FOXE3

Cataracts 34

Clinical Characteristics
Ocular Features: 

Two families with mutations in the FOXE3 associated with cataracts have been reported.  The lens opacities may be present at birth or found soon thereafter.  In 1 family with 5 affected sibs membranous cataracts were present along with corneal opacities, microcornea and nystagmus.  In another family, 7 sibs had posterior subcapsular cataracts but no other ocular findings.

Systemic Features: 

No systemic abnormalities were associated with the ocular findings.

Genetics

Homozygous mutations in the FOXE3 (1p33) gene segregated with the eye findings in the two families.  FOXE3 is a transcription gene and its mutations are responsible for a variety of ocular abnormalities.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical cataract removal may be indicated.  Amblyopia is a risk and requires rehabilitation.

References
Article Title: 

FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

Khan SY, Vasanth S, Kabir F, Gottsch JD, Khan AO, Chaerkady R, Lee MC, Leitch CC, Ma Z, Laux J, Villasmil R, Khan SN, Riazuddin S, Akram J, Cole RN, Talbot CC, Pourmand N, Zaghloul NA, Hejtmancik JF, Riazuddin SA. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun. 2016 Apr 6;7:10953. doi: 10.1038/ncomms10953. PubMed PMID: 27218149; PubMed Central PMCID: PMC4820811.

PubMed ID: 
27218149

Anterior Segment Mesenchymal Dysgenesis

Clinical Characteristics
Ocular Features: 

The unique status of this entity remains to be established as there are overlapping features with aniridia (106210), and Peters anomaly (604229), posterior embryotoxon, and iridogoniodysgenesis type 1 (601631) and type 2 (137600).  Anterior segment mesenchymal dysgenesis itself is clinically heterogeneous even within families.  Schwalbe line is often anteriorly placed and there may be iris adhesions to the cornea, with or without corneal opacities.  Some patients have microcornea.  All layers of the cornea are dysplastic from the epithelium to the endothelium suggesting abnormal migration or function of neural crest cells.  Lens opacities are highly variable but they can be progressive. Curiously, elevated intraocular pressure is usually not present.  Visual acuity is highly variable with some patients having 20/20 vision and others bare hand motions depending on the degree of opacification of the lens and cornea.

Systemic Features: 

No systemic abnormalities are present.

Genetics

This is an autosomal dominant disorder secondary to mutations in either PITX3 (10q24.32) or FOXE3 (1p32)  which are both transcription factors.  The latter gene is also mutant in congenital primary aphakia (610256) and some cases of Peters anomaly (604229).

See also Anterior Segment Dysgenesis 6 (617315) and Anterior Segment Dysgenesis 8 (617319) for autosomal recessive conditions in which mutations result in malformations of the anterior chamber.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated in some cases and corneal transplantation has been attempted in a few individuals.

References
Article Title: 

Aphakia, Congenital Primary

Clinical Characteristics
Ocular Features: 

There is complete absence of the lens and with it aplasia of the anterior segment including complete absence of the iris, ciliary body, and trabecular meshwork.  In an autopsied case, the cornea was thinned and lacked endothelium, Bowman layer, and Descemet membrane while the retina was dysplastic.  In the single family reported, 2 sibs had sclerocornea and one had megalocornea.  Normal pressure was reported in several eyes but a single eye in one patient at the age of 3 years developed buphthalmos with elevated pressure.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygosity of a nonsense mutation in the FOXE3 transcription factor gene (1p32) seems to be responsible for this autosomal recessive disorder.  The same gene has been implicated in rare cases of Peters anomaly (604229) and in anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known to restore vision.

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, PITX2,  CYP1B1, 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
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