cataract

Oculoauricular Syndrome

Clinical Characteristics
Ocular Features: 

This rare malformation syndrome affects primarily the eyes and ears.  The globes are small and usually have colobomas of both anterior and posterior segments.  The corneas likewise are small and often have opacities.  The anterior segment is dysplastic with anterior and/or posterior synechiae.  Glaucoma may be present.  The lenses may be small and often become cataractous.  There is a progressive rod-cone dystrophy associated with a pigmentary retinopathy.  Chorioretinal lacunae have been seen in the equatorial region.  The retinal degeneration is progressive, beginning with rod dysfunction but followed by deterioration of all receptors.  The onset in early childhood results in poor vision and nystagmus. 

Systemic Features: 

The external ears are abnormal.  The earlobes may have colobomas or may be aplastic.  The intertragic notch is often underdeveloped.  Audiograms and vestibular function tests, however, show normal function and MRI of the middle and inner ears likewise reveals no anatomic abnormalities.       

Among the few patients reported, dental anomalies, spina bifida oculta, and mild dyscrania have been noted in individual patients.

Genetics

This rare disorder has been reported in only a few families.  Based on parental consanguinity and homozygosity of mutations in the HMX1 gene (4p16.1) in affected sibs, this is an autosomal recessive disorder.  In one family there was a homozygous 26 bp deletion and in another a homozygous missense mutation.  The parents are heterozygous for the deletion.

HMX1 is a homeobox gene and the deletion abolishes its function by establishing a stop codon at position 112.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the extraocular malformations.  Glaucoma treatment and cataract surgery should be considered although permanent visual rehabilitation is unlikely given the progressive nature of the rod-cone dystrophy.

References
Article Title: 

Cataracts, Lamellar

Clinical Characteristics
Ocular Features: 

This type of heritable cataract is progressive and has a variable phenotype both within and between families.  It is usually seen bilaterally in early childhood but may be congenital in onset.  Fine, dispersed, pulverulent opacities of the primary lens fibers are seen in the embryonic nucleus often with increased density at the ends of the Y suture at 12, 2, and 6 o'clock presenting a triangular appearance.  However, the entire nucleus may be opaque as well.  Zonular and posterior subcapsular opacities may appear later but there is considerable variation among patients and they may also appear in a stellate pattern.  The lamellar pattern consists of a zone of opacification around a clear embryonic nucleus.  There may be considerable difference in the rate of progression of the opacities among patients and even between the two eyes.

This may be among the most common type of congenital, autosomal dominant cataract.  The first family was reported in 1878 and the family data has been updated and reported several times since then.  The most recent reported pedigree consisted of 965 individuals in 9 generations.  Among the 70 individuals added, 56 had cataract surgery performed between the ages of 1 month and 26 years with a mean of 8 years.  However, some adults never had cataract surgery. 

Another family with early onset, progressive, autosomal dominant cataracts mapping to the same locus has been reported (see Maumenee, 1979) but the opacification involves the secondary lens fibers at the posterior pole.  These may be variants of the same condition.

Systemic Features: 

This is a non-syndromal cataract disorder and no systemic disease has been associated.  

Genetics

This type of congenital cataract may be caused by mutations in the heat-shock transcription factor-4 gene (HSF4) located at 16q21-q22.1.  It is inherited in an autosomal dominant pattern. 

Another morphologically different autosomal dominant congenital cataract has been linked to the same locus (see Maumenee, 1979).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Volkmann type (115665), Coppock-like (604307), and congenital posterior polar (116600) cataracts. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant opacities require surgery. Amblyopia, if present, should be treated early.  

References
Article Title: 

Vitreoretinochoroidopathy

Clinical Characteristics
Ocular Features: 

Clinical features are variable in this ocular disorder. Small corneas and shallow anterior chambers have been described in some patients.  Chronic narrow angle glaucoma or frank angle closure glaucoma attacks may occur.  Microphthalmia has been reported but nanophthalmos has not been documented.  Presenile cataracts, nystagmus, and strabismus are sometimes present.  Some patients have normal vision but others have a severe reduction in acuity, even blindness.

