microcornea

Ehlers-Danlos Syndrome, Type VIA

Clinical Characteristics
Ocular Features: 

The globe is thin and fragile and ruptures easily.  This results from scleral fragility which is in contrast to type VIB EDS  (229200) in which the cornea seems to be more fragile.  Retinal detachment is always a risk but no quantitative assessment can be made since early case reports did not always provide good classification of EDS types.  Other ocular abnormalities such as keratoconus and structural changes in the cornea are less common but frequent changes in classification and lack of genotyping in early cases make definitive clinical correlations difficult.

Systemic Features: 

The primary clinical manifestations of this form (VIA) of Ehlers-Danlos syndrome are extraocular.   The skin is soft, thin, easily extensible, and bruises easily.  The joints are highly flexible with a tendency to dislocate.  Arterial ruptures are not uncommon, often with severe consequences.  Scoliosis begins almost at birth and often progresses to severe kyphoscoliosis.  Patients are floppy (hypotonic).  Intellect is normal and there are generally no developmental delays.  Thirty per cent of infants have a club foot at birth.

Genetics

This an autosomal recessive disorder caused by molecular defects in the PLOD1 gene (1p36.3-p36.2).  The gene product is an enzyme, lysyl hydroxylase 1, important for the normal crosslinking of collagen. Mutations in PLOD1 may result in hydroxylase dysfunction with abnormal hydroxylation of lysine, weakened crosslinks, and fragile tissue.  

The classification of Ehlers-Danlos disease is under constant revision as new mutations and clinical subtypes are found (see 130000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Joint dislocations, ocular trauma and vascular ruptures require prompt attention.  Longevity is not impacted by this syndrome.

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

Sclerocornea

Clinical Characteristics
Ocular Features: 

This is a disorder of the cornea and anterior chamber that is sometimes considered to be a form of anterior segment or mesenchymal dysgenesis.  The primary feature is corneal clouding, most prominent peripherally and extending to the central cornea to a variable extent.  Vascular arcades are usually present over the area of clouding and there is no clear limbal demarcation.  Corneal fibers are often disorganized and larger than normal.  The anterior chamber may appear shallow and the iris usually has a flat appearance, often with a posterior embryotoxon.  Iris processes to the cornea and anterior synechiae are frequently present.  Some degree of microcornea has also been noted in many cases.  Rotary and horizontal nystagmus are uncommon. Sclerocornea may be a feature of cornea plana as well and the distinction between these disorders is unclear, especially in reported dominant pedigrees in which hyperopia is a feature.

Most cases are bilateral but there is often considerable asymmetry between the two eyes.  Visual acuity is dependent on the extent of corneal opacification but may be normal.  It is not a progressive disease.

Systemic Features: 

No systemic abnormalities have been reported.  However, sclerocornea can be a feature of numerous somatic and chromosomal disorders (e.g., oculocerbral syndrome with hypopigmentation (257800 ).

Genetics

No DNA mutations have as yet been found.  Most cases occur sporadically, and others are part of anterior chamber dysgenesis disorders.  However, rare autosomal dominant pedigrees have been reported in which the degree of opacification and anterior chamber anomalies are not as severe as those in which the pattern is most consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Severe cases in which the central media is compromised may require corneal transplantation.  Glaucoma requires treatment as well.

References
Article Title: 

A review of anterior

Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior
segment dysgeneses.
Surv Ophthalmol. 2006 May-Jun;51(3):213-31. Review.

PubMed ID: 
16644364

Hereditary sclerocornea

Elliott JH, Feman SS, O'Day DM, Garber M. Hereditary sclerocornea. Arch
Ophthalmol. 1985 May;103(5):676-9.

PubMed ID: 
3994576

Macrophthalmia, Colobomatous, with Microcornea

Clinical Characteristics
Ocular Features: 

Several families have been reported in which multiple family members had various ocular malformations including bilateral extensive colobomas from the iris to the optic nerve, increased axial length, microcornea, posterior staphylomas, and high myopia. In a three generation Turkish family with 13 affected individuals other features such as flatter than normal corneas, shallow anterior chambers and iridocorneal angle abnormalities with elevated intraocular pressures were described.  

Systemic Features: 

None have been reported.

Genetics

This is a contiguous gene deletion disorder located at 2p22.2 which involves the CRIM1 and FEZ2 genes.  Penetrance is high in this presumed autosomal dominant condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.
 

References
Article Title: 

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