endothelial dystrophy

Anterior Segment, Brain, and Facial Anomalies

Clinical Characteristics
Ocular Features: 

The interpupillary distance appears abnormally wide.  VEP and ERG responses suggest abnormal retinal bipolar cells.  Specular microscopy reveals variable sizes and shapes of corneal endothelial cells with scattered vesicles and large 'holes' in the usual hexagonal array.  The iris may be malformed (no collarette, stromal hypoplasia) and there may be peripheral iridocorneal adhesions.  Elevated IOP, band keratopathy, corneal clouding, and keratoconus have been reported.  Visual acuity is impaired to some extent, from near normal (20/25) to NLP.  Progressive optic atrophy was observed in one patient.

Systemic Features: 

Four members of a 3 generation family had malformed pinnae (posterior placement and rotation).  Other features variably present were an empty sella turcica, posterior fossa cyst, and hydrocephalus. The propositus also was found to have abnormal auditory bipolar cells based on the audiogram and audio-evoked brainstem responses.

Genetics

Based on direct sequencing in one family (3 adults and 1 child), this condition seems to be caused by heterozygous variations or mutations in the VSX1 gene (20p11.21). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Monitoring for glaucoma and appropriate treatment are indicated.  Hearing tests should be performed early.  The usual treatments for keratoconus should be considered.  Excess brain fluid may need surgical drainage.

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References
Article Title: 

Corneal Dystrophy, Fuchs Endothelial, Late Onset 2

Clinical Characteristics
Ocular Features: 

The signs and symptoms of this disorder are similar to those of other adult endothelial dystrophies.  Guttae appear in the fourth or fifth decade of life and gradually increase in number.  Diffuse corneal edema eventually develops with a corresponding decrease in acuity.  In late stages the corneal edema involves all layers including the epithelium, leading to painful corneal erosions. 

Systemic Features: 

Some patients with FECD3 report hearing impairment but this has not been studied and may be simply an age-related association.  It is of interest that among an unclassified series of patients with FCD the frequency of hearing loss was higher than in matched controls.       

Genetics

A mutation in LOXHD1 (18q21.2-q21.32) was originally thought to be responsible for this form of Fuchs in a multigenerational pedigree but is now considered an insignificant variant.  More recent evidence suggests that heterozygous trinucleotide repeat expansions in the TCF4 transcription factor gene at 18q22 are responsible.

There is considerable genetic heterogeneity in adult endothelial dystrophy which makes the nosology confusing especially since the clinical features are similar.  A similar late onset autosomal dominant disease [Fuchs Endothelial Dystrophy, Late Onset (610158)], sometimes labeled FCD2, may result from mutations on chromosome 13, or from changes in ZEB1 on chromosome 10.  Many cases are sporadic, however, and additional genotyping will be necessary in individuals to further clarify the classification of late-onset Fuchs endothelial dystrophy.

There is also an early onset form of Fuchs endothelial dystrophy, (136800).  

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation for symptomatic patients would likely be helpful but results have not been reported specifically for this type of dystrophy.

References
Article Title: 

Corneal Dystrophy, Posterior Polymorphous 1

Clinical Characteristics
Ocular Features: 

This form of corneal dystrophy is often asymptomatic but some patients experience endothelial decompensation and corneal edema, which may even be seen soon after birth. The edema may extend into the epithelium.  The basic mechanism entails metaplasia of endothelial cells which seem to acquire some characteristics of epithelial cells.  Posterior corneal lesions of variable morphology appear in various patterns and are often surrounded by grayish halos.  When these become confluent the corneal edema is more severe and may resemble a congenital endothelial dystrophy.  The endothelial cell count is often low.  The Descemet layer also becomes abnormal.  The posterior border of the cornea appears nodular and grayish in color, often in a geographic pattern.  Surprisingly, endothelial function often is maintained and patients may remain asymptomatic for many years.

Some patients have features of anterior chamber dysgenesis with iris anomalies, anterior synechiae, and glaucoma.  It is also sometimes confused with EDICT syndrome (614303).

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

This is a genetically heterogeneous autosomal dominant disorder caused by several mutations including the promotor of OVOL2 at 20p11.23 responsible for PPCD1 described here.  Another locus for this disease has been mapped to 20q11, the same locus responsible for congenital hereditary corneal edema 1 (CHED1) and it is possible that these are allelic or clinical variants of the same mutation.  The latter is made more likely by the fact that both disorders have been found in relatives.  OMIM has combined the entities CHED1 and PPCD1 as a single disorder (122000).

