Retinoschisis can occur in the fovea or peripheral retina, and generally includes congenital/hereditary, acquired (age-related) and secondary types (1), with significant differences in etiology, site of onset, and clinical manifestations. X-linked retinoschisis is more common in male children and rare in females. Clinically, male patients mainly present with early onset visual impairment or vision loss, and retinal retinoschisis due to division of the inner retina. X-linked retinal retinoschisis (XLRS) are usually caused by mutations in retinoschisin 1 located in Xp22.13 (2), except for the rare cases of autosomal dominant retinal retinoschisis (3). In general, women are mostly carriers except for homozygous variants caused by conspecific marriage (4), and most female carriers have no significant visual function and electroretinogram (ERG) (5). However, a female patient with retinoschisis has been reported to have heterozygous variants of RS1 gene (6).

Hereditary retinal diseases caused by CRB1 gene variants may have different clinical manifestations. Online Mendelian Inheritance In Man (OMIM) includes Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), early-onset cone-rod dystrophy (EOCRD) and pigmentary paravascular chorioretinal atrophy (PPCRA) (7, 8). In 1977, Lewis et al. (9) first described Familial Foveal Retinoschisis (FFR), and reported that three female patients in a family presented with mild visual loss. FFR was first reported by Vincent et al. (10) as a recessive hereditary eye disease caused by CRB1 gene mutation.

The purpose of this study was to identify the pathogenic genes and clinical characteristics of female patients diagnosed with retinal retinoschisis in the outpatient department, and to improve the pathogenic gene profile and the natural course of the disease.

Crumbs homolog 1 (CRB1) gene encodes a transmembrane protein similar to Drosophila crumbs protein, located at 1q31.3 (OMIM:604210). Its transcript contains many EGF-like domains and laminin G domains. CRB1-A and CRB1-B are expressed in Muller cells and photoreceptor cells of the retina. Transcript A is the most abundant and located at the top of Muller cells during development. Transcript B is dominant in the adult retina and is localized in the inner and outer segments of photoreceptors (15). It can interact with membrane palmitoylated protein 5 (MPP5) to maintain cell apical polarity and mediate intercellular adhesion (16). In this case, the mutation site of the patient was concentrated in the exon 6 region, and the mutation site c.1366 T > C (p. Cys456Arg) was a new mutation site, which had not been reported before. According to the protein structure prediction, the mutation site was located in the EGF-like domain. The mutation may affect the protein structure and the interaction between proteins. The other mutation, c.1576C > T (p. Arg526*), is a known pathogenic mutation located in the laminin G domain. This mutation causes protein truncation and changes its function, thus affecting cell adhesion and signal transduction. Therefore, it may affect the interaction between retinal cells, resulting in the formation of retinoschisis or capsule-like structures between retinal layers.

In 1977, Familial Foveal Retinoschisis (FFR) was first described by Lewis et al., who reported that three female patients in a family presented with mild visual loss and binocular foveal retinoschisis changes similar to XLRS (9). OCT results of FFR patients show typical foveal retinoschisis or cystoid uplift in the fovea, and the peripheral retina is generally normal (9, 17, 18). Among the cases reported in the previous literature, 11 were female patients and only one was male (9, 10, 17–19). FFR is a recessive hereditary eye disease caused by CRB1 gene mutation, which was first reported by Vincent et al. (10). Considering the recessive inheritance and sporadic nature of the disease, Kabanarou et al. also referred to this disease as isolated foveal retinoschisis (18). Patients with CRB1 gene variants usually present with cystoid macular changes before the age of 30 (20, 21). In addition, over time, the patient’s fundus changes from foveoschisis to cyst-like degeneration, and finally develops into atrophic macular degeneration (22, 23). In most cases, this is the natural course of FFR caused by mutations in the CRB1 gene. The retina of patients usually begins to change around the age of 25–30, and the retina develops from foveal retinoschisis to macular or foveal cyst-like degeneration. However, the patient’s retina has entered the stage of cyst-like degeneration at the age of 12. The OCT results suggested that the thickness of the foveal retinoschisis had been increasing since the record was made in 2015 until August 2017, before the injury occurred. The day after the patient fell and hit the ground on her face, OCT showed that the retinoschesis relieved a lot and gradually disappeared in 2 years with only mild parafoveal cystoid macular degeneration. We cannot show any direct evidence that the quick relief of foveal retinoschesis after accident is caused by the force on her face, although it is possible.

