Ocular manifestations in Okihiro Syndrome

Abstract

Background and purpose

Two siblings diagnosed with Okihiro syndrome (also named Duane Radial Ray Syndrome) associated with ophthalmic manifestation including Duane syndrome and retinal nerve fiber layer (RNFL) hypoplasia were presented.

Methods

The first patient (15-years old female) was diagnosed of Duane syndrome presenting reduction of visual acuity and pale optic discs. She showed a diffuse decrease in the RNFL thickness, mainly in her left eye, retaining the typical RNFL morphology as double hump, demonstrated by OCT and scanning laser polarimetry. Neurophysiology evaluation found a decrease in visual evoked potentials and pattern electroretinogram amplitudes, and an increase of the latency of P100 component. The second patient (12 year-old female) presented with Duane malformation. Both patients underwent a complete ophthalmic evaluation with best corrected visual acuity, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials, pattern electroretinogram, and genetic study.

Results

The neuro-ophthalmic evaluation showed a subclinical reduction of RNFL average thickness provided by OCT and an increase of P50 and N95 latency by pattern electroretinogram. RNFL average thickness presented a score reduction in both patients, without typical glaucomatous morphology.

Conclusions

Our analyses suggest that Okihiro syndrome may affect retinal nerve fiber layer development and visual acuity.

INTRODUCTION

Okihiro syndrome, also known as Duane Radial Ray Syndrome (DRRS), is an autosomal dominant condition characterized by radial ray defects, Duane anomaly and bilateral deafness (1). Ocular manifestations are common findings, with Duane anomaly as the most prevalent manifestation (95% of cases), and congenital optic nerve hypoplasia or optic disc coloboma as less common features (2). Duane syndrome (DS) is a congenital eye movement disorder characterized by limitation of abduction and narrowing of the eyelid fissure with retraction of the globe on adduction (3). The number of associated malformations reported in these patients is high. The more common ones are anal stenosis, renal malformations, hemivertebra, external ear malformations, facial asymmetry or atrial septal defect (1).

In the majority of affected patients with Okihiro syndrome, mutations in the SALL4 gene of the chromosome 4 20q13, 13-13.2, have been identified (4). The SALL4 gene product is a zinc finger protein that is thought to act as a transcription factor. Therefore, it has been hypothesized that SALL4 mutations may interfere with the differentiation of stem cells during embryonic development (5). Severity of malformations depends on the residual activity of the mutated protein, so several members of the same family can present different phenotypic expressions (2). Neuro-ophthalmic anomalies have been reported in DRRS, including congenital optic nerve hypoplasia"morning glory” optic disc anomaly, and optic disc coloboma.

MATERIAL, SUBJECTS AND METHODS

Two siblings with healthy and unrelated parents were examined. Both patients underwent a complete ophthalmologic evaluation and a genetic study.

Patient 1: Patient 1 was a 15-years old female who presented at birth choanal atresia, epicanthus, facial asymmetry, polydactyly and absent right thumb. Reflexes, electroencephalogram and eye fundus examination were normal. A renal ultrasound showed mild left pelvicalyceal dilatation and a cysto-urethrogram showed grade II vesicoureteric reflux. Brain MRI showed bilateral enlarged ventricles, hypoplasia of the corpus callosum, and Arnold-Chiari anomaly. She had hemivertebras in levels D3-4-9-10 and ribs anomalies in the left side. She also had congenital torticollis. An audiogram was performed showing bilateral conductive and sensorineural hearing loss. Brain evoked auditory potentials confirmed the profound congenital sensorineural deafness. Visual evoked potentials (VEP) were normal. The karyotype was 46, XX. During development, the patient suffered growth retardation and precocious pseudopuberty with low levels of pituitary hormones and normal levels of ovary hormones. In her childhood she underwent surgical treatment of her gastroesophageal reflux, her scoliosis and her absent thumb (figure 1).

Figure 1.

The images show the result of the reconstruction surgery of right index finger and the atypical morphology of right hand in patient 1.

Ophthalmic examination showed reduction in best corrected visual acuity during the past last year in both eyes (from 0.8 to 0.5). Orthoptic assessment showed hypotropia and ptosis of the superior left eyelid, with Duane syndrome. Binocular vision was normal. The eye fundus showed a small and pale disc (figure 2). Automated perimetry study reported bilateral visual loss in central areas as an indication of possible anomalies in papilomacular axis. Macular optical coherence tomography (OCT) was normal, but retinal nerve fiber layer (RNFL) evaluation showed diffuse reduction of all measurements, retaining the normal morphology as double hump in the optic disc (figure 3). The RNFL average thickness was 95.34 µm in right eye and 93.69 µm in left eye, reflecting reduction in density of nerve fibers layer [normal values in children aged 5 to 18 years is 103–122 µm (6)]. Scanning laser polarimetry (GDx) showed atypical optic disc morphology and moderate reduction of the normal number of nerve fibers, especially in the temporal quadrant of both eyes (figure 3).

