Axenfeld-Rieger Syndrome (ARS) was previously known as Axenfeld anomaly; the latter term was used to describe one of three subvariants of this spectrum of disease. ARS is a disease that encompasses anterior segment ocular dysgenesis in addition to systemic abnormalities such as dental, cardiac, craniofacial and abdominal wall defects. ARS commonly correlates with 6p25 distal microdeletion. However, different presentations of this syndrome may share links with other genetic loci such as 4q25 or 13q14. Several genes have associations with ARS, including FOXC1, FOXC2, and FKHL7.
This spectrum of anomalies was initially described by Axenfeld and Rieger in the early 20 century, as a set of ocular abnormalities affecting mostly the anterior segment of the eye with conditions such as iris hypoplasia and polycoria, among others. Some authors still subcategorize ARS in three terms, commonly with overlapping presentations. Axenfeld anomaly is used to describe patients who present mostly with disorders associated with an anteriorly displaced and prominent Schwalbe line, a condition also known as “posterior embryotoxon.” Rieger anomaly characteristically presents with central iris defects, such as irregular pupils with stromal hypoplasia, and Rieger syndrome describes patients with Rieger anomaly in addition to systemic features.
ARS has been associated with mutations in several chromosomes including 4, 6, 9, 13, 18, and 21, affecting genes such as Forkhead-Like 7 (FKHL7) on chromosome 6p25.
FKHL7 is a gene from the forkhead/winged-helix transcription-factor family and linked to 6p25, it has been described as having a role in embryonic development and found mutated in some patients with ARS. Other cases have correlations with PITX2 mutations, in chromosome 4q25.
Approximately 40 to 70% of ARS cases correlate with mutations in FOXC1 and PITX2, in chromosomes 6p25 and 4q25, respectively.
Forkhead-Box C1 gene (FOXC1), along with the Pituitary Homeobox 2 gene (PITX2) are two of the most studied transcription factor-encoding genes associated with ARS. Research has characterized FOXC1 mutations as frameshift, nonsense, missense, deletions, and duplications. PITX2 has associations with splice-site mutations, deletions and chromosomal translocations in patients with ARS.
ARS is a rare disease with substantial clinical overlap with 6p25 deletion syndrome. Approximately 10 to 30% of patients with ARS present PITX2 mutations in 4q25 , and 40 to 70% present either FOXC1 or PITX2 gene abnormalities. Heterozygous mutations in the FOXC1 gene and PITX2 cause 16% and 10% of cases respectively.
ARS is believed to be caused by abnormal neural crest (NC) migration during early embryogenesis. Important ocular structures rely on adequate NC cell migration, such as ciliary body, cornea and iris stroma. Transcription factors in different genes strongly regulate these processes.
In late gestation, the primordial endothelium that covers the cornea should undergo resorption, disruption of this process may result in posterior embryotoxon and abnormal insertion of the iris causing pupillary changes such as pseudopolycoria or ectropion uveae.
The previously discussed abnormalities in the development of the anterior chamber may affect the development of the Schlemm’s canal impairing outflow of aqueous humor and increasing the risk of glaucoma.
ARS commonly correlates with ocular, dental, facial and abdominal abnormalities. Ocular findings include anterior iris stromal hypoplasia, anterior chamber synechiae, corneal opacity, microcornea, and glaucoma. Non-ocular systemic features in patients with the syndromic form of the disease may include hypodontia, maxillary hypoplasia, and periumbilical abnormalities.
Posterior embryotoxon describes the presence of a prominent and anteriorly displaced Schwalbe line, which is the anatomic line that demarcates the outer corneal endothelium. Approximately half of these patients will develop glaucoma.
Evaluation for patients with 6p25 microdeletion syndrome should be comprehensive and include a referral to an ophthalmologist, particularly for patients with posterior embryotoxon. Other studies should include neurodevelopmental evaluation, screening echocardiogram, brain imaging, and hearing and vision tests, including auditory brainstem response evaluation.
Childhood glaucoma is a fairly common complication in ARS. Patients should undergo prompt evaluation and treatment to preserve vision. While primary care providers may detect the clinical symptoms and initially diagnose, these patients will require further evaluation by different specialists as they may eventually require surgical interventions or specialized care to prevent permanent disabilities or blindness.
Treatment is individualized as the clinical presentation of patients with ARS is highly variable. Approximately half of the patients will develop glaucoma which may eventually require procedures such as trabeculectomy and trabeculotomy, these therapies have been effective in controlling intraocular pressure, as described in a retrospective analysis of 24 children diagnosed with ARS and early-onset glaucoma.
Anterior eye segment dysgenesis may present as an isolated finding in some patients or as part of various syndromes. As previously discussed, Axenfeld-Rieger Syndrome encompasses a broad spectrum of phenotypes with substantial clinical overlap. Suspicion of ARS is warranted in patients who present with posterior embryotoxon with attached iris strands, or patients with various iris changes including various degrees of stroma hypoplasia, corectopia, and polycoria. Other key clinical features for ARS are extraocular anomalies such as facial dysmorphism, dental dysplasia, maxillary hypoplasia, hearing loss, redundant periumbilical skin, and cardiac anomalies.
Prognosis varies on an individual basis as patients with ARS have varied clinical presentations and different degrees of comorbidities. While some patients may only present anterior ocular chamber abnormalities, others may also have cardiac defects of varying severity which may worsen their prognosis.
The spectrum of diseases associated with Axenfeld-Rieger syndrome may has associations with various complications, commonly ocular abnormalities such as posterior embryotoxon. At least 50% of these patients develop glaucoma.
Patients presenting with congenital glaucoma (CG) have links to FOXC2 and PITX2 mutations. CG may lead to severe complications including blindness or partial visual loss in children. Amblyopia is a relatively common complication of childhood glaucoma.
Patients with mutations in FOXC1 may present hearing loss in addition to ocular and heart complications.
One study described a family of three generations with three cases of ARS and heart disease; these patients presented FOXC1 mutations suggesting that this gene may be involved in cardiac development.
Patients and their families may benefit from knowing the type and risk of complications associated with this spectrum of disease, including a higher risk for glaucoma. In addition to ocular abnormalities, ARS carries associations with dental malformations and maxillary hypoplasia. Patients suffering these complications may benefit from referral to an orofacial specialist such as a maxillofacial surgeon.
Genetic counseling and possibly testing could be offered to patients as some variants of ARS are inherited in an autosomal dominant fashion.
Some authors describe different variants or subtypes of ARS, and various terms are used to describe different pathological presentations, including Axenfeld-Rieger Syndrome, Axenfeld anomaly and Rieger Anomaly in addition to others. All these presentations share an overlapping phenotype, and better communication between specialists (optometrist, ophthalmologist, and ophthalmic nurse) may be achievable by encompassing all these conditions under the same terminology.
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