Familial Exudative Vitreoretinopathy (FEVR)

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Familial Exudative Vitreoretinopathy (FEVR)
Classification and external resources
ICD-10 H35.0
ICD-9 362.12
OMIM 133780
DiseasesDB 32973


Disease Entity

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

ICD9:

  • 362.12 Exudative retinopathy


ICD10:

  • 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 diseases with abnormal retinal angiogenesis leading to incomplete vascularization of the peripheral retina. It can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive fashion.  Genes linked to the disease discovered so far are NDP, FZD4, LRP5, TSPAN12, KIF11 and ZN408. Classically, the severity of avascular peripheral retina tends to be asymmetric and varied penetrance within the same family. Similar to retinopathy of prematurity, this retinal ischemia may lead to secondary neovascularization causing traction, exudation, retinal folds, retinal detachment, foveal displacement, and retinal dysplasia.

History

In 1969, Criswick and Schepens first named and described 6 patients found in two families with FEVR. They described a familial disease that appeared similar to retinopathy of prematurity; however occurred in patients without prematurity, use of oxygen, and disease 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 temporally), and peripheral neovascularization.[1] In 1971, Gow and Oliver described a large family with FEVR, which exhibited an autosomal dominant inheritance pattern. They described three stages of the disease. Stage 1 was areas of white with pressure and white without pressure with areas of vitreous traction. 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 is the advanced phase of the disease with retinal detachments, massive subretinal exudates, and other end-stage disease findings. [2] 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 capillary nonperfusion in the periphery with associated neovascularization in those areas. [3] It wasn’t until 1992 when Li discovered that the autosomal dominant form of FEVR mapped to chromosome 11q.[4] Later discovered to harbor the FZD4 and LRP5 genes.[5][6][7] Since then FEVR has been described with autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns. Six genes so far have been implicated in FEVR: FZD4[6][7], NDP[8][9], LRP5[7][10], TSPAN12[11][12][13], KIF11[14][15] and ZN408. [16]

Epidemiology

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

Stages

In 1996, Pendergast and Trese proposed a clinical classification of FEVR based on ophthalmoscopic findings, which was simplified in 2011.[17][18] See Table 1. Of note, FEVR patients may not progress through these stages in a stepwise fashion and was meant for classifying at the time of presentation.

Table 1. Proposed classification of FEVR
Stage Clinical Features

1

Avascular retinal periphery

2

Retinal neovascularization

2A

Without exudate

2B

With exudate

3

Extramacular retinal detachment

3A

Without exudate

3B

With exudate

4

Macula-involving retinal detachment, subtotal

4A

Without exudate

4B

With exudate

5

Total retinal detachment

Pathophysiology

Criswick and Schepens initially postulated the cause of FEVR was caused by the “proliferation of fetal-type retinal vessels, much like those seen in retrolental fibroplasia.”[1] Fluorescein angiography then showed the pathogenesis to be from incomplete peripheral vascularization.[2] This incomplete vascularization can then lead to secondary neovascularization and its subsequent complications. More recently, through animal genetic models, the underlying pathogenesis is likely due to dysfunction in retinal angiogenesis. Many studies have suggested that there is also a component of atypical membrane formation in FEVR which causes abnormal traction. For instance, Yonekawa et al performed a structural OCT study which showed atypical epiretinal membranes which originate from an abnormal vitreous.[19] At this time, the underlying cause of the formation of these membranes is not fully understood.

Simplified diagram showing Norrin/FZD4 signaling.

Genetic Pathophysiology

Scientists have now linked 6 distinct genes that can lead to FEVR including FZD4[6][7], NDP[8][9], LRP5[7][10], TSPAN12[11][12][13], KIF11[14][15] and ZN408. [16]. NDP, FZD4, LRP5, and TSPAN12 are part of the Frizzled4/Norrin signaling pathway which has been shown to be necessary for retinal angiogenesis and an underlying pathogenesis for FEVR.[20] In retinal vascular development, Muller glia secrete Norrin (NDP gene), part of the TGF-beta superfamily which binds to Frizzled-4 (FZD4) on retinal endothelial cells leading to WNT signaling. LRP5 is a WNT coreceptor, while TSPAN12 is thought to increase FDZ4 multimerization  which enhances signaling. Mice knockout models of the Frizzled-4/Norrin 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. Although, LRP5-/- appear to have a less severe phenotype.[20][21][22] Mutations in NDP are also seen in Norrie’s disease, while mutations in LRP5 are seen in Osteoporosis-Pseudoglioma syndrome. In patients with FEVR from LRP5 mutations should be evaluated for osteoporosis as well.[8][9][10]

Diagnosis

History

In a large retrospective chart review of 145 patients, the clinical presentation of FEVR patients was studied. It showed that the mean age at presentation was 58.6 months. Differentiating them from ROP patients, 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 age was 25-42 weeks showing that there can be some overlap. 26% of these patients had a positive family history of FEVR. FEVR can be inherited in an autosomal dominant, autosomal recessive, and X-linked recessive pattern. The disease can be highly asymmetric between eyes with different staging. Per the above study, 43% of patients presented with the same clinical stage in both eyes.[18]

Physical Exam

Careful dilated fundus exam is important in these patients for adequate clinical staging and need for further management. An exam under anesthesia may be required for diagnosis, imaging modalities, and treatment. Many of these patients will have the same physical exam findings of retinopathy of prematurity, but were born full-term, with normal birthweight, and no oxygen requirement. 

