corneal opacities

Keratosis Follicularis Spinulosa Decalvans, X-Linked

Clinical Characteristics
Ocular Features: 

There is alopecia of the eyelashes and eyebrows.  The skin of the eyelids is thickened often with an associated chronic blepharitis followed by entropion (ectropion sometimes mentioned).  Photophobia and keratitis with 'corneal degeneration' are also features but it is unknown whether these are primary or secondary to trichiasis from the eyelid deformities.  The corneal findings usually precede the scarring alopecia of the scalp.

Systemic Features: 

Onset is in childhood.  Thickening of skin is generalized especially in the neck, ears, and the extremities with marked involvement of the palms and soles, especially in the calcaneal regions.  Scalp hair may be sparse, often in a streak pattern.  The follicles are inflamed and hyperkeratotic resulting in scarring alopecia.  Carriers have been reported to have dry skin with mild follicular hyperkeratosis and more extensive involvement of the soles.

Genetics

This is a rare disorder with genetic and clinical heterogeneity.  The majority of cases seem to be inherited in an X-linked recessive pattern secondary to mutations in the SAT1 gen located at Xp22.1. 

However, multigenerational families with male to male transmission have also been reported suggesting autosomal dominant inheritance (KFSD; 612843).  However, no associated mutations or loci have been reported for this condition.

 

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

Retinoids reduce the inflammatory component and lead to cessation of the scalp alopecia.  A decrease in photophobia has also been reported but the clinical basis for this is unknown.

References
Article Title: 

Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD)

Gimelli G, Giglio S, Zuffardi O, Alhonen L, Suppola S, Cusano R, Lo Nigro C, Gatti R, Ravazzolo R, Seri M. Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). Hum Genet. 2002 Sep;111(3):235-41.

PubMed ID: 
12215835

Keratoconus Posticus Circumscriptus

Clinical Characteristics
Ocular Features: 

The posterior corneal surface has area(s) of excavation (indentation) associated with overlying opacification.  The lens-corneal separation is reduced and iridocorneal adhesions are often present.  The clinical picture has been described as ‘posterior conical cornea’ or posterior keratoconus.

Systemic Features: 

The neck is short and has webbing.  The facies appear ‘coarse’, the posterior hairline is low, the nose is prominent, digits are short, and the vertebral anomalies may lead to scoliosis.  Individuals are short of stature and brachydactyly is often present.  Developmental delays and mental retardation are usually features.  Other variable anomalies have been reported.

Genetics

Autosomal recessive inheritance seems most likely in view of the family patterns.  Based on the few families reported, it is uncertain if this is a single entity with variable expression or a combination of disorders.  No gene or locus has been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond surgical repair of the cleft lip and palate or scoliosis is available.  Peripheral iridotomies have been done in the presence of shallow anterior chambers.

References
Article Title: 

Osteoporosis-Pseudoglioma Syndrome

Clinical Characteristics
Ocular Features: 

Retrolental masses often present at birth have been mistaken for retinoblastomas.  Hyperplasias of the vitreous, corneal opacities, and secondary glaucoma have been described.  Band keratopathy may account for some of the corneal clouding and opacities.  Most patients are blind soon after birth although some retain some vision into the second decade.

Systemic Features: 

Some patients have been described as mentally retarded but others have normal intelligence.  Hypotonia and hyperflexible joints have been noted.  Bone fractures are common sometimes resulting in scoliosis, short stature and limb deformities.  Radiography of the skeletal reveals porotic and thin bones.

Genetics

This disorder, sometimes called the ocular form of osteogenesis imperfecta, results from mutations in LRP5 (11q13.4).  The same gene is mutant in the EVR4 type of familial exudative vitreoretinopathy (601813) which has some of the same ocular and bone features.  Most descriptions of OPPG were published before the gene mutation was found and many reports do not include detailed ocular examinations.  Certainly the two disorders are allelic and likely the same condition. 

Mutations in LRP5 lead to EVR4 disease in both the heterozygous and homozygous configuration but most cases of OPPG have homozygous or compound heterozygous mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone fractures need to be repaired and glaucoma treated when present.  Bisphosphonate treatment may lead to increased bone density if initiated early.  The retrolental masses need to be carefully evaluated to rule out retinoblastoma.

References
Article Title: 

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13

Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146-51.

