Familial Exudative Vitreoretinopathy (FEVR)

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Familial Exudative Vitreoretinopathy (FEVR)


Disease Entity

Familial Exudative Vitreoretinopathy (FEVR) is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature:

ICD9:

  • 362.12 Exudative retinopathy

CD10:

  • H35.02 Exudative retinopathy:
    • H35.021 – right eye
    • H35.022 – left eye
    • H35.023 – bilateral
    • H35.029 – unspecified eye

Disease

Familial Exudative Vitreoretinopathy (FEVR) defines a group of inherited retinal diseases characterized by abnormal retinal angiogenesis leading to incomplete vascularization of the peripheral retina with subsequent retinal ischemia. As seen in retinopathy of prematurity (ROP), the avascular retina in FEVR may lead to hypoxia and stimulation of neovascular growth into the vitreous leading to later vitreoretinal traction, subretinal exudation and hemorrhages, retinal folds, tractional retinal detachment, and foveal displacement. FEVR is also associated with increased permeability of vessels and can present with exudative retinal detachment.

Familial exudative vitreoretinopathy is a genetically heterogenous disorder that exhibits variable penetrance across patients. The clinical appearance of FEVR tends to be asymmetric and vary significantly even among affected members of the same family. Patients with mild disease may be asymptomatic while those with severe disease can present with severe vision loss. The disease can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive fashion. Thus far, mutations in about 10 genes have been associated with FEVR. However, all known pathogenic variants of these genes accounted for about 50% of all FEVR cases worldwide. 

History

Familial exudative vitreoretinopathy was first reported by Criswick and Schepens in 1969.[1] They described a retinal vascular disease in 6 patients from two families that appeared similar to ROP; however, this disease occurred in patients without prematurity or use of oxygen and continued to progress several years after  birth. Some of the principal features seen were organized vitreous membranes, traction on the retina, heterotopia of the macula with temporal traction, subretinal and intraretinal exudates in the periphery (generally in the temporal retina), and peripheral neovascularization.

In 1971, Gow and Oliver described FEVR in a large family exhibiting an autosomal dominant inheritance pattern.[2] They described three stages of the disease. Stage 1 featured areas of white with pressure and white without pressure associated with vitreous traction. Stage 1 had no evidence of subretinal exudation or abnormal retinal vessels. Stage 2 had dilated tortuous retinal vessels in the periphery, exudation, local retinal detachments in the temporal periphery and a dragged disc. Stage 3 had more extensive retinal detachments, massive subretinal exudates, and other end-stage disease findings.

 In 1976, Canny and Oliver described the fluorescein angiography (FA) of patients with FEVR and its similarities to retinopathy of prematurity. The FA findings confirmed the presence of capillary nonperfusion in the periphery with associated neovascularization.[3] It was not until 1992 when Li discovered that the autosomal dominant form of FEVR mapped to chromosome 11q.[4] This was later discovered to harbor the FZD4 and LRP5 genes.[5][6][7] As of the most recent update of this article, at least 10 genes have been implicated in association with FEVR including FZD4,[6][7] NDP,[8][9] LRP5, [7][10][11] TSPAN12,[12][13][14] ZN408[15] KIF11,[16][17] [18][19]CTNNB1,[20][21] JAG1,[22] RCBTB1,[23] ATOH7,[24] DOCK6,[25] and ARHGAP31.[25]

Epidemiology

FEVR is described as a rare inherited disorder. The prevalence has not been reported yet.

Molecular genetics of FEVR have been reported across different racial and ethnic groups including Caucasian (e.g Dutch,[13][26] Canadian,[6] Italian[27]), Japanese,[28][29] [30]Chinese[31][32][33], Korean,[34] Indian,[35][36] and Mexican. [37] Approximately 35% to 50% of patients diagnosed with FEVR are found to have a corroborating genetic mutation. The contribution  of any given gene to the disease differs among study populations. [38] FEVR caused by NDP, FZD4, LRP5, and TSPAN12 mutations has reported from15 countries including USA, UK, China, Spain, India, Australia, Mexico, Japan, Netherlands, Italy, Canada, Korea, Sweden, Pakistan, and Israel. [39]

Stages

In 1998, Pendergast and Trese proposed a 5-stage clinical classification of FEVR based on ophthalmoscopic findings at the time of presentation.[40] [41] See Table 1. However, patients with FEVR may not progress through these stages in a stepwise fashion.

