X-Linked Juvenile Retinoschisis

Inherited maculopathy of males caused by pathogenic variants in RS1, with bilateral foveal schisis, a frequently electronegative electroretinogram and a risk of vitreous haemorrhage and retinal detachment; off-label carbonic anhydrase inhibitors and gene therapy under investigation

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding description and historical overview

X-linked juvenile retinoschisis (XLRS) was first described in 1898 by the Austrian ophthalmologist Josef Haas, in two affected brothers [5]. The term “schisis” designates the separation of the layers of the neurosensory retina, and the disease became one of the most frequent examples of inherited retinal dystrophy with macular involvement in males [5]. During the 20th century, the observation of families with transmission exclusively through the maternal line and with affected males in several generations established linkage to the X chromosome; fundoscopy described foveal cysts arranged in a radiating pattern, inferotemporal peripheral schisis and the membranes that float in the vitreous when the inner layer of the retina ruptures, known as “vitreous veils” [1, 5].

In Finland, over 30 years, more than 300 patients were diagnosed, about 70% originating from Western Finland and 20% from the north of the country [7]. The introduction of optical coherence tomography (OCT) and, later, spectral-domain OCT (SD-OCT) transformed diagnosis: intraretinal cavities became visible even when fundoscopy is unremarkable, and SD-OCT is now the main diagnostic technique [1, 5].

1.2. Milestones of molecular discovery

The locus was first linked to markers of the Xg blood group on the short arm of the X chromosome and then refined to an interval of about 1,000 kb at Xp22, between the markers DXS418 and DXS999 [5]. In 1997, Sauer and colleagues positionally cloned the XLRS1 gene, now designated RS1: the transcript was expressed exclusively in the retina, the protein contained a conserved cell–cell interaction motif and, in nine unrelated families, a nonsense variant, a frameshift variant, a splice acceptor site variant and six missense variants were identified segregating with the disease [15]. In 1998, the Retinoschisis Consortium published the variant spectrum of 234 cases, which served for years as the basis for the prevalence estimate and for the first correlations between variant type and protein function [1, 16].

In 1999, Huopaniemi and colleagues showed that, in one-third of known Finnish patients, there were seven distinct missense variants, all in exons 4 and 6, and that three of them, c.214G>A and c.221G>T in Western Finland and c.325G>C in Northern Finland, were founder variants responsible for most cases and for the high incidence in the country [7]. In the same year the first molecular evidence of a de novo variant in RS1 was published [17]. Subsequent studies described the expression of retinoschisin in photoreceptors and bipolar cells, its organisation into octamers linked by disulfide bonds and the mechanisms by which variants prevent secretion or assembly of the protein [5]. In 2004 and 2005, RS1 gene transfer in retinoschisin-deficient mice restored the ERG b-wave and retinal structure, which paved the way for the gene therapy trials begun in 2015 [1, 18, 19].

1.3. Nomenclature and reclassifications

GeneReviews uses the designation “X-linked congenital retinoschisis”, Orphanet prefers “X-linked retinoschisis” and keeps “X-linked juvenile retinoschisis” and XLRS as synonyms [1, 2]. The terms “juvenile macular degeneration”, “juvenile macular dystrophy”, “degenerative retinoschisis” and “vitreous veils of the retina” were used in the past for the same entity; “cone dystrophy” and “macular hole” were attributed in error to patients with XLRS [1]. The expression “degenerative retinoschisis” requires care, because it also designates idiopathic age-related peripheral retinoschisis, without a genetic basis, which is a differential diagnosis [1]. Orphanet classifies XLRS as a disorder (“Disorder” level), with the preferred parent “Rare ophthalmic disorder” (ORPHA:97966), and defines it as a rare disease of several structures of the eye with reduced visual acuity in males due to juvenile macular degeneration, in which vitreous haemorrhage, retinal detachment and neovascular glaucoma appear in advanced stages [2].

In GeneGuidance, the inheritance field attributed to OMIM appears as X-linked dominant, whereas GeneReviews, Orphanet, GeneGuidance's own clinical curation and the reference reviews describe X-linked recessive inheritance, with carriers almost always clinically normal [1, 2, 4, 5]. The description of affected females, almost all homozygous or compound heterozygous in consanguineous families, and of rare symptomatic heterozygous carriers with skewed X inactivation is compatible with X-linked recessive inheritance and not with dominant inheritance [5, 20]. OMIM entry 312700 itself, updated on 16 June 2026, classifies the phenotype–gene relationship as X-linked recessive (XLR), states that carriers generally remain asymptomatic and describes homozygous females, such as the daughter of an affected man and his second cousin, and a heterozygous girl with the classic picture; the dominant value in GeneGuidance is therefore a mapping error [4, 6]. This article adopts X-linked recessive inheritance.

1.4. Definition of the entity

XLRS is an inherited vitreoretinal dystrophy caused by loss of function of retinoschisin, which manifests in hemizygous males with bilateral foveal schisis, with or without peripheral schisis, reduced central visual acuity from the first decade and, in more than half of cases, an ERG in which the dark-adapted b-wave is smaller than the a-wave [1, 5]. The diagnosis is established in a male with suggestive ophthalmological findings and a hemizygous pathogenic or likely pathogenic variant in RS1 [1]. No other RS1 allelic disorders have been described [1]. This article covers a single entity; the general approach to inherited retinal dystrophies serves as the framework, and the entities in the differential diagnosis are mentioned only in section 6.

2. Molecular Genetics and Pathophysiology

2.1. The RS1 gene and retinoschisin

The RS1 gene is located at Xp22.13, spans 32.4 kb, has six exons and gives rise to a 3.1 kb mRNA [1, 5]. The Oxford Desk Reference gives the band “Xp22.1–22.1”, a typographical error in the book; the location at Xp22.13 is that of GeneReviews, OMIM and GeneGuidance [1, 4, 21]. The encoded protein, retinoschisin, is synthesised as a 224-amino-acid precursor with a 23-amino-acid N-terminal signal peptide, followed by a cysteine-rich segment and a discoidin domain that occupies most of the mature protein [5]. After cleavage of the signal peptide, retinoschisin is secreted and organises into homo-octameric complexes joined by disulfide bonds, which bind to the surface of photoreceptors and bipolar cells through negatively charged membrane lipids [4, 5]. Expression is specific to the retina, in the inner segments of cones and rods, most bipolar cells and the plexiform layers, and to the pineal gland; it is absent from Müller cells [5]. Transcription is regulated by the factors CRX, NRL and NR2E3, and the minimal promoter, between positions −177 and +32, contains CRX binding sites [5].

GeneReviews describes retinoschisin as a structural scaffold protein required for the architecture and organisation of the retina and for maintenance of the synapse between photoreceptor and bipolar cell, with a binding site for retinal Na/K-ATPase [1]. The original cloning had already identified a conserved cell–cell interaction motif, consistent with an adhesion function during retinal development [15]. ClinGen assigns RS1 a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0, with no actionability assertion [4].

2.2. Molecular, tissue and physiological mechanism

The mechanism is loss of function [1]. Missense variants in the discoidin domain cause severe protein misfolding and retention of the protein in the endoplasmic reticulum; variants in the signal peptide disturb synthesis and translocation of the protein; variants in the regions flanking the discoidin domain, especially those affecting cysteines, prevent assembly of the subunits into octamers via disulfide bonds; in all cases the result is the absence of functional protein in the extracellular space [5]. Intracellular retention of mutant retinoschisin has been described in cultured cells and is cited by the Oxford Desk Reference as the main pathological mechanism [21]. An insertion-deletion in exon 5 (described as c.354del1-ins18) gives rise to a truncated protein that is degraded by the proteasome pathway, without nonsense-mediated mRNA decay, with a null biochemical phenotype [22].

The absence of retinoschisin removes adhesion between neighbouring cells of the inner retina, which separates the layers and creates intraretinal cavities, mainly in the inner nuclear layer and the outer plexiform layer, and less often in the ganglion cell layer and the outer nuclear layer [4, 8, 23]. The synaptic component explains the dysfunction of transmission between photoreceptor and bipolar cell, which translates into a selective reduction of the ERG b-wave with a relatively preserved a-wave, the so-called electronegative ERG [4, 5]. The dysfunction affects the ON and OFF pathways at the level of the bipolar cells, and the multifocal ERG shows generalised cone dysfunction [5]. Over time, loss of the outer segment tips and disruption of the ellipsoid zone determine visual acuity, and the cavities flatten, giving way to macular atrophy [1, 23, 24].

2.3. Inheritance pattern

Inheritance is X-linked recessive [1, 2]. Hemizygous males are affected with almost complete penetrance, but with highly variable expressivity, from almost complete schisis at 3 months to normal visual acuity with an electronegative ERG [3, 5]. Heterozygous females, in the great majority, have normal fundus examination, visual function and ERG; rare carriers show white flecks or areas of peripheral schisis, without macular signs [1]. In a study cited in the review by Molday, only 2 of 9 obligate carriers had abnormalities on multifocal ERG [5]. The females with clinical disease described are almost always homozygous or compound heterozygous in consanguineous families; there is one case with Turner syndrome and rare heterozygous cases with skewed X inactivation, discussed in sections 8 and 10 [20].

