PAX6

Coloboma of the Optic Nerve

Clinical Characteristics
Ocular Features: 

Isolated colobomas of the optic nerve usually occur bilaterally.  The optic nerve cup is often huge and may have residual glial tissue in it.  Serous detachments of the macula are frequently observed and the risk for extensive retinal detachments is high.  Microphthalmos with a cyst (6% of eyes), simple microphthalmos (39% of eyes), and microcornea (84% of eyes) are frequently associated.  The visual prognosis is poor when both occur in combination with an optic nerve coloboma (less than 20/400 acuity in 67% of eyes).  Isolated optic nerve colobomas without other malformations have the best vision (only 7% have acuity of less than 20/400).  Retinal vessels are anomalous as well.  They are often increased in number and have a generally straight course in the peripapillary region.

It has been argued that the morning glory disc anomaly may be an expression of this syndrome but this remains to be established.

Systemic Features: 

No systemic disease is present.

Genetics

This malformation frequently follows an autosomal dominant pattern of transmission secondary to a mutation in the PAX6 gene.

PAX6 mutations are associated with a variety of ocular malformations, including uveal colobomas and various forms of anterior chamber dysgenesis.

Optic nerve dysplasia resembling optic pits or the morning glory disc anomaly is a feature of the papillorenal syndrome (120330) but this condition is caused by mutations in the PAX2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None.  Low vision aids may be helpful in some patients.

References
Article Title: 

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

Cataracts, Congenital, Autosomal Dominant

Clinical Characteristics
Ocular Features: 

Most cataracts arise as part of the aging process.  However, early onset lens opacities may be familial, often transmitted in an autosomal dominant pattern.  These have a highly variable appearance and may be unilateral or bilateral.  There can be considerable interocular asymmetry in morphology, density, location, and rate of progression.  This is also true of intrafamilial characteristics.  Age of onset is also variable. 

Systemic Features: 

By definition, simple autosomal dominant cataracts have no associated systemic abnormalities. 

Genetics

Lens opacities result from a variety of issues, including developmental, genetic and environmental causes.  They are often associated with heritable syndromes and generalized metabolic conditions.  

At least 25 loci scattered among multiple chromosome have been identified to cause simple autosomal dominant cataracts (See 604219).  It is not yet possible to make phenotypic – genotypic correlations due to the large variation in clinical characteristics. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction is indicated when the opacities become visually significant. 

References
Article Title: 

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. doi: 10.1016/j.ajhg.2013.11.002. Epub 2013 Nov 27. PubMed PMID: 24290379;

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 ruledout. 

The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Peters Anomaly

Clinical Characteristics
Ocular Features: 

Peters anomaly occurs as an isolated malformation but also as a feature of other syndromes.  It is often unilateral.  A wide variety of other ocular findings may occur with Peters anomaly as well. Here we limit our description to 'simple' Peters anomaly in which the findings are limited to the eye having the classic findings of adhesions of the iris to the posterior cornea and a central or paracentral corneal leukoma.  The lens may also be adherent to the cornea and is often opacified to some degree.  Descemet's membrane and portions of the posterior stroma are usually missing as well.  Glaucoma is frequently present.  Importantly, there is a wide range in the presentation of clinical features.

Systemic Features: 

Peters anomaly is a frequent feature of numerous syndromes, both ocular and systemic, among them the Peters-plus (261540) syndrome (sometimes called the Kivlin-Krause (261540) syndrome) and has been reported in a case with aniridia (106210).

Genetics

Isolated Peters anomaly usually occurs in an autosomal recessive pattern but autosomal dominant patterns have been reported as well.  The recessive disorder may be caused by a mutation in several genes, notably PAX6, PITX2CYP1B1, FOXC1, and FOXE3.  The latter gene is also mutated in anterior segment mesenchymal dysgenesis (107250) and congenital primary aphakia (610256).  The variety of clinical features are likely the result of a disruption in some common pathway or pathways.  Mutations in B3GALTL associated with the Peters-Plus syndrome have not been identified in isolated Peters anomaly.

This is a genetically and clinically heterogeneity condition as whole genome sequencing reveals numerous additional gene mutations in patients with both syndromic and isolated Peters anomaly.

PITX2 is also mutated in ring dermoid of the cornea (180550) and in Axenfeld-Rieger syndrome type 1 (180500).  PAX6 mutations also cause diseases of the cornea, fovea, optic nerve and iris.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma is the most serious threat to vision on Peters anomaly but also the most difficult to treat.  Less than a third of patients achieve control of intraocular pressure even with the most vigorous combinations of therapy.  Corneal opacities can be treated with transplantation but the prognosis is often guarded when glaucoma is present.

From eye bank and other data, it has been estimated that 65% of penetrating keratoplasties in infants for visually significant congenital corneal opacities are performed in patients with Peters anomaly. 

References
Article Title: 

Whole exome sequence analysis of Peters anomaly

Weh E, Reis LM, Happ HC, Levin AV, Wheeler PG, David KL, Carney E, Angle B, Hauser N, Semina EV. Whole exome sequence analysis of Peters anomaly. Hum Genet. 2014 Sep 3. [Epub ahead of print].

PubMed ID: 
25182519

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 TRIMM44 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 to vision and difficult to treat with the best results 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
Subscribe to RSS - PAX6