Table 1. Proposed FEVR Clinical Staging System 1998

Stage Clincal Features
1 Avascular retinal periphery without extraretinal vascularization
2 Avascular retinal periphery with extraretinal vascularization
2A Without exudate
2B With exudate
3 Extramacular retinal detachment
3A Primarily exudate
3B Primary tractional
4 Macula-involving retinal detachment, subtotal
4A Primarily exudative
4B Primary tractional
5 Total retinal detachment
5A Open funnel
5B Closed funnel

In 2014, using wide-field angiography, Kashani et al proposed a revised  clinical staging system of FEVR that includes fluorescein angiography.[38] See Table 2.

Table 2. Revised FEVR Clinical Staging System 2014

Stage Clinical Features
1 Avascular periphery or anomalous intraretinal vascularization
1A Without exudate or leakage
1B With exudate or leakage
2 Avascular retinal periphery with extraretinal vascularization
2A Without exudate or leakage
2B With exudate or leakage
3 Extramacular retinal detachment
3A Without exudate or leakage
4 Macula-involving retinal detachment, subtotal
4A Without exudate or leakage
4B With exudate or leakage
5 Total retinal detachment
5A Open funnel
5B Closed funnel

Pathophysiology

Criswick and Schepens initially postulated that FEVR was caused by the “proliferation of fetal-type retinal vessels, much like those seen in retrolental fibroplasia.” [1] Later, from studies using fluorescein angiography the pathogenesis was proposed to be related to incomplete peripheral vascularization,[2] and secondary neovascularization with subsequent vitreous hemorrhage and retinal detachment.[41] More recently, studies using genetically -modified animal models  provided evidence that the underlying pathogenesis was dysfunctional retinal angiogenesis.[42][43][44] Many studies have suggested a component of atypical membrane formation in FEVR with pathologic vitreoretinal traction. Yonekawa et al performed a structural OCT study, which showed atypical epiretinal membranes originating from an abnormal vitreous.[45] At this time, the underlying cause of the formation of these membranes is not fully understood.

Simplified diagram showing Norrin/FZD4 signaling.

Genetics

Thus far, genes associated with FEVR have been reported including:

  1. Frizzled-4 (FZD4, 11q14.2) [6][7]
  2. Norrie disease pseudoglioma (NDP, Xp11.3) [8][9][11]
  3. Low-density lipoprotein receptor related protein-5 (LRP5, 11q13.2) [7][10]
  4. Tetraspanin-12 (TSPAN12, 7q31.31) [12][13][14]
  5. Zinc finger protein-408 (ZFN408, 11p11.2) [15]
  6. Kinesin family member 11 (KIF11, 10q23.33) [16][17][18][19][46]
  7. Cadherin-associated protein, beta (CTNNB1, 3p22.1)[20][21]
  8. Jagged 1 (JAG1, 20p12.2)[22]
  9. RCC1 and BTB domain containing protein 1 (RCBTB1, 13q14.2)[23]
  10. Atonal bHLH transcriptation factor 7 (ATOH7, 10q21.3)[24]
  11. Dedicator of Cytokinesis 6 (DOCK6, 19p13.2)[25]
  12. RHO GTPase-activating protein 31 (ARHGAP31, 3q13.32-q13.33) [25]


FEVR exhibits three different forms of inheritance: autosomal dominant, autosomal recessive, and x-linked recessive.[47] Among these, autosomal dominant is the most common form.[48] Most of the known identified genes have been linked to certain forms of inheritance:

  • Autosomal dominant: FZD4, LRP5, TSPAN12, ZNF408, KIF11, CTNNB1, JAG1, ARHGAP31
  • Autosomal recessive: FZD4, LRP5, TSPAN12, RCBTB1, ATOH7, DOCK6
  • X-linked recessive: NDP

.