2.4. Variant spectrum

In 2012, the LOVD database (Leiden Open Variation Database) contained 191 unique variants: 155 (81%) substitutions (missense, nonsense, splicing and cryptic-site-creating), 25 (13%) deletions, 5 (3%) duplications, 3 (1.5%) insertions and 3 (1.5%) insertion-deletions; about 40% were predicted null alleles, 100 of the 191 were missense and 85 were located in the discoidin domain [5]. By 2017, the number of variants described exceeded 200, with about 10% deletions [3]. The p.(Glu72Lys) variant had been observed 66 times, and p.(Arg102Trp), p.(Arg102Gln), p.(Arg141Cys), p.(Pro192Ser), p.(Arg200Cys) and p.(Arg213Trp) had each been described in 17 or more unrelated families; residues Glu72, Pro192, Arg197 and Arg209 had four or more different substitutions, which defines them as recurrent mutation sites [5]. Large recent cohorts show broad spectra: 53 variants in 340 patients from the Netherlands and Belgium, 66 variants (7 novel) in 132 men from the United Kingdom, 64 variants (5 novel) in 107 Chinese patients and 37 variants (12 novel) in 67 Japanese patients from 56 families [8, 24–26].

The most relevant variants were described according to Human Genome Variation Society (HGVS) nomenclature and normalised in VariantValidator against the MANE Select transcript NM_000330.4 [27]. The c. and p. numbering coincides with the historical numbering, because codon counting already included the signal peptide; GeneReviews uses the previous version of the transcript (NM_000330.3) and the 2025 Finnish cohort uses the Ensembl transcript ENST00000379984.3, with the same numbering [1, 28]. The exon 3 deletion, frequent in the Netherlands and Belgium, was not normalised, because the breakpoints are not described in the abstract of the publication [24].

Table sources: normalisation in VariantValidator; frequencies and context from Molday 2012, Hahn 2022, Järvinen 2025 and Kirkby 2023 [5, 20, 24, 27, 28].

In ClinVar, consulted on 10 October 2026, the nine missense variants in the table are classified as pathogenic: c.214G>A, c.304C>T, c.305G>A, c.421C>T, c.574C>T, c.598C>T and c.637C>T reviewed by an expert panel (2025 and 2026 assessments), and c.221G>T and c.325G>C with criteria provided by multiple submitters without conflict; the c.266del variant of the section 10 case has no ClinVar record [29].

2.5. Founder variants

In Finland, the three founder variants explain most cases. Huopaniemi and colleagues attributed the disease in Western Finland to c.214G>A and c.221G>T and in Northern Finland to c.325G>C [7]. In the cohort of 52 men from Helsinki published in 2025, 24 (46%) had c.214G>A, 11 (21%) c.221G>T and 5 (10%) c.325G>C, that is, 40 of 52 (77%; 95% confidence interval, 95% CI, 66 to 88%) had one of the three variants; the authors report 82% among the patients tested, versus 95% in the 1999 study, and described two novel variants, c.272G>T and c.331G>C [28]. In the Netherlands and Belgium, the c.214G>A variant, considered a founder variant in that population, was found in 101 of 340 patients (38.7%) and the exon 3 deletion in 38 (14.6%) [24]. GeneReviews accepts that, in patients of Finnish ancestry, testing may begin with targeted analysis of the three founder variants [1].

2.6. Genotype–phenotype correlations

The correlation between genotype and phenotype is partial and depends on the outcome analysed. GeneReviews summarises that variants with predictable loss of function (nonsense, splicing and those affecting cysteines involved in disulfide bonds) are associated with greater functional deterioration on the ERG, and that missense variants tend towards milder phenotypes, possibly owing to residual function [1, 30, 31]. In the National Eye Institute (NEI) cohort of 68 males aged 4.5 to 55 years, 27 with “less severe” variants and 41 with “more severe” variants, the a-wave was above the lower limit of normal in 72% and did not vary with age or variant class, whereas the b-wave and the b/a ratio were lower in the more severe group and in older patients [32]. In a British study of 57 patients, the dark-adapted ERG was electronegative in 62% of patients with missense variants and in 100% of patients with nonsense, splicing or frameshift variants, and the pattern ERG was abnormal in 88% and 100%, respectively [33].

For visual acuity, the results diverge. In the Iowa cohort (52 patients from 33 families), null genotypes were associated with at least moderate visual impairment with an odds ratio (OR) of 7.81 (95% CI 2.17–28.10) [34]. In the United Kingdom cohort, null variants were associated with worse final visual acuity and more complications [8]. In Korea, in 83 patients, the comparison between truncating and missense variants showed no difference in visual acuity, but the group with retinoschisin secreted in functional assays had better final visual acuity (0.61 ± 0.30 versus 0.87 ± 0.81 in the logarithm of the minimum angle of resolution, logMAR; P = 0.021) and less ellipsoid zone disruption [35]. In the Netherlands and Belgium, the rate of visual acuity decline did not differ between variants predicted to be severe or mild (P = 0.239), and in Finland no genotype–phenotype correlation was found [24, 28]. The 2017 Oxford Desk Reference reports no obvious correlation [21]. In the family with the c.354del1-ins18 variant, with a null biochemical phenotype, two boys aged 1.5 and 5 years had foveal cysts with an almost normal ERG, and four relatives aged 32 to 45 years had marked loss of the b-wave, a strongly electronegative ERG and, in three of them, macular atrophy, with the b/a ratio inversely related to age [22]. In interpreting the ERG, the patient's age must be considered alongside the variant type.

2.7. Intrafamilial variability, modifiers and allelic disorders

Severity and progression vary even within the same family, as shown by the descriptions of Irish families, of siblings with the same variant and of families with null variants [1, 22, 36]. The sources consulted do not identify genetic modifiers with an established clinical role. No allelic disorders of RS1 have been described [1]. De novo variants have been described but are rare, and maternal germline mosaicism is possible, with an unquantified risk [1, 17].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Overview

XLRS is an exclusively ocular disease: the sources consulted describe no systemic manifestations [1, 2]. The picture is a bilateral and, in most patients, symmetrical maculopathy, with onset in the first decade, sometimes as early as 3 months, and diagnosis usually at the start of schooling, when the child fails school vision screening or is seen for strabismus [1, 4]. Typical visual acuity at presentation lies between 20/60 and 20/120, and in most patients it stabilises near 20/100 [1, 5]. The disease is congenital in onset, but diagnosis is often late [5].

3.2. Macula

Foveal schisis is present in practically all affected males and, on fundoscopy, is organised into a pattern of small cysts arranged radially around the fovea, described as a “spoke wheel”; loss of the foveal reflex is common [1, 4, 5]. In a study by Apushkin and colleagues cited by GeneReviews, with no denominator given in this source, the appearance of the foveal lesions was distributed among radial striae (3%), microcystic lesions (34%), honeycomb cysts (8%), combinations of these patterns (31%) and non-cystic changes: pigment mobilisation (8%), loss of the foveal reflex (8%) and an atrophic-appearing lesion (8%) [1, 37]. On SD-OCT, the cavities extend to the vascular arcades and lie between the nerve fibre layer and the nuclear layer [5]. In the United Kingdom cohort (Moorfields, 132 men, 1999–2020), foveoschisis was present in 172 of 215 eyes (80%), parafoveal schisis in 171 of 215 (79.5%) and foveal atrophy in 44 of 215 (20.5%); the cavities were in the inner nuclear layer in 95%, the outer nuclear layer in 53.6% and the ganglion cell layer in 50.8% of eyes analysed [8]. In the French cohort (Quinze-Vingts, 52 men aged 3 to 57 years), there was foveoschisis in 78% of eyes, isolated parafoveal schisis in 10% and foveal atrophy in 11%, central macular thickness was 373.6 ± 140 µm, the cavities involved the inner nuclear layer in 88% and 81% of eyes had photoreceptor defects, all with interruption of the outer segment tips [23]. In a paediatric series from Miami (Bascom Palmer, 33 boys, 2013–2024), cystoid spaces were present in all assessable eyes, macular schisis in 87.5%, retinal folds in 57.9%, the spoke-wheel pattern in 54.5% and there were unilateral findings for several features [38].

Macular evolution depends on age. The cavities are most evident in childhood; in the Chinese cohort of 107 patients, cavity volume increased until the third decade and decreased thereafter [25]. In middle age the cysts flatten, the spoke-wheel pattern gives way, from about age 30, to nonspecific pigmentary changes, and slowly progressive macular atrophy appears mainly in the fifth and sixth decades; some degree of retinal pigment epithelium (RPE) atrophy is common, and some men have macular pigmentary changes after age 50 [1, 5]. In the Iowa cohort, outer retinal loss was detectable in 50 of 54 eyes (92.6%) by age 20 and outer retinal atrophy in 29 of 66 eyes (43.9%) by age 40 [34]. GeneReviews contains an internal inconsistency, describing the schisis as separation of the nerve fibre layer in the summary and as cavities crossing the deeper layers in the suggestive findings; SD-OCT studies show that the inner nuclear layer is the most affected layer, with variable involvement of the others [1, 8, 23].

Fundus autofluorescence (FAF) frequently shows the spoke-wheel pattern or foveal hyperautofluorescence. In the United Kingdom, FAF was normal in 16 of 106 eyes (15.1%), spoke-wheel in 45 (42.5%), with foveal hyperautofluorescence in 13 (12.3%) and with central reduction in 18 (17.0%) [8]. In France, the spoke-wheel pattern was observed in 51 of 94 eyes (54%) [23], and in the AXIS trial in 28 of 33 eyes (84.8%), with normal FAF in 2 of 33 [10]. In AXIS, a golden fundus sheen (golden sheen) was the most common fundoscopic finding, in 11 patients (17 eyes) [10].

