cases, the left eye is more often affected (72 percent). Amblyopia (reduced visual acuity in an eye) due to a lack of binocular vision occurs in about 10% of DS cases and is more common in familial autosomal dominant CHN1 gene familial cases.
Duane syndrome is usually an isolated finding (approximately 70 percent), but may be associated with other malformations. Major anomalies associated with DS can be grouped into five categories: skeletal, auricular (having to do with the ears), ocular (having to do with the eyes) and neural (having to do with the nervous system) and renal (having to do with the kidneys and urinary tract).
DS can also be associated with other well-defined syndromes. These include Okihiro's, Wildervanck, Holt-Oram, Goldenhar and Möbius syndromes.
The majority of Duane syndrome cases are sporadic in origin, with only approximately ten percent of patients showing a familial pattern (running in families). Both dominant (most common) and recessive forms of DS have been documented. In some families with dominant DS, it has skipped a generation (shown reduced penetrance) and ranged in severity within the same family (shown variable expressivity). Most familial cases are not associated with other anomalies.
DS is a Congenital Cranial Dysinnervation Disorder (CCDD), see earlier. Genetic, and possibly environmental factors, are known to play a role.
Data to support abnormal development of cranial nerve VI (abducens nerve) in DS come from neuropathological, neuroradiological, and neurophysiological evidence. Neuropathological evidence comes from autopsies of individuals with DS. Such autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence of the abducens nerve (cranial nerve VI), which normally supplies the lateral rectus muscle. In place of the abducens nerve was a nerve branch from the oculomotor nerve (cranial nerve III), which normally supplies other ocular muscles. Recent neuroradiological studies in DS support the postmortem findings and also show, by magnetic resonance imaging (MRI) studies, an absence of the abducens nerve (cranial nerve VI).
Neurophysiological evidence for neuronal involvement in DS comes from electromyographic (EMG) studies, which show that the medial and lateral recti muscles are electrically active in individuals with DS. When individuals with DS attempt to move their eyes inward, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening narrowing.
Genetic linkage studies of two large DS families (with affected members having type 1 and/or type 3 DS inherited autosomal dominantly) without associated abnormalities established the location of a DS gene on chromosome 2. Mutations in the CHN1 gene are the cause, hyperactivating a2-chimaerin, and mutations have been found in a further eight families.
A genetic cause for individuals with DRRS (Duane radial ray syndrome; Okihiro Syndrome), that is Duane syndrome (unilateral or bilateral) with a skeletal change of radial dysplasia (unilateral or bilateral) ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide cases), has been found. Other features include deafness, renal and ocular manifestations. Inheritance is autosomal dominant. Truncating mutations and SALL4 gene deletions have been identified in DRRS families, there is haploinsufficiency (the level of the protein is not sufficient for normal functioning). No SALL4 gene mutations were found in 25 sporadic cases of isolated DS.
DS can also be found as part of a complex autosomal recessive disorder that can include deafness, facial weakness, vascular malformations and leaning difficulties due to homozygous mutations in the HOXA1 gene.
In addition, cytogenetic results (a study of chromosomes) of individuals with Duane syndrome and other abnormalities have, in rare cases, shown abnormalities that suggest other locations for genes responsible for causing DS. Deletions of chromosomal material on chromosomes 1, 4, 5 and 8, and the presence of an extra marker chromosome thought to be derived from chromosome 22, have been documented in DS individuals. In addition DS has recently been reported with chromosomal duplications.
Given the evidence that DS results from an absence of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some cases, it is thought that DS results from a disturbance of normal embryonic development by either a genetic or an environmental factor at the time when the cranial nerves and ocular muscles are developing (between the third and sixth week of pregnancy).
Duane syndrome has been seen in diverse ethnic groups. The frequency of DS in the general population of individuals with eye movement disorders (strabismus) is approximately one to 5 percent. Most individuals are diagnosed by the age of 10 years. The female to male ratio of individuals with DS is 60:40, showing a slightly higher preponderance of female patients.
