retinal detachment

Vitreoretinal Degeneration, Snowflake Type

Clinical Characteristics
Ocular Features: 

The retina and vitreous are primarily affected in this disorder.  The age of onset is unknown but characteristic signs can be seen early in the second decade of life.   Early changes include thickening of the cortical vitreous and white dots in the superficial layers of the retina.  The latter are minute yellow-white crystalline deposits more common in the peripheral retina.  Many (83%) patients have early onset cataracts.  Corneal guttae are common (80% of patients).  The vitreous undergoes fibrillar degeneration with liquefaction and eventually appears optically empty.  Many patients experience symptoms of floaters.  The vitreous changes most closely resemble that seen in Wagner syndrome (143200) but with important differences.  In the latter disorder the vitreous changes are membranous, the retinal changes are deeper in location, RPE changes are evident, the choroid and RPE are involved, and the risk of retinal detachment is much higher.  Only 21% of patients with snowflake vitreoretinal degeneration have retinal detachments compared with about 50% in Wagner syndrome.  Retinal vasculature change such as perivascular sheathing and attenuation of arterioles may be seen in both disorders but occur far less commonly in snowflake degeneration.

Based on lack of visual symptoms, the photoreceptors are minimally involved.  Electrophysiologic studies reveal an elevated dark adaptation and reduced scotopic B waves.  Most patients retain excellent vision.  However, the optic nerve may have a waxy pallor and frequently appears flat and lacks a visible cup. 

Systemic Features: 

None.

Genetics

Snowflake vitreoretinal degeneration is an autosomal dominant disorder.   Heterozygous missense mutations have been found in KCNJ13 (2q37) in a single family.  Mutations in the same gene have been identified in rare cases of Leber congenital amaurosis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may be removed.  Patients need to be observed throughout life to enable prompt intervention when retinal detachments occur.

References
Article Title: 

Stickler Syndrome, Type IV

Clinical Characteristics
Ocular Features: 

Evidence of vitreoretinal degeneration is common and the risk of retinal detachment is high.  High myopia is common.  Cataracts are not a feature in contrast to types I and II Stickler syndrome.

It is likely that the ocular phenotype will be expanded with the report of additional families.

Systemic Features: 

Sensorineural hearing loss and short stature are often present. The latter is not usually a feature in other types of Stickler syndrome.  However, midface hypoplasia and micrognathia may be present in all types as well as in Marshall syndrome.  Midline clefting usually does not occur.

Genetics

A reported pedigree suggests autosomal recessive inheritance based on parental consanguinity and the lack of parent-to-child transmission.  Affected individuals have homozygous deletion mutations leading to loss of function in COL9A2 (1p33-p32) while parents are heterozygous.  A family with mutations in COL9A1 (6q12-q14), usually causing multiple epiphyseal dysplasia, has been reported to have autosomal recessive Stickler syndrome as well.  Homozygous individuals had typical ocular and auditory findings of autosomal dominant Stickler syndrome but with evidence of epiphyseal dysplasia.

Type I Stickler syndrome (108300, 609508) is an autosomal dominant disorder with somewhat similar ocular manifestations resulting from mutations in COL2A1.

Type II Stickler syndrome (604841) with a somewhat similar ocular phenotype is also an autosomal dominant disorder but caused by mutations in COL11A1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The myopia and hearing loss can be corrected.  Lifelong vigilance and prompt treatment are required for the vitreoretinal disease.

References
Article Title: 

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Pierson Syndrome

Clinical Characteristics
Ocular Features: 

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some individuals.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features: 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References
Article Title: 

Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ß2 gene

Arima M, Tsukamoto S, Akiyama R, Nishiyama K, Kohno RI, Tachibana T, Hayashida A, Murayama M, Hisatomi T, Nozu K, Iijima K, Ohga S, Sonoda KH. Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ss2 gene. J AAPOS. 2018 Aug 16. pii: S1091-8531(18)30497-X. doi: 10.1016/j.jaapos.2018.03.016. [Epub ahead of print].

PubMed ID: 
30120985

Ophthalmological aspects of Pierson syndrome

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

Norrie Disease

Clinical Characteristics
Ocular Features: 

Norrie disease often presents at birth or soon thereafter with leukocoria.  There may be no response to light even at this early stage.  Microphthalmos, iris atrophy, and synechiae are often noted as well.  The posterior chamber contains a whitish-yellow mass associated with retinal folds and sometimes retinal detachment (pseudoglioma).  The vitreous may appear membranous and fibrovascular, often with traction on the retina.  Cataracts frequently develop early.  These signs may be unilateral or bilateral.  Corneal abnormalities such as opacities or sclerocornea may be present.  The mass in the posterior pole has to be distinguished from a retinoblastoma but the appearance may also resemble familial exudative vitreoretinopathy, Coats disease, persistent hyperplastic vitreous retinopathy, or retinopathy of prematurity.