3.3. Peripheral retina and vitreous

Peripheral schisis, typically bilateral and inferotemporal, is present in about half of patients in the Swedish series cited by GeneReviews and in fewer than 50% according to the review by Molday [1, 5, 39]. The proportion varies between cohorts: 30% of eyes in France, 38.9% of patients in the United Kingdom, 46.2% of eyes in Iowa (40.4% in the inferior temporal quadrant), 68% of patients in the European multicentre study and 21% of eyes in Finland [8, 23, 28, 34, 40]. The differences reflect different units of analysis (eye or patient), ages and examination methods. When the inner layer of the peripheral schisis degenerates and ruptures, membranes are left floating in the vitreous, the “vitreous veils”; figure 2 of GeneReviews shows a partial-thickness retinal hole in the periphery [1, 5]. There may be peripheral pigmentary scars from resolution of old inner-layer breaks, white spots and, occasionally, the Mizuo phenomenon, a change in retinal colour after dark adaptation when the light is switched on [1, 5].

3.4. Complications: vitreous haemorrhage and retinal detachment

GeneReviews estimates retinal detachment (RD) at 5–22% and vitreous haemorrhage (VH) at 4–40% of patients, without stating the source cohorts [1]. The review by Molday estimates VH or RD in about 5% of affected males, mainly in the first decade, and notes that VH usually clears spontaneously; macular holes are rare [5]. Recent cohorts show values within these ranges: complications (VH, RD or both) in 20 of 108 patients (18.5%) in the United Kingdom, RD in 8 of 104 eyes (7.7%) in Iowa, RD in 9 of 59 patients (15%) and VH in 5 (8%) in the European multicentre study, and VH in 10 eyes (10%) with no RD or neovascular glaucoma in Finland, where the median age at first VH was 10 years (0.5–24) and VH was more frequent in eyes with peripheral schisis (p < 0.001) [8, 28, 34, 40]. In Iowa, RD was associated with worse final visual acuity (0.875 versus 0.487 logMAR; p < 0.0001) [34].

The series from the Netherlands and Belgium dedicated to complications (49 patients with VH or RD, median follow-up of 19.0 years) showed a median age of 15.3 years at first VH and of 7.5 years at RD, peripheral schisis in 94% of eyes with VH and in 80% of eyes with RD, and bilateral VH in 10 of 39 patients (26%) [41]. VH resolved without intervention in 42 of 49 eyes (86%), with recurrence in 22 (45%). There was RD in 25 eyes of 21 patients: rhegmatogenous in 16 (64%), tractional in 7 (28%) and exudative in 3 (12%) [41]. Orphanet includes neovascular glaucoma among the manifestations of advanced stages [2]. Surgical results are given in section 7.

3.5. Refraction, motility and colour vision

Hypermetropia is common: in Finland it was present in 80% of patients on autorefraction at the initial visit, and 96% were emmetropic or hypermetropic at the end of follow-up [5, 28]. Strabismus, nystagmus, axial hypermetropia, colour vision defect and foveal ectopia are part of the picture, and strabismus is a frequent reason for first presentation [4]. Patients do not report night blindness, which helps to distinguish XLRS from congenital stationary night blindness [1]. Contrast sensitivity was normal in 85 of 99 eyes in the North American prospective cohort [42].

3.6. Severe infantile form

A rare infantile form presents with extensive bullous retinoschisis that mimics retinal detachment [21]. Infants with severe schisis may have true retinal detachment, and the bullae may regress leaving pigmented lines [1, 20]. In the French paediatric surgical series, the mean age of the 36 patients operated on was 6.8 ± 5.6 years [43].

3.7. Natural history of visual acuity

GeneReviews describes a mild deterioration of visual acuity in the first and second decades, followed by relative stability until the fifth or sixth decade, when macular atrophy may reduce it to legal blindness (visual acuity below 20/200) [1]. Larger and more recent cohorts have refined this model. In the Netherlands and Belgium (340 patients, mean follow-up of 13.2 years, 0.1–50.1), the median ages for mild visual impairment and for low vision were 12 and 25 years; visual acuity improved slightly in the first two decades and then declined by 0.44% per year (P < 0.001), and the predicted prevalence of severe visual impairment and of blindness at age 60 was 35% and 25% [24]. In China (107 patients, 440 visits), the curve was triphasic, with slight improvement in childhood, a prolonged plateau until middle age and faster decline thereafter, and Kaplan-Meier analysis projected 40% of patients blind at age 60 [25]. In Finland, 22 of 52 patients (42%) had visual impairment according to World Health Organization criteria, and visual acuity continued to decrease in the third decade [28]. The systematic review of 12 studies up to February 2019 found a very slow decline, of 0.22 to 0.5 letters per year [44].

Over short observation periods, the disease appears stable: in the United Kingdom cohort, the mean change in best-corrected visual acuity (BCVA) over 6.7 years was 0.04 and 0.01 logMAR [8]; in Iowa, initial and final visual acuity did not differ (0.498 versus 0.521 logMAR; p = 0.203) [34]; in the European multicentre study, over 4.3 years there was no change in BCVA, but central retinal thickness and macular volume decreased [40]; and in the prospective study of 56 males aged 7 or older followed for 18 months, most had no relevant change [42]. In that study, the correlation between visual acuity and age was weak (R = −0.24), cavity volume correlated weakly with age (R = −0.33) and did not correlate with visual acuity [42]. Visual acuity correlates better with ellipsoid zone integrity (ρ = −0.759) and with photoreceptor outer segment length (ρ = −0.592) than with cavity thickness [23, 24]. In Finland, low BCVA was associated with macular atrophy (p < 0.001), ellipsoid zone disruption (p = 0.007) and peripheral schisis (p = 0.006) [28].

Many of these cohorts include patients treated with CAIs. The North American prospective cohort describes separately the patients who started CAIs during the study, with a mean gain of 3.15 ± 7.8 letters [42]; in the other retrospective cohorts, the visual acuity curves mix treated and untreated patients, which limits their interpretation as pure natural history [24, 34, 40].

3.8. Carriers and affected females

Heterozygous carriers almost always have normal ophthalmological examination, visual function and ERG; very rarely they show white flecks or areas of peripheral schisis, without macular signs [1]. A 2023 literature review identified 15 reports with 30 females with XLRS: 19 belonged to consanguineous families and were homozygous or compound heterozygous, known or presumed, one had Turner syndrome and 10 were heterozygous, most without molecular confirmation [20]. Among these carriers are a 41-year-old woman with bilateral inferotemporal schisis, a 13-year-old girl with visual acuity of 20/25 and small central scotomas, a 56-year-old carrier with radial folds of the internal limiting membrane without foveal schisis, five obligate carriers of whom four had peripheral changes and a 54-year-old carrier with inferior schisis and an outer-layer hole [20]. A 5-year-old child heterozygous for the paternal variant c.305G>A p.(Arg102Gln) had mild macular signs without foveal schisis [20]. The case of a symptomatic carrier girl with skewed X inactivation is given in section 10.

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In infants, suspicion arises with early strabismus, nystagmus or extensive bullous retinoschisis mimicking retinal detachment; the severe infantile form and true detachment in infants with severe schisis have been described [1, 21]. At preschool and school age, the typical scenario is a boy with bilateral reduced visual acuity, between 20/60 and 20/120, detected at school vision screening, often hypermetropic, without complaints of night blindness and with an absent foveal reflex or radiating foveal cysts [1, 4]. In the Iowa cohort, the median age at onset was 5 years and, in China, 70% of patients presented by age 10 [25, 34]. Subtle foveal schisis may be mistaken for bilateral amblyopia, and a diagnosis of “refractive amblyopia” that does not improve with optical correction and occlusion should prompt macular SD-OCT [1].

In adolescents and adults, suspicion arises with bilateral maculopathy of uncertain cause, macular atrophy in a young man, inferotemporal peripheral schisis or vitreous veils, VH in a boy without trauma, or an electronegative ERG [1, 5]. In older adults, the absence of schisis, retinal thinning and epiretinal membranes make clinical diagnosis difficult, and genetic testing gains importance [5]. Onset may be late: in the United Kingdom, age at onset ranged from 0 to 58 years [8].

4.2. Family history

A family history compatible with X-linked inheritance, with affected males connected through unaffected females and no male-to-male transmission, supports the diagnosis, but its absence does not exclude it [1]. In a male with a positive family history, the presence of retinoschisis practically establishes the diagnosis; in a male without a family history, diagnosis is more difficult and depends on molecular testing [1]. In a female child with suggestive findings, a history of a father with poor vision since childhood should prompt consideration of XLRS [20].

4.3. Warning and urgent signs

Urgent signs are those of vitreoretinal complications: sudden onset of floaters or a shadow in the visual field, an abrupt fall in visual acuity or loss of the red reflex, which may reflect VH or RD [1, 41]. An extensive area of peripheral schisis may mask a true detachment, so in case of doubt the patient should be seen by a retinal surgeon [1]. In an infant, VH that does not clear requires close surveillance because of the risk of amblyopia, and in younger children RD may not be reported by the patient [1, 5]. Head trauma and contact sports should be avoided (section 7.9).

4.4. Newborn screening

There is no newborn screening for XLRS in the sources consulted. Early detection is achieved by examining at-risk boys in families with the disease and by childhood and school vision screening [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

GeneReviews defines the suggestive findings in a male: bilaterally reduced visual acuity, typically between 20/60 and 20/120; absence of complaints of night blindness; macular schisis, often spoke-wheel, with or without inferotemporal peripheral schisis (about 50%) and vitreous veils; SD-OCT with foveal schisis; ERG with a dark-adapted b-wave reduced relative to the a-wave in more than half of males; and a family history compatible with X-linked inheritance [1]. The diagnosis is established in a male proband with suggestive ophthalmological findings and a hemizygous pathogenic or likely pathogenic variant in RS1, identified by molecular testing [1]. A hemizygous variant of uncertain significance (VUS) in RS1 neither establishes nor excludes the diagnosis [1]. An electronegative ERG supports the diagnosis, but is neither confirmatory nor specific [4].

