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Last updated:
April 07, 2020
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NORD gratefully acknowledges N.J. Gutowski, MD, Consultant Neurologist and Associate Professor, Royal Devon and Exeter Hospital and University of Exeter Medical School, Exeter, UK, for assistance in the preparation of this report.
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. When the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some patients, 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 sub-classification 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% of cases) followed by type 3 (15%) and type 2 (7%). Involvement of both eyes (bilateral) is less common than involvement of one eye only (unilateral). Approximately 80-90% of cases are unilateral. Of the unilateral cases, the left eye is more often affected (72%). 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%), 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 10% 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.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
DS is a congenital cranial dysinnervation disorder (CCDD). 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. These autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence / failure to develop normally of the abducens nerve (cranial nerve VI) which normally supplies the lateral rectus muscle. In place of the abducens nerve is 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 / failure to develop normally 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.
In familial DS cases both eyes are more likely to be affected. DS type 2 is not seen in those with a positive family history nor in those patients where mutations in genes have been found to cause DS; suggesting a different cause.
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 the a2-chimaerin protein. Mutations in the CHN1 gene have also been found in other families.
Autosomal dominant DS can also be due to mutations in the MAFB gene on chromosome 20, either as a loss of function or as a dominant negative mutation causing deafness and DS. The combination of focal segmental glomerulosclerosis (FSGS), DS and deafness has been shown to be due to a rare MAFB mutation.
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 and 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 learning difficulties due to two mutations in the HOXA1 gene.
DS is also associated with mutations in the CDH2 gene which encodes for the N-cadherin protein. These mutations cause a syndromic neurodevelopmental disorder with global developmental delay and/or intellectual disability, axonal pathfinding defects including corpus callosum agenesis or hypoplasia, associated with ocular, cardiac and genital anomalies.
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 been reported with chromosomal duplications.
Given the evidence that DS results from an absence / failure to develop normally of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some patients, 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 1-5%. Most individuals are diagnosed by the age of 10 years. The female to male ratio of individuals with DS is approximately 60:40, showing a slightly higher preponderance of female patients.
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.
Treatment
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Accogli A, et al. De novo pathogenic variants in N-Cadherin cause a syndromic neurodevelopmental disorder with corpus callosum, axon, cardiac, ocular and genital defects. Am J Hum Genet. 2019;105:854-868.
Sato Y, et al. A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome. Kidney Int. 2018;94:396-407.
Park JG, Tischfield MA, Nugent AA, et al. Loss of MAFB function in humans and mice causes Duane Syndrome, aberrant extraocular muscle innervation, and inner-ear defects. Am J Hum Genet. 2016;98:1220-7.
Gutowski NJ, Chilton JK. The congenital cranial dyinnervation disorders. Arch Dis Child. 2015;100:678-81.
Baroncini A, Bertuzzo S, Quarantini R, et al. 8q12 microduplication including CHD7: clinical report on a new patient with Duane retraction syndrome type 3. Mol Cytogenet. 2013;6:49.
Ferrario JE, Baskaran P, Clark C, et al. Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin. Proc Natl Acad Sci USA 2012;109:14669-74.
Chan WM et al. Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch Ophthalmol.. 2011; 129 :649-52.
Miyake N et al. Expansion of the CHN1 strabismus phenotype. Invest Ophthalmol Vis Sci. 201; 52 :6321-8.
Weis A, Bialer MG, Kodsi S. Duane syndrome in association with 48,XXYY karyotype. J AAPOS 2011;15 :295-6.
Bayrakli F et al. 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.
Smith SB, Traboulsi EI. Duane syndrome in the setting of chromosomal duplications. Am J Ophthalmol. 2010; 150: 932-8.
Stark Z et al. Atypical Silver-Russell phenotype resulting from maternal uniparental disomy of chromosome 7. Am J Med Genet A. 2010; 152A: 2342-5.
Miyake N, et al. Human CHN1 mutations hyperactivate a2-chimaerin and cause Duane’s retraction syndrome. Science 2008; 321: 839-843.
Demer JL, Clark RA, Lim KH, et al. Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane’s retraction syndrome linked to DURS2 locus. Invest Ophthalmol Vis Sci. 2007;48:194-202.
Demer JL, Clark RA, Lim KH, et al. Magnetic resonance imaging of innervational and extraocular muscle abnormalities in Duane-radial ray syndrome. Invest Ophthalmol Vis Sci. 2007;48:5505-11.
Kato Z, Yamagishi A, Kondo N. Interstitial deletion of 1q42.13-q43 with Duane retraction syndrome. J AAPOS. 2007 Feb;11(1):62-4.
Demer JL, Ortube MC, Engle EC, et al. High-resolution magnetic resonance imaging demonstrates abnormalities of motor nerves and extraocular muscles in patients with neuropathic strabismus. J AAPOS 2006;10:135-42.
Kim, JH, Hwang, J-M. Presence of the abducens nerve according to the type of Duane’s retraction syndrome. Ophthalmology 2005;112:109-113.
Tischfield MA et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet. 2005 Oct;37(10):1035-7.Wabbels BK, Lorenz B, Kohlhase J. No evidence of SALL4-mutations in isolated sporadic duane retraction “syndrome” (DURS). Am J Med Genet A 2004;131:216-8.
Borozdin W, Boehm D, Leipoldt M, et al. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet 2004 Sep;41(9):e113.
Gutowski NJ, Bosley T, Engle E. The Congenital Cranial Dysinnervation Disorders (CCDDs). Neuromuscular Disorders 2003; 13: 573-578.
Al-Baradie R. et al. Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family. Am J Hum Genet. 2002; 71: 1195-1199.
Kohlhase J et al. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002; 11: 2979-2987.
Evans JC, Frayling TM, Ellard S and Gutowski NJ. Confirmation of linkage of Duane’s syndrome and refinement of the disease locus to an 8.8cM interval on chromosome 2q31. Hum. Genet. 2000: 106: 636-638.
Gutowski N. Duane’s syndrome. Eur J Neurol. 2000; 7: 145-149.
Appukuttan B., et al., Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am J Hum Genet..1999;65:1639-46.
Parsa CF, et al., Absence of the abducens nerve in Duane syndrome verified by magnetic resonance imaging. Am J Ophthalmol. 1998;125:399-401.
Chew CKS, et al., Duane’s retraction syndrome associated with chromosome 4q27-31 segment deletion. Am J Ophthalmol.1998;119:807-09.
Vincent C, et al., A proposed new contiguous gene syndrome on 8q consists of bronchio-oto-renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Hum Mol Genet.1994;3:1859-66.
Cullen P, et al., Association of a familial Duane anomaly and urogenital abnormalities with a bisatellited marker derived from chromosome 22. Am J Med Genet.1993;47:925-30.
Shauly Y, et al., Ocular and systemic characteristics of Duane syndrome. J Pediatr Ophthalmol Strabismus. 1993;30:178-83.
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