A biological pathway linked to FEVR is the WNT signaling pathway.[49] Norrin can be a ligand for WNT and trigger signaling through the same receptors. In the retina, the WNT signaling cascade regulates normal retinal vascular formation and involves activation of receptor FZD4 and LRP5 as well as TSPAN12.[50]

NDP, FZD4, LRP5, and TSPAN12 are part of the Norrin/β-catenin signaling pathway (also known as Norrin/Frizzled-4 pathway), which has been shown to be necessary for retinal angiogenesis. Variants in any of these genes has been associated with FEVR.[42][50] In retinal vascular development, Müller glia secrete Norrin (NDP gene), part of the TGF-beta superfamily that binds to Frizzled-4 (FZD4) on retinal endothelial cells and triggers WNT signaling. LRP5 is a WNT coreceptor, and TSPAN12 is believed to increase FZD4 multimerization  which enhances signaling. Mouse knockout models of the Norrin/Frizzled-4 pathway (Fzd4-/-, Ndp -/-, Lrp5 -/-, and Tspan12-/-) show a stereotypic phenotypic pattern of retinal vascular defects including: absence of the intraretinal capillary plexi, artery and vein tortuosity, intraocular hemorrhage, and secondary delayed regression of the hyaloid vasculature. However, Lrp5-/- appear to have a less severe phenotype.[42][44][51]

Mutations in NDP are also seen in Norrie disease. Mutations in LRP5 are seen in Osteoporosis-pseudoglioma syndrome, which is characterized by the presence of low bone mass density. Patients with FEVR caused by LRP5 mutations should be evaluated for osteoporosis. [8][9][10]

Mutations in RCBTB1 are reported in association with Coats disease.[23] ATOH7 was identified as the gene associated with persistent fetal vasculature syndrome.[52][53] KIFF11 mutations, identified in approximately 5-8% of patients with FEVR, [19] are also associated with a rare autosomal dominant inherited syndrome called microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR). [16] Most recently, mutations of Adams-Oliver syndrome (AOS) genes: DOCK6 and ARHGAP31 were found in two patients presenting with FEVR and microcephaly.[25]

In a retrospective study of 89 patients with retinal folds associated with FEVR, it was observed that patients with mutations in NDP, TSPAN12, or KIF11 were more likely to have bilaterally symmetrical severe retinopathy in contrast to those with mutations in LRP5 and FZD4 who had milder but a broader phenotypic spectrum and greater asymmetry.[54] In a study involving a large cohort of 389 patients screened for genetic variants by a single clinic, patients with mutations in NDP and KIF11 had more severe disease than those with mutations in the other 4 genes evaluated (LRP5, FZD4, TSPAN12, ZNF408). [32] The same study also showed that variants in LRP5 and FZD4 exhibited more significant variation in phenotype than variants in TSPAN12 and NDP. However, the literature is not in agreement about genotype-phenotype relationships, and there is much variability in the phenotype of family members with the same mutation as well as in the same individual between eyes.

Diagnosis

History

The presence of bilateral avascular peripheral retina in the setting of full-term birth without supplemental oxygenation and a progressive clinical course distinguish FEVR from ROP. A positive family history provides additional evidence of the diagnosis. However, a negative family history is less useful, because a positive family history of FEVR can be present less than 10% of the time in some studies and up to 50% in others.[49] Furthermore, many family members with FEVR are asymptomatic and are not aware of the diagnosis.

In a retrospective chart review of 273 eyes in 145 patients, Ranchod et al described the clinical presentation of FEVR patients.[41] The mean age at presentation was 58.6 months. Compared to patients with ROP, the mean birth weight was 2798g and gestational age was 37.8 weeks. However, the range of birth weights was from 740-4763g and range of gestational ages was 25-42 weeks showing that there can be overlap with ROP. Twenty-six (18%) of patients with FEVR had a positive family history of FEVR. However, an additional 28 patients (19%) had a family history of ocular disease potentially representing undiagnosed FEVR. As FEVR can be highly asymmetric between eyes of the same patient, the study reported less than half (43%) of patients with the same clinical stage in both eyes, whereas 71% had bilateral disease within 1 stage of each other.

Physical Exam

Careful dilated fundus examination with wide angle fluorescein angiography is important in patients with FEVR for accurate clinical staging and management. An examination under anesthesia may be required for diagnosis, imaging acquisition, and treatment. Many of these patients will have clinical findings similar to retinopathy of prematurity, but full-term birth, normal birthweight, and no history of oxygen requirement should alert the physician to the possibility of FEVR. 

Fundus photograph of the right eye with a patient with FEVR. Notice the subtle vessel straightening but otherwise normal appearance. Compare to the left eye of the same patient showing noticeable asymmetry.