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.
 
Fundus photograph of the left eye of the same patient. Notice the marked vessel straightening and dragged fovea.
 

Signs

  1. Avascular peripheral retina - This can be appreciated on careful fundus examination, however in subtle cases or asymptomatic family members fluorescein angiography can be invaluable in uncovering this finding. Classically, the  temporal quadrant is most often involved with a v-shaped demarcation, however this avascularity can extend 360 degrees. In addition, the demarcation is 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.
  3. Retinal (falciform) folds - Radial retinal folds were seen in 28% of eyes in one study. Most often are seen in the temporal location, but can be seen in any location.[18]
  4. Neovascularization - Due to the avascular retina, retinal ischemia induces neovascularization.
  5. Subretinal exudates - Variable amounts of subretinal exudation can be seen. Massive exudation can be seen that can mimic Coat’s disease.
  6. Retinal detachments - Tractional and rhegmatogenous retinal detachments can be seen.
  7. Persistent fetal vasculature

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 angiogram of the left eye, which shows a wedge of peripheral avascular retina in the temporal periphery. Notice the retina vascular dragging and anomalous architecture.

Fluorescein Angiography

Fluorescein angiography is an important test to help with diagnosis especially in the mild stages where only peripheral avascularity can be seen. This avascular zone is classically described as a v-shaped pattern in the temporal periphery, but this can extend 360 degrees.[23] In addition, the temporal avascular zone is noted to be larger than the rest of the periphery.[23] is This can be especially useful in screening family members where subtle peripheral avascularity can be more readily seen.[24] Kashani et al. described a  variety of retinal vascular anomalies in FEVR using wide-field angiography, including:[25]

  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

Genetic Testing

Genetic testing can be offered for confirmation purposes and screening of family members if the genetic defect is known. In addition, it may be helpful in unclear diagnosis. However, a study in China showed mutations in the 6 known genes only account for 38.7% of patients with FEVR.[26] Genetic testing maybe helpful with differentiating between Norrie’s disease, Incontinentia Pigmenti and FEVR. In addition, if a defect in the LRP5 gene is found, testing for osteoporosis should be performed.[10]

Clinical Course

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 course with a 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, usually the disease remains 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.”[27] 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.[17] Further studies are needed for long term outcomes of these patients.

Differential Diagnosis

  1. Retinopathy of prematurity - In contrast to FEVR, there is a history of prematurity and use of oxygen, no family history, and has a peripheral ridge in early stages. Subretinal or intraretinal exudation is rare.[27]
  2. Norrie’s disease - In contrast to FEVR, patients can have microphthalmia, corneal opacification, developmental delay and deafness. 
  3. Osteoporosis-pseudoglioma syndrome - Vitreoretinal dysplasia with bone fractures.
  4. Coats’ disease - Usually unilateral and most commonly in males. In contrast to FEVR, neovascularization and tractional membranes are not usually seen.[27]
  5. Incontinentia pigmenti - X-linked dominant and lethal in males. In contrast to FEVR, they have pathognomonic skin findings and can be associated with developmental delay and seizures.
  6. Toxocara canis - Usually unilateral with associated uveitis.
Photocoagulation performed in area of retinal peripheral avascularity.

Management

Management of FEVR depends on the clinical stage of the disease. Due to the consequences of neovascularization on visual outcomes, an early diagnosis can be vision preserving. One study showed that 58% of asymptomatic family members had  clinical and angiographic evidence of Stage 1 and 2 FEVR.[24] Therefore, adequate screening, especially of family members is important.

For Stage 1 disease, patients likely have a low likelihood of progression to advanced stages[17], so these patients may be observed. However, treating the avascular zones with laser photocoagulation can be considered, especially if the other eye is at an advanced stage. For Stage 2 disease, laser photocoagulation of the avascular zones is recommended to promote regression of neovascularization and clearing of exudation. In one study, 6 out 7 eyes with stage 2B disease showed stabilization of their disease over a mean follow up of 23.5 months.[17] Patients with more advanced disease with retinal detachments require surgical management.  Scleral buckling or vitrectomy can be considered depending on the clinical scenario with concurrent ablation of the avascular retina. Patients with Stage 3A or partial exudative retinal detachments had favorable outcomes with scleral buckling alone.[17] Few studies have studied the use of anti-VEGF in the treatment of FEVR. One case report of a patient with FEVR with neovascularization showed regression with one injection of bevacizumab with short term follow up.[28] In a larger study, intravitreal bevacizumab was used as an adjunct therapy to either laser or surgical management, dependent on clinical staging.[29] Further studies will be needed to know which clinical scenarios would anti-VEGF treatment would be beneficial.

