anterior segment dysgenesis

Cataracts, Congenital with Corneal Opacity and Glaucoma

Clinical Characteristics
Ocular Features: 

The ocular features are evident at birth or within the first year of life and may be asymmetrical.  The phenotype is heterogeneous but does not appear to be progressive.  The anterior chambers are of normal depth and the fundi are normal when visualization is possible.  The corneal opacification is usually denser peripherally and resembles corneoscleralization but it can extend centrally to a variable degree.  In individuals with glaucoma and buphthalmos the cornea is more opaque and usually vascularized. In such eyes the cornea is thinned.  In most patients the corneal diameters were 5-8 mm in diameter but in those with elevated pressures the anterior segment was obviously buphthalmic. Iridocorneal adhesions may be present.  The lenses are cataractous but the capsules are normal.  Microphthalmia has been reported in some patients.  Vision is often in the range of hand motions.    

Systemic Features: 

None.

Genetics

Homozygous mutations in PXDN (2p25.3) encoding peroxidasin are believed responsible for this autosomal recessive condition.  Mammalian peroxidasin localizes to the endoplasmic reticulum but is also found in the extracellular matrix and is believed important to the maintainence of basement membrane integrity.  The protein is one of several that aids in the extracellular breakdown of hydrogen peroxide and free radicals.  In mouse eyes it localizes to the corneal and lens epithelium but its role in maintaining transparency of the lens and cornea is unknown.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No information regarding treatment is available but cataract and corneal surgery may be beneficial.   

References
Article Title: 

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

Choi A, Lao R, Ling-Fung Tang P, Wan E, Mayer W, Bardakjian T, Shaw GM, Kwok PY, Schneider A, Slavotinek A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2014 Jun 18. doi: 10.1038/ejhg.2014.119. [Epub ahead of print] PubMed PMID: 24939590.

PubMed ID: 
24939590

Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma

Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 2011 Sep 9;89(3):464-73.

PubMed ID: 
21907015

Oculoauricular Syndrome

Clinical Characteristics
Ocular Features: 

This rare malformation syndrome affects primarily the eyes and ears.  The globes are small and usually have colobomas of both anterior and posterior segments.  The corneas likewise are small and often have opacities.  The anterior segment is dysplastic with anterior and/or posterior synechiae.  Glaucoma may be present.  The lenses may be small and often become cataractous.  There is a progressive rod-cone dystrophy associated with a pigmentary retinopathy.  Chorioretinal lacunae have been seen in the equatorial region.  The retinal degeneration is progressive, beginning with rod dysfunction but followed by deterioration of all receptors.  The onset in early childhood results in poor vision and nystagmus. 

Systemic Features: 

The external ears are abnormal.  The earlobes may have colobomas or may be aplastic.  The intertragic notch is often underdeveloped.  Audiograms and vestibular function tests, however, show normal function and MRI of the middle and inner ears likewise reveals no anatomic abnormalities.       

Among the few patients reported, dental anomalies, spina bifida oculta, and mild dyscrania have been noted in individual patients.

Genetics

This rare disorder has been reported in only a few families.  Based on parental consanguinity and homozygosity of mutations in the HMX1 gene (4p16.1) in affected sibs, this is an autosomal recessive disorder.  In one family there was a homozygous 26 bp deletion and in another a homozygous missense mutation.  The parents are heterozygous for the deletion.

HMX1 is a homeobox gene and the deletion abolishes its function by establishing a stop codon at position 112.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the extraocular malformations.  Glaucoma treatment and cataract surgery should be considered although permanent visual rehabilitation is unlikely given the progressive nature of the rod-cone dystrophy.

References
Article Title: 

Axenfeld-Rieger Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

As in RIEG1 and RIEG3, glaucoma is the most serious ocular problem.  In a large family with 11 affected members, 9 had glaucoma.  All had the classic ocular signs of anterior segment dysgenesis, primarily posterior embryotoxon and iris adhesions (for a full description of the ocular features see Axenfeld-Rieger syndrome, RIEG1 [180500]).

Systemic Features: 

Oligodontia, microdontia, and premature loss of teeth are common in type 2.  Maxillary hypoplasia is less common as is hearing loss.  Umbilical anomalies were not present in any affected individuals.  Cardiac defects are rare.

Genetics

This is an autosomal dominant disorder as in the other types.  The locus is at 13q14 but no molecular defect has been defined.  At least two individuals purported to have type 2 were found to have deletions of this segment of chromosome 13 but at least one had an umbilical defect.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The high risk of glaucoma demands lifelong monitoring of intraocular pressure.

References
Article Title: 

Axenfeld-Rieger Syndrome, Type 3

Clinical Characteristics
Ocular Features: 

The most important ocular feature is glaucoma, found in greater than 50% of patients.  It is frequently difficult to control and blindness is far too common.  The ocular phenotype has many similar features found in type 1 (RIEG1) but is discussed separately in this database since it is caused by a different mutation (see Axenfeld-Rieger syndrome, type 1 for a full description of the phenotype).  It has the typical findings of anterior segment dysgenesis including anterior displacement of Schwalbe’s line, iris stromal hypoplasia, correctopia, and, of course, glaucoma.

Systemic Features: 

Patients with this type of Axenfeld-Rieger disorder are less likely to have the systemic anomalies such as craniofacial and dental defects often seen in RIEG1.  However, they often have a sensorineural hearing impairment and many have cardiac valvular and septal defects not usually seen in RIEG1.

Genetics

This is an autosomal dominant disorder resulting from a mutation in the FOXC1 gene located at 6p25.  Mutations in the same gene also cause iris hypoplasia/iridogoniodysgenesis (IGDA) (IRID1) 601631) which is sometimes reported as a unique disorder but is either allelic or the same disorder as the type of Axenfeld-Rieger syndrome discussed here.

Type 1 Axenfeld-Rieger syndrome (180500) results from mutations in PITX1 mutations.  However, digenic cases have also been reported with mutations in both PITX1 and FOXC1 genes.

The mutation responsible for type 2 Axenfeld-Rieger syndrome (601499) has as yet not been identified.  Diagnosis is best made by ruling out mutations in PITX1 and FOXC1 although it is claimed that maxillary hypoplasia and umbilical defects are less common in type 2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All patients with Axenfeld-Rieger syndromes must be monitored and treated for glaucoma throughout their lives.

References
Article Title: 

Aniridia

Clinical Characteristics
Ocular Features: 

Aniridia is both the name of a disease 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.  The tear film is often unstable.

Attempts have been made to divide aniridia into several types based upon the type and degree of ocular abnormalities but modern genotyping allows more specific determination of classification, especially when systemic features are also considered.

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) has been found in other families.  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 the PAX6 gene may be the only gene defect associated with aniridia.  More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.  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.

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 to vision and difficult to treat although good 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 frequently fail.

Low vision aids are often helpful.  Tinted lenses can minimize photophobia.  Occupational and vocational training should be considered for older individuals.

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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