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Axenfeld-Rieger Syndrome

What is Axenfeld-Rieger Syndrome ?

The human eye is anatomically complex, consisting of many different parts and layers that work together to produce clear vision. The cornea, a transparent layer at the front of the eye, focuses light entering the eye. The underlying colored part, the iris, is similar to a diaphragm in a camera. The iris surrounds an opening, the pupil, which allows light to enter the eye. The iris adjusts the amount of light entering the eye by increasing or decreasing the diameter of the pupil. The anterior chamber is a fluid-filled space between the cornea and the iris. At the base of the cornea, a structure called the trabecular meshwork drains the fluid inside the anterior chamber to maintain the pressure inside the eye (intraocular pressure).

Axenfeld-Rieger Syndrome (ARS) is a disorder affecting the eye with significant variation in symptoms. This disorder is characterized by abnormalities in the anterior segments of the eye including in the cornea, iris, and the anterior chamber.  About half of ARS cases will develop glaucoma, a condition characterized by an increased pressure in the eye that damages the eye and may lead to blindness. Although ARS primarily affects the eye, other organs can be affected in some individuals. Examples include dental abnormalities, cardiac anomalies, and craniofacial anomalies. Three types of ARS have been described, each with a distinct genetic cause.

ARS is a genetic disorder inherited in an autosomal dominant manner. This means that if one of the two copies of the associated genes is defective, the individual will be affected. Mutations in the PITX2 gene are associated with ARS type 1, and mutations in the FOXC1 gene are associated with ARS type 3. There is evidence suggesting the mutations on chromosome 13 lead to ARS type 2, but the exact gene has not been identified yet.

 

 

The human eye is anatomically complex, consisting of many different parts and layers that work together to produce clear vision. The cornea, a transparent layer at the front of the eye, focuses light entering the eye. The underlying colored part, the iris, is similar to a diaphragm in a camera. The iris surrounds an opening, the pupil, which allows light to enter the eye. The iris adjusts the amount of light entering the eye by increasing or decreasing the diameter of the pupil. The anterior chamber is a fluid-filled space between the cornea and the iris. At the base of the cornea, a structure called the trabecular meshwork drains the fluid inside the anterior chamber to maintain the pressure inside the eye (intraocular pressure).

Axenfeld-Rieger Syndrome (ARS) is a disorder affecting the eye with significant variation in symptoms. This disorder is characterized by abnormalities in the anterior segments of the eye including in the cornea, iris, and the anterior chamber.  About half of ARS cases will develop glaucoma, a condition characterized by an increased pressure in the eye that damages the eye and may lead to blindness. Although ARS primarily affects the eye, other organs can be affected in some individuals. Examples include dental abnormalities, cardiac anomalies, and craniofacial anomalies. Three types of ARS have been described, each with a distinct genetic cause.

ARS is a genetic disorder inherited in an autosomal dominant manner. This means that if one of the two copies of the associated genes is defective, the individual will be affected. Mutations in the PITX2 gene are associated with ARS type 1, and mutations in the FOXC1 gene are associated with ARS type 3. There is evidence suggesting the mutations on chromosome 13 lead to ARS type 2, but the exact gene has not been identified yet.

 

ARS affects approximately 1 in 200,000 individuals.

Synonyms for Axenfeld-Rieger Syndrome has not been added yet.

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.

Tips or Suggestions of Axenfeld-Rieger Syndrome has not been added yet.

American Academy of Ophthalmology. Axenfeld-Rieger syndrome. Available from https://www.aao.org/bcscsnippetdetail.aspx?id=354d7aec-3ecb-4b88-b7b0-246f30078899

Ganesh A, Levin A. Glaucoma Associated With Axenfeld-Rieger Spectrum and Peters Sequence. Glaucoma Today. 2013. Available from http://glaucomatoday.com/2013/08/glaucoma-associated-with-axenfeld-rieger-spectrum-and-peters-sequence/

Genetic Home Reference. Axenfeld-Rieger syndrome. Available from  https://ghr.nlm.nih.gov/condition/axenfeld-rieger-syndrome#diagnosis

