PAX6

Aniridia 2

Clinical Characteristics
Ocular Features: 

A 17-year-old male with this condition was diagnosed at the age of two years with bilateral iris hypoplasia.  Cataracts were seen at the age of 17 years.  There was no foveal depression.

In a 5 generation Chinese family there were additional signs including optic atrophy, ectopia lentis, pigmentary retinopathy, and 'dysplasia' of the trabecular meshwork in 5 members.

Systemic Features: 

No systemic abnormalities have been reported.  A single extensively studied patient, who had no developmental problems, was normal by renal ultrasound, audiometric studies, and neurologic evaluations.

Genetics

Autosomal dominant aniridia is the result of PAX6 (a transcription regulator gene) dysfunction.  In the majority of cases there are mutations in the PAX6 gene itself as in AN1.  There are reports, however, of familial aniridia in which direct PAX6 mutations have been excluded.  Two additional forms of aniridia in which there are alterations in genes that modulate the expression of PAX6 have been reported.  AN2 described here with mutations in ELP4, a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene, plus AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Aniridia 2 has been reported in one patient with a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene.  The gene product is a cis-regulatory enhancer.  

Other evidence for aniridia resulting from regulatory modification of PAX6 gene function comes from families in which there are structural alterations such as deletions in chromosome 11, downstream of the PAX6 gene location.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported.

References
Article Title: 

A deletion 3' to the PAX6 gene in familial aniridia cases

D'Elia AV, Pellizzari L, Fabbro D, Pianta A, Divizia MT, Rinaldi R, Grammatico B, Grammatico P, Arduino C, Damante G. A deletion 3' to the PAX6 gene in familial aniridia cases. Mol Vis. 2007 Jul 23;13:1245-50.
 

PubMed ID: 
17679951

Coloboma, Isolated

Clinical Characteristics
Ocular Features: 

Colobomas of the uveal tract are often found in association with other ocular anomalies including those with systemic disease. They are usually located in the inferonasal quadrant as a result of defective closure of the embryonic fissure in the optic cup.  Most involve the nearly complete iris and resemble a keyhole but they may also be partial resulting in an oval pupil.  They are sometimes unilateral in which case the involved iris may be more heavily pigmented than the contralateral one.  They may involve only the iris (simple coloboma) but often are more extensive with involvement of the ciliary body, retina, lens, choroid, and even the optic nerve.  They are frequently associated with microphthalmia (or microphthalmia with cyst [5.6%]) and microcornea (79%). 

Systemic Features: 

None by definition.

Genetics

Isolated colobomas are clinically and genetically heterogeneous resulting from mutations in SHH (7q36.3), PAX6 (11p13), and ABCB6 (2q35) among others.  Large pedigrees with typical autosomal dominant transmission patterns have been reported.

Homozygous mutations in SALL2 (14q11.1-q12.1) have also been reported in patients with isolated colobomas.  Studies of sall2-deficient mice show defects in closure of the anterior optic fissure while posterior closure proceeds normally.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Simple iris colobomas usually do not require treatment.  The visual prognosis depends upon the structures involved.  Those with microcornea usually have a lower acuity and, of course, eyes with the most extensive involvement of the uveal tract and/or the optic nerve may have the least vision. Low vision aids can be helpful in selected individuals.

References
Article Title: 

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Kelberman D, Islam L, Lakowski J, Bacchelli C, Chanudet E, Lescai F, Patel A, Stupka E, Buck A, Wolf S, Beales PL, Jacques TS, Bitner-Glindzicz M, Liasis A, Lehmann OJ, Kohlhase J, Nischal KK, Sowden JC. Mutation of SALL2 causes recessive ocular coloboma in humans and mice. Hum Mol Genet. 2014 Jan 12. [Epub ahead of print].

PubMed ID: 
24412933

ABCB6 Mutations Cause Ocular Coloboma

Wang L, He F, Bu J, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li DY, Phillips JD, Yang Z. ABCB6 Mutations Cause Ocular Coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8.

PubMed ID: 
22226084

Optic Nerve Hypoplasia, Bilateral

Clinical Characteristics
Ocular Features: 

The hallmark of this syndrome is bilateral optic nerve dysplasia including aplasia and hypoplasia. It may occur in isolation or as part of other syndromes, especially in those having abnormalities of the central nervous system.  All components of the nerve head are abnormally small including the entire disc area, the cup, and the neuroretinal rim. It has been reported that retinal vein tortuosity is predictive of patients with endocrinopathies.  Retinal arteries often appear straight and narrow but this may not be seen in all cases.  Visual acuity ranges from 20/50 to NLP but usually 20/200 or better.  Many patients have nystagmus and strabismus.