Histology shows hemorrhagic necrosis of an undifferentiated glial mass.  The primary defect seems to lie in the neuroretina with absence of the ganglion cells and dysplasia of the remaining layers.  Many eyes become phthisical.

Systemic Features: 

Many individuals have growth and developmental delays with cognitive impairment and/or behavioral disorders (50%).  Frank psychoses have been reported in some patients.  Approximately 10% of patients have a chronic seizure disorder. Sensorineural deafness of some degree develops by the second decade in up to 100% of individuals.

Peripheral vascular disease (varicose veins, venous stasis ulcers, and erectile dysfunction) is present in nearly all men over the age of 50 years, perhaps the result of small vessel angiopathy.  Its age of onset is similar to that of the hearing deficit and the time course of progression is similar.

Genetics

This is an X-linked disorder as a result of mutations in the NDP gene (Xp11.4) encoding norrin.  Many mutations causing Norrie disease are novel or at least rare as might be expected for a disorder that leads to a marked reduction in reproductive fitness in males.  Carrier females usually do not have any evidence of disease.

Mutations in NDP also are responsible for a sex-linked form of familial exudative vitreoretinopathy, EVR2 (305390).  They have also been found in some cases of persistent hyperplastic primary vitreous and even in Coates' disease.  The latter conditions are usually present unilaterally, however, and some consider bilaterality to be a characteristic of NDP-related retinopathies.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Mutations in the Norrie disease gene

Schuback DE, Chen ZY, Craig IW, Breakefield XO, Sims KB. Mutations in the Norrie disease gene. Hum Mutat. 1995;5(4):285-92.

PubMed ID: 
7627181

Familial Exudative Vitreoretinopathy, EVR2

Clinical Characteristics
Ocular Features: 

The basis for many of the ocular complications likely begins with incomplete development of the retinal vasculature.  Resulting retinal ischemia leads to neovascularization, vitreous hemorrhage and traction, and retinal folds, with some 20% going on to develop rhegmatogenous or traction detachments.  There is, however, considerable clinical variability, even within families, with some infants blind from birth whereas some (41%) adults have only areas of remaining avascularity or evidence of macular dragging.  In fact, some affected individuals are asymptomatic and diagnosed only as part of extensive family studies.  Intraretinal lipid is often seen.  Considerable asymmetry in the two eyes is common.  Secondary cataracts often occur and phthisis bulbi results in some patients.  The clinical picture is sometimes confused with retinopathy of prematurity.

Systemic Features: 

No consistent systemic abnormalities have been identified in EVR2.

Genetics

Familial exudative vitreoretinopathy is the name given to a clinically and genetically heterogeneous group of disorders caused by mutations in several genes.  Autosomal dominant (e.g., EVR1; 133780), and X-linked inheritance (this condition) have been reported with the former much more common. 

The X-linked form of FEVR (EVR2 described here) results from mutations in the NDP gene (Xp11.3) and is allelic to Norrie disease (310600).

Retinopathy of prematurity can be called a phenocopy of FEVR.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Retinal, vitreal, and cataract surgery are indicated in appropriate cases.

References
Article Title: 

Familial Exudative Vitreoretinopathy, EVR4

Clinical Characteristics
Ocular Features: 

The basis for many of the ocular complications likely begins with incomplete development of the retinal vasculature.  Resulting retinal ischemia leads to neovascularization, vitreous hemorrhage and traction, and retinal folds with some 20% going on to develop rhegmatogenous or traction detachments.  There is, however, considerable clinical variability, even within families, with some infants blind from birth whereas some (41%) adults have only areas of remaining avascularity or evidence of macular dragging.  In fact, some affected individuals are asymptomatic and diagnosed only as part of extensive family studies.  Intraretinal lipid is often seen.  Considerable asymmetry in the two eyes is common. Secondary cataracts often occur and phthisis bulbi results in some patients.  The clinical picture is sometimes confused with retinopathy of prematurity.

Systemic Features: 

Osteoporosis and endosteal hyperostosis has been reported among individuals with mutations in LRP5.

Genetics

The EVR4 form of FEVR results from mutations in the LRP5 gene (11q13.4) and the clinical features may be seen in both heterozygotes and homozygotes.  Thus the disease is inherited in both autosomal dominant and autosomal recessive patterns.  The osteoporosis-pseudoglioma syndrome (259770) is allelic to this condition.