OMIM. Axenfeld-Rieger Syndrome, Type 1; RIEG1. 2017. Available from https://www.omim.org/entry/180500

OMIM. Axenfeld-Rieger Syndrome, Type 2; RIEG1. 2017. Available from https://www.omim.org/entry/601499

OMIM. Axenfeld-Rieger Syndrome, Type 3; RIEG1. 2017. Available from https://www.omim.org/entry/602482

Orphanet. Axenfeld-Rieger syndrome. 2011. Available from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=782

Seifi M,  Walter M. Axenfeld-Rieger syndrome.Clinical Genetics. 2018;93:1123–1130. DOI: 10.1111/cge.13148

Song, Wei and Xiaodan Hu. “The rare Axenfeld-Rieger syndrome with systemic anomalies: A case report and brief review of literature” Medicine. 2017; 96(33):7791. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571701/

Tonoki H, Harada N, Shimokawa O, Yosozum A, Monzaki K, Satoh K, et al. Axenfeld–Rieger Anomaly and Axenfeld–Rieger Syndrome: Clinical, Molecular-Cytogenetic, and DNA Array Analyses of Three Patients With Chromosomal Defects at 6p25. Americal Journal of Medical Genetics. 2011: 2925-2932. DOI 10.1002/ajmg.a.33858

Waldron J, McNamara C, Hewson A, McNamara C, Axenfeld–Rieger Syndrome (ARS): A review and case report. Special Care in Dentistry. 2010; 30(5): 218-222. doi: 10.1111/j.1754-4505.2010.00153.x

Zeynep T, Bach-Holm D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. European journal of human genetics. 2009;17(12):1527-39.

 

riegers Created by mickeykostelnik
Last updated 27 Feb 2015, 07:36 PM

Posted by Karenlgibbs
27 Feb 2015, 07:36 PM

My 16 year old son was diagnosed when he was 13 with the Rieger anomaly. He gets his pressure checked every 6 months and has a visual field test annually. He sees his ophthalmologist annually. So far he doesn't have Glaucoma. And, thankfully, no other signs or symptoms somfar. Glad to have founf this group today as nobody seems to know anything about Axenfeld-Rieger.

Posted by Ffamily2400
11 Sep 2013, 09:31 PM

Hi Eviejo2004! It's extremely difficult to find individuals. I am from the US in the state of Florida. Would love to hear from your experiences here's my email elizabethgonzalo@gmail.com My 6 year old daughter doesn't have her front teeth either. She's been losing her lower baby teeth. Doctors have told us that her top front teeth just aren't present. She's doing well at school she's currently in the 1st grade and still gets checked out by her cardiologist and ophthalmologist.

Posted by Eviejo2004
11 Sep 2013, 09:11 PM

Hi guys!!! Finally I've found a site for Reigers. My 8 year old daughter was diagnosed with the syndrome at 6 weeks old. She doing ok. No front teeth and the some of her adult teeth are a bit "peggy". She wears glasses and has regular pressure checks. We have just been referred for heart scans, ECGs etc to see of there's any underlying heart probs, but fingers crossed, none as yet. She's struggling a little at school with her reading n writing but her memory n knowledge are second to none!!! I'd love to hear more from you all as in the UK there's nothing for us parents of children with Reigers. Hope to hear from you soon xxxx

View Full Thread (9 more posts)
Diagnosis Created by Ffamily2400
Last updated 30 Dec 2009, 03:06 PM

Posted by Ffamily2400
30 Dec 2009, 03:06 PM

My daughter has been clinically diagnosed with this syndrome. She has all the characteristic mentioned. She will be turning 3 in a few days & she's missing her 4 front teeth & was born with ompholocele which required surgery when she was born. I would really appreciate any input on families that are or know anyone that experienced the samething. Thanks

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riegers

Created by mickeykostelnik | Last updated 27 Feb 2015, 07:36 PM

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Created by Ffamily2400 | Last updated 30 Dec 2009, 03:06 PM


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