pseudopolycoria

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: 

Aniridia 1

Clinical Characteristics
Ocular Features: 

Aniridia is the name of both a disorder and a group of disorders.  This because aniridia is both an isolated ocular disease and a feature of several malformation syndromes.  Absence of the iris was first reported in the early 19th century.  The hallmark of the disease is bilateral iris hypoplasia which may consist of minimal loss of iris tissue with simple radial clefts, colobomas, pseudopolycoria, and correctopia, to nearly complete absence.  Goniosocopy may be required to visualize tags of iris root when no iris is visible externally.  Glaucoma is frequently present (~67%) and often difficult to treat.  It is responsible for blindness in a significant number of patients.  About 15% of patients are diagnosed with glaucoma in each decade of life but this rises to 35% among individuals 40-49 years of age.  Hypoplasia and dysplasia of the fovea are likely responsible for the poor vision in many individuals.  Nystagmus is frequently present.  The ciliary body may also be hypoplastic. 

Visual acuity varies widely.  In many families it is less than 20/60 in all members and the majority have less than 20/200.  Photophobia can be incapacitating.  Posterior segment OCT changes suggest that outer retinal damage suggestive of a phototoxic retinopathy may also be a factor in the reduced acuity.  Cataracts (congenital in >75%), ectopia lentis (bilateral in >26%), optic nerve hypoplasia, variable degrees of corneal clouding with or without a vascularized pannus, and dysgenesis of the anterior chamber angle are frequently present. 

Increased corneal thickness (>600 microns) has been found in some series and should be considered when IOP measurements are made.  In early stages of the disease, focal opacities are present in the basal epithelium, associated with sub-basal nerves.  Dendritic cells can infiltrate the central epithelium and normal limbal palisade architecture is absent. 

Meibomian gland anomalies also contribute to the corneal disease.  The glands may be decreased in number and smaller in size contributing to deficiencies of the tear film and unstable surface wetting.

Systemic Features: 

In addition to 'pure' aniridia in which no systemic features are found, at least six disorders have been reported in which systemic anomalies do occur.  Three of these have associated renal anomalies, including Wilms tumor with other genitourinary anomalies and mental retardation, sometimes called WAGR (194072) syndrome, another (612469) with similar features plus obesity sometime called WAGRO (612469) syndrome reported in isolated patients, and yet another with partial aniridia (206750) and unilateral renal agenesis and psychomotor retardation reported in a single family.  Aniridia with dysplastic or absent patella (106220) has been reported in a single three generation family.  Cerebellar ataxia and mental retardation with motor deficits (Gillespie syndrome; 206700) have been found in other families with anirdia.  Another 3 generation family has been reported in which aniridia, microcornea and spontaneously resorbed cataracts occured (106230).

About one-third of patients with aniridia also have Wilms tumor and many have some cognitive deficits.

Genetics

The majority of cases have a mutation in the paired box gene (PAX6) complex, or at least include this locus when chromosomal aberrations such as deletions are present in the region (11p13).  This complex (containing at least 9 genes) is multifunctional and important to the tissue regulation of numerous developmental genes.   PAX6 mutations, encoding a highly conserved transcription regulator, generally cause hypoplasia of the iris and foveal hypoplasia but are also important in CNS development.  It has been suggested that PAX6 gene dysfunction may be the only gene defect associated with aniridia.  More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.  

AN1 results from mutations in the PAX6 gene.  Two additional forms of aniridia have been reported in which functional alterations in genes that modulate the expression of PAX6 are responsible: AN2 (617141) with mutations in ELP4 and AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Associated abnormalities may be due to a second mutation in the WT1 gene in WAGR (194072) syndrome, a deletion syndrome involving both WT1 and PAX6 genes at 11p13.  The WAGRO syndrome (612469) is caused by a contiguous deletion in chromosome 11 (11p12-p13) involving three genes: WT1, PAX6, and BDNF.  All types are likely inherited as autosomal dominant disorders although nearly one-third of cases occur sporadically.

Mutations in PAX6 associated with aniridia can cause other anterior chamber malformations such as Peters anomaly (604229).

Gillespie syndrome (206700 ) is an allelic disorder with neurological abnormalities including cerebellar ataxia and mental retardation.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the associated threats to vision such as glaucoma, corneal opacities, and cataracts.  Glaucoma is the most serious threat and is the most difficult to treat. The best results have been reported with glaucoma drainage devices.  All patients should have eye examinations at appropriate intervals throughout life, focused on glaucoma screening.  It is well to keep in mind that foveal maldevelopment often precludes significant improvement in acuity and heroic measures must be carefully evaluated.  Specifically, corneal transplants and glaucoma control measures frequently fail.

Low vision aids are often helpful.  Tinted lenses can minimize photophobia.  Occupational and vocational training should be considered for older individuals.  Surface wetting of the cornea should be periodically evaluated and appropriate topical lubrication used as needed. 

Young children with aniridia should have periodic examinations with renal imaging as recommended by a urologist.

In mice, postnatal topical ocular application of ataluren-based eyedrop formulations can reverse malformations caused by PAX6 mutations.

References
Article Title: 

Familial aniridia with preserved

Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol. 1977 May;83(5):718-24.

PubMed ID: 
868970
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