Duane Retraction Syndrome 1

Description

Duane retraction syndrome is a congenital eye movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, adduction, or both, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. Undiagnosed in children, it can lead to amblyopia, a permanent uncorrectable loss of vision (Appukuttan et al., 1999).

Genetic Heterogeneity of Duane Retraction Syndrome

Duane retraction syndrome-1 (DURS1) maps to chromosome 8q13. DURS2 (604356) is caused by mutation in the CHN1 gene (118423) on chromosome 2q31. DURS3 (617041) is caused by mutation in the MAFB gene (608968) on chromosome 20q12.

Clinical Features

This unusual congenital form of strabismus was first described by Duane (1905), who collected reports of 54 cases. The condition is bilateral in 20% of cases.

As discussed by Al-Baradie et al. (2002), Duane syndrome type 1 refers to marked or complete limitation of abduction with minimal or no limitation of adduction. Duane syndrome type 2 refers to marked or complete limitation of adduction with minimal or no limitation of abduction. Duane syndrome type 3 refers to marked or complete limitation of both abduction and adduction. The presence of more than 1 Duane syndrome type within a single pedigree was described by Chung et al. (2000), Evans et al. (2000), and Al-Baradie et al. (2002); see, e.g., 607343.0004.

Kim and Hwang (2005) analyzed whether the presence of the abducens nerve might depend upon the type of DRS. The abducens nerve on the affected side could not be observed using MRI in 18 of 18 eyes (16 patients) with type 1 DRS or in 3 of 5 eyes with type 3 DRS. Conversely, the abducens nerve was observed in 2 of 2 eyes with type 2 DRS and 2 of 5 eyes with type 3 DRS. The abducens nerve was observed in 60 of 60 eyes screened as controls. Thus, in terms of the presence or absence of the abducens nerve, type 1 and type 2 DRS were homogeneous and type 3 DRS was heterogeneous.

In the study of 25 cases of sporadic Duane retraction syndrome by Wabbels et al. (2004), there was the usual excess of females with M/F ratio of 9/16 (64% females). There was bilateral involvement in only 12% of cases; the left eye was involved in 72%.

Association with other Anomalies

Duane anomaly with associated deformity of the upper extremity was reported by Gifford (1926), Crisp (1918) and Mennerich (1923).

Ferrell et al. (1966) described association of Duane anomaly with a heart-hand syndrome (probably Holt-Oram syndrome; see 142900) in a dominant pattern of inheritance.

Hayes et al. (1985) gave the designation Okihiro syndrome (607323) to the combination of Duane anomaly, radial ray abnormalities, and deafness. This syndrome is referred to here as the Duane-radial ray syndrome (DRRS) for mnemonic reasons.

Wildervanck syndrome (314600) 'consists of congenital, perceptive deafness, Klippel-Feil anomaly (fused cervical vertebrae), and abducens palsy with retractio bulbi (Duane syndrome).'

Vincent et al. (2005) reported an 18-month-old girl with sporadic blepharophimosis, ptosis, and epicanthus inversus (110100) associated with bilateral type 1 Duane syndrome.

Inheritance

Up to 10% of cases of Duane anomaly are familial, with autosomal dominant inheritance (Gutowski, 2000).

Transmission through 4 generations was reported by Cooper (1910) and through 3 generations by Waardenburg (1923), Laughlin (1937), and Zentmayer (1935).

Population Genetics

Appukuttan et al. (1999) cited a prevalence of approximately 0.1% in the general population and indicated that Duane retraction syndrome accounts for 5% of all strabismus cases.

Mapping

Vincent et al. (1994) described a 'new' contiguous gene syndrome resulting from a de novo 8q12.2-q21.2 deletion and characterized by the branchiootorenal (BOR) syndrome (113650), the Duane syndrome, hydrocephalus (600256), and aplasia of the trapezius muscle (see 600257). This was the first reported localization of the gene responsible for Duane syndrome.

Further information concerning the location of the Duane syndrome gene was provided by Calabrese et al. (1998) who reported on an insertion of the 8q13-q21.2 region onto band 6q25 in a patient presenting with Duane syndrome, mental retardation, and other dysmorphism. FISH analysis using a chromosome 8 radiation hybrid marker indicated a concurrent deletion within the 8q rearranged region. Studies by STR-PCR analysis and FISH using a YAC contig disclosed a deletion in 8q13. Comparison of the 2 known patients with Duane syndrome associated with deletion of 8q identified a small region of overlap of less than 3 cM extending from D8S533 to D8S1767. YAC analysis in the patient of Calabrese et al. (1998) showed that the 8q rearrangement was rather complex since 8q deletion and insertion occurred in 2 distinct segments separated by a region that maintained its location on 8q. The 7-year-old girl studied by Calabrese et al. (1998) presented with microcephaly, bilateral deficiency of ocular abduction, impairment of adduction, bilateral globe retraction, and narrowing of the interpalpebral fissure in adduction (Duane syndrome type 1, according to the classification of Huber (1974)), prominent nasal root, anteverted nares, and micrognathia. The patient had a short neck, brachydactyly, and left clubfoot. Mental retardation was severe.

Ott et al. (1999) reported preliminary linkage analysis of a large Hispanic family showing bilateral autosomal dominant Duane retraction syndrome. They used microsatellite analysis to examine genomic DNA from 91 members of the 118-member pedigree spanning 3 generations and containing 25 affected individuals. They studied chromosomes 4, 8, and 22 because of previous reports of documented karyotypic abnormalities in unrelated patients with Duane retraction syndrome. No marker on any of these chromosomes had a lod score over 0.5, thus excluding them as candidate sites. The authors concluded that Duane retraction syndrome may result from mutations in a heterogeneous group of genes.

Rickard et al. (2001) performed microsatellite analysis in a patient with a large deletion of the region of the EYA1 gene (601653) on 8q13.3, and compared its boundaries with other reported rearrangements of the region to which Duane syndrome had been mapped. The critical region for Duane syndrome was narrowed to an interval of approximately 1 cM between markers D8S553 and D8S1797.

Cytogenetics

Pizzuti et al. (2002) determined that a de novo reciprocal translocation t(6;8)(q26;q13) interrupted the CPAH gene (CPA6; 609562) in a 31-year-old man exhibiting features of Duane retraction syndrome. However, 18 patients with sporadic Duane retraction syndrome had polymorphic variants of the CPAH gene, but no pathogenetic abnormalities.

Molecular Genetics

In 25 cases of sporadic Duane retraction syndrome, Wabbels et al. (2004) found no mutations in the exons or neighboring intronic regions of the SALL4 gene (607343). The results suggested that SALL4 mutation analysis is not recommended in nonfamilial Duane retraction syndrome, but careful clinical evaluation of the hands, the ears, the heart, and the kidney is required to exclude Okihiro syndrome (607323), which occurs in sporadic cases, and which in familial cases, like other autosomal dominant disorders, shows marked intra- and interfamilial variability.

Because of the identification of a patient with apparently isolated Duane anomaly, who was found additionally to have asymptomatic left carotid hypoplasia (see 142955.0001), Tischfield et al. (2006) analyzed the HOXA1 gene in 101 probands with isolated Duane anomaly (DA) and 30 with DA and other symptoms. More probands had type 1 than type 3, and there were only a few cases of type 2. None in this group harbored a mutation in SALL4 or ROBO3 (608630), and none were members of a pedigree whose phenotype maps to the DURS2 locus. No mutation was detected in any proband; the authors concluded that HOXA1 mutations are a rare cause of isolated Duane anomaly, and recommended screening for clinically silent vascular anomalies in these patients.