5.2. Ophthalmological examinations

SD-OCT is the main diagnostic technique: in young patients it shows characteristic intraretinal foveal schisis, and in middle age the cystic spaces become less evident through flattening, with an appearance of partial macular atrophy [1, 5]. In an uncooperative child, a single foveal scan may suffice for diagnosis [5]. The 2022 American Academy of Ophthalmology (AAO) clinical statement on inherited retinal degenerations includes XLRS in group 4 (dystrophies with macular involvement) and recommends a high-density SD-OCT volume with central thickness measurement to monitor the schisis [9]. Automated quantification of schisis volume on OCT images, by deep-learning segmentation, developed with data from Singapore, the United Kingdom, the Netherlands and the USA, has been proposed as a structural endpoint for trials (section 7.5) [45].

FAF shows increased foveal autofluorescence or a spoke-wheel pattern, but the findings should be confirmed on SD-OCT [1, 5]. The AAO recommends FAF with reduced illumination and colour photographs used sparingly in maculopathies, because of light toxicity [9]. Fluorescein angiography is normal in boys, without leakage, and shows atrophic and RPE changes in older patients; it does not contribute to the differential diagnosis [1, 5].

The full-field ERG shows, in more than half of affected males, a markedly reduced dark-adapted b-wave with a relatively preserved a-wave, the electronegative ERG [1]. The review by Molday estimates this configuration in about 50% of patients and stresses that a relatively normal ERG does not exclude XLRS [5]. Some boys have a technically normal b-wave, which constitutes a false negative, and b-wave reduction worsens in older men with severe variants [1, 32]. The proportion depends on genotype: 62% with missense variants and 100% with null variants in the British study; in that study, a delayed 30 Hz flicker was found in all patients with null variants and in all but six eyes with missense variants, the pattern ERG was abnormal in 88% and 100%, the On-Off b-wave was subnormal in 39% and 89%, and the S-cone response was abnormal in 50% in both groups [33]. In France, the b/a ratio was reduced in 45 of 64 eyes (70%) [23]. The ERG shows dysfunction of the ON and OFF pathways at the level of the bipolar cells, and the multifocal ERG shows generalised cone dysfunction [5]. The AAO recommends full-field ERG at the initial assessment and multifocal ERG in group 4 [9].

In children under 2 years, the AAO accepts ERG with skin electrodes or handheld OCT, often under sedation; between 2 and 6 years, examinations under sedation allow a more complete assessment, weighing the risks [9].

5.3. Molecular testing algorithm

GeneReviews proposes two pathways [1]. In option 1, when the phenotype is distinctive, single-gene testing is performed: RS1 sequencing for missense, nonsense, splicing variants and small insertions and deletions and, if negative, gene-targeted deletion and duplication analysis, by quantitative polymerase chain reaction (PCR), long-range PCR, multiplex ligation-dependent probe amplification (MLPA) or targeted microarray. In patients of Finnish ancestry, testing may begin with the three founder variants. Alternatively, and this is the pathway recommended by GeneReviews for this disease, an inherited retinal dystrophy panel that includes RS1 and the genes of the differential diagnosis is used, with copy-number analysis. In option 2, when XLRS has not been considered, the exome (more often) or genome identifies the variant [1]. The AAO recommends genetic testing by panel or exome at the initial assessment of inherited retinal dystrophies and repeat testing if the result is inconclusive [9].

Table sources: GeneReviews, AAO 2022, Huopaniemi 1999 and Järvinen 2025 [1, 7, 9, 28].

5.4. Yield, sensitivity and limitations of testing

In GeneReviews, sequencing detects 90–95% of RS1 pathogenic variants and gene-targeted deletion and duplication analysis detects 5–10% [1]. These values are proportions of the known variants detectable by each method and not the clinical sensitivity of the test. The European clinical utility gene card (EuroBiotech Journal, 2017) gives a clinical sensitivity of 90–96% in affected males, based on GeneReviews, and a clinical specificity of about 99.99% based on the authors' laboratory data; the analytical sensitivity and specificity of Sanger sequencing and MLPA exceed 99.99% [3]. In that report, the test was available, in 2017, in 11 accredited laboratories in the European Union and 9 in the USA [3]. For inherited retinal dystrophies as a whole, the AAO gives identification of the causal variant in 56–76% of patients, a value that does not apply to XLRS alone [9].

A negative result does not exclude the disease [3, 9]. Possible causes are variants in regulatory regions (5' and 3' untranslated regions) or deep intronic variants not included in the test, rearrangements that sequencing does not detect when copy-number analysis has not been performed, or variants in other genes [3]. Deep intronic variants were not sought in the section 10 case, because they were not routinely available, and the authors state that there is no published evidence of their existence in XLRS [20]. Somatic mosaicism in the proband is not described in the sources consulted; maternal germline mosaicism is possible [1]. The exon 3 deletion, which accounts for 14.6% of patients in the Netherlands and Belgium, is detected only if the test includes copy-number analysis [24].

5.5. Report, classification and segregation

The report should state the gene, the transcript with version (NM_000330.4, MANE Select), the variant in HGVS c. and p. nomenclature, the genomic coordinates with the genome assembly, the zygosity (hemizygous in a male, heterozygous in a female) and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); for clinical decision-making, the pathogenic and likely pathogenic classes are equivalent [1, 27]. The section 10 case shows the importance of checking coordinates: the article published position g.18,655,371 in GRCh37, and VariantValidator returns g.18665371 for the same variant [20, 27]. In the presence of a VUS, extending the study to relatives to assess segregation and, when necessary, reassessing the phenotype is recommended [3]. In a male, segregation with disease in affected males and absence in unaffected males in the family support pathogenicity; confirmation of the mother as a carrier is useful for counselling [1].

5.6. Carrier detection

Carrier detection is molecular and is most informative when the familial variant is known; without an available affected individual, sequencing followed by deletion and duplication analysis is performed [1]. Eye examination and ERG in carriers are almost always normal and cannot be used to exclude carrier status [1, 4]. In Finland, the founder variants enabled carrier testing on a national scale [7].

5.7. Assessment after diagnosis

The initial assessment includes a complete ophthalmological examination, with BCVA, refractive error, investigation for amblyopia, visual fields by Goldmann or other perimetry, fundoscopy, OCT and ERG, and a medical genetics consultation with genetic counselling [1]. The AAO adds a history with pedigree, BCVA measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, biomicroscopy, intraocular pressure (IOP), indirect ophthalmoscopy, FAF, kinetic perimetry, microperimetry when available and low-vision assessment at baseline and then every 1–2 years [9]. An interview study of parents of boys with XLRS describes the support needs of families after diagnosis [1].

5.8. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing (PGT) are possible; the views of professionals and families on prenatal diagnosis vary, and the decision is personal [1]. Risks and reproductive options are given in section 8.

6. Differential Diagnosis

6.1. Comparative table

Table sources: GeneReviews, Molday 2012, Oxford Desk Reference, Smith's Recognizable Patterns, Oh 2020 and Kirkby 2023 [1, 5, 20, 21, 46, 47].

6.2. Electronegative ERG in a boy

The main differential of an electronegative ERG in a boy is X-linked congenital stationary night blindness, caused by variants in CACNA1F or NYX [1, 5]. Patients with XLRS rarely report night blindness, and SD-OCT shows schisis in XLRS and not in congenital stationary night blindness [1, 5]. SD-OCT also makes it possible to distinguish XLRS from cone dysfunction and other macular dystrophies [5].

6.3. Peripheral schisis and congenital detachment

When peripheral schisis is extensive, the differentials are Norrie disease, in which RD is complete at birth, X-linked FEVR, also caused by NDP, and autosomal dominant FEVR (FZD4, LRP5, TSPAN12); the ophthalmoscopic appearance is different [5]. The NDP spectrum includes persistent hyperplastic primary vitreous, Coats disease and advanced retinopathy of prematurity [21]. Incontinentia pigmenti may mimic the detachment of FEVR, but is lethal in males and is not a differential in a boy [5, 21]. Traumatic RD and retinopathy of prematurity are distinguished by the history [5]. The bullous infantile form of XLRS may mimic a detachment [21]. The distinction between schisis and RD has practical consequences: RD (full-thickness elevation) in a normal eye is repairable, whereas RD associated with retinoschisis is generally difficult to treat [1].

6.4. Foveal schisis without XLRS

Isolated foveal schisis is not sufficient for a diagnosis of XLRS: a family with rod-cone dystrophy and foveal schisis was described in 1978 [1]. Enhanced S-cone syndrome and Goldmann-Favre syndrome (NR2E3) mimic XLRS, but the ERG shows markedly reduced a- and b-waves and altered timings, and vision is more affected, with severe night blindness and field loss [1, 5]. In a female case, macular OCT suggested enhanced S-cone syndrome, but the history, the absence of a pigment band and the electrophysiology were not compatible with NR2E3 retinopathy [20]. CRB1-associated maculopathy may mimic juvenile XLRS in males without a family history [47]. Autosomal recessive foveoschisis occurs in families with affected females [5]. OMIM mentions occasional reports of autosomal dominant retinoschisis (OMIM 180270), which account for the small fraction of congenital retinoschisis that is not X-linked [6]. Orphanet records other entities with schisis: the syndrome of microphthalmia, retinitis pigmentosa, foveoschisis and optic disc drusen (ORPHA:251279, MFRP) and idiopathic stellate foveomacular retinoschisis, which is not hereditary (ORPHA:714150) [2].

