retinal detachment

Joint Laxity, Short Stature, and Myopia

Clinical Characteristics
Ocular Features: 

Three of four brothers in one family had high myopia and two had retinal detachments as well as iris and chorioretinal colobomas.  In a second family with five sibs a teenage female was reported to have glaucoma and vision of legal blindness.  She and one brother had high myopia as well (parameters not reported).

Systemic Features: 

In one consanguineous family a brother and sister had multiple large joint dislocations including elbows, hips, knees and ankles.  The sister exhibited severe kyphoscoliosis while her brother had only mild kyphosis.  A single individual in each of the two sibships had hearing loss.

Three brothers in another consanguineous family had joint laxity and mild pectus carinatum.

Short stature was noted in all 5 affected individuals.  Cognitive development was reported as normal.

Genetics

Five individuals from 2 consanguineous Saudi sibships have been reported.  Homozygous mutations in the GZF1 gene (20p11.21) segregated as expected for an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.   Retinal detachment surgery and joint dislocation reduction should be considered in appropriate individuals.

References
Article Title: 

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

Patel N, Shamseldin HE, Sakati N, Khan AO, Softa A, Al-Fadhli FM, Hashem M, Abdulwahab FM, Alshidi T, Alomar R, Alobeid E, Wakil SM, Colak D, Alkuraya FS. GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome. Am J Hum Genet. 2017 May 4;100(5):831-836.

PubMed ID: 
28475863

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: 

Retinal Nonattachment, Congenital

Clinical Characteristics
Ocular Features: 

The common denominator in this condition is, of course, congenital nonattachment of the retina.  Many eyes are small as well.  Some patients in addition have a vascularized hyperplastic vitreous and often present with blindness and a congenital leukocoria.  Many at some stage have lens opacification, as well as glaucoma and anterior chamber anomalies including anterior synechiae and some degree of corneal opacification.  These signs are often progressive beginning in childhood.  Pendular nystagmus and esotropia are common.  MRI studies reveal optic nerves and the chiasm that are either absent or abnormally small.

Systemic Features: 

This condition is nonsyndromic and has no systemic abnormalities.

Genetics

Congenital retinal nonattachment consists of a group of sometimes familial conditions for which no responsible gene has been identified.  In a genomic study of 21 consanguineous NCRNA Pakistani families 3 had mutations in ATOH7 and 10 had mutations in familial exudative vitreoretinopathy genes.  Genotyping did not reveal associated mutations in the remaining 38% of these families. It is likely that multiple entities are represented but until the molecular etiologies are identified, no more specific classification is possible.

Studies in mice document that the Atoh7 gene is important to retinal ganglion cell neurogenesis.  In humans, both autosomal recessive PHPV and congenital nonattachment of the retina are associated with microsatellite linkage and haplotype matching to a region at 10q21 adjacent to the ATOH7 gene but so far no causative mutation has been found in this region.  However, studies in large consanguineous kindreds in which a deleted DNA segment adjacent to ATOH7 segregated with the NCRNA phenotype suggest that a transcription regulator may be at fault in the timing and level of ATOH7 expression.

The disorder known as persistent hyperplastic primary vitreous is generally not considered hereditary since it usually occurs unilaterally and sporadically.  It is sometimes found in association with a number of syndromal conditions as well.  However, it has also been reported in familial patterns consistent with both autosomal recessive and autosomal dominant patterns.  DNA mapping of individuals with bilateral disease found in a consanguineous Pakistani kindred with presumed autosomal recessive disease suggests that a locus at 10q11-q21 may be responsible.

Evidence for autosomal dominant inheritance of persistent hyperplastic primary vitreous comes from rare families with an apparent vertical transmission of the condition.

Congenital nonattachment of the retina is also seen in the osteoporosis-pseudoglioma syndrome (250770).  However, this is a syndromal disorder with neurologic and joint disease in addition to porotic, thin, fragile bones (sometimes called the ocular form of osteogenesis imperfecta) resulting from mutations in LRP5 on chromosome 11.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

With rare exceptions, the retina cannot be reattached successfully and phthisis with blindness is the usual outcome.

References
Article Title: 

Knobloch Syndrome 2

Clinical Characteristics
Ocular Features: 

In an 18 month infant, ectopia lentis, cataract, and myopia with poor vision were noted.  This individual subsequently developed retinal degeneration and a serous retinal detachment.

Systemic Features: 

Only one patient has been reported.  While the clinical signs resemble Knobloch 1 syndrome, brain imaging does not reveal malformations in this syndrome.  The only systemic sign, in addition to an occipital encephalocele, is a minor delay in fine motor skills.