For other forms of posterior polymorphous corneal dystrophy see, PPCD2 (609140) and PPCD3 (609141).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Few patients require treatment since the endothelial changes are frequently stable. Among those that do undergo corneal transplantation, the changes often recur in the donor button.

References
Article Title: 

Corneal Dystrophy, Congenital Endothelial 1

Clinical Characteristics
Ocular Features: 

(OMIM has combined this disorder with PPCD1 (122000) based on genetic and clinical evidence.)

Early onset limbus-to-limbus corneal clouding is the outstanding feature.  Some asymmetry is often present.  Vision is minimally impaired if at all in many children but slow progression occurs and adults often become visually impaired.  Nystagmus does not develop.  Photophobia and tearing are common.  The corneal appearance can lead to the erroneous diagnosis of congenital glaucoma.  However, some infants actually do have congenital glaucoma as well leading some to suggest this may be a disorder of anterior chamber dysgenesis.  The edematous cornea may be of 2-3 times normal thickness.  It may appear generally hazy and sometimes has a diffuse ground glass appearance.  

The posterior surface often appears mottled and has been described as having a peau d'orange appearance.  The endothelium is attenuated or even absent histologically and abnormal, disorganized collagen fibrils have been found in a thickened Descemet layer by electron microscopy.  The remaining endothelial cells are often vacuolated and heaped in double layers, with some containing melanin granules.  Some atrophy and edema of the epithelium with partial loss of Bowman's can be seen histologically.

Systemic Features: 

No systemic abnormalities are found in this disorder.

Genetics

This is an autosomal dominant disorder that maps to a locus on chromosome 20 (20p11.2-q11.2).   The molecular defect seems to involve the promotor of OVOL2 (20p11.23).  It is of interest that the posterior polymorphous corneal dystrophy 1 (PPCD1, 122000) mutation has been mapped to the same pericentric region, and it has been suggested that the two conditions may be allelic. These are now combined into a single entity in OMIM. 

This disorder should not be confused with congenital endothelial dystrophy type 2, CHED2 (217700) which is autosomal recessive, has an earlier presentation, and maps to a different region of chromosome 20.  Harboyan syndrome (217400) has similar corneal features but maps to a different location on chromosome 20 and is associated with sensorineural deafness.

The nosology of the corneal dystrophies is still evolving.  In the 2015 edition of the IC3D, this condition designated CHED1 is eliminated based on clinical and pathologic similarities to those in posterior polymorphous corneal dystrophy 1 (PPCD1, 122000).  However, while the loci for PPCD2 and CHED1 are located in the same pericentric region of chromosome 20, the purported mutations occur in different genes. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty carries a good visual prognosis, even when done late in life.

References
Article Title: 

IC3D classification of corneal dystrophies--edition 2

Weiss JS, Moller HU, Aldave AJ, Seitz B, Bredrup C, Kivela T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbe A, Kenyon KR, Kinoshita S, Lisch W. IC3D classification of corneal dystrophies--edition 2. Cornea. 2015 Feb;34(2):117-59. Erratum in: Cornea. 2015 Oct;34(10):e32.

PubMed ID: 
25564336

EDICT Syndrome

Clinical Characteristics
Ocular Features: 

This is a rare disorder with multiple anterior segment anomalies.  The corneal stroma is thinned in the range of 330 to 460 um with uniform steepening (no cone).  The epithelium may be irregular and edematous, the stroma is diffusely hazy, and the endothelium is irregular with many guttae.  Anterior polar cataracts are likely congenital and often require removal before the age of 20 years.  The pupils are often eccentric and difficult to dilate.  The iris stroma may appear atrophic.  Visual acuity, even in the aphakic condition, is in the range of 20/30 to 20/160.

Histological studies show attenuation of the endothelium with cellular overlapping and aggregates of fibrillar material that stains for cytokeratin.  Descemet membrane is thickened as is the epithelial basement membrane and both intracellular and extracellular lipid deposition is seen throughout the stroma and the Bowman membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant disorder resulting from a heterozygous single base substitution (57C-T) in the MIR184 gene (15q25.1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract removal and penetrating keratoplasty can be helpful.  It is unknown whether the donor corneal tissue develops similar opacities.

