corneal edema

Corneal Dystrophy, Posterior Polymorphous 4

Clinical Characteristics
Ocular Features: 

The posterior corneal surface becomes highly irregular as the endothelial cells become variable in size and in number.  There may be focal areas of multilayering of endothelial cells.  Most patients have a significant reduction in endothelial cell density which eventually leads to corneal edema and blurred vision.  Some patients have anterior synechiae and corectopia with secondary glaucoma.

Corneal edema has been noted in infants at several months of age.  Painful bullous keratopathy or uncontrollable glaucoma may lead to enucleation in adult life.

Systemic Features: 

The posterior corneal surface becomes highly irregular as the endothelial cells become highly irregular in size and in number.  There may be focal areas of multilayering of endothelial cells.  Most patients have a significant reduction in endothelial cell density which eventually leads to corneal edema and blurred vision.  Some patients have anterior synechiae and corectopia with secondary glaucoma.

Corneal edema has been noted in infants at several months of age.  Painful bullous keratopathy or uncontrollable glaucoma may lead to enucleation in adult life.

Genetics

Heterozygous mutations in the GRHL2 gene (8q22.3-q24.12) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation may benefit selected patients.E

References
Article Title: 

Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4

Liskova P, Dudakova L, Evans CJ, Rojas Lopez KE, Pontikos N, Athanasiou D, Jama H, Sach J, Skalicka P, Stranecky V, Kmoch S, Thaung C, Filipec M, Cheetham ME, Davidson AE, Tuft SJ, Hardcastle AJ. Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. Am J Hum Genet. 2018 Mar 1;102(3):447-459.

PubMed ID: 
29499165

Keratoendotheliitis Fugax Hereditaria

Clinical Characteristics
Ocular Features: 

Recurrent ocular inflammatory episodes begin between the ages of 3 and 12 years (median age of onset 11 years).  These episodes can last from a few days to several weeks and may recur several times a year.  Episodes are milder and less frequent in older individuals.  There is often conjunctival hyperemia accompanied by pain, blurry vision, and photophobia during the acute phase.    In addition, the posterior stroma is edematous and hazy, pseudoguttata may be present, and some patients have a mild anterior chamber reaction.  Visual acuity is normal in most individuals but may be mildly reduced during acute attacks or rarely in older patients with central corneal opacities.  Occasional corneal erosions have been reported.  Between attacks the endothelial cells can appear normal.

Systemic Features: 

No systemic features have been found.

Genetics

Heterozygous mutations in the NLRP3 gene (1q44) encoding cryopyrin have been identified in European (Finnish) populations with this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported although some patients obtained improvement in symptoms with the use of oral NSAIDs and topical corticosteroids.

References
Article Title: 

Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene

Turunen JA, Wedenoja J, Repo P, Jarvinen RS, Jantti JE, Mortenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivela TT. Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene. Am J Ophthalmol. 2018 Jan 20. pii: S0002-9394(18)30023-0. doi: 10.1016/j.ajo.2018.01.017. [Epub ahead of print].

PubMed ID: 
29366613

Glaucoma, Congenital Primary E

Clinical Characteristics
Ocular Features: 

Glaucoma is usually present at birth but sometimes not detected for several months.  Intraocular pressures are generally greater than 21 mm Hg.  Increased optic nerve cupping greater than 40% was also used to make the diagnosis in many individuals.  Ten families have been reported and in half the disease was unilateral only.

Systemic Features: 

No consistent systemic features are present.

Genetics

Heterozygous mutations in the TEK (9p21.2) gene (600221) are responsible for this disorder.  The TEK receptor is a tyrosine kinase primarily expressed in endothelial cells in mice, rats and humans.  In Tek-knockout mice Schlemm's canal and the trabecular meshwork are hypoplastic and dysmorphic.

For additional mutations and congenital glaucoma conditions see Glaucoma, Congenital Primary A.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Standard glaucoma therapies should be applied early and lifelong monitoring is necessary.

References
Article Title: 

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, Feng L, Limviphuvadh V, Whisenhunt KN, Maurer-Stroh S, Yanovitch TL, Kalaydjieva L, Azmanov DN, Finzi S, Mauri L, Javadiyan S, Souzeau E, Zhou T, Hewitt AW, Kloss B, Burdon KP, Mackey DA, Allen KF, Ruddle JB, Lim SH, Rozen S, Tran-Viet KN, Liu X, John S, Wiggs JL, Pasutto F, Craig JE, Jin J, Quaggin SE, Young TL. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 2016 Jul 1;126(7):2575-87.

PubMed ID: 
27270174

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: 

Pearson Marrow-Pancreas Syndrome

Clinical Characteristics
Ocular Features: 

Although systemic disease is usually evident during infancy, ocular symptoms such as ptosis and ophthalmoplegia may not be apparent until adulthood in those that survive.  The ocular myopathy in adults can resemble Kearns-Sayre syndrome (530000) as the result of a phenotypic shift from a predominantly hematopoietic disorder to a mitochondrial myopathy.  Bilateral zonular cataracts and strabismus have been reported in a 3 year old male.  A midperiphery pigmentary retinopathy has been observed.  Endothelial cell failure leads to corneal edema. 

