FOXC1

Iridogoniodysgenesis, Type 1

Clinical Characteristics
Ocular Features: 

Glaucoma often develops in the latter part of the first decade of life but has been diagnosed in the neonatal period.  It affects at least half of patients with IRID1.  The disorder may be suspected in at-risk families by the hypoplasia of the iris stroma resulting in a dark chocolate color with prominent vessels. The irides may also have a dark slate gray color.  Further, the anterior iris surface appears smooth without the usual crypts.  There are no defects in the pigment layer of the iris, and the sphincter is intact while the pupil is in the normal position.  In many patients the iris is inserted anteriorly with numerous iris processes spanning the angle and inserting into the Schwalbe line.  In yet other patients tissue seems to fill the angle obscuring other anatomical structures.

Systemic Features: 

Systemic signs and symptoms are usually absent although CNS imaging has revealed cerebellar vermis hypoplasia in one family.

Genetics

This type of iridogoniodysgenesis results from alterations in the forkhead transcription factor gene (FOXC1) (6p25.3).  It is inherited in an autosomal dominant pattern.  Rare individuals may have deletions in the 6p area while duplications in FOXC1 are more common than point mutations.

Mutations in the same gene may also be responsible for Axenfeld-Rieger syndrome type 3 (602482), Peters anomaly (604229), and anterior segment mesenchymal dysgenesis (107250).

Another iridogoniodysgenesis disorder (IRID2) (137600) is caused by mutations in the PITX2 gene (4q25-q26), while iridogoniodysgenesis and skeletal anomalies (609515) is an autosomal recessive disorder due to as yet unknown mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All members of families in which this disorder segregates should have close surveillance for the presence of glaucoma which obviously requires treatment when present.

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, a transcription factor 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 the PITX1 transcription factor gene and type 4 from mutations in PRDM5, also a transcription factor gene.  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: 

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
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