Juvenile X-linked retinoschisis (JXLR) is an X-linked recessive (XLr) disorder with an estimated prevalence from 1:5,000 to 1:25,000. JXLR has complete penetrance and variable expressivity. JXLR is variable among family members. While carrier females show no clinical signs, affected females with biallelic mutations can present with a wide clinical spectrum, including macular schisis or macular atrophy, associated with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. On rare occasions, peripheral examination may reveal white flecks or schisis or macular dysfunction by multifactor electroretinogram (mf-ERG). This can be explained by skewed X-inactivation.
Affected individuals are usually diagnosed in the first decade of life. The schisis can affect many layers of the retina, mainly including the inner nuclear, outer nuclear, ganglion cell, and nerve fiber layers. Fundus examination often reveals a macular spoke-wheel pattern (▶ Fig. 28.1). Foveal lesions can present as large radial striations, microcystic spaces, honeycomb-like cysts, foveal pigment mottling, loss of the foveal reflex, or foveal atrophy. Carbonic anhydrase inhibitors can be effective in improving visual acuity and reducing foveal schisis. Approximately half of affected individuals also present with vitreous veils and peripheral schisis (▶ Fig. 28.2). Peripheral schisis may also be accompanied by inner or full-thickness retinal holes and subsequent retinal detachment. Retinal detachment can be seen in up to 20% of affected patients. Vitreous hemorrhage is seen in up to 40% of individuals with severe JXLR. Vitreous hemorrhage may be the presenting sign even in infancy. It is due to rupture of vessels that bridge an inner retinal hole. Surgical repair of retinal detachment is difficult. In patients older than 50 years, posterior pole pigmentary changes and retinal pigment epithelium (RPE) atrophy are common.
Fig. 28.1 Macular spoke-wheel pattern in a male with juvenile X-linked retinoschisis.
Fig. 28.2 Peripheral retina of a patient with juvenile X-linked retinoschisis, revealing peripheral schisis as marked by the arrows.
28.2 Molecular Genetics
The RS1 gene (Xp22.13) is the only known gene in which pathogenic variants cause JXLR. The product is retinoschisin, which is predominantly expressed in the inner segments of the photoreceptors. Retinoschisin is an extracellular protein, although the specific function is still unknown. Nonsense mutations are usually associated with severe phenotypes. Missense, splice site, or frameshift mutations or intragenic deletion result in JXLR phenotype.
28.3 Differential Diagnosis
28.3.1 Goldmann–Favre Vitreoretinal Degeneration and Enhanced S-Cone Syndrome (OMIM 268100)
These conditions are caused by autosomal recessive (AR) NR2E3 mutations. Unlike JXLR, females may be affected. Patients generally present with severely impaired visual acuity, visual field loss, and night blindness. Intraretinal cystoid spaces can be seen with peripheral retinoschisis. ERG shows markedly reduced a- and b-waves.
28.3.2 Retinitis Pigmentosa
Patients with RP (retinitis pigmentosa), as opposed to JXLR, present with optic nerve pallor, narrowing of retinal vessels, and “bone spicule” pigmentary clumping with a severely affected full-field (ff) ERG. They may have cystoid macular edema (CME) or intraretinal cystoid spaces that resemble JXLR.
28.3.3 VCAN Vitreoretinopathies
VCAN vitreoretinopathies can be confused with JXLR because of vitreous abnormalities. VCAN-related vitreoretinopathies can be distinguished from JXLR because of autosomal dominant (AD) inheritance (females can be affected), optically empty vitreous on slit-lamp examination, presenile cataract, night blindness, progressive chorioretinal atrophy, and moderately to severely affected scotopic, and photopic ERG without electronegative waveforms.
28.3.4 Cystoid Macular Edema
There are many causes for CME, such as inflammation, diabetes mellitus, uveitis, intraocular surgery, optic nerve pits, or AD CME. Diagnosis is based on a leakage on intravenous fluorescein angiography (IVFA; perifoveal petaloid pattern), which is not seen in JXLR.
28.3.5 Other Disorders with Intraretinal Cystoid Spaces
Other disorders with intraretinal cystoid spaces, including fenestrated sheen dystrophy, pathologic myopia, degenerative macular schisis, drug-induced (niacin), vitreomacular traction, isolated foveomacular schisis, and a wide range of retinal dystrophies.
28.3.6 Traumatic Macular Retinoschisis of Abusive Head Trauma
Traumatic macular retinoschisis of abusive head trauma should not be confused with JXLR as its appearance is completely different and may be a misnomer. Hemorrhage is seen to accumulate most often under the internal limiting membrane (ILM). There may be circumlinear hemorrhagic or hypopigmented folds at the edge of the schisis cavity. Retinal hemorrhages are usually present. The lesion can be unilateral.
28.3.7 Proliferative Vitreoretinopathy
This condition most commonly develops as a complication of rhegmatogenous retinal detachment. Advanced stages of JXLR can be confused with proliferative vitreoretinopathy.
28.4 Uncommon Manifestations
Severe and atypical findings in young patients include macular atrophy and pigmentary changes. The Mizuo phenomenon, which is characteristic of Oguchi disease, can also be seen in JXLR. It presents as a golden-brown fundus with a yellow-gray metallic sheen in the light-adapted state. After 3 to 12 hours of complete dark adaptation, the fundus appears normal. The disappearance of the shiny, yellow, fundus reflex is known as the Mizuo–Nakamura phenomenon.
Gunn’s dots are tiny white dots sometimes visible overlying the nerve fiber layer that correspond to visible reflections of the ILM, created by the footplate of the Muller cells, and rarely can be seen in patients with JXLR.
28.5 Clinical Testing
28.5.1 Optical Coherence Tomography
JXLR affects primarily the inner retinal layers. This test reveals the typical intraretinal cystoid spaces (▶ Fig. 28.3). With age, some cystic spaces may flatten and atrophy may appear, especially in patients beyond the first two decades of life.
Fig. 28.3 Retinal optical coherence tomography showing macular schisis in juvenile X-linked retinoschisis.