To describe the clinical findings in 3 patients with Duane syndrome and 3 different chromosomal duplications that may indicate the location of genes involved in the pathogenesis of this ocular motility disorder.
Observational case series.
setting: Clinical practice. patient or study population: Three patients with Duane syndrome and chromosomal duplications from the clinical practice of 1 of the authors. observation procedures: Chart review and retrieval of clinical data and results of pertinent clinical tests, in this case chromosomal studies. main outcome measure: Reporting of details of clinical findings and duplicated chromosomal regions.
Two patients had unilateral type I Duane syndrome and 1 had bilateral type I Duane syndrome. Two had cognitive delay, and all 3 had other systemic abnormalities, including a variety of congenital malformations. The chromosomal abnormalities that were detected using microarray analysis were 2q13(RP11-20G1,RP11-461N11) × 3, 10q24.2q26.3(101,532,585-135,284, 169) × 3, 20q13.12(44,796,613-44,945, 818) × 3, and 22q11.1q11.22(RP11-701M12, RP11-71G19) × 3.
Patients with Duane syndrome and associated congenital malformations or developmental delay should be evaluated for the presence of underlying chromosomal duplications. The regions of chromosomes 2, 10, and 22 that we report may harbor genes involved in the pathogenesis of Duane syndrome.
Duane syndrome refers to a spectrum of congenital ocular motility abnormalities that result from dysinnervation of the extraocular muscles. Most cases have anomalous innervation of the lateral rectus by a branch of the third rather than the sixth nerve and lead to type 1 Duane syndrome, characterized by lack of abduction beyond midline, normal adduction, and globe retraction with co-contraction of the medial and lateral rectus muscles in attempted adduction. Types 2 and 3 are also recognized, in which there are other ocular motility defects. There are also a multitude of less common and unusual forms of Duane syndrome with combinations of anomalous motility patterns that defy the normal laws of ocular motility. The genetics of Duane syndrome are complex, and although 2 genes have been associated with particular complex forms of Duane syndrome, the etiology in most patients remains unclear. A number of cases have been reported in association with chromosomal rearrangements. We present 3 patients who have Duane syndrome and hitherto unreported associated chromosomal duplications.
The first patient was referred because of type I Duane syndrome of the left eye ( Table ). She was born by cesarean section at 31 weeks gestation because of maternal pre-eclampsia and fetal distress. She weighed 2 pounds and was 14 inches in length at birth, and had an uneventful stay in the neonatal intensive care unit. She gained weight slowly and was followed by a geneticist and a pediatric endocrinologist because of failure to thrive and meet developmental milestones. The diagnosis of Duane syndrome was made at the age of 10 months. Patching and glasses were recommended, but she did not cooperate with either. Aside from Duane syndrome, short stature, and a hemangioma over her right scapula, physical exam was unremarkable. In light of a history of inadequate caloric intake and a family history of constitutional short stature on the patient’s maternal side, it was originally believed that the patient was likely a normal child who was slow to catch up developmentally from a premature birth.
|Patient||Chromosomal Abnormality||Motility Disorder||Other Clinical Findings|
|1||2q13(RP11-20G1,RP11-461N11) × 3||Left type I Duane syndrome|
|2||10q24.2q26.3(101,532,585-135,284, 169) × 3, 20q13.12(44,796,613-44,945, 818) × 3||Left type I Duane syndrome|
|3||22q11.1q11.22(RP11-701M12, RP11-71G19) × 3|
Microarray analysis and fluorescence in situ hybridization (FISH) was performed at the age of 5 years because growth retardation had not improved. The analysis was conducted using the SignatureChip 4.0 microarray (Signature Genomic Laboratories, LLC, Spokane, Washington, USA). A duplication of chromosome 2 at 2q13(RP11-20G1,RP11-461N11) × 3 was found. The nearest proximal clone that was not duplicated was RP11-468G5, and the nearest distal clone that was not duplicated was RP11-265B3. RP11-265B3 overlaps with RP11-461N11, so the distal boundary of the duplication is well defined. RP11-468G5, however, is 13.5 Mb upstream of RP11-20G1, so the proximal boundary is poorly defined. This duplication was not confirmed by FISH, based upon criteria that at least 70% of cells must show a duplication pattern to be reported. Therefore the duplication may be below the resolution of the FISH assay.
On initial presentation to our pediatric eye service, it was discovered that the patient’s father had been diagnosed with amblyopia, but the cause was unknown. The patient’s vision was 20/30 OD and 20/80 OS. She had hypermetropic astigmatism in both eyes. She was unable to abduct her left eye, and this eye drifted upward in attempted abduction. Her palpebral fissures narrowed in adduction, but adduction was 80% of normal. Her pupillary, external, slit-lamp, and fundus examinations were otherwise unremarkable.
The second patient was referred to our clinic at the age of 19 years because of left type I Duane syndrome and a partial trisomy of chromosome 10. He was born full-term with a birth weight of 6 pounds 8 ounces, and with several congenital anomalies. His head examination is significant for an irregular hair growth pattern; prominent brow; thick eyebrows and eyelashes; triangular, low-set, posteriorly rotated ears with simple helices; narrow nasal bridge; pointed nasal tip; thick columella; bifid uvula; dental crowding; and a small chin ( Figure 1 ). He has narrow shoulders, gynecomastia, and an asymmetrical posterior thorax with kyphosis. Musculoskeletal examination reveals limited motion of the shoulders, elbows, wrists, and fingers; hyperextended left wrist with ulnar deviation; and broad thumbs. His left leg is longer than the right and he has an inability to straighten the left leg. The right knee is larger than the left and he has an inability to fully extend the right knee. He has limited ankle flexion, his feet are turned outward, and the great toes are angulated. Spasticity is present in all 4 extremities, and the patient has a wide-based gait. The patient also has global developmental delay with mental retardation, bowel and bladder incontinence, and a hypoplastic right kidney.
This patient underwent chromosomal staining and FISH analysis shortly after birth, demonstrating the presence of extra material on the end of chromosome 2p, but the origin of this material could not be identified at the time. His parents were found to have normal chromosomal staining patterns. At the age of 19, microarray analysis and repeat FISH was conducted by the ChildLab Cytogenetics Laboratory of Nationwide Children’s Hospital in Columbus, Ohio, USA using the SignatureSelect OS 105K v1.1 microarray (Signature Genomic Laboratories, LLC). This microarray identified trisomy of a 33.75-Mb region of chromosome 10 (10q24.2q26.3(101,532,585-135,284,169) × 3), a region containing over 300 genes. A trisomy of 20q13.12 was also discovered, though this region contains only the 3′ portion of 1 gene, SLC2A10 . FISH demonstrated that the extra chromosome 10 material was translocated to chromosome 2p25.3, with no loss of material at 2p. The extra copy of 20q13.12 was adjacent to the normal copy and was thought unlikely to be of clinical significance.
In addition to Duane syndrome, the patient’s ophthalmic history was significant for accommodative esotropia treated with glasses and patching beginning at 4 years of age. He had a remote history of head tilting, but this was attributed to torticollis and was corrected with cervical fusion surgery at the age of 6 years. On presentation to our clinic, the patient’s corrected visual acuity was 20/20 in the right eye and 20/40 in the left eye, demonstrating amblyopia. Abduction of the left eye was limited to 10 degrees, while adduction was limited to 50 degrees and elevation was limited to 40 degrees. The right eye had normal motility. In addition, the patient had blepharophimosis, thick long lashes, iris transillumination, and an anomalous optic nerve that appeared smaller than normal in diameter, with fine macular and extramacular drusen in both eyes ( Figure 2 ).