In this case, the female patient has been diagnosed with congenital retinoschisis, which may be due to the fact that the early symptoms of foveoschisis are basically the same as the manifestations of foveoschisis in XLRS. However, the rapid reduction of foveoschisis after trauma, the absence of RS1 gene mutation, and the female sex of the patient are contrary to the common clinical manifestations of XLRS. The clinical manifestations of this patient are also different from the common clinical manifestations caused by CRB1 gene mutation. It has been reported that FFR caused by CRB1 gene may have different ERG manifestations (10). However, the ERG results of XLRS patients usually show that the a-wave amplitude is basically normal or slightly decreased, the b-wave amplitude is decreased, and the b/a ratio is decreased. It is particularly noteworthy that although the parafoveal foveoschisis can also present as a “bridge-like” or “spoke-like” change in the early stage of FFR patients; However, the foveal retinoschisis is mainly cystoid retinoschisis. However, on the second day after the external force collision, the retinoschisis in the fovea, which had been relatively stable, was rapidly relieved, and the vision was improved. Even if we cannot be sure that the impact of the face on the ground is the root cause of the apparent reduction of foveal retinoschisis the next day, we cannot exclude the possibility that the cystoid retinoschisis retracted in a short time due to the release of the fluid in the raised capsule from the small tear by the impact of trauma. Because we have also encountered the phenomenon of retinal flattening at the foveal retinoschisis after trauma in patients with XLRS. Although the natural course of FFR also transitions from foveal retinoschisis to cystoid degeneration, it is likely that the collision accelerated the rate of change in this patient’s foveal retinoschisis. Although there is no direct scientific evidence to prove that trauma can accelerate the process of the disease, external factors may have a certain impact on the disease (24). At present, some researchers use carbonic anhydrase inhibitors (CAI) to treat retinoschisis or cystoid macular edema caused by CRB1 gene mutation (25, 26). It is also meaningful to take preventive measures to protect macula in atrophy stage.

In summary, hereditary retinal diseases caused by mutations in the CRB1 gene may have different clinical phenotypes, Including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), early onset cone-rod dystrophy (EOCRD), paravertebral chorioretinitis pigmentosa (PPCRA) (7, 8), and less severe isolated foveal retinoschisis, which vary in onset time and symptoms. The retinoschisis caused by CRB1 gene mutation reported in this case may be the mild phenotype, the least impact on vision, and the best prognosis in the spectrum of retinal diseases caused by CRB1 gene. The course of the disease can be divided into three stages: the retinoschisis stage, the cystoid edema stage, and the atrophy stage (Figure 4) (10). Whether the environment, drugs and external forces can affect or change the prognosis of this disease has not yet been confirmed by evidence-based medicine. Moreover, whether the cause of these different clinical manifestations caused by CRB1 gene mutation is related to the relevant special sites of CRB1 mutation remains to be elucidated. It is particularly noteworthy that although the exact cause of familial foveal retinoschisis caused by CRB1 gene variants is unknown, the majority of patients with familial foveal retinoschisis are female. This is an important clinical difference between the early stage of this disease and sex-linked retinoschisis caused by RS1 gene mutation.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of Shenyang He Eye Specialist Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

JP conceptualized and designed the study and analyzed the cases and revised the manuscript. JP, YR, and SL recruited the patients. DW and DXi collected the data. JP, SL, and YR obtained patients’ consent, examined, and followed-up the patients. SL and YR analyzed the genetic testing results, reviewed the literature, and wrote the manuscript. ZL, DXu, YS, and ZW provided administrative and technical support. All authors approved the final manuscript.

This work was supported by the National Natural Science Foundation of China (81970840) and the Shenyang Science and Technology Project (No.20-301-4-00).

DXu and JP were employed by Shenyang Weijing Biotechnology Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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