The vitreous is often liquefied and some patients have a fibrillary vitreous with pleocytosis.  Preretinal white dots and neovascularization are often seen, even in children.  Peripapillary atrophy may extend to the macula which may have cystic edema.  Peripherally in annular fashion there is often a pigmentary retinopathy extending to an equatorial demarcation line at the posterior border.  The ERG is usually moderately abnormal with evidence of rod and cone dystrophy generally in older patients in which some degree of dyschromatopsia is often present.  Some patients demonstrate a concentric reduction in visual field that progresses with age.  A reduced light/dark ratio has also been documented in several families.  Retinal detachment is a risk.  A posterior staphylomas has been noted in a few patients. 

Systemic Features: 

No systemic abnormalities have been reported. 

Genetics

This is an autosomal dominant disorder resulting from mutations in BEST1 (11q13), which is also responsible for Best vitelliform macular dystrophy (153700). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No prophylactic treatment has been reported but patients need lifelong monitoring to detect and treat glaucoma, retinal neovascularization, and detachments. 

References
Article Title: 

Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)

Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT, Manson FD, Black GC. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3683-9.

PubMed ID: 
15452077

Oculodentodigital Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been reported as small and sometimes appear deep-set.  The epicanthal folds are prominent and the lid fissures are small.  Microcornea and evidence of anterior chamber dysplasia including posterior synechiae, anterior displacement of Schwalbe’s line, and stromal hypoplasia in the peripupillary area may be present.  Many eyes have some persistence of the pupillary membrane. Nystagmus and strabismus has been seen in some individuals.  A few patients have evidence of a persistent hyperplastic primary vitreous, even bilaterally. Cataracts may be present as well and a few patients have been reported with open angle glaucoma.  Most patients have normal or near normal visual acuity.

Systemic Features: 

The clinical features of this syndrome are highly variable.  Hair is sparse and the nails are usually dysplastic.  The nose appears small and peaked with underdevelopment of the nasal alae, and the mandible may be broad.  The cranial bones are often hyperostotic and the long bones as well as the ribs and clavicle are widened.  The middle phalanges of the digits are usually hypoplastic or may be absent.  Syndactyly of fingers and toes is often a feature and camptodactyly is common.  The teeth are small and carious with evidence of enamel dysplasia.   Hair often grows slowly and is sparse.  A variety of neurological deficits have been reported but no consistent pattern has been recognized.  However, white matter lesions and basal ganglia changes have been documented on MRI.

Genetics

Both autosomal recessive and autosomal dominant inheritance have been proposed but in both cases the mutations are in the same gene, GJA1, located at 6q21-q23.2.

This disorder is allelic to Hallermann-Streiff syndrome (234100).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general condition is available.  Cataracts and glaucoma require attention when present, of course.

References
Article Title: 

Cataracts, Congenital Cerulean

Clinical Characteristics
Ocular Features: 

Tiny lens opacities of blue or white color generally appear from birth through 18 and 24 months of age but may not be diagnosed until adulthood.  They first appear at the outer edge of the fetal lens nucleus or in more superficial cortical layers depending on the type.  Infants may be visually impaired from birth and develop nystagmus and amblyopia.  The opacities are usually bilateral and progressive.  Lens removal may be required in early infancy but often not until the 2nd to 4th decades.

Systemic Features: 

No systemic abnormalities are associated with cerulean cataracts.

Genetics

Lens opacities can, of course, be associated with chromosomal aberrations, developmental conditions, intrauterine infections, and metabolic errors as well as single gene mutations.   About 23% are familial but even among these there is considerable genetic and clinical heterogeneity that confounds the nosology despite notable recent progress in genotyping.  Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Cerulean cataracts of congenital or childhood onset can be due to mutations in genes that encode various lens crystallins.  Type 1 (CCA1; 115660) or 'blue dot' cerulean cataracts result from mutations in a gene located at 17q24 but its identity is as yet unknown. Intriguingly, it is located in the same chromosomal vicinity as the galactokinase deficiency gene (GALK1).  The lens opacities follow an autosomal dominant pattern of transmission. The mutation, however, does not appear to involve a gene that codes for any of the major structural proteins of the lens.