References
Article Title: 

Corneal Dystrophy, Fuchs Endothelial, Late Onset

Clinical Characteristics
Ocular Features: 

There are a number of endothelial corneal dystrophies to which Fuchs name has been attached, including two that are early in onset, or even congenital (CHED1; 121700), (CHED2; 217700) and at least three that have an adult onset, one (Fuchs endothelial dystrophy, early onset; 136800) which has a relatively early onset and two considered to have a late onset: the one described here and another known as Fuchs Endothelial Dystropy, Late Onset 2 (613267).  Evidence for multiple distinct types comes from genotyping which reveals considerable genetic heterogeneity in spite of similar phenotypes (see Genetics).  All are progressive and degenerative with various degrees of visual disability.  Most have histologic changes in both the endothelial cells and Descemet membrane.

The entity described here likely is the classical disease described in the older literature.  It is certainly the most common, occurring in 4% of the population over the age of 40 years and for unknown reasons is more often found in females.  Guttae are formed as excrescences of Descemet's membrane and develop initially in the central cornea, beginning about the 5th decade, gradually increasing in number and size toward the periphery. They tend to be relatively large, sharply peaked and often positioned at the cell-cell junctions of endothelial cells.  These are often best visualized by corneal transillumination.  Histologically, the posterior portion of Descemet membrane contains bundles and sheets of abnormal collagen.  Progressive corneal edema follows as endothelial cells are lost and the remaining ones are unable to maintain normal stromal hydration.  Fingerprint lines may be present.  The corneal edema may involve both stroma and epithelium and in advanced stages may lead to painful epithelial erosions.  The disease is relentless and early blurring of vision progresses to significant visual handicaps often requiring corneal transplantation in the 7th and 8th decades.

Corneal guttae are common in older individuals but usually are located more peripherally.  The diagnosis of Fuchs can best be made where the guttae are concentrated centrally and associated with stromal and epithelial edema.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Late onset Fuchs of this type is due to a mutation on chromosome 13 (13pter-q12.13) but the specific molecular basis for the disease remains unclear.  Many cases occur sporadically but some pedigrees are consistent with autosomal dominant inheritance.  For unknown reasons females are more commonly affected and often have more severe disease.  Recent reports suggest that missense mutations in ZEB1 may be responsible for at least some cases of late-onset Fuchs.  This mutation has also been found in cases of type 3 posterior polymorphous dystrophy (609141) suggesting that the two conditions may be allelic.

Other rare forms of late onset endothelial dystrophy to which the eponymic designation of Fuchs has been applied include FECD3 (613267) in which various mutations in the TCF4 locus on chromosome 18 (18q21.2-q21.3) (and expanded TGC trinucleotide repeats) have been implicated.  Other variants of Fuchs endothelial dystrophy include FECD4 (613268) with a mutation in SLC4A11 (20p13-p12), FECD5 (613269) with a possible mutation on chromosome 5 (5q33.1-q35.2), FECD6 (613270) due to a mutation in ZEB1 on chromosome 10 (10p11.2), and FECD7 (613271) that can be mapped to chromosome 9 (9p24.1-p22.1).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation has a good prognosis and posterior lamellar grafting may be the technique of choice.  In some patients, visually significant cataracts are present before the cornea is severely involved and a triple procedure may be considered.  However, this is best determined by pachymetry.  Individuals with a preoperative corneal thickness of even >600 micrometers can do well after cataract surgery for a number of years before the cornea needs to be replaced.

References
Article Title: 

E2-2 protein and Fuchs's corneal dystrophy

Baratz KH, Tosakulwong N, Ryu E, Brown WL, Branham K, Chen W, Tran KD, Schmid-Kubista KE, Heckenlively JR, Swaroop A, Abecasis G, Bailey KR, Edwards AO. E2-2 protein and Fuchs's corneal dystrophy. N Engl J Med. 2010 Sep 9;363(11):1016-24.

PubMed ID: 
20825314

Corneal Dystrophy, Fuchs Endothelial, Early Onset

Clinical Characteristics
Ocular Features: 

This is one of several adult onset corneal endothelial dystrophy (see Fuchs endothelial corneal dystrophy, late onset, (610158) for more forms of adult Fuchs endothelial dystrophy).  The onset of this type is considerably earlier than in the more common adult onset type (610158) .  Endothelial disease has been noted as early as three years of age but onset is likely later than in the congenital forms (CHED1; 121700), (CHED2; 217700).  In early onset Fuchs dystrophy, most individuals have evident disease by the third and fourth decades and many have advanced disease by the fourth and fifth decades.  The sex ratio among affected individuals is closer to 1:1 in this disorder compared with the more common adult onset type in which the disease is more common in females.

