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Exudative vitreoretinopathy 2, X-linked(EVR2; FEVRX)

MedGen UID:
337030
Concept ID:
C1844579
Disease or Syndrome
Synonyms: EXUDATIVE VITREORETINOPATHY, FAMILIAL, 2; Familial exudative vitreoretinopathy, X-linked; FEVR, X-LINKED
 
Gene (location): NDP (Xp11.3)
 
Monarch Initiative: MONDO:0010588
OMIM®: 305390

Definition

Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, even within families, with severely affected patients often registered as blind during infancy, whereas mildly affected patients with few or no visual problems may have such a small area of avascularity in their peripheral retina that it is visible only by fluorescein angiography. It is believed that this peripheral avascularity is the primary anomaly in FEVR and results from defective retinal angiogenesis. The sight-threatening features of the FEVR phenotype are considered secondary to retinal avascularity and develop because of the resulting retinal ischemia; they include the development of hyperpermeable blood vessels, neovascularization, vitreoretinal traction, retinal folds, and retinal detachments (summary by Poulter et al., 2010). For a discussion of genetic heterogeneity of FEVR, see EVR1 (133780). [from OMIM]

Additional description

From MedlinePlus Genetics
Familial exudative vitreoretinopathy is a hereditary disorder that can cause vision loss that worsens over time. This condition affects the retina, the specialized light-sensitive tissue that lines the back of the eye. In people with this disorder, blood vessels do not fully develop at the outer edges (periphery) of the retina, which reduces the blood supply to this tissue. This prolonged reduction in blood supply (chronic ischemia) causes continued damage to the retina and can lead to worsening of the condition. 

The signs and symptoms of familial exudative vitreoretinopathy vary widely, even within the same family. In many affected individuals, the retinal abnormalities never cause any vision problems. Other people with this condition develop abnormal vessels that leak. This  causes chronic inflammation which, over time, can lead to fluid under the retina (exudate). A reduction in the retina's blood supply causes the retina to fold, tear, or separate from the back of the eye (retinal detachment). The resulting retinal damage can lead to vision loss and blindness. Other eye abnormalities are also possible, including eyes that do not look in the same direction (strabismus) and a visible whiteness (leukocoria) in the normally black pupil.

Some people with familial exudative vitreoretinopathy also have a condition known as osteoporosis-pseudoglioma syndrome, which is characterized by reduced bone density. People with this condition have weakened bones and an increased risk of fractures.  https://medlineplus.gov/genetics/condition/familial-exudative-vitreoretinopathy

Clinical features

From HPO
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Retinal detachment
MedGen UID:
19759
Concept ID:
C0035305
Disease or Syndrome
Primary or spontaneous detachment of the retina occurs due to underlying ocular disease and often involves the vitreous as well as the retina. The precipitating event is formation of a retinal tear or hole, which permits fluid to accumulate under the sensory layers of the retina and creates an intraretinal cleavage that destroys the neurosensory process of visual reception. Vitreoretinal degeneration and tear formation are painless phenomena, and in most cases, significant vitreoretinal pathology is found only after detachment of the retina starts to cause loss of vision or visual field. Without surgical intervention, retinal detachment will almost inevitably lead to total blindness (summary by McNiel and McPherson, 1971).
Retinal neovascularization
MedGen UID:
20550
Concept ID:
C0035320
Pathologic Function
In wound repair, neovascularization (NV) involves the sprouting of new vessels from pre-existent vessels to repair or replace damaged vessels. In the retina, NV is a response to ischemia. The NV adheres to the inner surface of the retina and outer surface of the vitreous. NV are deficient in tight junctions and hence leak plasma into surrounding tissue including the vitreous. Plasma causes the vitreous gel to degenerate, contract, and eventually collapse which pulls on the retina. Since retinal NV is adherent to both retina and vitreous, as the vitreous contracts the NV may be sheared resulting in vitreous hemorrhage or the NV may remain intact and pull the retina with the vitreous resulting in retinal elevation referred to as traction retinal detachment.
Retinal fold
MedGen UID:
115826
Concept ID:
C0229197
Finding
A wrinkle of retinal tissue projecting outward from the surface of the retina and visible as a line on fundoscopy.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
High myopia
MedGen UID:
78759
Concept ID:
C0271183
Disease or Syndrome
A severe form of myopia with greater than -6.00 diopters.
Falciform retinal fold
MedGen UID:
488857
Concept ID:
C0344550
Congenital Abnormality
An area of the retina that is buckled so that a sector-shaped sheet of retina lies in front of the normal retina. This feature is of congenital onset.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Shallow anterior chamber
MedGen UID:
602215
Concept ID:
C0423276
Finding
Reduced depth of the anterior chamber, i.e., the anteroposterior distance between the cornea and the iris is decreased.
Subretinal exudate
MedGen UID:
488893
Concept ID:
C0423431
Finding
A type of retinal exudate located in the subretinal space between the sensory retina and the retinal pigment epithelium.
Peripheral retinal avascularization
MedGen UID:
338687
Concept ID:
C1851406
Finding
Retinal vascular tortuosity
MedGen UID:
349827
Concept ID:
C1860475
Anatomical Abnormality
The presence of an increased number of twists and turns of the retinal blood vessels.
Intraretinal exudate
MedGen UID:
870315
Concept ID:
C4024758
Finding
Retinal exudate within the retinal tissue itself.
Peripheral vitreous opacities
MedGen UID:
870367
Concept ID:
C4024811
Finding
Exudative vitreoretinopathy
MedGen UID:
892913
Concept ID:
C4072980
Disease or Syndrome
Retinal hole
MedGen UID:
1642357
Concept ID:
C4551442
Disease or Syndrome
A small break in the retina.

