Clinical Manifestations of Retinoschisis in a consanguineous family : a case report and review of literature

Retinoschisis, also known as macular degeneration, is more common in males than in females because of its X-linked chromosome⁵, even though females are carriers⁴. It is recessively inherited and characterised by a bilateral presentation and progressive vitreoretinal atrophies⁶. According to Lesch and colleagues, its prevalence is between 1:5,000 and 1:25,000, whereas optic coloboma prevalence is approximately 2 to 14/per 100,000 live births⁷.

Pathogenesis

The pathogenesis of this condition is genetically dependent on RS1 gene mutations (Xp22.2-p22.1), the only known structure so far, identified in 1997 by Sauer and colleagues⁸. Many reports have highlighted the role of the RS1 gene as the genetic basis of this disease^9,10,11. RS1 gene encodes retinochisin¹², a secretable extracellular adhesion protein (i.e., a 224 amino-acid protein) present in photoreceptors in bipolar cells⁹ and which is involved in cell adhesion cell-cell interactions on membranes surfaces. This gene has three components: an RS1 domain (RS1D, 39AA) which has a secretory layer (LS, 23 AA); a discoidin domain and a C-terminal segment (5AA). Therefore, the fundamental structure of the RS gene is the discoidin domain (157 AA), which is crucial for the normal development of the retina. Hence, any lesion on that structure will lead to retinal splitting in its layers⁶. This observation found credence in Molday and colleagues’ report¹². From their experimental studies¹², mutations in the discoidin domain cause “severe protein misfolding and retention in the endoplasmic reticulum (ER)", in addition to signal sequencing disorders that lead to aberrant proteins synthesis and mutations in the surrounding discoidin domain, causing defective disulphide-linked subunit assembly". According to Slavonitek and colleagues' findings⁷, Xiu and colleagues² stress that mutations, either monogenic or chromosomal, are responsible for 25-30% of cases of retinoschisis, leaving the remaining unresolved questions to further research. In that regard, we failed to determine the genetic basis in this patient in identifying mutations in the RAX gene, which are the genetic etiology². The RAX gene is known to house the phenotype in eye development. It is a 'paired-like homeobox-containing gene initially expressed in the anterior region of developing embryos and later in the ventral hypothalamus and retina¹³. Based on this anatomic specification, Xiu and colleagues² advance by quoting Pan and colleagues’ animal experiments on Xenopus and Zebrafish², that alterations on the RAX gene in the early embryonic phase led to microphthalmia or anophthalmia. In contrast, alterations in the mature retina could induce photoreceptor degeneration'. Clinical characteristics are mostly blurred vision and a reduction in visual acuity with sometimes loss of peripheral vision that may lead to blindness in severe form.

From George and colleagues’ findings¹⁴, retinoschisis is often clinically associated with strabismus, nystagmus, axial hyperopia, and defective colouration, also known as red-green dyschromatopsia, and fovea ectopy. The disease commonly affects young boys (<10 years) who then will present with visual disturbances or reading difficulties with mild to a severe loss of visual acuity¹².

Clinical features

The disease is characterised by splitting the macula layers (or schisis) and microcytic changes of the macula area as early as the third month of life and most commonly during the first decade of life. These changes give a spoked-wheel pattern with different forms, among which the severe form leads to blindness consecutive to full retinal detachment^15,16. According to Roesch and colleagues¹⁷, the more advanced stage manifests with vitreous haemorrhage, retinal detachment, and neurovascular glaucoma, leading to blindness.

Diagnostic investigations

High suspicion index in the presence of a young infant male patient with complaints of visual acuity disturbance should raise the diagnosis of retinoschisis, like in the Hungarian study on X-linked young retinoschisis⁶. So, in assessing these patients, an ophthalmologic examination should include a few investigations to ascertain this diagnosis: the fundus examination, the electroretinogram (ERG) and the optical coherence tomography (OCT)⁶. Fundoscopy is not specific because it can be normal or abnormal, showing "a-waves characteristics of photoreceptor function or even more often, b-waves that originate from the retinal cells activity" ¹⁸. Nevertheless, it is worth recalling significant findings like in fundoscopy. As described by Tantri and colleagues, "radially oriented intraretinal foveomacular cysts present in the spoke-wheel pattern, with the absence of foveal reflex in most cases, whereas in some other cases, one can see bilateral peripheral retinoschisis in the inferotemporal part of the retina"19. Besides these investigations, genetic screening is mandatory to determine the molecular and gene mutations (e.g., missense mutations, insertion mutations, or frameshift). Molecular analysis through DNA extraction on peripheral blood of family members, direct sequencing to amplify the axons components via polymerase chain reaction (PCR) and haplotype analysis using microsatellite markers will help in identifying the common haplotypes, the recurrent mutations and eventually the novo-mutations⁴ (Riveiro Alvarez et al., 2009). Altogether, these investigations assist in the determination of different lesions encountered in this pathology like foveal schisis on fundoscopy, waves characteristics (a and b-waves) on ERT and macular laminar splitting on OCT. In this present case report, OCT was used and confirmed the presence of macular schisis.

The specific findings were “ cystoid macular oedema, thinning of the outer nuclear ellipsoid disappeared in the periphery (figure 2). The vessels and the epiretinal membrane were normal” (figure 3). They were slightly different from the ones described elsewhere, such as nerve fibre (NFL), ganglion cell (GCL), inner nuclear (INL), outer plexiform (OPL) and photoreceptor layers (PRL)⁴.

The next step would be to proceed with the genetic screening when we get a sizable sample because one single case is not sufficient to conclude how frequently this pathology may be in our population.