Strabismus is a large category of eye movement disorders in which the eyes are not properly yoked together, and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment or the angle of deviation between the two eyes remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment or the angle of deviation varies with gaze direction. Extraoccular (outside of the eye) fibrosis syndromes are grouped under incomitant strabismus and include Duane syndrome, Brown syndrome, and the congenital fibrosis of the extraocular muscles (CFEOM) syndromes. There are many cases of strabismus and treatments can include surgery and eye patching. Strabismus may be an isolated finding or found in association with other birth defects.
Brown syndrome is an incomitant strabismus condition that falls under the heading of extraocular fibrosis syndromes. It presents as an eye movement disorder in which an individual's affected eye is unable to look inward toward the nose and up. The affected eye may be out of alignment with the unaffected eye and may show a downshoot and/or a widening of the eye opening when looking inward and up. When looking straight, the affected eye may be downward. (For more information on this disorder, choose "Brown" as your search term in the Rare Disease Database.)
Congenital Fibrosis of the Extraocular Muscles (CFEOM) refers to a group of congenital, nonprogressive eye movement disorders that fall under the subheading of extraocular fibrosis syndromes and the larger heading of incomitant strabismic disorders. The classic CFEOM presentation includes bilateral ptosis (droopy eyelids) with the eyes in a downward position (CFEOM type 1). Affected eyes have variable ability (from none to normal) to move horizontally and a complete inability to move above the horizontal midline. Individuals compensate by tilting their heads backward with the chin elevated in order to see. In some families, an affected individuals's presentation can range from very mild to the classic presentation described above. CFEOM can be sporadic, or inherited in either an autosomal dominant or recessive fashion. Family linkage studies have identified regions containing a gene for CFEOM on chromosomes 11, 12, and 16. The CFEOM type 1 phenotype inherited autosomal dominantly is most commonly due to mutations in the KIF21A gene on chromosome 12. The rarer CFEOM type 2 phenotype inherited autosomal recessively is due to mutations in the PHOX2A gene on chromosome 11. CFEOM type 3 is a variable asymmetric phenotype where at least 1 affected family member does not meet CFEOM1 criteria, it is inherited autosomal dominantly and is due to mutations in the TUBB3 gene on chromosome 16. Autopsy information has shown an absence of the superior division of the oculomotor nerve (cranial nerve III) in one patient with classic CFEOM type 1, suggesting an innervational (nerve) cause rather than a myogenic (muscle) problem. (For more information on these disorders, choose "Congenital Fibrosis of the Extraocular Muscles" as your search term in the Rare Disease Database).
When the presence of DS is suspected, a thorough ocular (eye) examination is required, with special attention to the presence of other ocular or systemic malformations. Measurements of the ocular misalignment, ocular range of motion, head turn, globe (eyeball) retraction, palpebral fissure (eye opening) size, upshoots and downshoots and visual acuity are indicated. In addition, an examination of the cervical (neck) and thoracic (chest) spine, palate (roof of mouth), vertebrae, hands, and a hearing test is recommended to rule out disorders associated with DS.
The standard management of Duane syndrome may involve observation, treatment of amblyopia (such as patching of the better seeing eye) or possibly surgery. The goal of surgery is the elimination or improvement of an unacceptable head turn, the elimination or reduction of significant misalignment of the eyes, the reduction of severe retraction, and the improvement of upshoots and downshoots. Surgery does not eliminate the fundamental abnormality of innervation and no surgical technique has been completely successful in eliminating the abnormal eye movements. Simple horizontal muscle recession procedures, vertical rectus muscle transposition procedures, or combinations of the two may be successful in improving or eliminating head turns and misalignment of the eyes. The choice of procedure must be individualized.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Duane syndrome Resources
Further information can be found at the reviewer's web page: http://www.rdehospital.nhs.uk/prof/molecular_genetics/default.html
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