retinal folds

Familial Exudative Vitreoretinopathy, EVR7

Clinical Characteristics
Ocular Features: 

The ocular features are primarily limited to the posterior chamber where there are areas of retinal avascularity, exudation, retinal holes, and detachments.  Areas of degeneration and pigmentary retinopathy may be present.  Vascular proliferation may be part of the process with vitreous traction and folds.  Progression of retinal damage is highly variable and surgical outcomes are unpredictable.  Long term vision outcomes are sometimes as good as 20/40 but in many eyes NLP or hand motion vision is the end result.  

Secondary changes in the anterior chamber and cornea from repeated surgeries may lead to glaucoma, cataracts, and corneal decompensation. 

Systemic Features: 

There are no consistent systemic abnormalities.

Genetics

Missense and nonsense heterozygous mutations in the CTNNB1 gene (3p22.1) segregate with this autosomal dominant condition found in two families of Japanese origin.  A Chinese 3-year-old with FEVR having a single BP insertion in the CTNNB1 gene also had global developmental delay and dysmorphic facies.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The prognosis for vision is poor as the retinal damage often continues to evolve and additional folds and detachments develop.  Attempts to close retinal holes and repair detachments are important.

References
Article Title: 

Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR

Panagiotou ES, Sanjurjo Soriano C, Poulter JA, Lord EC, Dzulova D, Kondo H, Hiyoshi A, Chung BH, Chu YW, Lai CHY, Tafoya ME, Karjosukarso D, Collin RWJ, Topping J, Downey LM, Ali M, Inglehearn CF, Toomes C. Defects in the Cell Signaling Mediator v-Catenin Cause the Retinal Vascular Condition FEVR. Am J Hum Genet. 2017 Jun 1;100(6):960-968.

PubMed ID: 
28575650

Familial Exudative Vitreoretinopathy, EVR6

Clinical Characteristics
Ocular Features: 

Clinical features of this type of exudative retinopathy are based upon the findings in a single large Dutch pedigree containing 16 affected individuals.  The age of onset is unknown but this condition has been described in a 3 year old.  Characteristics of FEVR6 are often seen in individuals during the second or third decades when decreasing vision becomes a challenge.  While some individuals can have normal acuity, others have severe vision loss, often to finger-counting range.

Ocular findings are limited to the fundus consisting of areas of hypo- or hyperpigmentation, dragging of the macula, peripheral retinal avascularity, leaky and stretched capillaries, and exudates.  There may be falciform retinal folds and detachments.  Some patients have white masses of fibrous tissue in or overlying the retina.  Cataracts have been described in several patients.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

FEVR6 results from heterozygous mutations in the ZNF408 gene (11p11.2).  Homozygous mutations in the same gene are responsible for retinitis pigmentosa 72 (616469).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Retinal detachment surgery, while technically difficult, may provide some benefit.

References
Article Title: 

ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature

Collin RW, Nikopoulos K, Dona M, Gilissen C, Hoischen A, Boonstra FN, Poulter JA, Kondo H, Berger W, Toomes C, Tahira T, Mohn LR, Blokland EA, Hetterschijt L, Ali M, Groothuismink JM, Duijkers L, Inglehearn CF, Sollfrank L, Strom TM, Uchio E, van Nouhuys CE, Kremer H, Veltman JA, van Wijk E, Cremers FP. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9856-61.

PubMed ID: 
23716654

Chorioretinopathy with Microcephaly 3

Clinical Characteristics
Ocular Features: 

The eyes are not notably small although several patients have been reported to have significant hyperopia.  Vision can be impaired and some individuals have early-onset nystagmus.  The ERG responses are attenuated and may be absent.  The retina is dysplastic with multiple atrophic punched-out lesions, attenuated retinal vessels, and sparse pigmentation. Large retinal folds have been described and one patient developed a retinal detachment.  Optic atrophy was noted in one individual.

Systemic Features: 

Microcephaly of 3-4 standard deviations below normal is a constant feature.  Motor and language abilities can be mildly delayed and  several patients have had mild learning difficulties.   Brain imaging has been normal in most individuals but a shortened and thin corpus callosum was present in one patient.

Genetics

Family and genetic evidence suggest autosomal recessive inheritance.  Compound heterozygous mutations in the TUBGCP4 gene (15q15.3) code for part of a protein complex involved in microtubule organization.

For a somewhat similar condition with a different mutation involving the same microtubule complex see Chorioretinopathy with Microcephaly 1 (251270).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids may be helpful in selected patients.

References
Article Title: 

Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strahle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H. Mutations in TUBGCP4 Alter Microtubule Organization via the g-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy. Am J Hum Genet. 2015 Apr 2;96(4):666-74.

PubMed ID: 
25817018

Familial Exudative Vitreoretinopathy, EVR3

Clinical Characteristics
Ocular Features: 

Abnormal retinal angiogenesis with retinal ischemia is the development defect that leads to the clinical features of the familial exudative vitreoretinopathies.  It is usually bilateral.  There is considerable clinical heterogeneity in the appearance of both the retina and the vitreous but common to all is the presence of peripheral areas of avascularity in the retina that may be seen in newborns.  This may only be visible using fluorescein angiography in mild cases.  The vessels may be hyperpermeable resulting in patchy exudates in the retina.  Neovascularization often develops with retinal and vitreous bleeding and eventually retinal traction resulting in retinal folds and detachments. Severe disease with early onset may result in blindness in infants but milder disease may be asymptomatic even as adults.  Cataracts may result.