6.5. X-linked retinitis pigmentosa

X-linked retinitis pigmentosa (RPGR, RP2, OFD1) is an incorrect referral diagnosis in many patients with XLRS and accounts for 5–15% of probands with retinitis pigmentosa [1]. It is distinguished by intraretinal pigment dispersion and clumping, vascular attenuation and optic disc pallor, and by markedly reduced a- and b-waves on the ERG [1].

6.6. Cohen syndrome

Cohen syndrome (VPS13B, autosomal recessive, with more than 150 cases described, many Finnish) includes myopia before age 5 that progresses to high myopia in the second decade, strabismus, poor vision in bright light, constricted fields, progressive pigmentary retinopathy with “bull's-eye” maculae, spherophakia, photoreceptor outer segment abnormalities, retinoschisis and optic atrophy [46]. The systemic findings (truncal obesity, hypotonia, intellectual disability, postnatal microcephaly, intermittent neutropenia) and myopia distinguish it from XLRS, in which hypermetropia predominates [28, 46].

6.7. Acquired causes

Cystoid macular oedema of diabetic, inflammatory or postoperative cause may mimic foveal schisis; fluorescein angiography is normal and without leakage in XLRS in boys [1]. Bilateral amblyopia is an incorrect referral diagnosis when foveal schisis is subtle [1]. Degenerative retinoschisis is idiopathic, peripheral, mainly age-related and without a genetic basis, and the separation occurs in the outer retina (outer nuclear and plexiform layers), whereas in XLRS it may involve proximal layers [1]. The European technical report includes in the differential cystoid macular oedema, retinitis pigmentosa, degenerative retinoschisis, RD, amblyopia and erosive vitreoretinopathy [3]. In older adults, the absence of schisis, retinal thinning and epiretinal membranes make the differential difficult, and asymmetry or unilateral findings do not exclude XLRS [5, 8, 38].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no authorised treatment or cure for XLRS in any jurisdiction as of 10 October 2026 [4, 48, 49]. Management rests on refractive correction and treatment of amblyopia in children, surveillance and surgical treatment of vitreoretinal complications, low-vision aids and services, school support, injury prevention and genetic counselling [1, 5]. CAIs are used off-label to reduce the macular cavities, and gene therapy is in clinical trials [4, 11]. The 2022 AAO statement applies to inherited retinal degenerations in general, is not specific to XLRS and contains no treatment recommendations for this disease [9]. No XLRS-specific guideline or ERN-EYE guidance on the disease was found [9, 12].

7.2. Refractive correction and amblyopia

Refractive errors and amblyopia are treated according to standard care [1]. Amblyopia prevention therapy is indicated after surgery for VH or RD and in children with severe retinoschisis or hypermetropia [1]. VH that does not clear in a young child is itself a cause of deprivation amblyopia, which contributes to the indication for vitrectomy (section 7.4) [5].

7.3. Carbonic anhydrase inhibitors

7.3.1. Drugs, approved indications and use in XLRS

Three CAIs are used in XLRS: oral acetazolamide (Carbinib® in Portugal; Diamox® in other countries) and topical dorzolamide (Trusopt® and generics) and brinzolamide (Azopt®) [4, 50–53]. None has an approved indication for XLRS: dorzolamide and brinzolamide are indicated for lowering IOP in ocular hypertension and open-angle glaucoma, and acetazolamide, in the USA, as an adjunct in the oedema of heart failure, drug-induced oedema, centrencephalic epilepsies, chronic open-angle glaucoma, secondary glaucoma, preoperatively in acute angle-closure glaucoma and for the prevention of acute mountain sickness [51, 54–56]. Use in XLRS is therefore always off-label [4]. In Portugal, the Trusopt® SmPC adds pseudoexfoliative glaucoma to the indications, and that of Carbinib® indicates acetazolamide as an adjunct in chronic simple glaucoma, secondary glaucoma and preoperatively in acute angle-closure glaucoma, in abnormal fluid retention and, in combination, in epilepsy [52, 53]. All three drugs inhibit carbonic anhydrase. The proposed mechanism in XLRS is inhibition of carbonic anhydrase in the retinal pigment epithelium, especially the membrane-bound form IV, which increases fluid transport out of the retina by active ion transport or by a change in pH; increased adhesion of the retina to the pigment epithelium and increased retinoschisin production have also been proposed, without direct demonstration [57]. Acetazolamide and brinzolamide are sulfonamides, absorbed systemically even when applied to the eye, with the possibility of severe hypersensitivity reactions common to sulfonamides [51, 55, 56].

7.3.2. Posology

There is no standard regimen in XLRS [58]. The doses below are those used in trials and case series, and the label doses refer to the approved indications.

In the retrospective cohort from the Netherlands and Belgium, the exposure variable was expressed in milligrams of acetazolamide per day and in drops of topical CAI per day, which shows the heterogeneity of the regimens used in practice [58].

7.3.3. Evidence: observational studies

The first studies with topical dorzolamide 2% were observational and uncontrolled. In a prospective study from Chicago, without a control group, 8 adult patients (median age 31 years, 21 to 47 years) with visual acuity of 20/100 or better and foveal cystic lesions received dorzolamide 2% (Trusopt®) three times daily in each eye, with reassessment after 1 month and follow-up for 2 to 6 months; significant change was defined by the variability between visits in 4 untreated patients (central foveal thickness >19.6%; foveal zone thickness >17.1%) [61]. Seven patients had a reduction of the lesions in at least one eye: in 4 in both eyes and in 2 in one eye already at the first month, with further sustained improvement, and in one patient only after the second month; the eighth did not respond after 1 month and stopped [61]. Five patients gained at least 7 ETDRS letters in at least one eye (one gained 13 letters), with a mean change in visual acuity described by the authors as modest, and the lesions changed little on ophthalmoscopy; the article does not describe adverse effects of dorzolamide [61]. In a retrospective study from Chicago of 29 eyes of 15 adult patients (18 to 53 years), treated with dorzolamide 2% three times daily in both eyes for 4 to 41 months (with reduction to twice daily in 5 patients), there was a response in 20 eyes (69%) of 11 patients, recurrence of the cavities after an initial response in 5 of those 20 (25%), absence of response with stability in 4 eyes (14%) and worsening without response in 5 eyes (17%); 16 eyes (55%) improved by at least 7 letters; in 3 of the 5 eyes with recurrence there was renewed improvement when the frequency was returned from twice to three times daily [62]. In the Cleveland series (10 patients, 18 eyes, mean follow-up of 8.38 years with dorzolamide 2% two to three times daily), central subfield thickness went from 429.88 to 372.28 µm (P = 0.10) and visual acuity from 0.45 to 0.34 logMAR (P < 0.01), without adverse effects [64]. In an Italian prospective series of 19 patients aged 7 to 63 years treated with oral acetazolamide for 6 months, there was significant improvement in BCVA (p = 0.013), central retinal thickness (p = 0.004) and macular sensitivity (p < 0.001); clinically significant BCVA improvement (0.14 logMAR) occurred in 7 eyes (23.3%) of 7 patients (41%), two patients stopped (one because of a urinary problem in the first month) and no paraesthesia or fatigue was reported [60].

The larger cohorts show a more consistent structural than functional effect. In the retrospective cohort from the Netherlands and Belgium (42 patients, median baseline age 14.7 years, median follow-up 4.0 years), 25 patients (60%) received oral acetazolamide, 24 (57%) topical CAIs and 11 (26%) the combination; central foveal thickness decreased by 14.37 µm per 100 mg/day of acetazolamide (95% CI −19.62 to −9.10; P < 0.001) and by 7.52 µm per drop/day of topical CAI (95% CI −13.67 to −1.32; P = 0.017); the change in visual acuity with oral CAIs, of −0.0059 logMAR per 100 mg (P = 0.008), was not clinically significant, and 7 patients (17%) stopped because of adverse effects [58]. In Iowa, CAIs improved central subfield thickness (p = 0.026) but not visual acuity (p = 0.380), and in the European multicentre study they did not significantly change central retinal thickness (p = 0.34) [34, 40]. In the AGTC prospective study, patients who started CAIs during the study gained on average 3.15 ± 7.8 letters, with a gain of at least 15 letters at 8 of 110 visits in 3 patients, without correlation with cavity volume [42].

7.3.4. Evidence: prospective and randomised trials

A prospective randomised study from Sydney included 11 patients with XLRS (molecular confirmation in 7): one group received acetazolamide for 3 months followed by 3 months without treatment and the other the reverse sequence; with one eye randomised per patient, BCVA went from 0.52 ± 0.17 to 0.46 ± 0.16 logMAR (P < 0.006), with improvement in 6 patients and no change in 5, and central macular thickness from 314.5 to 294.2 µm (P = 0.31) [57]. AXIS, conducted at Amsterdam UMC, is the only published randomised trial with an untreated control group [10, 59]. It enrolled patients with XLRS aged 12 or older with foveal cystic cavities on SD-OCT; of 142 patients screened, 65 were eligible, 26 consented and 19 were randomised between January 2023 and February 2024: 10 patients (17 eyes) to acetazolamide and 9 (16 eyes) to control [10]. The median age was 21.8 years in the treated group and 25.7 years in the control group, baseline BCVA 60.0 ± 11.2 and 67.2 ± 10.6 letters and central subfield thickness 468.8 ± 99.4 and 426.1 ± 128.6 µm [10].

Table source: Hensman 2026, AXIS trial [10].