Systemic Features: 

Low birth weight, failure to thrive, hypoplastic anemia and exocrine pancreatic dysfunction are often seen in infancy.  Precursor cells in the marrow show typical vacuolization. Malabsorption and insulin-dependent diabetes often develop.  The pancreas and bone marrow may become fibrotic.  Patients with the classic syndrome as a child can develop features of the Kearns-Sayre syndrome if they survive childhood.  Progressive muscle weakness in pharyngeal, facial, neck, and limb muscles is sometimes seen in older individuals and muscle biopsy reveals ragged-red fibers characteristic of mitochondrial disease.  Some patients have an organic aciduria and others develop hepatic failure with elevated transaminase, bilirubin and lipid levels.  Kidney damage results in Fanconi syndrome.  Young children may recover from the refractory anemia eventually but metabolic acidosis with life-threatening lactic acidosis is a constant threat and responsible for many childhood deaths.

Genetics

Deletions in mtDNA involving numerous genes are responsible for this condition.  As a result, it is maternally transmitted but somewhat inconsistently due to mitochondrial heteroplasmy.  Both sexes are affected.  The irregular size of the mtDNA deletions and the tissue distribution of affected mitochondria results in considerable variation in clinical expression.  Defective oxidative phosphorylation seems to be the underlying cause of many of the signs and symptoms.

Treatment
Treatment Options: 

This multisystem disease requires careful monitoring throughout life.  Blood transfusions may be required and careful attention needs to be given to nutrition and metabolic dysfunction.  A few patients have required insulin.  In spite of vigorous treatment of electrolyte imbalances, correction of acidosis, and hormonal supplements, many patients do not survive beyond childhood.  Organ failure requires individualized treatment.

References
Article Title: 

Pearson Syndrome

Farruggia P, Di Marco F, Dufour C. Pearson Syndrome. Expert Rev Hematol. 2018 Jan 16. doi: 10.1080/17474086.2018.1426454. [Epub ahead of print].

PubMed ID: 
29337599

Keratoconus 4

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a ‘scissoring’ pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations at the 2p24 locus on chromosome 2 seem to cause KTCN4 based on genome-wide linkage analysis in families from multiple out-bred populations.  The pattern of inheritance is autosomal dominant.

Other forms of hereditary keratoconus caused by different mutations are:  Mutations in VSX1 (20p11.2) cause KTCN1, KTCN2 (608932) is linked to a mutation on chromosome 16 (16q22.3-q23.1), and KTCN3 (608586) results from a mutation on chromosome 3 (3p14-q13).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 3

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN3 seems to be caused by a mutation located at 3p14-q13 as determined from linkage studies in a 2 generation Italian family.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by mutations in the VSX1 gene at 20p11.2), KTCN2 (608932) from a mutation on chromosome 16 (16q22.3-q23.1), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 2

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN2 seems to be caused by a mutation located at 16q22.3-q23.1 as determined from linkage studies in 20 Finnish families.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by a mutation in the VSX1 gene (20p11.2), KTCN3 (608586) from a mutation on chromosome 3 (3p14-q13), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 1

Clinical Characteristics
Ocular Features: 

The cornea progressively thins mostly in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy may show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively often thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse.

Genetics

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and other chromosomal disorders. It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years. Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder. Only keratoconus associated with single gene mutations are considered here.

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations in the VSX1 homeobox gene (20p11.2) have been found in what is called KTCN1 keratoconus (the same gene is mutant in posterior polymorphous corneal dystrophy 1 [122000]), inherited as an autosomal dominant trait.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN2 (608932) linked to a mutation on chromosome 16 (16q22.3-q23.1), KTCN3 (608586) by a mutation on chromosome 3 (3p14-q13), KTCN4 (609271) caused by a mutation on chromosome 2 (2p24), KTCN5 (614622) mapped to 5q14.1-q21.3, KTCN6 (614623) mapped to 9q34, KTCN7 (614629) mapped to 13q32, KTCN8 (614628) mapped to 14q24, and KTCN9 (617928) associated with a mutation in the TUBA3D gene located at 2q21.1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

VSX1: a gene for posterior polymorphous dystrophy and keratoconus

Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR, Heathcote G, Westall C, Sutphin JE, Semina E, Bremner R, Stone EM. VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet. 2002 May 1;11(9):1029-36.

PubMed ID: 
11978762

Corneal Dystrophy, Posterior Polymorphous 2

Clinical Characteristics
Ocular Features: 

This is primarily a disease of the posterior cornea although the secondary edema may extend to the epithelium.  The disease may be apparent at birth or shortly thereafter by the presence of excrescences or nodules in the endothelial layer with stromal edema.  Descemet membrane can be highly irregular in thickness.  The endothelial cells in PPCD may acquire some characteristics of epithelial cells.

Systemic Features: 

No systemic abnormalities have been reported for PPCD2.

Genetics

This is a rare autosomal dominant disorder and few families have been reported.  The mutant gene, COL8A2 (1p34.3-p32.3) is the same as that causing early onset Fuchs endothelial dystrophy (136800) and both dystrophies have been described in the same family.   The mutation alters the synthesis of alpha 2 chains, part of type VIII collagen, a major component of the Descemet membrance.

For other forms of posterior polymorphous corneal dystrophy, see PPCD3 (609141), and PPPCD1 (122000).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Corneal transplantation may be indicated by the third decade or later.  The corneal lesions tend to recur, however.

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

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