Genetics

This autosomal recessive disorder results from homozygous loss of function mutations in the ADAMTS18 gene (16q23.1).  The gene product has been found in the lens and retina in the murine eye.

Mutations in ADAMTS18 have also been found in the syndrome of Micorcornea, Myopia, Chorioretinal atrophy, and Telecanthus.  It may also be responsible for a retinal dystrophy.

Knobloch 2 syndrome was identified in a single female born to consanguineous parents.

This disorder is separate to Knobloch 1 syndrome (267750) based on the causative mutations.  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The skull defect can be closed and the lenses can be removed if indicated.

References
Article Title: 

Knobloch Syndrome 1

Clinical Characteristics
Ocular Features: 

The ocular findings include high myopia, vitreoretinal degeneration, dislocated lenses, cataracts, and retinal detachment.  Some patients have early onset (2-4 years old) night blindness and progress to total blindness before 20 years of age.  Nystagmus, strabismus, small optic discs, glaucoma, and cataracts have been reported.  Poor vision and progressive loss of acuity are common.  The vitreous appears to be condensed into sheets and there may be distortion of the vitreoretinal interface with irregular white dots and lines.  Pigmentary changes are common in the retina which some have described as consistent with choroidal sclerosis and chorioretinal atrophy.  Atrophic changes are often seen in the macula.

Systemic Features: 

The degree of skull and brain defects is variable.  Some patients have only occipital scalp defects while others have occipital encephaloceles.  The scalp defect may contain heterotopic neuronal tissue suggesting neuronal migratory defects.  Brain imaging has revealed a variety of defects and some patients have cognitive deficits and personality changes.  Cerebellar atrophy with ataxia is found in some patients.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the COL18A1 gene (21q22.3).  Mutated COL18A1 leads to defects in type XVIII collagen which is a component of basement membranes throughout the body, especially in the eye.

In spite of some clinical similarities, this disorder is genetically distinct from Knobloch 2 syndrome (608454).  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely supportive.  Attempts at repair of retinal detachments often fail and phthisis bulbi is not uncommon.

References
Article Title: 

Myopia, AR, with Cataracts and Vitreoretinal Degeneration

Clinical Characteristics
Ocular Features: 

Axial myopia and poor vision are noted during childhood.  Most individuals have refractive errors in the range of-5 to -18 diopters with a mean spherical equivalent of -11.3 diopters.  The axial length ranges from 25.1 and 30.5 mm.  Peripheral vitreoretinal degeneration and cataracts are usually present after the onset of myopia.  Lenticular opacities may necessitate cataract surgery in 11 of the 13 myopic patients in one kindred, usually by the second decade of life.  Lens instability or frank subluxation was noted in 8 patients.  At least five eyes suffered retinal detachments secondary to retinal dialyses and blindness of at least one eye occurred in 23% of patients.

Systemic Features: 

Deafness was reported in a single patient.

Genetics

This condition results from homozygous mutations in the gene LEPREL1 (3q28) encoding prolyl 3-hydroxylase.  It was identified in a large consanguineous Israeli Bedouin kindred containing seven affected males and 6 affected females.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract and retinal surgery may be indicated. However, the instability of the lens can lead to complications. The nature and location of retinal tears likewise make repairs difficult and blindness is a relatively frequent complication.

References
Article Title: 

Coloboma of the Optic Nerve

Clinical Characteristics
Ocular Features: 

Isolated colobomas of the optic nerve in the absence of other malformations may occur unilaterally or bilaterally.  The optic nerve cups are often huge and may have residual glial tissue in them.  Serous detachments of the macula are frequently observed and the risk for extensive retinal detachments is high. Microphthalmos with a cyst (6% of eyes), simple microphthalmos (39% of eyes), and microcornea (84% of eyes) are frequently associated.  The visual prognosis is poor when these occur in combination with an optic nerve coloboma (less than 20/400 acuity in 67% of eyes).  Isolated optic nerve colobomas without other malformations have the best vision (only 7% have acuity of less than 20/400).  Retinal vessels are anomalous as well.  They are often increased in number and have a generally straight course in the peripapillary region.

It has been argued that the morning glory disc anomaly may be an expression of this syndrome but this remains to be established.

Systemic Features: 

No systemic disease is present.

Genetics

This malformation frequently follows an autosomal dominant pattern of transmission secondary to a mutation in the PAX6 gene.

The PAX6 gene impacts DNA transcription and mutations are therefore often associated with a variety of ocular malformations, including uveal colobomas and various forms of anterior chamber dysgenesis.

Optic nerve dysplasia resembling optic pits or the morning glory disc anomaly is a feature of the papillorenal syndrome (120330) but this condition is caused by mutations in the PAX2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None.  Low vision aids may be helpful in some patients.

References
Article Title: 

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