Recent clinical studies

Etiology

Flores Pimentel MA, De la Huerta I, Duncan JL, Slavotinek AM, Moore AT, de Alba Campomanes AG
Retin Cases Brief Rep 2021 May 1;15(3):324-329. doi: 10.1097/ICB.0000000000000796. PMID: 30074570
Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P
Mol Genet Genomic Med 2019 Jan;7(1):e00503. Epub 2018 Nov 25 doi: 10.1002/mgg3.503. PMID: 30474316Free PMC Article
Yonekawa Y, Wu WC, Kusaka S, Robinson J, Tsujioka D, Kang KB, Shapiro MJ, Padhi TR, Jain L, Sears JE, Kuriyan AE, Berrocal AM, Quiram PA, Gerber AE, Paul Chan RV, Jonas KE, Wong SC, Patel CK, Abbey AM, Spencer R, Blair MP, Chang EY, Papakostas TD, Vavvas DG, Sisk RA, Ferrone PJ, Henderson RH, Olsen KR, Hartnett ME, Chau FY, Mukai S, Murray TG, Thomas BJ, Meza PA, Drenser KA, Trese MT, Capone A Jr
Ophthalmology 2016 Aug;123(8):1802-1808. Epub 2016 May 22 doi: 10.1016/j.ophtha.2016.04.033. PMID: 27221737Free PMC Article
Gilmour DF
Eye (Lond) 2015 Jan;29(1):1-14. Epub 2014 Oct 17 doi: 10.1038/eye.2014.70. PMID: 25323851Free PMC Article
Rosenfeld PJ, Flynn HW Jr, McDonald HR, Rubsamen PE, Smiddy WE, Sipperley JO, Boniuk I, Packer AJ
Ophthalmic Surg Lasers 1998 Mar;29(3):190-7. PMID: 9547772

Diagnosis

Hoyek S, Wang M, Berrocal AM, Wong A, Place EM, Mason-Suares H, Lin AE, Mukai S, Patel NA
Ophthalmic Genet 2023 Apr;44(2):198-203. Epub 2022 Jul 14 doi: 10.1080/13816810.2022.2098987. PMID: 35834361
Huang L, Sun L, Li X, Li S, Zhang T, Zhang Z, Ding X
Br J Ophthalmol 2023 Aug;107(8):1151-1155. Epub 2022 Mar 31 doi: 10.1136/bjophthalmol-2021-320084. PMID: 35361573Free PMC Article
Peng Y, Zhao R, Dai E, Peng L, He Y, Li S, Yang M
Eur J Ophthalmol 2022 Nov;32(6):3220-3226. Epub 2022 Jan 17 doi: 10.1177/11206721221074209. PMID: 35037517
Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P
Mol Genet Genomic Med 2019 Jan;7(1):e00503. Epub 2018 Nov 25 doi: 10.1002/mgg3.503. PMID: 30474316Free PMC Article
Plager DA, Orgel IK, Ellis FD, Hartzer M, Trese MT, Shastry BS
Am J Ophthalmol 1992 Aug 15;114(2):145-8. doi: 10.1016/s0002-9394(14)73977-7. PMID: 1642288

Prognosis

Hoyek S, Wang M, Berrocal AM, Wong A, Place EM, Mason-Suares H, Lin AE, Mukai S, Patel NA
Ophthalmic Genet 2023 Apr;44(2):198-203. Epub 2022 Jul 14 doi: 10.1080/13816810.2022.2098987. PMID: 35834361
Scott NL, Tran KD, Russell JF, Hinkle JW, Cernichiaro-Espinosa LA, Lauer A, Berrocal AM
Ophthalmic Surg Lasers Imaging Retina 2019 Feb 1;50(2):120-124. doi: 10.3928/23258160-20190129-10. PMID: 30768221
Sun W, Xiao X, Li S, Jia X, Wang P, Zhang Q
Invest Ophthalmol Vis Sci 2019 Jan 2;60(1):93-97. doi: 10.1167/iovs.18-25142. PMID: 30640974
Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P
Mol Genet Genomic Med 2019 Jan;7(1):e00503. Epub 2018 Nov 25 doi: 10.1002/mgg3.503. PMID: 30474316Free PMC Article
Rosenfeld PJ, Flynn HW Jr, McDonald HR, Rubsamen PE, Smiddy WE, Sipperley JO, Boniuk I, Packer AJ
Ophthalmic Surg Lasers 1998 Mar;29(3):190-7. PMID: 9547772

Clinical prediction guides

Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P
Mol Genet Genomic Med 2019 Jan;7(1):e00503. Epub 2018 Nov 25 doi: 10.1002/mgg3.503. PMID: 30474316Free PMC Article
Chen ZY, Battinelli EM, Fielder A, Bundey S, Sims K, Breakefield XO, Craig IW
Nat Genet 1993 Oct;5(2):180-3. doi: 10.1038/ng1093-180. PMID: 8252044
Plager DA, Orgel IK, Ellis FD, Hartzer M, Trese MT, Shastry BS
Am J Ophthalmol 1992 Aug 15;114(2):145-8. doi: 10.1016/s0002-9394(14)73977-7. PMID: 1642288

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