The ocular disease may be confused with retinal dysplasia (as seen in pseudogliomas and Norrie disease [310600]) or retinopathy of prematurity.

Systemic Features: 

 No systemic features have been reported in EVR3.

Genetics

This is likely an autosomal dominant disorder based on pedigree evidence but no specific mutation has been found.  A disease locus at 11p13-p12 has been identified by linkage studies, located near the FZD4 gene containing the mutation responsible for EVR1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Appropriate vitreoretinal surgery to release vitreous traction and to repair retinal detachments should be considered.  Cataract removal may be beneficial.  Low vision aids could be helpful in milder cases with residual vision.

References
Article Title: 

Chorioretinal dysplasia, lymphedema, and microcephaly

Clinical Characteristics
Ocular Features: 

The congenital lymphedema results in thickened and ptotic eyelids with prominent epicanthal folds.  Congenital ptosis is not uncommon in the general population in the absence of lymphedema so that this feature by itself is insufficient to diagnose this syndrome.  Retinal folds with variable degrees of pigmentary changes are often present.  Narrowed retinal vessels, atrophic nerve heads and progressive chorioretinopathy have been reported.  Visual acuity is often reduced, sometimes severely, and nystagmus may be present.

Systemic Features: 

Coarse hair follicles over the dorsum of the hands and feet and white nails when combined with the thickened, ptotic eyelids suggest the presence of lymphedema.  The hair pattern is often altered on the arms, nape of the neck, and the back.  White lines in the palms are also suggestive.  The 'facial phenotype' includes full cheeks, flat nasal bridge and underdeveloped supraorbital ridges, up slanting palpebral fissures, broad nose with rounded tip, anteverted nares, and a long philtrum, thin upper lip, and sometimes micrognathia. The ears may appear large.  Children with this syndrome are often hypotonic during the newborn period but this feature is less evident later in childhood and improves more rapidly than the resolution of the lymphedema. The lymphedema usually improves during early childhood and is often confined to the dorsum of the hands and feet at that time.  Psychomotor development is variably delayed and some but not all patients are mentally retarded. Microcephaly is a consistent feature.

Not all features are present in all patients and, specifically, there are often microcephalic relatives who lack other signs.

Genetics

This is an autosomal dominant disorder which may consist of more than one entity but at least some cases result from heterozygous mutations in KIF11 (10q23.33).  The gene encodes a member of the kinesin family of proteins responsible for cytoplasmic mechanisms that are essential for spindle assembly and function as well in transportation of other intracellular organelles.  Mutations in this gene have also been implicated in familial exudative vitreoretinopathy (FEVR) and there is phenotypic overlap with the condition described here.

It is not unusual for microcephalic individuals to also have chorioretinal dysplasia and/or pigmentary retinopathy.  See microcephaly, chorioretinal dysplasia, mental retardation (156590), for a somewhat similar autosomal dominant condition, as well as microcephaly with chorioretinopathy, AR (251270) for an autosomal recessive condition with this combination.  Neither of these conditions is associated with congenital lymphedema, however.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations

Robitaille JM, Gillett RM, LeBlanc MA, Gaston D, Nightingale M, Mackley MP, Parkash S, Hathaway J, Thomas A, Ells A, Traboulsi EI, Heon E, Roy M, Shalev S, Fernandez CV, MacGillivray C, Wallace K, Fahiminiya S, Majewski J, McMaster CR, Bedard K. Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations. JAMA Ophthalmol. 2014 Aug 14.

PubMed ID: 
25124931

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet. 2013 Nov 27.  [Epub ahead of print).

PubMed ID: 
24281367

Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy

Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print].

PubMed ID: 
22284827

Chorioretinal dysplasia, microcephaly, and mental retardation

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been well defined in this condition since few families have been reported.  Microphthalmia is present in some patients.  The corneas may be small and there is often some conjunctival growth over the limbus.

The retinal features consist of lacunar depigmentation of the RPE and in some cases resemble the lesions of congenital toxoplasmosis.  Eighty to 90 per cent of patients have areas of atrophic and dysplastic-appearing lesions of the retina and choroid with vascular attenuation.  The edges of lacunae may have patchy hyperpigmentation.  These lesions are usually static but may show mild progression.  Visual acuity is generally stable or only mildly progressive.  However, other patients have a severe reduction in acuity.  ERG responses are reduced.

Systemic Features: 

The amount of microcephaly may be minimal and at least some patients have 'bulging' foreheads.  The amount of mental deficiency varies from mild to severe.  IQ levels are generally in the range of 60-70.   Hypotonia has been reported in more severe cases.  Skull size is usually 2-3 standard deviations below the mean and generally has some frontal prominence.

Genetics

This seems to be an autosomal dominant disorder although no loci or mutations have been identified.  It is likely that the category of disease known as microphthalmia-chorioretinal syndrome consists of a heterogeneous group of disorders.  No locus or specific mutation has been identified.

It differs from the microcephaly, lymphedema, chorioretinopathy syndrome (152950) in which retinal folds, ptosis and lymphedema are associated with a typical facial phenotype.  For other disorders in this database having a somewhat similar phenotype see: chorioretinopahty and microcephaly type 1 (251270) and type 2 (616171).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is supportive.  Low vision aids may be helpful.

References
Article Title: 
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