Signs

  1. Avascular peripheral retina - This can be appreciated on careful dilated fundus examination.  However, in subtle cases or asymptomatic family members, wide angle fluorescein angiography is helpful in uncovering this finding. Classically, the temporal quadrant is most often involved with a v-shaped demarcation. However, the avascular zone can extend 360 degrees. The demarcation has been described as a "brush-border."
  2. Dragged retinal vessels and macula - Retinal arteries and veins can be dragged, usually temporally with apparent straightening of the vessels. In addition, the macula can be dragged temporally.
  3. Retinal (falciform) folds - Radial retinal folds were seen in 28% of eyes in one study. Retinal folds are most often seen in the temporal location, but they can be seen in any location.[41]
  4. Neovascularization  -The avascular retina is believed to lead to retinal hypoxia, which can induce extraretinal neovascularization.
  5. Subretinal exudates - Variable amounts of subretinal exudation can be seen. Massive exudation can mimic Coats disease.
  6. Retinal detachments - Tractional and/or rhegmatogenous retinal detachments can be seen in severe cases, occurring in 21–64% of affected individuals.[47] In the Ranchod et al series, of the 91 patients who presented with a retinal detachment in the worse eye, 62 (68%) presented with some degree of retinal detachment in the fellow eye as well.[41]
  7. Persistent fetal vasculature
  8. Epiretinal membranes

Ancillary Tests

Fluorescein angiogram of the right eye, which shows peripheral avascular retina with two areas of hyperfluorescence and late leakage corresponding to retinal neovascularization.

Fluorescein Angiography

Fluorescein angiography is helpful in the diagnosis and evaluation of FEVR especially in cases with only peripheral avascular retina. The avascular zone is classically described as a v-shaped pattern in the temporal periphery, typically larger than the rest of the periphery but can extend 360 degrees.[55] In a case series of 74 subjects from 17 families, Kashani et al described a variety of retinal vascular anomalies in FEVR using wide-field fluorescein angiography, including:[56]

  1.  Telangiectasias in the macula or periphery
  2.  Optic disc leakage
  3. Arterial tortuosity
  4. Peripheral capillary agenesis
  5.  Anomalous vascularization or supernumerary vascular branching in areas of vascular-avascular junctions
  6. Aberrant circumferential vessels.
  7. Delayed AV transit
  8. Choroidal nonperfusion
  9. Venous-venous shunting
  10. Central macular edema

.

The majority of index patients (71%) had late-stage FEVR and poor visual acuity in the Kashani et al study. More than half of the asymptomatic relatives demonstrated clinical and angiographic findings consistent with early stages of the diseases and a third were found to have avascular retina with exudate or were at risk of developing exudate.

With the increasing use of wide field fluorescein angiography, FEVR is increasingly recognized to have a broad range of appearances. This imaging modality is helpful for diagnosis and management of FEVR. Fluorescein leakage without clinical exudation raises concern for the exudative phase of the disease. Because exudation has been reported to complicate laser photocoagulation, detection of leakage on a fluorescein angiogram allows for timely treatment before exudation occurs.[56]

Optical Coherence Tomography

Optical coherence tomography (OCT) can show posterior segment microstructures present in FEVR including:[45]  

  1. Posterior hyaloidal organization
  2. Vitreomacular traction
  3. Vitreopapillary traction
  4. Diminished foveal contour
  5. Persistence fetal foveal archiecture
  6. Cystoid macular edema
  7. Intraretinal exudates
  8. Distortion of the ellipsoid zone

Genetic Testing

Genetic testing is offered for diagnostic confirmation and to screen family members if the genetic defect is known. In addition, it is helpful if the diagnosis is unclear such as in differentiating from other vitreoretinopathies with similarities to FEVR, such as Norrie disease, persistent fetal vasculature syndrome, incontinentia pigmenti, and retinopathy of prematurity. Results from genetic testing may help guide systemic management. For example, if a defect in the LRP5 gene is found, evaluation for osteoporosis should be performed.[10]

Mutations in genes implicated in FEVR thus far account for less than 50% of all FEVR cases. For example, a 2017 study of Chinese families found that mutations in six known genes at the time (LRP5, FZD4, TSPAN12, NDP, ZNF408, and KIF11) only accounted for 38.7% of patients with FEVR. [33] Thus, physicians and patients should be aware of the high likelihood of a negative genetic test suggesting there are other genes in the disease pathogenesis yet to be identified.  

