iris hypoplasia

Anterior Segment Dysgenesis 6

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions can be seen.  Increased intraocular pressure is a risk and ectopia lentis is often present.  Peters anomaly and defects in all layers of the cornea may be present.

No foveal hypoplasia is present.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

A single male patient of native American/French Canadian background has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2).

See Anterior Chamber Dysgenesis 8 for another autosomal recessive disorder with somewhat similar clinical features.  Three families with 4 affected individuals have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions.

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lifelong pressure monitoring is important.

References
Article Title: 

Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly

Vincent A, Billingsley G, Priston M, Williams-Lyn D, Sutherland J, Glaser T, Oliver E, Walter MA, Heathcote G, Levin A, Heon E. Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly. J Med Genet. 2001 May;38(5):324-6. PubMed PMID: 11403040; PubMed Central PMCID: PMC1734880.

PubMed ID: 
11403040

Anterior Segment Dysgenesis 8

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome with considerable clinical heterogeneity.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions are often seen.  Intraocular pressure may be elevated in older individuals.  Ectopia lentis is often present.  Lenticular opacities consisting primarily of posterior cortical opacification are common.  Visual acuity varies from 6/6 to 6/24.

No foveal hypoplasia is present but one of four reported patients was described with bilateral optic nerve dysplasia.     

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Three families with 4 affected individuals with similar clinical features have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

A single male patient of native American/French Canadian background with somewhat similar clinical features has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2) but this is likely a unique condition (Anterior Segment Dysgenesis 6).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions. 

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Several patients have had cataract surgery.  Monitoring intraocular pressure throughout life is necessary and prompt treatment for glaucoma is important.

References
Article Title: 

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

Donnai-Barrow Syndrome

Clinical Characteristics
Ocular Features: 

A number of ocular features have been described in this disorder, including telecanthus, hypertelorism, and iris hypoplasia with marked iris transillumination.  Myopia is commonly present and retinal detachments are a risk.  Several patients had iris colobomas.  Cataracts, small optic nerves, and macular hypoplasia have been reported as well.  The lid fissures usually slant downward. 

Systemic Features: 

The facial dysmorphology, in addition to the periocular malformations, includes a prominent brow or frontal bossing, posterior rotation of the ears, a flat nasal bridge and a short nose.  Sensorineural hearing loss is universal and at least some patients have complete or partial agenesis of the corpus callosum, and an enlarged anterior fontanel.  Diaphragmatic and umbilical hernias often occur together.  Low-molecular-weight proteinuria in the absence of aminoaciduria is a frequent feature.  Developmental delays are often seen but occasional patients have normal intellect.  Rare patients have seizures. 

Genetics

This is a rare autosomal recessive disorder caused by homozygous mutations in the LRP2 (low-density lipoprotein receptor-related protein 2 or megalin) gene located at 2q24-q31.  Some patients have an ocular phenotype resembling the Stickler syndrome (609508).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is focused on specific manifestations such as cataract and retinal detachment surgery. Patients need to be monitored throughout life for retinal disease.  Omphaloceles and diaphragmatic hernias need to be repaired.  Hearing aids may be beneficial. 

References
Article Title: 

Pierson Syndrome

Clinical Characteristics
Ocular Features: 

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some patients.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features: 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References
Article Title: 

Ophthalmological aspects of Pierson syndrome

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

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: 

Rothmund-Thomson Syndrome

Clinical Characteristics
Ocular Features: 

Patients have been reported with juvenile and infantile cataracts.  Reported prevalence varies possibly because the diagnostic criteria have not been established and more than one disorder may be represented by the title.  Rothmund (an ophthalmologist) originally reported two families of 5 children in which lens opacities were found, but Thomson, who was a dermatologist, in a later report did not mention cataracts.  The lens opacities are usually nuclear or posterior cortical in location and may be evident in 50% of patients.  Iris stromal changes such as hypoplasia have also been reported.  Eyelashes and/or eyebrows may be sparse.  This is likely the same disorder as the previously described ‘mesodermal dysgenesis of the iris and skeletal dysplasia’ and formerly listed as 270240 in OMIM.

Systemic Features: 

This is a clinically heterogeneous disorder.  Skin atrophy with pigmentary changes, telangiectasia, short stature, premature aging, and skeletal abnormalities are characteristic.  There is an increased risk of malignancy, particularly osteosarcomas and skin cancer.  Saddle nose, sparse hair, hypogonadism, dysplastic nails, and teeth anomalies have also been described.

The skin is usually normal at birth but an erythematous rash typically appears in the first six months of life accompanied by swelling and blistering.  Eventually areas of hypo- and hyperpigmentation appear in a reticulated pattern with spots of punctate atrophy and telangiectasia.  Hyperkeratosis of the soles of the feet is common.  The skeletal abnormalities of dysplasia, radial ray defects, and missing bones are often evident at birth while osteopenia and delayed bone maturation are evident later.

Genetics

This is an autosomal recessive disorder in which most patients have mutations in the RECQL4 gene (8q24.3).

Mutations in the same gene cause Baller-Gerold syndrome (218600) suggesting that the two disorders are allelic but the phenotypes are considerably different.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the primary disorder but patients must be monitored for malignancies.  Visually significant cataracts should be removed.  It has been recommended that patients avoid excessive sun exposure to reduce the risk of skin cancers.

References
Article Title: 

Axenfeld-Rieger Anomaly, Plus

Clinical Characteristics
Ocular Features: 

This rare disorder has ocular features of Rieger anomaly with significant systemic features but different than those found in the Axenfeld-Rieger syndrome.  The iris is hypoplastic and the pupil may be distorted secondary to anterior synechiae.  Schwalbe line is prominent.  There are no reports of glaucoma but this may be biased by the small number of patients reported.  Hypertelorism, prominent eyes and strabismus have been described.  Several patients have had absence of the extraocular muscles.

Systemic Features: 

Hypotonia, lax joints, midface hypoplasia, prominent forehead, and short stature have been described.  Some, but not all patients have a degree of psychomotor retardation.  Mild hearing impairment has been reported.

Genetics

This is likely an autosomal dominant disorder in which mutations of the PITX2 and FOXC1 genes common in Axenfeld-Rieger syndrome have been ruled out.  No locus has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

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.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

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

References
Article Title: 

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