Of the treated patients, 3 responders continued on 125 mg twice daily, 2 returned to 250 mg twice daily and 3 stopped because of insufficient response [10]. In the structure–function analysis, a 100 µm reduction in central subfield thickness corresponded to a gain of 0.9 letters, and a 1 mm³ reduction in cavity volume to 2.4 letters [10]. The authors concluded that oral acetazolamide had no clinically relevant benefit in the overall population and that a subgroup, possibly with an intact central outer retina, may benefit; they also stressed that the cavities fluctuate spontaneously, which explains resolution in control eyes [10].

In REAXIS, 5 of the 9 patients in the AXIS control group (9 eyes) started oral acetazolamide 250 mg twice daily at week 32, with assessment of response at week 48 (reduction ≥25% in central foveal thickness → 125 mg twice daily; no response → discontinuation) and follow-up to week 64 [67]. Central subfield thickness decreased by 72.8 µm between the control and treatment periods (95% CI −117.2 to −28.4; p = 0.001), with a variable response; BCVA increased by 2.2 letters (95% CI 0.60 to 3.8; p = 0.01), low-luminance visual acuity by 4.6 letters (95% CI 2.4 to 6.8; p < 0.001) and microperimetry sensitivity by 0.6 dB (p = 0.04) [67]. Two patients continued on 125 mg twice daily to the end, two stopped at week 48 for lack of anatomical response and one stopped at week six because of fatigue, paraesthesia, dysgeusia, tinnitus and dry mouth, which resolved; the most frequent effects were fatigue (4 patients), paraesthesia (3) and dysgeusia (3), with no serious adverse effects [67]. This is an intra-individual comparison with 5 patients, without masking, which does not change the negative result of the randomised trial.

7.3.5. Adverse effects and management

In AXIS (10 treated patients), there were no serious adverse effects; paraesthesia of the hands and feet occurred in 7 patients (70%), dysgeusia in 6 (60%), fatigue in 5 (50%), polyuria in 4 (40%), dry mouth in 4 (40%), nausea in 4 (40%), dizziness in 2 (20%), and reflux, tinnitus, dyspnoea and rash in 1 each; there was one dose reduction for tolerability and no discontinuation for adverse effects [10]. In the retrospective cohort, 17% of patients stopped because of adverse effects [58]. The US acetazolamide label lists, among others, metabolic acidosis, hypokalaemia, hyponatraemia, blood dyscrasias, fulminant hepatic necrosis, crystalluria and a risk of nephrolithiasis with prolonged treatment, paraesthesia, tinnitus, transient myopia and choroidal effusion, and warns about the combination with high-dose acetylsalicylic acid [56]. The contraindications to acetazolamide are hypersensitivity (with possible cross-reactivity with sulfonamides), reduced serum sodium or potassium, marked renal or hepatic disease, adrenal insufficiency, hyperchloraemic acidosis, cirrhosis and, with prolonged treatment, chronic non-congestive angle-closure glaucoma; these were also the AXIS exclusion criteria [10, 56]. The Portuguese SmPC of Carbinib® adds hypersensitivity to sulfonamides as a contraindication, recommends periodic monitoring of electrolytes and the full blood count during prolonged treatment, and warns about acute generalised exanthematous pustulosis, non-cardiogenic pulmonary oedema (even after a single dose), choroidal effusion and choroidal detachment, renal lithiasis, worsening of acidosis in obstructive pulmonary disease and the suicidal ideation described with antiepileptics [52]. The Portuguese SmPC of Trusopt® contraindicates dorzolamide in severe renal impairment (creatinine clearance below 30 ml/min) and hyperchloraemic acidosis, recommends caution in hepatic impairment and nasolacrimal occlusion for 2 minutes to reduce systemic absorption, and calls for assessment of the risk of metabolic acidosis in children with renal tubular immaturity [53]. Severe reactions to sulfonamides, including Stevens-Johnson syndrome and toxic epidermal necrolysis, require immediate discontinuation [51, 56].

For brinzolamide, the European SmPC gives as the most frequent adverse effects dysgeusia (6.0%) and transient blurred vision after instillation (5.4%), contraindicates the drug in hypersensitivity to sulfonamides, severe renal impairment (creatinine clearance below 30 ml/min) and hyperchloraemic acidosis, does not recommend it in hepatic impairment and recommends nasolacrimal occlusion or gentle eyelid closure after instillation to reduce systemic absorption [51]. In short paediatric trials, about 12.5% of children had adverse reactions, mainly non-serious local ocular reactions [51]. The US label warns about corneal oedema in patients with low endothelial cell counts [55]. The preservative benzalkonium chloride discolours soft contact lenses, which should be removed before instillation and reinserted 15 minutes later [51]. When more than one eye drop is used, they should be administered at least 5 minutes apart according to the brinzolamide SmPC and the US dorzolamide label, and 10 minutes apart according to the Portuguese dorzolamide SmPC [51, 53, 54].

7.3.6. Practical reading

Molday's 2012 review recommended a therapeutic trial with dorzolamide monitored with visual acuity and SD-OCT, maintained long term according to the individual response, and noted that, if the oedema worsens on treatment, discontinuation followed by retreatment may be useful [5]. The Hospital La Paz (Madrid) protocol uses topical brinzolamide for foveoschisis and adds oral acetazolamide when there is no improvement or when the foveoschisis is very extensive at diagnosis [66]. The authors of the Chicago series proposed a scheme: baseline examination with visual acuity and OCT, dorzolamide 2% three times daily in both eyes, reassessment at 2 months and, if there is improvement, a further 2 months; at 4 months, if the improvement is maintained, reduction to twice daily with reassessment 2 months later; return to three times daily if there is recurrence; discontinuation if there is no response or if there is recurrence after 6 months at three times daily; and continuation for up to about 5 months before concluding that there is no response, because some patients respond late [62]. EyeWiki, a tertiary source, states that topical or systemic CAIs have described benefit on the cystic spaces [68]. These recommendations predate AXIS, which did not show clinically relevant benefit in the overall population [10]. The available evidence therefore supports structural reduction of the cavities in some patients, particularly with oral CAIs, but not a consistent functional gain [10, 34, 58]. When a trial of treatment is decided on, the response is assessed with SD-OCT and BCVA before and after initiation (AXIS used week 16 as the decision point, and the dorzolamide series described a response from the first month onwards), it is discontinued in non-responders, and the off-label status, the lack of paediatric data in the labels and the adverse effects are discussed with the family [10, 51, 56, 61]. The phase 3 trial of ATSN-201 excludes patients who have used CAIs in the previous month, which matters for anyone considering participation [11].

7.4. Vitreoretinal surgery

Isolated schisis, without detachment, is at best difficult to treat surgically, because it mainly affects the inner layers [1]. Pars plana vitrectomy is indicated for VH that does not resolve spontaneously, also to prevent amblyopia, and for RD [5]. Prophylactic treatment of the schisis with laser or surgery is not recommended in Molday's review, because of the risk of serious long-term complications, including RD; EyeWiki describes prophylactic laser as controversial, because it may cause iatrogenic breaks [5, 68].

In the series from the Netherlands and Belgium, 21 of the 25 eyes with RD (84%) underwent surgery; reattachment after primary surgery was 43% and after multiple procedures 90%, and in the 15 eyes operated on after 2005 final reattachment was 93%; postoperative BCVA improved in 10 of 21 eyes (48%), was unchanged in 5 (24%), worsened in 2 (10%) and was not available in 4 (19%) [41]. In the meta-analysis of 14 observational series with more than 200 eyes, the pooled primary reattachment rate was 0.73 (95% CI 0.46–0.99; I² = 83%) and the final rate 0.89 (95% CI 0.84–0.94; I² = 0%), with reoperation in 20–40%, mainly for proliferative vitreoretinopathy, and improvement in BCVA in about 50–80% of eyes, limited by pre-existing macular disease, chronicity and amblyopia [69]. In the French paediatric series (36 patients, 47 eyes, mean age 6.8 years), the indications were RD in 24 eyes (51%), progressive macular schisis in 16 (34%) and VH in 7 (15%); complete anatomical success in RD was 75% after a mean of 2.0 ± 1.0 operations, 88% in rhegmatogenous RD versus 43% in tractional RD (p = 0.04), and the retina was attached at the end in 44 eyes (94%); surgery for progressive macular schisis stabilised or improved the structure, without significant improvement in visual acuity, and postoperative complications (cataract, ocular hypertension) were frequent [43]. The authors reserve surgery for macular schisis for documented progression or foveal threat, and the Spanish series of 17 children describes poor surgical results, particularly in younger children [43, 66]. Molday's review considered the benefit of RD surgery limited [5]; the more recent series show higher reattachment rates, but with frequent reoperations and variable functional gain [41, 69].

7.5. Gene therapy

7.5.1. Rationale and preclinical evidence

XLRS is a candidate for gene augmentation therapy, because it results from loss of function of a secreted protein that acts locally [5]. In mice lacking retinoschisin, transfer of RS1 restored the ERG b-wave with reversal of the electronegative configuration and produced prolonged recovery of retinal structure and function [18, 19]. The first human trials used the intravitreal route and showed lack of efficacy and inflammation; the more recent programmes use the subretinal route, one of the three routes (subretinal, intravitreal and suprachoroidal) used in ocular gene therapies with adeno-associated viruses (AAV) at the clinical stage [11, 70–72]. The central schisis cavities hinder submacular injection with conventional vectors; the laterally spreading AAV.SPR capsid transduced macular and foveal photoreceptors in non-human primates from a peripheral subretinal injection, without detaching the central retina, with expression several millimetres from the injection bleb [70]. With the AAV.SPR-hGRK1-RS1 vector, retinoschisin, although secreted, remained confined to the transduced area; in Rs1-deficient mice there was dose-dependent improvement in function and structure, and a good laboratory practice toxicology study in primates established safety at the highest dose evaluated [70].

