keratitis

Hereditary Mucoepithelial Dysplasia

Clinical Characteristics
Ocular Features: 

Impaired epithelial cohesion is the fundamental defect in this disorder.  Photophobia may be present in infants and this is soon evident as secondary to keratitis with eventual formation of a pannus and corneal neovascularization.  Vision is impaired early and as the disease progresses, many patients by early adulthood are severely impaired.  Cataracts are present in the majority of individuals, often present as early as the second decade of life.  Eyelashes and eyebrows may be sparse.  Nystagmus has been reported in some patients.

Systemic Features: 

This is a panepithelial disease of impaired cohesion due, at least in part, to a reduced number of desmosomes and defective gap junctions.  Oral, nasal, vaginal, cervical, perineal, urethral, and bladder mucosa, in addition to external ocular surfaces, are involved.  With exception of the ocular involvement, the lesions are usually not painful, but may be during acute flare-ups.  Demarcated erythematous patches are often seen in the oral mucosa.  Non-scarring alopecia, keratosis pilaris, and perineal intertrigo are usually present.  Histological examination of oral mucosa and skin shows dyskeratotic features, decreased number of desmosomes, and intracytoplasmic vacuoles.

Genetics

Pedigrees suggest autosomal dominant inheritance but few families have been reported.  The location of the responsible mutation, if any, has not been found. 

Somewhat similar genodermatoses are KID syndrome (148210), an autosomal dominant disorder with neurosensory hearing loss and sometimes mental and physical delays secondary to mutations in GJB2, and IFAP (308205), an X-linked condition with mental and physical delays and severe organ deformities.  Cataracts are not features of KID or IFAP syndromes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been found.

References
Article Title: 

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 

Tyrosinemia, Type II

Clinical Characteristics
Ocular Features: 

Keratitis is the outstanding ocular manifestation but not all patients have corneal involvement.  Symptoms include photophobia, pain, tearing, and redness which may occur as early as one year of age.  Corneal neovascularization, ulceration and scarring may lead to decreased visual acuity.  Linear and star-like corneal opacities in the epithelium resembling dendrites (pseudodendritic keratitis) have been described together with thickening of the conjunctiva.  The corneal lesions do not stain.  The conjunctival epithelium, fibrocytes, and blood vessel endothelial cells contain an accumulation of large inclusion bodies and tyrosine crystal-like structures. 

Systemic Features: 

Hydroxyphenylpyruvic acid is elevated in the urine and serum tyrosine levels are increased as the result of a defect in tyrosine aminotransferase.  Some patients have severe mental and somatic retardation.  The palms and soles can have painful punctate keratosis which may extend to the digits.  Developmental milestones such as walking are often delayed.  The keratotic lesions may be up to 2 cm in size. 

Genetics

Tyrosinemia type II is an autosomal recessive disorder caused by mutations in the tyrosine aminotransferase (TAT) gene at 16q22.1-q22.3. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The hyperkeratosis and corneal opacities may improve with a diet low in phenylalanine and tyrosine but can recur after liberalization of the diet.  Benefits, if any, on CNS symptoms are unknown. 

References
Article Title: 

Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation

Pena-Quintana L, Scherer G, Curbelo-Estevez ML, Jimenez-Acosta F, Hartmann B, Roche F, Meavilla-Olivas S, Perez-Cerda C, Garcia Segarra N, Giguere Y, Huppke P, Mitchell GA, Monch E, Trump D, Vianey-Saban C, Trimble ER, Vitoria-Minana I, Reyes-Suarez D, Ramirez-Lorenzo T, Tugores A. TYROSINEMIA TYPE II: Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation. Clin Genet. 2017 Mar 3. doi: 10.1111/cge.13003. [Epub ahead of print].

PubMed ID: 
28255985

Keratitis, Hereditary

Clinical Characteristics
Ocular Features: 

The disorder begins in the first year of life with a band of vascularized opacification inside the limbus.  Evidence of inflammation is seen in the anterior stroma and the Bowman membrane becomes replaced by fibrovascular tissue.  The disease is recurrent and progressive and there is usually asymmetry between the two eyes.  Non-penetrance and considerable variation in expression have been reported.  Acute episodes are characterized by photophobia, tearing, mucous discharge, and punctate keratitis.  The limbal opacification may progress centrally and eventually leads to a reduction in vision.  Deficits in visual acuity may lead to deprivation amblyopia and secondary esotropia.

In a 4 generation family, foveal hypoplasia, iris stromal defects, and ectropion uveae were seen in several of the fifteen affected individuals.  It has been suggested that this may be a variant of aniridia. 

Systemic Features: 

No systemic disease has been found. 

Genetics

This is an autosomal dominant disorder reported in several multigeneration families.  Mutations in the PAX6 gene (11p13) seem to be responsible.  The same gene is mutant in Gillespie syndrome (206700), aniridia (106210) and Peters anomaly (604229). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no effective treatment.  Penetrating keratoplasty in several individuals has been followed by similar disease in the donor tissue. 

References
Article Title: 

Dominantly inherited keratitis

Kivlin JD, Apple DJ, Olson RJ, Manthey R. Dominantly inherited keratitis. Arch Ophthalmol. 1986 Nov;104(11):1621-3.

PubMed ID: 
3778274
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