FEVR is a hereditary disorder involving abnormal retinal vascular development and has various clinical manifestations . Up to now, it is acknowledged that 6 pathogenic genes are associated with FEVR, including LRP5 (Autosomal recessive or scattered inheritance gene), FZD4 and TSPAN12 (Autosomal dominant or recessive gene), ZNF408 (Autosomal dominant gene), NDP (X-Linked recessive gene) and KIF11 which was found recently and was related to the microcephaly-lymphedema-chorioretinal dysplasia (MLCRD) syndrome. It was reported that 40 ~ 50% of FEVR cases were related to the mentioned genes .
Our study probably enrolled the biggest cohort of FEVR infant patients by clinical collection and genetic-screening technology. Based on the evidence of gene chip sequencing analysis and genotype–phenotype co-separation [18, 19], 335 infant cases were detected as positive single-gene. About 78.8% of probands carried genes that is affiliated to the family of Wnt/Norrin signaling pathway. About 17.61% (59 of 335) of probands carried KIF11 gene and only 3.58% (12 of 335) of probands carried ZNF408. The results showed that FEVR induced by NDP and TSPAN12 mutations had a better symmetry than that induced by LRP5 and FZD4. Patients with NDP mutations showed severer clinical manifestations, followed by patients with TSPAN12 mutations. These findings were similar with findings of Tang et al.  Tang et al.found that FEVR patients with TSPAN12 mutations showed severe manifestation and rapid progression. The young patients showed severer clinical manifestation than that of adult patients. In our study, 58.1% of FEVR infant patients were over Stage 4. In addition, FEVR was a progressive disease. As the age of probands getting older, the severity of FEVR would accordingly change, which contributed to the different stages of FEVR. The higher clinical stages and the shorter axial length were, the severer clinical manifestation would be.
The treatment of FEVR included clinical observation, laser coagulation, intravitreal injection of anti-VEGF drugs and surgery [10, 12, 21,22,23,24,25,26,27,28,29,30,31]. Fundus fluorescein angiography (FFA) is a significant examination for helping diagnosis and deciding treatment. Clinical observation is suitable for patients without symptoms or leakage point on FFA. Previous studies suggested that only close follow up was required for patients over 3 years old and whose affected eye was at stage 2A or milder. However, argon laser coagulation is actively used for the eyes that are at stage 2B, accompanied by intraretinal and subretinal exudation or retinal neovascularization . Laser coagulation is appropriate for the eyes with leakage on FFA, which can enclose the leaking blood vessel ends, reduce exudation and prevent mechanical traction after development of fibrous membrane. Intravitreal injection of anti-VEGF drugs is used for the eyes with broad exudation and neovascularization and the eyes that are hard to receive laser coagulation. Anti-VEGF drugs can reduce development of neovascularization and exudation, and suppress progression of FEVR. In our study, the cases at Stage 1 to 3 were mostly given intravitreal injection and/or retina photocoagulation with the last follow-up vision above 20/67. Surgery intervention is an important treatment for severe complications of progressive FEVR, such as vitreous hemorrhage, retinal tear or retinal detachment, secondary epiretinal membrane, secondary cataract or glaucoma and so on. In our study, appropriate surgery was chosen for different severity of FEVR patients, which was good for alleviating the complications of surgery. The patients under one year old accounted for the majority with a proportion of 69.44% for the patients at Stage 4 to 5, which demonstrated that the younger patients showed severer manifestation and close follow-up was necessary for patients under three years old. The stage 4th to 5thpatients were treated with the transcorneal vitrectomy with lensectomy or LSV, whose lens maintained transparent after LSV (11 of 14[78.58%]) corresponding to the previous study (74.1%) . 37.03% of postoperative patients could achieve retinal unfold and partial retinal attachment after surgery. However, after long-term follow up and clinical observation, we comprehensively found that some patients might need to receive second surgery because of severe postoperative reaction, such as hemorrhage, exudation and fibrous membrane in pupil. 69.54% of them received second surgery owing to pupil closure. At the last follow-up, 20% (60 of 300) were with vision above 20/200 and under stable statement. Therefore, present study [10,11,12,13] recommended staged lensectomy and PPV are meaningful to alleviate the postoperative reaction and restore the depth of anterior chamber. For patients with occurrence of severe complications, we suggest that surgery is needed to maintain eyeball integrity, treat complications, prevent the occurrence of retinal detachment and maximize the restoration of visual function.
After analyzing the clinical features of 202 FEVR cases, Zhao et al. found that RD accounted for 33.6% in FEVR patients and 32.92% of affected eyes were misdiagnosed as simple RD.  The rate of correct diagnosis at first visit were 37.13% . Our study dominantly focused on the infant FEVR patients that were under 3 years old. 20% (67 of 335) of infant cases were initially diagnosed as strabismus and ophthalmologists ignored the abnormalities of fundus. In addition to simple strabismus, a certain percentage of strabismus is caused by fundus diseases, such as persistent hyperplastic primary vitreous, X-linked retinoschisis, congenital macular hypoplasia, optic nerve hypoplasia, retinitis pigmentosa, incontinentia pigmenti achromians, Norrie disease, Coats’ disease and so on. These cases reminded ophthalmologists to examine patients’ fundus comprehensively when doctors meet the patients with a diagnosis of strabismus. If necessary, examining fundus of parents or gene testing is meaningful for avoiding misdiagnosis or late diagnosis resulting in severe FEVR. Early screening is an important way of early diagnosis for FEVR and treatment. If the progression of FEVR is stable and remain at Stage 1, the visual function can still be maintained. By contrast, if the progression of FEVR keep developing and causes damage to retina, the prognosis may not be optimistic. FEVR is a disease with extremely diverse manifestations, ranging from none of complaints or completely normal fundus to blindness and atrophy of the eyeball due to vitreous hemorrhage (VH) and RD. FEVR has a long time of development. The onset of FEVR happened when patients are in their infancy. The infant patients seldom showed obvious symptoms and manifestations in the early course of FEVR. At the late course, severe vision loss or even blindness happened due to VH or RD. Sometimes patients in the stationary phase could develop into active phase. Comprehensive fundus examination should be conducted on infants with strabismus. Long-time follow up or follow-up through life is consequently necessary for FEVR patients. The illness of some patients might intend to be active, even after they received treatments [33, 34]. Once the doctors perceive the advancement of the illness, patients should be given treatment immediately to avoid losing their visual function.
Considering the retrospective study, the limitations of our study are as follows. First, although our study enrolled a relatively large sample size, FEVR is a rare disease, and more patients probably provided strongly evidence-based clues. Second, due to FEVR is a disease that has a long development through life, the patients under 3 years that we enroll may introduce a selection bias and elder FEVR children should be observed in future. Likewise, the follow-up time ought to be extended. Third, due to the X-linked recessive manner of NDP mutation, there may exist potential bias in statistical analysis. Finally, cultural or social factors may affect family decision making, which may lead to unpredictable bias.
In conclusion, our long-term study suggested a correlation between clinical phenotypes and gene mutations in FEVR patients. Overall, we found LRP5 mutation accounted for the highest proportion. And the NDP mutation showed the severest clinical manifestation and KIF11 spontaneous mutation accounted for the majority. From the present evidence, we summarized that the main surgical methods for cases at Stage 4 to 5 were transcorneal vitrectomy with lensectomy or LSV and the proportion of surgical treatment was much higher in patients under 1 year old, indicating that the earlier FEVR occurred, the worse the prognosis would be. Consequently, active surgical intervention and lens sparing were necessary for the cases at Stage 4 to 5.