Differential Diagnosis

  1. Retinopathy of prematurity - In contrast to FEVR, there is a history of prematurity with possible use of oxygen. Family history is often absent. Subretinal or intraretinal exudation is less common.[57]The clinical course of ROP often is not progressive in the years after birth as is seen in FEVR.[41]
  2. Norrie disease - In contrast to FEVR, patients can have microphthalmia, corneal opacification, developmental delay and deafness. [50] 
  3. Coats disease - Usually unilateral and with a male predilection (80%). In contrast to FEVR, neovascularization and tractional membranes are not usually seen.[57]
  4. Incontinentia pigmenti - X-linked dominant and lethal in males. In contrast to FEVR, patients have pathognomonic skin findings at birth and can have neurologic issues including developmental delay, paralysis and seizures.
  5. Persistent fetal vasculature- Typically sporadic and unilateral. However, FEVR can manifest as persistent fetal vasculature, and genetic testing is often considered.
  6. Toxocara canis - Usually unilateral with associated uveitis.

Clinical Course

When it was first reported in 1969, FEVR was presented as a progressive disease.[1] In 1980, Ober et al presented a case series of 3 families affected by autosomal dominant FEVR and showed that the disease can be asymptomatic and nonprogressive.[58] It was observed that the disease was not more advanced in older compared to younger patients within families. In general, the disease tends to have a progressive course during childhood and adolescence and can become latent after 20 years of age. However, late progression with vision threatening complications, including vitreous hemorrhage and retinal detachment, can occur at any age after varying periods of quiescence.[59]

Benson evaluated the natural history of FEVR in 39 patients. It was found that patients who were diagnosed before the age of 3 had a more severe clinical course with very poor visual prognosis. The most rapid progression is generally seen in children and adolescents. If patients do not have progression before the age of 20, the disease can remain stable. In the study, 3 eyes of 4 patients who were asymptomatic to the age of 15 had a final visual acuity of counting fingers or worse. In addition, late deterioration can be seen with retinal detachments occurring 6 to 17 years after “apparent stabilization.”[57] A case series by Ranchod et al demonstrated a high propensity toward retinal detachment in the fellow eye in patients presenting with retinal detachment (62 out of 91, 68%). Pendergast and Trese showed that patients with Stage 1 disease did not progress to a more advanced stage with a mean follow up on 33 months. [40] Long-term follow up of these patients is important to detect reactivation.

Photocoagulation performed in area of retinal peripheral avascularity.

Management

The management of FEVR depends on the clinical stage of the disease. Due to the vision threatening sequelae of neovascularization, an early diagnosis and treatment can be vision preserving. One study showed that 58% of asymptomatic family members had clinical and angiographic evidence of Stage 1 and 2 FEVR.[38] Therefore, screening of family members of patients with FEVR is recommended. Due to the association with osteoporosis-pseudoglioma syndrome caused by the LRP5 mutation, all FEVR patients who do have access to genetic testing should have DEXA scan to assess bone mineral density.[10] If positive for osteroporosis, then the patient should be referred to rheumatology for bisphosphonate therapy.[60]

Patients with Stage 1 disease[40] can be observed and followed over time. For stage 2 disease, laser photocoagulation of the avascular zones is recommended to promote regression of neovascularization and resolution of exudation. Patients with more advanced disease with retinal detachments require surgical management.  Scleral buckling and/or vitrectomy can be considered depending on the clinical scenario with with laser photocoagulation of the peripheral avascular retina. Patients with Stage 3A or partial exudative retinal detachments have been reported to have favorable outcomes with scleral buckling alone.[40]

Few studies have evaluated the use of anti-VEGF in the treatment of FEVR. One case report of a patient with FEVR with neovascularization showed regression after one injection of bevacizumab with short term follow up.[61] In a larger study, intravitreal bevacizumab (IVB) was used as an adjunct therapy to either laser or surgical management. [62]  Rapid progression of tractional retinal detachment occurred in  3 eyes of patients with stage 3B FEVR who were treated with IVB as an adjunct to surgery with scleral buckling and indirect diode laser (2 eyes) or vitrectomy with membrane peeling and endolaser (1 eye). In contrast, all 7 eyes with stage 2 or 3A FEVR in the same series achieved stabilization of disease with laser and IVB alone and did not develop progressive tractional retinal detachment. Further studies are needed to assess the utility of anti-VEGF therapy in the management of FEVR.

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