Mutations in the FZD4 gene cause a phenotypically indistinguishable condition (EVR1; 133780) but is always inherited in an autosomal dominant pattern.  There is also an X-linked form (EVR2) caused by a mutation in NDP (305390).

Retinopathy of prematurity can be called a phenocopy of FEVR.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Retinal, vitreal, and cataract surgery are indicated in appropriate cases.

References
Article Title: 

Familial Exudative Vitreoretinopathy, EVR1

Clinical Characteristics
Ocular Features: 

The basis for many of the ocular complications likely begins with incomplete development of the retinal vasculature.  Resulting retinal ischemia leads to neovascularization, vitreous hemorrhage and traction, and retinal folds, with some 20% going on to develop rhegmatogenous or traction detachments.  There is, however, considerable clinical variability, even within families, with some infants blind from birth whereas some (41%) adults have only areas of remaining avascularity or evidence of macular dragging.  In fact, some affected individuals are asymptomatic and diagnosed only as part of extensive family studies.  Intraretinal lipid is often seen.  Considerable asymmetry in the two eyes is common.  Secondary cataracts often occur and phthisis bulbi results in some patients.  The clinical picture is sometimes confused with retinopathy of prematurity.

Systemic Features: 

No systemic features have been associated with EVR1 disease.

Genetics

Familial exudative vitreoretinopathy is the name given to a clinically and genetically heterogeneous group of disorders caused by mutations in several genes.  Both autosomal dominant (EVR1 described here) plus EVR4 (601813) and X-linked inheritance (EVR2; 305390) have been reported with the former much more common.  Similarities in the clinical presentation of Congenital Nonattachment of the Retina may cause diagnotic confusion. 

Mutations in the frizzled-4 gene FZD4 (11q14-q21) have been associated with the EVR1 form of this disease inherited in an autosomal dominant pattern.  Retinopathy of prematurity can be called a phenocopy of FEVR.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Retinal, vitreal, and cataract surgery are indicated in appropriate cases.

References
Article Title: 

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 

Glaucoma, Pigment Dispersion Syndrome

Clinical Characteristics
Ocular Features: 

This is a form of open angle glaucoma with early onset (usually before the age of 40 years).  Marked pigment deposition in the trabecular meshwork, on the lens, zonules, and the corneal endothelium can often be seen prior to elevation of the intraocular pressure. It can be present asymmetrically, even unilaterally, but primarily in early stages.  The pigment source in humans seems to be the iris in which hypopigmentation leads to radial transillumination defects and mouse models corroborate this.  The iris configuration is sometimes described as flat or even concave.  The pattern of pigment deposition on the posterior surface of the cornea is known as a Krukenberg spindle and considered diagnostic.  Untreated, the characteristic optic nerve damage and visual field changes of glaucoma eventually occur.  Early-onset and rapidly progressive nuclear cataracts have been reported in some patients.

In one longitudinal study of 113 patients diagnosed with pigment dispersion and followed for 24 years, 23 had glaucoma initially and 9 more eventually required treatment for elevated pressure. The mean age at diagnosis was 42 years and myopic males were the most commonly affected.

The syndromic nature of PDS is suggested by the association of lattice degeneration, retinal tears, and detachments in a significant number of individuals.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal dominant form of glaucoma-related optic neuropathy that shares some features with open angle juvenile glaucoma (137750), such as myopia and early onset.  The pigment dispersion syndrome described here, however, maps to a different locus (7q35-q36).  Another candidate locus is located at 18q11-q21 but the causative mutations remain elusive.

A four generation family with an apparent autosomal recessive pattern has been reported.

The autosomal dominant pattern is not always apparent from history alone and examination of relatives is necessary to document the familial nature of this disease. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual glaucoma therapies are indicated.  Some have advised limiting vigorous impact sports to reduce the amount of pigment released.  All individuals with pigment dispersion must be followed vigilantly for development of glaucoma as the risk is high.  It has been estimated to be 10% within 5 years and 15% in 15 years, regardless of age and family history.  Further, the pigment dispersion is progressive along with the risk of elevated pressure as eventually 30 -50% of patients develop glaucoma.  However, regression of pigment deposition, decrease of iris transillumination and even stabilization of pressure has also been noted in some, mostly younger, patients.

Laser iridotomy has been suggested as therapeutically useful in the reduction of the IOP but there is no statistical confirmation of this.

References
Article Title: 

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