Additional Resources

References

  1. 1.0 1.1 Criswick V, Schepens C. Familial Exudative Vitreoretinopathy. American Journal of Ophthalmology. 1969;68(4):578-594.
  2. 2.0 2.1 Gow J. Familial Exudative Vitreoretinopathy. Archives of Ophthalmology. 1971;86(2):150. 
  3. Canny CLB, Oliver GL. Fluorescein Angiographic Findings in Familial Exudative Vitreoretinopathy. Archives of Ophthalmology. 1976;94(7):1114-1120. 
  4. Li Y, Fuhrmann C, Schwinger E, Gal A, Laqua H. The Gene for Autosomal Dominant Familial Exudative Vitreoretinopathy (Criswick-Schepens) on the Long Arm of Chromosome 11. American Journal of Ophthalmology. 1992;113(6):712-713. 
  5. Li Y, Müller B, Fuhrmann C, et al. The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533. Am J Hum Genet. 1992;51(4):749–54
  6. 6.0 6.1 6.2 Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32(2):326–30.
  7. 7.0 7.1 7.2 7.3 7.4 Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004;74(4):721–30. doi:10.1086/383202.
  8. 8.0 8.1 8.2 Plager DA, Orgel IK, Ellis FD, Hartzer M, Trese MT, Shastry BS. X-linked recessive familial exudative vitreoretinopathy. Am J Ophthalmol. 1992;114(2):145–8.
  9. 9.0 9.1 9.2 Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5(2):180–3. doi:10.1038/ng1093-180.
  10. 10.0 10.1 10.2 10.3 Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.
  11. 11.0 11.1 Poulter JA, Ali M, Gilmour DF, et al. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):248–53. doi:10.1016/j.ajhg.2010.01.012.
  12. 12.0 12.1 Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):240–7. doi:10.1016/j.ajhg.2009.12.016.
  13. 13.0 13.1 Poulter JA, Davidson AE, Ali M, et al. Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR). Invest Ophthalmol Vis Sci. 2012;53(6):2873–9. doi:10.1167/iovs.11-8629.
  14. 14.0 14.1 Robitaille JM, Gillett RM, LeBlanc MA, et al. Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations. JAMA Ophthalmol. 2014;132(12):1393–9. doi:10.1001/jamaophthalmol.2014.2814.
  15. 15.0 15.1 Hu H, Xiao X, Li S, Jia X, Guo X, Zhang Q. KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy. Br J Ophthalmol. 2016;100(2):278–83. doi:10.1136/bjophthalmol-2015-30687
  16. 16.0 16.1 Collin RW, Nikopoulos K, Dona M, et al. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci USA. 2013;110(24):9856–61. doi:10.1073/pnas.1220864110.
  17. 17.0 17.1 17.2 17.3 17.4 Pendergast SD, Trese MT. Familial exudative vitreoretinopathy. Results of surgical management.Ophthalmology. 1998;105(6):1015–23. doi:10.1016/S0161-6420(98)96002-X.
  18. 18.0 18.1 18.2 Ranchod TM, Ho LY, Drenser KA, Capone A, Trese MT. Clinical presentation of familial exudative vitreoretinopathy. Ophthalmology. 2011;118(10):2070–5. doi:10.1016/j.ophtha.2011.06.020.
  19. Yonekawa Y, Thomas BJ, Drenser KA, Trese MT, Capone A. Familial Exudative Vitreoretinopathy: Spectral-Domain Optical Coherence Tomography of the Vitreoretinal Interface, Retina, and Choroid.Ophthalmology. 2015;122(11):2270–7. doi:10.1016/j.ophtha.2015.07.024.
  20. 20.0 20.1 Xu Q, Wang Y, Dabdoub A, et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116(6):883–95.
  21. Ye X, Wang Y, Cahill H, et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell. 2009;139(2):285–98. doi:10.1016/j.cell.2009.07.047.
  22. Junge HJ, Yang S, Burton JB, et al. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell. 2009;139(2):299–311. doi:10.1016/j.cell.2009.07.048.
  23. 23.0 23.1 Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy.Ophthalmology. 1984;91(12):1524–30.
  24. 24.0 24.1 Kashani AH, Learned D, Nudleman E, Drenser KA, Capone A, Trese MT. High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(1):262–8. doi:10.1016/j.ophtha.2013.08.010.
  25. Kashani AH, Brown KT, Chang E, Drenser KA, Capone A, Trese MT. Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(11):2220–7. doi:10.1016/j.ophtha.2014.05.029.
  26. Rao F-QQ, Cai X-BB, Cheng F-FF, et al. Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017;58(5):2623–2629. doi:10.1167/iovs.16-21324.
  27. 27.0 27.1 27.2 Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995;93:473–521.
  28. Tagami M, Kusuhara S, Honda S, Tsukahara Y, Negi A. Rapid regression of retinal hemorrhage and neovascularization in a case of familial exudative vitreoretinopathy treated with intravitreal bevacizumab.Graefes Arch Clin Exp Ophthalmol. 2008;246(12):1787–9. doi:10.1007/s00417-008-0949-6.
  29. Henry CR, Sisk RA, Tzu JH, et al. Long-term follow-up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases. J AAPOS. 2015;19(6):541–8. doi:10.1016/j.jaapos.2015.09.006.