Type 2 (CCA2; 601547) results from mutations in the CRYBB2 gene (22q11.2-q12.2) encoding the beta-B2-crystallin protein.  Inheritance is autosomal dominant.

Type 3 (CCA3; 608983) is caused by mutations in CRYGD (2q33-q35) coding gamma-D-crystallin.  It has been reported in a single family in which it seemed to appear earlier and progress more rapidly than other types.  The pedigree pattern was consistent with autosomal dominant inheritance.  Mutations in the same gene also cause an allelic disorder designated nonnuclear polymorphic congenital cataracts or PCC (601286), which may simply be clinical heterogeneity of the same condition.

Type 4 (CCA4; 610202) is due to mutations in the MAF gene (16q22-q23) and is also inherited in an autosomal dominant pattern.  Lens opacities have a later, more juvenile onset and the lens opacities are located in a lamellar distribution in superficial cortical layers.  These are progressive and often result in posterior subcapsular opacification that requires lens extraction in adults.

Type 5 (CCA5; 614422) is the result of a mutation in a locus at 12q24 and is dominantly inherited.  The opacities are located throughout the lens but are most numerous in the cortex.   They are most commonly diagnosed in the second decade of life and lens extractions are required a decade or so later.

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include Volkmann type (115665), Coppock-like (604307), lamellar (116800), and congenital posterior polar (116600) cataracts. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known to prevent the opacities but serial evaluations and cataract surgery are required to prevent amblyopia as the opacities progress.

References
Article Title: 

Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state

Plotnikova OV, Kondrashov FA, Vlasov PK, Grigorenko AP, Ginter EK, Rogaev EI. Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am J Hum Genet. 2007 Jul;81(1):32-43.

PubMed ID: 
17564961

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

Peroxisome Biogenesis Disorder 1A (Zellweger)

Clinical Characteristics
Ocular Features: 

Ocular signs resemble those of other peroxisomal disorders with cataracts and retinopathy.  The lethal consequences of ZWS have hampered delineation of the full spectrum of ocular manifestations but many infants have these features plus optic atrophy and horizontal nystagmus.  Most infants do not follow light.  Pupillary responses may be normal in early stages but disappear later. Hypertelorism has been described but metrics are often normal.

Systemic Features: 

Many infants have hepatomegaly at birth and may develop splenomegaly as well.  Jaundice often occurs with intrahepatic biliary dysgenesis.   Severe hypotonia is present at birth but improves in those patients who survive for several years.  Psychomotor retardation can be profound and seizures may occur but sensory examinations are normal.  Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes.  Pipecolic acid levels are low in serum and absent in the CSF.  Most infants do not survive beyond 6 months of age.

 

Genetics

This is a peroxisome biogenesis disorder with a complex biochemical profile resulting from a large number of mutations in at least 13 PEX genes.  It is inherited in an autosomal recessive pattern.

What was formerly called Zellweger Syndrome is now more properly called Zellweger Spectrum Disorder, or sometimes a peroxisomal biogenesis disorder in the Zellweger spectrum of disorders.  The spectrum also includes neonatal adrenoleukodystrophy (601539) and Infantile Refsum disease (601539). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Cerebral Amyloid Angiopathy

Clinical Characteristics
Ocular Features: 

Posterior polar cataracts appear during the third decade of life.

Systemic Features: 

Progressive hearing loss has its onset in the third decade and becomes severe in the 5th decade.  Progressive dementia, often in the form of paranoid psychosis, begins about age 50.  Cerebellar ataxia and intention tremor have their onset in midlife.  There is a diffuse atrophy throughout the brain and cranial nerves are demyelinated.  Blood vessels throughout the CNS, spinal cord and retina show an amyloid angiopathy.  Intracranial hemorrhage is a significant risk and, when lobar in location, carries a significant risk of mortality within months.  Death generally occurs in the 5th and 6th decades of life.