This disorder shares many characteristics with septooptic dysplasia (182230) but the optic nerve anomalies are usually unilateral in the latter disorder and the disc rim often has a double margin.  Mutations in different genes are responsible for the two disorders. 

Systemic Features: 

Pituitary dysfunction and endocrinopathy may lead to life-threatening illness caused by adrenal crisis or hypoglycemia.  An absent or abnormal septum pellucidum is present in 49% of patients and 64% have a hypothalamic-pituitary axis abnormality.  Among those with an abnormal septum pellucidum, 56% have some kind of endocrinopathy. Other midline brain defects and cerebral anomalies have also been reported.

 

Genetics

Bilateral optic nerve hypoplasia is inherited in an autosomal dominant pattern based on the few families reported.  Mutations in the PAX6 (11q13) gene are responsible.

A somewhat similar disease with extensive CNS and endocrinological abnormalities is septooptic dysplasia (182230) caused by mutations in the HESX1 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the optic nerve hypoplasia but individuals need to be monitored for endocrinopathy and treated appropriately.  Low vision aids and sometimes mobility training can be helpful for some patients. 

References
Article Title: 

Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging

Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003 Nov;88(11):5281-6.

PubMed ID: 
14602752

Foveal Hypoplasia 1

Clinical Characteristics
Ocular Features: 

This is a poorly defined syndrome with features overlapping aniridia, hereditary keratitis, ocular albinism, and iris anomalies as in Peters anomaly.  However, presenile cataracts seem to be unique to this disorder.  The foveal hypoplasia may occur without other anomalies although the fundus is usually lightly pigmented.  As expected, acuity is subnormal from birth, in the range of 20/50, and dyschromatopsia may be present.  Some patients have nystagmus.  Weak iris transillumination has been reported and a small limbal pannus may be present. Lens opacities may become visually significant in the third to fourth decade of life.  OCT has shown abnormal foveal thickness with multiple inner retinal layers somewhat similar to the situation in oculocutaneous albinism (203100) and it has been suggested that 'foveal dysplasia' is a better description than 'foveal hypoplasia'. 

Systemic Features: 

No systemic disease is present. 

Genetics

This disorder is associated with mutations in the PAX6 gene (11p13) and inherited as an autosomal dominant.

The protein product of the PAX6 gene is a transcription factor that attaches to DNA and regulates the expression of other genes.  PAX6 plays a major role primarily in development of the eye and central nervous system but evidence suggests it is also active postnatally.  Hundreds of mutations have been found in disorders such as hereditary keratitis, aniridia, Peters anomaly, hypoplasia and colobomas of the optic nerve.  This database contains 8 conditions in which mutations in PAX6 seem to be responsible, including syndromal conditions such as Stromme and Gillespie syndromes in which there may be cognitive disabilities. 

True isolated foveal hypoplasia without lens or corneal disease does exist as well but this condition (FVH2) is not well defined.  Homozygous mutations in SLC38A8 have been found to cosegregate with this form of foveal hypoplasia among families of Jewish Indian ancestry.  Hypopigmentation is not a feature of isolated foveal hypoplasia secondary to such mutations but misrouting of optic nerve axons may be present.  Nystagmus and reduced vision but no anterior segment abnormalities were present.

With the widespread utilization of OCT measurements, we have learned that underdevelopment of the fovea can be a feature of numerous ocular disorders (more than 20 in this database).  In most conditions, the foveal dysplasia is part of a disease complex as in foveal hypoplasia with anterior segment dysgenesis (609218).

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated when lens opacities become visually significant. 

References
Article Title: 

Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism

Poulter JA, Al-Araimi M, Conte I, van Genderen MM, Sheridan E, Carr IM, Parry DA, Shires M, Carrella S, Bradbury J, Khan K, Lakeman P, Sergouniotis PI, Webster AR, Moore AT, Pal B, Mohamed MD, Venkataramana A, Ramprasad V, Shetty R, Saktivel M, Kumaramanickavel G, Tan A, Mackey DA, Hewitt AW, Banfi S, Ali M, Inglehearn CF, Toomes C. Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism. Am J Hum Genet. 2013 Dec 5;93(6):1143-50.

PubMed ID: 
24290379

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

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

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.  The tear film is often unstable.

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.

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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