7.5.2. Clinical trials

vg, vector genomes.

In the NEI trial, the final registry entry shows that adverse events affecting ocular function increased with dose (3, 3, 12, 6 and 30 events in cohorts 1 to 5), without severe ocular inflammation after day 8, without reduction in ERG amplitude attributed to treatment and without participants with systemic anti-AAV or anti-RS1 antibodies up to year 5 or 7, which differs from the dose-dependent increase in anti-AAV8 antibodies described in the 2018 publication with the first 9 participants [73, 74]; there were serious adverse events of reduced visual acuity (cohorts 3 and 5) and of VH (cohort 3), and non-serious events of vitritis, anterior chamber inflammation, iridocyclitis, retinal vasculitis, uveitic glaucoma, ocular hypertension, cataract, retinal tear and retinal haemorrhage [74]. Immunological analysis of 11 participants showed, before the vector, a pro-inflammatory profile (raised CD4/CD8 ratio, increased interferon gamma and tumour necrosis factor alpha) and, 14 days later, systemic immune activation, with increased HLA-DR+ CD8+ T lymphocytes and activated macrophages in 10 of 11; in the 6 participants with ocular inflammation, the inflammation score correlated modestly with the baseline CD4/CD8 ratio [83]. In the AGTC trial, inflammatory adverse events (keratic precipitates, vitritis, cells in the anterior chamber and vitreous, floaters) increased with dose, and there were subcapsular cataract, optic neuritis and retinal tear in the medium- and high-dose groups [76]. In 2023, a natural history review summarised that no gene therapy trial in XLRS had met its primary efficacy endpoint [34].

7.5.3. Limits of the evidence

The intravitreal trials and the Chinese trial are early-phase, without masking and with the fellow eye as the only control; the Chinese trial, published in 2026, is the most favourable peer-reviewed result to date, but it included 12 patients and had safety as its primary endpoint [71]. The clinical results of ATSN-201 exist only in sponsor press releases and conference presentations, without publication in a journal; the two 2026 press releases contain an internal inconsistency in the number of adults, and the minimum age for part C differs between the June press release (6 years) and the registry and the October press release (5 years) [11, 49, 78]. The trial results cannot be compared indirectly with one another: they differ in route, vector, dose, patient age, baseline severity and endpoints. The spontaneous fluctuation of the cavities, documented in the control eyes in AXIS, requires caution in interpreting closure of the schisis as proof of efficacy [10]. The endpoints used in trials have limitations of their own: visual acuity changes very slowly in the natural history (0.22 to 0.5 letters per year) and is, even so, the measure most likely to show an effect; automated quantification of schisis volume had the largest effect size in a simulated CAI trial (Cohen's d 0.972 versus 0.685 for central subfield thickness and 0.521 for central foveal thickness) and would require 18 patients per arm, versus 35 and 59, for 80% power [44, 45]. The negative or non-efficacious trials (NEI, AGTC) are included in the table. The Chinese natural history cohort suggests a therapeutic window in early adulthood, and the cohort from the Netherlands and Belgium in the first three decades [24, 25]. Men with XLRS who are considering participation in a gene therapy trial describe motivations that should be discussed during consent [84].

7.6. Regulatory status

The FDA does not publish a list of RMAT designations by product, so the US designations of ATSN-201 rest on the sponsor's press releases [86]. No gene therapy for XLRS is authorised by the FDA or by the European Commission as at 10 October 2026 [11, 48].

7.7. Developments in the last 12 months

The absence of published results from the ZM-01, LX103, JWK002 and IVB102 trials in the searches performed does not prove that none exist. The Chinese trial published in the New England Journal of Medicine could not be reliably linked to any of the Chinese registrations in ClinicalTrials.gov [71].

7.8. Low vision, school and driving

Low-vision services, often provided by optometrists, large-print books, front-row seating in the classroom and high-contrast material are the main measures [1]. In the USA, public schools are required by federal law to provide services to children with visual impairment, through an individualised education programme, reviewed annually and with a vision consultant on the team, or through a 504 plan, which may include front-row seating, assistive technology, scribes, extra time, modified assignments and enlarged text [1]. The AAO recommends a low-vision assessment at baseline and then every 1–2 years, and lists as resources Retina International, the Foundation Fighting Blindness, Fighting Blindness Canada, the CNIB, the American Foundation for the Blind and the National Council of State Agencies for the Blind [9]. Many patients obtain a restricted driving licence, and bioptic telescopic lenses may be useful for driving; legality varies between jurisdictions [1].

7.9. Agents and circumstances to avoid, pregnancy, perioperative care and transition

Head trauma and contact or high-impact sports should be avoided because of the risk of RD and VH [1, 68]. Acetazolamide should be avoided in the situations contraindicated in the label (section 7.3.5), and its combination with high-dose acetylsalicylic acid requires caution [56]. In pregnancy, the European SmPC of brinzolamide does not recommend its use, nor in women of childbearing potential not using contraception, because of reproductive toxicity in animals with systemic administration; during breastfeeding, a decision must be made whether to discontinue breastfeeding or the drug [51]. The Portuguese SmPC of dorzolamide states that it should not be used in pregnancy, because of teratogenicity in rabbits at maternally toxic doses, and requires the same decision during breastfeeding; that of acetazolamide states that it should not be used in pregnancy, especially in the first trimester, because of teratogenicity in animals, and reports low levels in breast milk [52, 53]. As XLRS affects almost only males, pregnancy is relevant mainly in the rare affected women; the sources consulted do not describe the course of the disease during pregnancy. Nor do they describe specific perioperative recommendations beyond those for vitreoretinal surgery, or programmes for transition from paediatric to adult ophthalmology; the change from annual surveillance in childhood to intervals of 1–2 years in adulthood (section 11) is the natural moment for that transition [1, 9].

7.10. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Risks by relative

The father of an affected boy is neither affected nor hemizygous and does not need evaluation [1]. The mother is an obligate carrier if there is more than one affected individual in the family; if she has more than one affected son with no other affected relatives and the variant is not detected in her leucocyte DNA, germline mosaicism is the most likely explanation [1]. In a simplex case (a single affected individual in the family), the mother may be a carrier or the variant may have arisen de novo in the proband; de novo variants have been described but are rare [1, 17].

Table sources: GeneReviews, Molday 2012, Kirkby 2023 and Abeshi 2017 [1, 3, 5, 20].

8.2. Cascade testing and at-risk relatives

GeneReviews recommends clarifying the genetic status of older and younger at-risk male relatives, even if asymptomatic, to identify early those who will benefit from surveillance and treatment of complications; when the familial variant is known, molecular testing is performed and, when it is not, an ophthalmological examination [1]. Molecular testing can also identify the relative in whom a de novo variant arose [1]. Carrier detection is by molecular testing, because the eye examination and ERG of carriers are almost always normal (section 5.6) [1, 4]. In Finland, the founder variants allowed carrier testing on a national scale [7]. Genetic testing also opens access to clinical trials, which require molecular confirmation [3, 11].

8.3. Symptomatic carriers

Rarely, a heterozygous carrier has clinical signs, usually mild and peripheral [1, 20]. Skewed X inactivation may explain a more marked phenotype, as in the case in section 10, in which the inactivation ratio was about 86:14 [20]. The authors suggest considering XLRS in girls with atypical findings and an affected father, and studying X inactivation in these rare cases [20].

8.4. Prenatal diagnosis and preimplantation genetic testing

Once the familial variant has been identified, prenatal diagnosis and PGT are possible [1]. Family planning is ideally undertaken before pregnancy, and genetic counselling should be offered to young adults who are affected, carriers or at risk [1]. Views on prenatal diagnosis vary, and the decision is a personal one [1]. The AAO task force recommends counselling by trained professionals for everyone tested, with discussion of the reproductive implications, anxiety and guilt, and the effects on family relationships [91]. The 2022 AAO guidance recommends genetic counselling after the result and again later in life [9].

8.5. Minors

In at-risk boys, testing addresses a disease with onset in childhood and with useful measures from an early age (refractive correction, prevention of amblyopia, surveillance for complications, educational support), so GeneReviews recommends early evaluation of at-risk male relatives [1]. Carrier testing in girls has mainly reproductive implications; the sources consulted contain no specific recommendations on the age at which to offer it.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence

As those affected are almost only males, the prevalence in males is approximately double the prevalence in the general population, an inference by GeneGuidance and not an observed figure [4]. The estimates vary with the source, the period and the method of ascertainment, and none derives from a population study with a defined denominator in the sources consulted.

9.2. USA

North American data come from clinical cohorts and not from prevalence studies: the NEI cohort (68 males; clinical and genetic study with 351 participants including carriers), the Iowa cohort (52 patients), the AGTC prospective natural history study (56 males) and the Miami paediatric series (33 boys) [32, 34, 38, 42, 92]. The Foundation Fighting Blindness inherited retinal disease registry (My Retina Tracker, with an estimated 20,000 participants) serves as a recruitment base for trials [14, 93].

9.3. Europe and founder populations

In Finland, three founder variants (c.214G>A, c.221G>T and c.325G>C) account for 77% of patients in the Helsinki cohort and 95% in the 1999 study, with a regional distribution: Western Finland for the first two and Northern Finland for the third [7, 28]. In the Netherlands and Belgium, c.214G>A is present in 38.7% of patients and the exon 3 deletion in 14.6% [24]. There are published cohorts from the United Kingdom (132 males), France (52 males), several European centres (Oxford, Bonn, Hamburg, Ljubljana, Tübingen; 59 patients), Sweden, Lithuania, Ireland and Spain (17 children from Hospital La Paz) [1, 8, 23, 36, 39, 40, 66]. The phenotype and complication rate vary between cohorts: Finland recorded no RD in 52 patients, whereas the European multicentre study recorded RD in 15% [28, 40].