Genetics

Pedigree patterns in the few reported families are consistent with autosomal dominant inheritance.  A mutation has been found in the ITM2B gene located at 13q14.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Heredopathia ophthalmo-oto-encephalica

Stromgrem, E. Heredopathia ophthalmo-oto-encephalica. In: Myrianthopoulos, N.C. Handbook of Clinical Neurology. Neurogenetic directory. New York: Elsevier/North Holland (pub.) 42, Part I: 150-152, 1981.

Galactokinase Deficiency

Clinical Characteristics
Ocular Features: 

This is a considerably more rare disorder of galactose metabolism compared with classic galactosemia (230400).  Both disorders cause cataracts in the neonatal period but the early systemic effects of galactokinase deficiency are less severe.  In the latter disorder, cataracts usually develop later, often during the first decade of life and less commonly during the neonatal period that is characteristic of classic galactosemia.  Galactitol  accumulation causing osmotic changes in the lens accounts for the cataracts and may also be responsible for the development of pseudotumor cerebri found infrequently.  Good dietary control may prevent the formation and progression of cataracts and it has been reported that they may regress as well but only prior to the rupture of cell membranes.

Systemic Features: 

Late complications include abnormalities in mental and/or motor development, dyspraxia, and hypogonadotropic hypogonadism which occur in spite of severe reduction in galactose intake.  Ovarian failure is common.

Genetics

This is an autosomal recessive disorder caused by mutations in the GALK1 gene (17q24) encoding galactokinase.  It is extremely rare but should be considered in any patient with cataracts found within the first two decades of life.  Deficient activity of the galactokinase enzyme can be demonstrated in erythrocytes.

For other disorders of galactose metabolism, see galactosemia (230400) and galactose epimerase deficiency (230350).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Early dietary restriction of non-galactose polycarbohydrates and deficient in lactose may prevent the formation of cataracts or sometimes result in regression.

References
Article Title: 

Wagner Syndrome

Clinical Characteristics
Ocular Features: 

This is one of several hereditary vitreoretinal degenerative disorders in which vitreous degeneration occurs and the risk of retinal detachment is high (others being Goldmann-Favre [268100], Stickler [609508, 108300], and Marshall [154780] syndromes).  An optically empty central vitreous is a common feature in this heterogeneous group.  Other reported ocular findings in Wagner syndrome include perivascular sheathing and pigmentation, progressive chorioretinal dystrophy, ectopic fovea with pseudoexotropia, tractional retinal detachments, glaucoma (neovascular in some), and vitreous veils with fibrillar condensation.  Cataracts occur in virtually all patients over the age of 45 years.  The ERG in the majority of patients shows elevated rod and cone thresholds on dark adaptation (63%) and subnormal b-wave amplitudes (87%).  Mild difficulties in dim light are noted by some patients.  Visual acuities are highly variable ranging from normal in many patients to blindness in others.  Peripheral visual fields may be severely constricted.

Systemic Features: 

Cleft palate has been seen in some patients but these likely had Stickler syndrome (609508, 108300, 604841 ) since hearing loss along with other joint and skeletal manifestations are absent.  Further, cases reported to have Wagner syndrome with palatoschisis have not been genotyped so it is likely that they were misdiagnosed.

Genetics

Wagner syndrome results from a mutation in the VCAN gene encoding versican (5q14.3), a chondroitin sulfate proteoglycan-2 found in the vitreous among other tissues.  It is an autosomal dominant disorder.  It has been proposed that erosive vitreoretinopathy (ERVR) (143200) is allelic to Wagner’s syndrome but it may also simply be a variable expression of the same disorder.  Both map to 5q13-q14.  Overlapping of clinical signs and symptoms among hereditary disorders of vitreoretinal degeneration has created some confusion in their classification but this will hopefully be clarified as more families are genotyped.  Stickler syndrome (609508, 108300), for example, is known to be caused by a mutation in an entirely different gene (COL2A1) on a different chromosome.

Snowflake type vitreoretinal degeneration (193230), another autosomal dominant disorder, has a superficial resemblance but mutations in a different gene (KCNJ13) are responsible.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no therapy specifically for this disorder but the usual treatments for retinal detachments, cataract and glaucoma should be applied where appropriate.

References
Article Title: 

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