ARS

ARS affects approximately 1 in 200,000 individuals.

ARS is an autosomal dominant disorder with high penetrance. The term autosomal dominant describes a genetic disorder in which if one of the two copies of the gene is defective, the individual is affected. High penetrance means that if a defective gene is present in an individual, that individual is very likely to show symptoms. Mutations in two genes, Pituitary Homeobox 2 (PITX2) on chromosome 4 and Forkhead box 1 (FOXC1) on chromosome 6 are associated with ARS type 1 and 3 respectively. There is evidence suggesting that mutations on chromosome 14 cause type 2 ARS, but the exact gene has not been identified.

Both PITX2 and FOXC1 code for transcription factors, proteins that bind to particular regions of DNA and regulate the activity of other genes. Mutations in these transcription factors disrupt the regulation of other genes that are required for normal embryonic development and normal formation of the structures in the anterior segment of the eye.

During embryonic development, three germ layers are formed: endoderm, mesoderm, and ectoderm. The endoderm will eventually form most of the internal organs such as the stomach and the lungs, the mesoderm will form the muscles, bones, and blood vessels, and the outermost layer, the ectoderm will form the nervous tissues such as the brain and parts of the eye, the mouth (including tooth enamel), and the skin. During development, the ectoderm will fold and form the neural tube and the neural crest which form the early nervous system. Although the exact mechanism of ARS is unknown, it appears to begin as a defect in the ectoderm causing developmental abnormalities in the ectoderm and neural crest. Impairment of this process leads to abnormal development of the anterior segment of the eye, facial structures, and teeth.

Abnormalities in organs other than the eye are present in individuals with PITX2 mutations more than those with FOXC1 mutations. However, individuals with FOXC1 duplications, where a region of the gene is abnormally duplicated in the DNA sequence, are more likely to develop glaucoma.

ARS presents with ocular features (eye abnormalities) and non-ocular features. Most commonly affected ocular structure in ARS are the iris, the cornea, and the anterior chamber. The ocular abnormalities often affect both eyes, although it can be asymmetrical and in rare cases, only one eye might be affected.

The iris abnormalities include underdevelopment (iris hypoplasia) or thinning of the iris (iris stromal atrophy). In more severe cases, this may result in the formation of holes in the iris that can appear as if the individual has more than one pupil (pseudopolycoria). Iris hypoplasia may also lead to the displacement of the pupil from its normal position (corectopia). If severe, iris hypoplasia may even appear as aniridia, the complete absence of the iris. Less commonly, ARS may present with strabismus, a condition where the two eyes are misaligned with each other. This is because the extraocular muscles which are responsible for eye movements attach to the eye at abnormal insertion points. Other ocular findings may include corneal opacity, and defects in the lens of the eye.

About 50% of individuals affected by ARS develop glaucoma. Glaucoma occurs when the buildup of fluid inside the eye increases the internal pressure of the eye, damaging the optic nerve, and if untreated, eventually resulting in blindness.

The non-ocular features of ARS vary significantly and include dental and facial abnormalities and cardiac and valvular anomalies. The affected individuals may have fewer than normal teeth (oligodontia) or at least one tooth that appears smaller than normal (microdontia).  In individuals with oligodontia, primary upper teeth, and permanent incisors and second premolars are most commonly missing. Maxillary hypoplasia or an underdeveloped upper jaw may also be present. Maxillary hypoplasia can create the illusion of a jutted forward lower jaw or an enlarged chin as the upper jaw is abnormally small. Facial features may include hypertelorism or widely spaced eyes, a prominent forehead, a flattened mid-face, and nasal bridge, small lower lip and large everted upper lip.

Cardiac anomalies may be symptomatic or asymptomatic. Heart anomalies include abnormalities of the valves of the heart such as the narrowing of the valves (e.g. pulmonary valve stenosis and aortic valve stenosis), Tetralogy of Fallot, and atrial septal defect (ASD). Tetralogy of Fallot is a condition in which an abnormal opening is present between the lower chambers of the heart (ventricular septal defect), the opening of the vessel that connects the heart to the lungs is partially obstructed (pulmonary valve stenosis), the vessel that receives blood from the lower left chamber of the heart and sends it to the rest of the body receives blood from both lower chambers (overriding aorta), and the muscles surrounding the lower right chamber becomes abnormally thickened (right ventricle hypertrophy). ASD is a condition in which an abnormal opening is present between the upper chambers of the heart (atria).

Other non-ocular abnormalities include extra folds of skin around the belly button (redundant periumbilical skin), abnormalities in the pituitary gland, and hearing loss.

Diagnosis of ARS is made based on clinical examination and eye evaluation including imaging of the anterior segment of the eye through biomicroscopy, intraocular pressure measurement, gonioscopy, and ophthalmoscopy. Gonioscopy is an eye examination where a lens is used to view the inside of the eye and assess whether the fluid drainage system is properly functioning. Ophthalmoscopy is another eye examination technique that is used to view the back of the eye. A commonly observed feature in ARS during gonioscopy is an anteriorly displaced, thickened Schwalbe's ring (posterior embryotoxon). Schwalbe's ring is found on the interior surface of the cornea and defines the anterior border of the trabecular meshwork, the eye's drainage system. However, the presence of posterior embryotoxon does not confirm ARS as it can also be found in 10-15% of the normal population. The presence of craniofacial abnormalities can assist in diagnosing ARS, particularly in individuals with mild ocular features. When clinical and ophthalmological evaluations suggest ARS, genetic testing can confirm the diagnosis.

Gonioscopy and ophthalmoscopy can assist in identifying ocular feature of ARS and glaucoma. Genetic testing can assist in identifying mutations in FOXC1 and PITX2 to confirm the diagnosis.

Treatment of ARS mostly involves control and management of glaucoma.  Treatment of glaucoma in individuals affected by ARS is similar to the management of any other glaucoma. However, when an ARS diagnosis is confirmed, cardiac evaluation is essential as options for glaucoma management are considered as some of the options can exacerbate cardiac outflow in individuals with affected hearts.

Individuals with ARS must be regularly monitored for glaucoma and their intraocular pressure and the appearance of the optic nerve must be frequently checked. Glaucoma therapies reduce the buildup of fluid inside the eyes and include alpha-adrenergic agonists, beta blockers, carbonic anhydrase inhibitors, osmotic agents, and prostaglandin analogues. Other options include surgical treatment such as trabeculectomy where a small hole is made in the wall of the eye (sclera) to decrease the intraocular pressure, and aqueous shunts which are devices that drain intraocular fluid to a small external reservoir behind the eyelid. Laser iridotomy and laser trabeculoplasty and laser cycloablation are laser therapies aimed to treat glaucoma. In laser iridotomy, a small hole is made on the rim of the iris, allowing fluid to pass between the anterior chamber and the area behind the iris, lowering intraocular pressure. Laser trabeculoplasty directly improves the drainage of fluids through the trabecular meshwork.

Prognosis is usually good in absence of glaucoma and life expectancy is not affected. In presence of glaucoma, prognosis depends on when it is detected as optic nerve damage is irreversible. The sooner glaucoma is detected, the better the prognosis is.

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