Figure 2.

Fundus exploration of both eyes shows intense papillar pallor in patient 1.

Figure 3.

Optical Coherence Tomography and scanning laser polarimetry show diffuse decrease of retinal nerve fiber layer thickness (RNFL), retaining the typical morphology as double hump in the optic disc of patient 1. RNFL average thickness shows reduced scores. Both eyes show small optic discs without a glaucomatous morphology.

VEP showed an increase in the latency of main component P100 (127 msec. in right eye and 125 msec. in left eye). The amplitude of VEP was slightly diminished in both eyes, being lower in the right eye (10.46 µV) than in the left one (12.32 µV). In scotopic conditions the amplitude flash showed normal and symmetrical registries within normal limits. Pattern electrorretinogram (pERG) reported normal latency with decrease of P50 (1.6 µV) and N95 amplitudes (3.4 µV) [(normal values are 2.1–2.7 µV and 4.3–5.8 µV, respectively, as shown by Holder GE (7)].

Patient 2 was the 12-year-old sister of patient 1 and the second dizygotic twin of a normal girl. At her birth she presented an incomplete Okihiro phenotype, showing Duane malformation associated with mild hypoplastic right thumb. Several audiograms were performed with normal results, and other malformations were discarded. Her anomalies did not compromise the patient´s functions on a day-to-day basis. On examination, she showed hypotropia and ptosis of the superior eyelid in the left eye (DS), visual acuity of 1.0 in Snellen Scale, normal automated perimetry examination and binocular vision and typical papillary morphology, but OCT measurements showed subclinical slight reduction of RNFL thickness (93.3 in right eye and 92.5 in left eye) (6) and pERG reported normal latency with decrease in P50 and N95 amplitude (1.9 and 4.1 µV, respectively) (8).

RESULTS

The first patient (15-years old female) was diagnosed with Duane syndrome presenting with reduction of visual acuity and pale optic discs. She showed a diffuse decrease in the RNFL thickness, mainly in her left eye, retaining the typical RNFL morphology as double hump, demonstrated by OCT and scanning laser polarimetry. Neurophysiological evaluation found a decrease in visual evoked potentials and pattern electroretinogram amplitudes, and an increase of the latency of P100 component. The second patient (12 year-old female) presented with Duane malformation. The siblings’ parents and four brothers did not have any apparent physical disabilities.

The neuro-ophthalmic evaluation showed a subclinical reduction of RNFL average thickness provided by OCT and an increase of P50 and N95 latency by pattern electroretinogram. RNFL average thickness presented a score reduction in both patients, without typical glaucomatous morphology.

DISCUSSION

Paradisi & Arial S reported, phenotypic features of DRRS are variable and deafness is found in only 8.3% of the patients (9). We report two related patients with DRRS and different phenotypes: Patient 1 showed showed the full classic phenotype of Okihiro syndrome, including radial ray defects, unilateral Duane anomaly, bilateral conductive and sensorineural deafness, and other malformations; while patient 2 only presented DS and a mild radial ray alteration that did not affect the child development.

Our analyses suggest that Okihiro syndrome may affect retinal nerve fiber layer development and visual acuity. We have evaluated RNFL of patients in order to measure congenital fiber defects and to correlate functional and structural alterations. The RNFL was slightly decreased in both eyes compared with age-matched children, but the decrease was found to be severe using neurophysiologic tests, indicating a predominantly functional impairment.

Several authors have described that pERG displays subclinical abnormalities in RNFL, mainly in the N95 component (7). Although the exact pERG generators have not been fully elucidated yet, current evidence suggests that the N95 component of the pERG is a contrast-related component generated in relation to retinal ganglion cell function, while the P50 component is partly ganglion cell-derived, though with a contribution from structures distal to the ganglion cells in the visual pathways (8).

CONCLUSIONS

In Okihiro syndrome there is a reduction of the RNFL thickness, but we have to distinguish between congenital cases caused by optic disc hypoplasia and progressive cases that present fiber loss with development. The follow-up of RNFL structure and function can be made using ocular imaging technologies such as OCT and scanning laser polarimetry. In these patients, the role of the ophthalmologist is to carry out a differential diagnosis of the syndrome because it can be associated with severe, sometimes life-threatening conditions (congenital heart disease, renal malformation…). Besides, patients must undergo a periodical ophthalmic examination of their visual quality, visual fields and optic nerve function to detect compressions in the optic tract that some patients may develop with age. Visual function in patients with Okihiro syndrome is very important because they are deaf and vision is the probably the main sense they have to interact with the environment that surround them.