In this early onset disorder the guttae are small and more rounded than those in the later onset endothelial dystrophies, and are closer to the center of the endothelial cells.  The progression of corneal decompensation is temporally similar to that of the late onset dystrophies, resulting in clinically advanced disease within 3 to 4 decades.  The progression of disease has been documented through quantifying the number of guttae over time.   Among 26 patients, the number increased as much as 29.1% over a 30 month period, and an exponential increase was noted after age 50 years.  The inferotemporal quadrant of the cornea had the greatest proportion of guttae.  As in other forms of endothelial corneal dystrophy, Descement's  membrane is thickened and exhibits nodularity with secondary apoptosis of endothelial cells.

Systemic Features: 

None have been reported.

Genetics

A mutation in the COL8A2 gene, L450W, located on chromosome 1 (1p34.3-p32.3) seems to be responsible for this disease.  The gene codes for the alpha-2 chain of collagen VIII which is an important component of Descemet's membrane.  Like many other collagen diseases, this disorder is transmitted as an autosomal dominant.

This gene is also mutant in posterior polymorphous corneal dystrophy 2 (609140) and both types of dystrophy have been reported in the same family suggesting they may be the same disorder with variable expressivity.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation is the treatment of choice for advanced disease.

References
Article Title: 

Missense mutations in COL8A2,the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Biswas S, Munier FL, Yardley J, Hart-Holden N, Perveen R, Cousin P, Sutphin JE, Noble B, Batterbury M, Kielty C, Hackett A, Bonshek R, Ridgway A, McLeod D,Sheffield VC, Stone EM, Schorderet DF, Black GC. Missense mutations in COL8A2,the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001 Oct 1;10(21):2415-23.

PubMed ID: 
11689488

Inheritance of Fuchs' combined dystrophy

Magovern M, Beauchamp GR, McTigue JW, Fine BS, Baumiller RC. Inheritance of Fuchs' combined dystrophy. Ophthalmology. 1979 Oct;86(10):1897-923.

PubMed ID: 
399801

Corneal Dystrophy, Congenital Endothelial 2

Clinical Characteristics
Ocular Features: 

Corneal clouding is usually evident at birth and in virtually all cases in the first decade of life.   Corneal edema is usually progressive and often leads to stromal scarring, neovascularization, and deposition of plaques eventually.  The ground glass appearance of the cornea at least initially is most pronounced peripherally.  When the ground glass appearance is present in young children, it may lead to the misdiagnosis of congenital glaucoma and some children have had glaucoma surgery.  However, no anatomic abnormalities of the anterior chamber angle have been observed and glaucoma does not seem to occur in this disorder as it does in CHED1.  Photophobia and tearing are uncommon. 

The corneal epithelium may become atrophic with partial loss of Bowman's membrane replaced by subepithelial fibrosis.  Corneal sensitivity is normal.  The stroma may have spheroidal degeneration resembling posterior polymorphous dystrophy.  Generalized edema may lead to marked thickening of the entire cornea.  The endothelium undergoes degeneration and cell loss is common, while those that remain often contain melanin granules.  Descemet's membrane is greatly thickened.  This condition may be stable in some individuals while others clearly have evidence of progression, and a few have some regression in childhood.  Vision may be quite good and few patients develop nystagmus.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder resulting from mutations in the SLC4A11 gene located on chromosome 20 (20p13-12).  This disorder must be distinguished from Harboyan syndrome (#217400, CDPD1) from which it differs by the absence of neurosensory deafness.  The two disorders are allelic, however.  A clinically similar but less severe and genetically distinct form of congenital endothelial dystrophy, CHED1 (121700), can have a later age of presentation, maps to a different region of chromosome 20 ( 20p11.2-q11.2), and is inherited in an autosomal dominant pattern. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corneal transplantation can be successful in restoring vision in 90% of cases, even when performed in adults.

References
Article Title: 

Congenital hereditary

McCartney A, Rice NS, Garner A, Steele AD. Congenital hereditary
corneal oedema of Maumenee: its clinical features, management, and pathology.
Br J Ophthalmol. 1987 Feb;71(2):130-44.

PubMed ID: 
3548808
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