PubMed ID: 
8659519

Dermochondrocorneal Dystrophy

Clinical Characteristics
Ocular Features: 

A corneal dystrophy is part of this syndrome.  Patients develop confluent, drop-like subepithelial whitish-brown infiltrates of the central cornea with some anterior stromal involvement together with stellate anterior cortical cataracts.  The intervening stroma appears hazy.  The epithelial surface remains intact but may be irregular over the superficial stromal infiltrates. The corneal opacities follow the skin and hand deformities and may be accompanied by a vascularized pannus.  Diagnosis can usually be made in the first decade of life.  Visual acuity in young adults may be reduced to the 20/80 - 20/100 range.

Systemic Features: 

Xanthomatous nodules are primarily located on the pinnae, hands, elbows, and nose.  Most of the nodules are small and primarily of cosmetic significance.  They have also been reported in oral mucosa and gingival tissue.  Hyperplasia of the oral mucosa is common.  Deformities of the hands and feet are also seen.

Genetics

Both autosomal dominant and autosomal recessive modes of inheritance have been proposed but insufficient numbers of families have been reported to be conclusive.

Treatment
Treatment Options: 

Corneal grafts could be visually beneficial but the vascularized pannus increases the risk of rejection.  CO2 laser treatment can reduce the cutaneous chondromes.  Gingival lesions and hyperplasia of the oral mucosa may require surgical treatment.

References
Article Title: 

Dyskeratosis, Hereditary Benign Intraepithelial

Clinical Characteristics
Ocular Features: 

The conjunctival surface has elevated, granular-appearing white epithelial plaques usually in the interpalpebral areas.  These may extend onto the cornea and cause interference with vision.  The plaques may also shed spontaneously.  The lesions may have prominent blood vessels with associated conjunctival hyperemia with considerable cosmetic implications.

The plaque-like growths remain localized and do not invade tissue.  The surface epithelium is hyperkeratotic with acanthosis and individual cell dyskeratoses.

Systemic Features: 

The oral and lingual mucosa may also be involved.

Genetics

A segment of DNA localized at 4q35 is duplicated resulting in triple alleles for 2 linked markers suggesting that gene duplication is responsible for the disorder.  It occurs almost exclusively among members of a triracial isolate (Haliwa Indians) in North Carolina.

Families with autosomal dominant transmission have been reported.  In one French Canadian family in which mother and son were affected a nonsense mutation in NLRP1 (17p13.2) was found.  This may be a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Local excision as needed.

References
Article Title: 

Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis

Soler VJ, Tran-Viet KN, Galiacy SD, Limviphuvadh V, Klemm TP, St Germain E, Fourni?(c) PR, Guillaud C, Maurer-Stroh S, Hawthorne F, Suarez C, Kantelip B, Afshari NA, Creveaux I, Luo X, Meng W, Calvas P, Cassagne M, Arne JL, Rozen SG, Malecaze F, Young TL. Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis. J Med Genet. 2013 Jan 24. [Epub ahead of print].

PubMed ID: 
23349227

Corneal Dystrophy, Reis-Bücklers

Clinical Characteristics
Ocular Features: 

This is an anterior corneal dystrophy involving the epithelium and Bowman membrane.  Opacities consisting of spots and lines form in the central portion of the anterior cornea creating haziness with relative sparring of the periphery.  These can be seen as early as 4-5 years of age but few symptoms occur until the epithelium breaks down causing painful corneal erosions.  Visual acuity eventually drops as the corneal haze increases along with increasing irregularity of the epithelial surface.

Ultrastructural studies reveal degenerative changes in all epithelial cells and almost complete Bowman membrane replacement with disoriented collagen fibrils.

A comparative histological study of Reis-Bucklers and Thiel-Behnke dystrophies concluded that these are distinct CDB (corneal dystrophy Bowman) disorders and suggested the former be called CDB type I, and the latter CDB type II.  Type II is considered unique on the basis of the ‘curly’ fibers seen in the Bowman and subepithelial layers, while type I has bandshaped granular Masson-positive subepithelial deposits and ‘rod-shaped bodies’ resembling granular dystrophy.  Type I described here generally leads to greater vision loss than type II.

Systemic Features: 

No systemic disease is associated with Reis-Bucklers corneal dystrophy.

Genetics

This disorder seems to be closely related to the more common Thiel-Behnke dystrophy as the corneal disease is caused in both cases by missense mutations in the TGFBI gene on chromosome 5 (5q31). The mutation in Reis-Bucklers results in a p.Arg124Leu amino acid substitution whereas most cases of Thiel-Behnke dystrophy are the result of a p. Arg555Gln substitution.  Both disorders are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Ablation of the diseased cornea can improve vision and provide temporary relief from the erosions.

References
Article Title: 

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature

Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995 Jul;14(4):333-54. Review.