9.4. Asia

In Korea, 83 male patients showed an association between the retinoschisin secretion profile and final visual acuity [35]; in Japan, 67 patients from 56 families had 37 variants, 12 of them novel [26]; in China, 107 patients with 64 variants allowed the natural history to be modelled [25]. The first published subretinal gene therapy trial was conducted in China, and there are four registered Chinese trials [71, 79–82].

9.5. Portugal and Brazil

The sources consulted contain no data on prevalence, cohorts or variants of XLRS in Portugal or Brazil. This absence in the sources does not demonstrate that no published data exist.

9.6. Special populations

In young children, examinations may require sedation or anaesthesia (section 5.2), and treatment with CAIs has no paediatric safety data in the acetazolamide and brinzolamide labels [9, 51, 56]. Affected women are rare and mostly come from consanguineous families [20]. Part C of the phase 3 trial of ATSN-201 admits women with biallelic variants [11].

9.7. European network and patient organisations

The relevant European network is ERN-EYE, the European Reference Network for rare eye diseases [12]. Patient organisations and resources include Retina International, the Foundation Fighting Blindness with its registry, the NEI eyeGENE and, in the United Kingdom, the Royal National Institute of Blind People (RNIB) [1, 13, 14, 21].

10. Illustrative Clinical Case

10.1. Main case: symptomatic carrier with skewed X inactivation

In 2023, Kirkby and colleagues described a 2-year-old girl referred to a tertiary eye hospital in Oxford because her parents noticed that she bumped into objects on her right side; there was no complaint of night blindness [20]. The parents had observed right esotropia since 2 weeks of age. She was born at 39 weeks by vaginal delivery and had been treated in the neonatal period for presumed sepsis. Cycloplegic refraction was +2.50/−0.75 × 180 in the right eye and +1.00/−1.00 × 180 in the left eye [20]. Her 30-year-old father had had poor vision since childhood, nystagmus and early-onset esotropia, was registered as severely sight impaired, had never had a formal diagnosis or genetic testing, and the referring hospital had noted bilateral foveal schisis; there was no consanguinity and no other relatives with eye disease [20].

The child was examined under anaesthesia at 2 years and at 3 years and 7 months, with no progression between the two examinations [20]. In the left eye there was an area of thinned and elevated retina in the inferior periphery, with a circular outer-layer break visible on fluorescein angiography, and OCT confirmed inferior schisis (figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC10298380/figure/genes-14-01193-f001/) [20]. In the right eye there was a well-demarcated inferotemporal peripheral island of RPE atrophy, two concentric rings of pigment and yellow material, presumably lipid, without schisis on OCT (figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC10298380/figure/genes-14-01193-f002/) [20]. The maculae looked normal on examination, but OCT showed retinas thickened in all layers, without lamination, with small hyporeflective intraretinal cysts and mild bilateral foveal hypoplasia [20]. The ERG under anaesthesia was not electronegative, but the b-wave was reduced in the right eye relative to the left, with photopic b/a ratios of 1.8 and 2.8 (figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC10298380/figure/genes-14-01193-f003/) [20]. The father's examination showed macular RPE changes, a vitreous veil in the mid-periphery and large macular intraretinal cavities, coalescing centrally in the left eye (figure 4, https://pmc.ncbi.nlm.nih.gov/articles/PMC10298380/figure/genes-14-01193-f004/) [20].

A next-generation sequencing panel of 111 retinal genes identified in the child the heterozygous variant NM_000330.4:c.266del p.(Tyr89LeufsTer37) in RS1 (published as c.266delA on transcript NM_000330.3), a novel single-nucleotide frameshift deletion classified as pathogenic by the British National Health Service laboratory; the father had the same variant, and the asymptomatic mother was not tested [20, 27]. Deep intronic variants were not sought, as they were not routinely available in that setting [20]. X-inactivation analysis by methylation of the androgen receptor locus showed a skewed pattern of about 86:14 [20].

The case illustrates several points of this article. A girl whose father is affected is an obligate carrier, and XLRS should be considered in her when there are atypical findings; macular OCT suggested enhanced S-cone syndrome, but the history, the absence of pigmentary banding and the electrophysiology were not compatible with NR2E3 retinopathy [20]. A non-electronegative ERG did not exclude the diagnosis, as happens in some affected boys [5]. Genetic testing also gave the father the molecular diagnosis he had never had. The article published the genomic position g.18,655,371 on GRCh37, whereas VariantValidator returns NC_000023.10:g.18665371del for the same variant [20, 27]. The course described is limited to the interval between the two examinations under anaesthesia, and the article does not describe any treatment [20].

10.2. Complementary case: structural response to dorzolamide in a boy

Thangavel and colleagues described an 8-year-old boy with reduced vision for 4 months, with no relevant family or systemic history, with a BCVA of 6/24 in the right eye and 6/18 in the left [65]. There was bilateral spoke-wheel foveoschisis, without peripheral schisis; FAF showed hyperautofluorescent radial striae and, as an incidental finding, a hypoautofluorescent torpedo lesion inferior to the right fovea (figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC7574065/figure/F1/) [65]. SD-OCT showed a central macular thickness of 678 µm and 603 µm, and the full-field ERG had a negative b-wave [65]. With dorzolamide 2% eye drops three times daily, after one month BCVA was 6/18 and 6/12, and central macular thickness 128 and 135 µm (figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC7574065/figure/F2/) [65]. The article does not describe genetic testing, so the diagnosis lacks molecular confirmation. The response of a single patient after one month does not represent the expected effect: in the retrospective cohort from the Netherlands and Belgium the structural effect of CAIs was small and without functional significance, the cavities fluctuate spontaneously and the only randomised trial showed no clinically relevant benefit (section 7.3) [10, 58]. The use of dorzolamide in XLRS is off-label [54].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The visual prognosis is one of reduced central vision that is stable for decades, with slow decline after the second decade and worsening in later adulthood. Visual acuity at presentation lies between 20/60 and 20/120 and stabilises around 20/100 in most patients [1, 5]. In the Netherlands and Belgium, low vision appeared at a median age of 25 years and the predicted prevalence of severe visual impairment and blindness at 60 years was 35% and 25%; in China, the projection was 40% of patients blind at 60 years [24, 25]. The decline in visual acuity in the natural history is 0.22 to 0.5 letters per year [44]. Slowly progressive macular atrophy appears mainly in the fifth and sixth decades and can lead to legal blindness [1]. RD is associated with worse final visual acuity, and VH and RD are the main causes of complete visual loss [34, 68]. The anatomical prognosis of RD surgery has improved, with final reattachment in 89% in the meta-analysis and 93% in eyes operated on after 2005 in the series from the Netherlands and Belgium [41, 69]. Peripheral schisis is associated with more complications and worse visual acuity, and the authors of the Finnish cohort and of the cohort from the Netherlands and Belgium recommend closer follow-up of these patients, without a defined interval [28, 41].

11.2. Surveillance

GeneReviews recommends annual examination of children under 10 years of age by a paediatric ophthalmologist, for refractive errors and amblyopia, or by a retinal specialist, for peripheral schisis and detachment; older children and adults, who are better able to report visual changes, can be monitored less frequently [1]. For inherited retinal degenerations, the AAO recommends assessment every 1–2 years [9]. Patient education and close follow-up are the only means of identifying complications early [1].

The interval after 10 years of age is not defined in GeneReviews and has been filled with the AAO recommendation for inherited retinal degenerations, which is not specific to XLRS [1, 9].

12. Summary and Concluding Remarks

X-linked juvenile retinoschisis is an X-linked recessive inherited maculopathy caused by loss of function of retinoschisin, a secreted protein that maintains adhesion between retinal cells and the synapse between photoreceptors and bipolar cells. It affects boys from the first decade, with visual acuity of 20/60 to 20/120, spoke-wheel foveal schisis, inferotemporal peripheral schisis in about half and, in about half, an electronegative ERG; carriers are almost always normal. The estimated prevalence lies between 1:5,000 and 1:25,000 males, with a founder effect in Finland and a frequent variant in the Netherlands and Belgium.

Diagnosis rests on SD-OCT and is confirmed by identification of a hemizygous variant in RS1, with sequencing and copy-number analysis; a normal ERG or a negative test does not exclude the disease. The differential diagnosis includes X-linked congenital stationary night blindness, NR2E3 retinopathy, X-linked retinitis pigmentosa, the VCAN and NDP vitreoretinopathies, CRB1 maculopathy, Cohen syndrome and acquired causes of schisis and macular oedema.

The natural history is one of relative stability for decades, with slow decline and macular atrophy in adulthood; VH and RD are the most sight-threatening complications and justify annual surveillance until 10 years of age, surveillance every 1–2 years thereafter, prevention of trauma and vitrectomy when VH does not resolve or there is RD. CAIs reduce the cavities in some patients, but the randomised AXIS trial showed no clinically relevant benefit of oral acetazolamide, and their use is off-label. No therapy is authorised. Intravitreal gene therapy trials showed no efficacy and caused inflammation; a Chinese phase 1 trial with subretinal injection, published in 2026, described closure of the schisis and a gain in visual acuity in 12 children and adolescents, and ATSN-201 has entered phase 3 with results expected in 2028. Genetic counselling, cascade testing of at-risk relatives and links to ERN-EYE and patient organisations complete the care.

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