PubMed ID: 
7671605

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

Corneal Dystrophy, Lattice Type II

Clinical Characteristics
Ocular Features: 

This is a systemic amyloidosis disorder with significant corneal disease.  The corneal stroma contains linear deposits which are more discrete, more peripheral, more delicate, and more radial than those in lattice type I with which it is sometimes confused.  There is also less accumulation of amorphous amyloid material than in type I.  The onset is often later as well, and rarely seen in childhood.  Corneal sensitivity is reduced.  Vision is less affected than in type I lattice dystrophy and patients rarely require keratoplasty, and, if so, later in life.

Amyloid deposits are found in the cornea, sclera, choroid, lacrimal gland, ciliary nerves, and adnexal blood vessels.  Ptosis and extraocular muscle dysfunction is not significant.

Systemic Features: 

Amyloid deposits are found throughout the body including blood vessels, heart, kidney, skin and nerves.  A "mask-like" facies with a protruding lower lip, dry itchy skin, peripheral and cranial neuropathy, and renal failure are clinical features but often have their onset late in life.  Facial paralysis and bulbar palsy may be the result.

Genetics

While this is considered an autosomal dominant disorder, presumed homozygous cases have been reported in Finland where the first cases were described.  These cases seem to have more severe disease with an earlier onset than found among patients with heterozygous mutations.  Mutations in the GSN gene located at 9q34 are responsible.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can be beneficial but is rarely needed for visual rehabilitation.  The amyloid deposits may recur in the donor tissue.  The reduced corneal sensitivity secondary to neural involvement increases the risk of post-operative neurotrophic epithelial defects.

References
Article Title: 

Hereditary gelsolin amyloidosis

Kiuru-Enari S, Haltia M. Hereditary gelsolin amyloidosis. Handb Clin Neurol. 2013;115:659-81. PubMed PMID: 23931809.

PubMed ID: 
23931809

Corneal Dystrophy, Lattice Type I

Clinical Characteristics
Ocular Features: 

Lattice corneal dystrophy type I is one of the more common corneal dystrophies and occurs throughout the world.  Randomly oriented linear opacities resembling cotton threads accumulate in the central portions of the stroma.  These usually become apparent in the first decade of life although they are sometimes seen in infancy.  The peripheral cornea is relatively spared and intervening stromal areas are clear.  This is a progressive disorder in which vision during childhood is often normal but by the fifth and sixth decades most patients have severe visual impairment due to increasing accumulations of amyloid.  Corneal erosions may occur in the absence of stromal infiltrates.

Systemic Features: 

No systemic disease is found in LCD1 (as opposed to LCD type II).

Genetics

Type I lattice dystrophy is an autosomal dominant disorder as the result of mutations in the TGFBI gene (5q31).  Other corneal dystrophies (granular I or Groenouw type I, combined granular/lattice or Avellino type, Thiel-Behnke, Reis-Bucklers, epithelial basement membrane disease) have mutations in the same region of the same gene casting doubt on the value of using solely clinical and histologic distinctions in current classifications of these corneal disorders.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Recurrent corneal erosions benefit from standard treatments while penetrating keratoplasty may be necessary by the fifth decade to improve acuity.

References
Article Title: 

Corneal Dystrophy, Posterior Amorphous

Clinical Characteristics
Ocular Features: 

The iris abnormalities consisting of iridocorneal adhesions to Schwalbe's line and pupillary abnormalities suggest that PACD is a congenital disorder, perhaps a form of anterior chamber dysgenesis.  The corneal stroma and Descemet membrane contain sheet-like opacities with clear intervening areas.  These opacities are concentrated in the posterior stroma and are sometimes seen from limbus to limbus whereas in other cases they occur mostly peripherally.  The cornea may be thinner than normal and somewhat flattened.  There is little or no progression of the corneal opacification and vision varies widely.  Glaucoma has not been reported.

Histological and EM studies have revealed some fracturing and disorganization of the posterior stromal lamellae and focal attenuation of the endothelium.

Systemic Features: 

There is no associated systemic disease.

Genetics

A limited number of families with this disorder have been reported and the pattern in each is  generally consistent with autosomal dominant inheritance.  This may be a deletion syndrome based on the finding in a 1 year old African male with a heterozygous de novo deletion at 12q21.33-q22 containing 11 genes.  Anong the missing genes are those for the 4 small leucine-rich proteoglycans associated with this form of corneal dystrophy.  The parents did not have the deletion though.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is generally not required but penetrating keratoplasty can benefit those whose vision is significantly impaired.

References
Article Title: 

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