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Last updated:
April 08, 2008
Years published: 1991, 1997, 1998, 2006, 2022
NORD gratefully acknowledges Mahmoud Moustafa, MDCM Candidate, McGill University School of Medicine, and Michael Walter, PhD, Professor, University of Alberta College of Health Sciences; Faculty of Medicine and Dentistry; Department of Medical Genetics, for assistance in the preparation of this report.
Summary
Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder that affects the eye as well as other parts of the body. It is estimated to occur in approximately 1 person in 50,000 worldwide. The disorder affects males and females equally and has been observed in patients from various ethnic backgrounds from all over the world.
Signs and symptoms of ARS can be divided into ocular and non-ocular (systemic). Ocular features include, among others, an underdeveloped iris (iris hypoplasia), displacement of the pupil of the eye so that it is not centered (corectopia), full thickness tears in the iris of the eyes, an opaque ring around the outer edge of the cornea (posterior embryotoxon) and very rarely a small cornea (microcornea). Non-ocular features include, among others, dental and craniofacial abnormalities, hearing loss, excessive skin around the navel and very rarely a smaller than usual anal opening (refer to the ‘Signs & Symptoms’ section of this report for more information).
ARS is the result of abnormal embryonic development, so the condition is usually diagnosed during infancy or childhood. A serious consequence of ARS is glaucoma, which usually develops later in childhood or adulthood. Glaucoma is often due to increased fluid pressure within the eyeball and can lead to complete permanent blindness if left untreated. Thus, the main course of treatment is the effective management of glaucoma, medically or surgically (if medications are not effective).
Introduction
The Axenfeld anomaly is defined as eye peripheral anterior segment defects and was first described in 1920 by the German ophthalmologist Theodor Axenfeld. Later in 1934, Rieger described the Rieger anomaly as central changes in the iris of the eye along with features mentioned in Axenfeld anomaly.
Axenfeld syndrome and Rieger syndrome are defined as Axenfeld anomaly and Rieger anomaly accompanied by systemic effects, respectively. Distinction between these four conditions was difficult and clinically irrelevant due to the overlap of clinical features between them as well as the involvement of the same gene changes (mutations). Thus, they are now all grouped under the same condition referred to as Axenfeld-Rieger syndrome.
Ocular signs and symptoms
Ocular features of ARS usually occur in both eyes. The main ocular signs include an underdeveloped iris (iris hypoplasia), displacement of the pupil of the eye so that it is not centered (corectopia), one or more full thickness tears in the iris of the eye and an opaque ring around the outer edge of the cornea (posterior embryotoxon). Other features include adhesions in the front of the eye, between the iris and the edge of the cornea.
Glaucoma is a group of diseases in which the eye’s optic nerve is damaged. This damage is often secondary to increased pressure within the eyeball. Glaucoma is seen in approximately 50% of patients with ARS and can lead to complete permanent blindness if not treated. Fluid in the eye normally drains out of the eye through the angle formed by the junction of the iris and the cornea. Defects in the formation of the angle of the eye and/or adhesions that block this drainage route that are associated with ARS can lead to glaucoma.
Systemic signs and symptoms
Systemic signs include dental abnormalities including a congenital condition in which fewer teeth than normal are present (hypodontia), a tooth or teeth that are smaller than normal (microdontia), six or more missing teeth (oligodontia), complete absence of teeth (anodontia) and/or cone-shaped teeth.
Other characteristics include craniofacial abnormalities resulting in a prominent forehead, face that appears to be flattened, widely spaced eyes (hypertelorism), broad flat bridge of the nose, under-developed bones of the upper jaw, thin upper lip and/or a protruding lower lip.
Some patients with ARS may also present with failure of the skin around the navel to decrease in size after birth (a condition that is sometimes mistaken for an umbilical hernia) and very rarely an unusually small anal opening (anal stenosis). Rarely, a patient may in fact present with umbilical hernia — a protrusion of intestine through a weakness in the abdominal wall around the navel.
Other rare manifestations include a congenital abnormality in which the urethra in males opens from a different location than its usual one on the head of the penis (hypospadias), abnormalities of the pituitary gland — an important hormone-producing gland found in the brain, arachnoid cysts — fluid-filled balloons under one of the membranes covering the brain and spinal cord, growth delay, heart defects and hearing abnormalities.
ARS is caused by changes (mutations) in several different genes and follows an autosomal dominant pattern of inheritance.
Dominant genetic disorders typically occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. The word ”autosomal” means that the genetic disorder is not associated with one of the sex chromosomes, but rather with the non-sex (or autosomal) chromosomes.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 4q25-q26” refers to a region between bands 25 and 26 on the long arm of chromosome 4. Chromosome 13q14 refers to a site at band 14 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Several genetic studies have found two main genes associated with ARS: FOXC1 and PITX2. A wide spectrum of mutations in these genes contributes to the development of the disease. However, the genetic cause of ARS remains unclear in around 60% of patients.
There are three types of ARS. ARS type I is associated with mutations in the PITX2 gene on chromosome 4 (4q25), whereas ARS type III is associated with mutations in the FOXC1 gene on chromosome 6 (6p25). ARS type II has been associated with chromosome 13 (13q14), but a specific gene is not yet identified. Typically, patients who present with associated systemic abnormalities tend to have a PITX2 mutation, whereas patients who only present with ocular features, sometimes alongside heart defects and hearing loss, tend to have a FOXC1 mutation. Other genetic changes are also rarely associated with ARS: deletion of the PAX6 gene on chromosome 11 (11p13) as well as deletion of the chromosome 16q23-q24 region.
PTXI2 and FOXC1 are both genes that code for transcription factors that control other genes to regulate steps in embryonic development. The mechanism of ARS is not fully clear, but it is believed that the structural abnormalities seen in ARS originate from defects in the development and functions of cells that form the eye.
ARS has also been reported to be associated with of gain of function mutations or extra copies of genes. This might increase the activity of proteins involved in the development of the eyes.
ARS is estimated to occur in about 1 in 1/50,000 newborns worldwide. It has been observed in patients from different ethnic origins including the Middle East as well as European, African, Asian, and South and North American populations. ARS seems to affect males and females in about equal numbers and is usually diagnosed in infants and children. Glaucoma, on the other hand, usually develops later in childhood or in adulthood.
ARS is commonly recognized by the presence of characteristic ocular features that may include non-ocular abnormalities. Depending on the clinical situation, genetic testing can help confirm a suspected diagnosis of ARS.
Clinical testing and work-up
The work-up includes an initial examination of the eye to detect ocular abnormalities associated with the disease. Regular eye examinations are also done to monitor possible development of glaucoma. A physical examination for non-ocular features associated with ARS is also done.
Treatment
The main course of treatment in ARS is the management of glaucoma (if present) with medications, usually consisting of eye drops. These medications are mainly used to lower the pressure inside the eyeball (intra-ocular pressure). If eyedrops are not sufficient to control the glaucoma, surgery could be considered.
For the non-ocular features of ARS, effective coordination of care with other healthcare professionals is important for complete evaluation and treatment.
With age, certain patients with an uncentered pupil (corectopia) or multiple full thickness holes in the eye may experience an increased intolerance for light (photophobia). For these patients, special eye lenses may be beneficial.
Genetic counseling may also be helpful for patients and their families.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Genetic and Rare Diseases (GARD) Information Center
National Association for Parents of Children with Visual Impairments (NAPVI)
TEXTBOOKS
Mannis MJ, Holland EJ, eds. Cornea. Fourth edition. Elsevier; 2017. https://mcgill.on.worldcat.org/oclc/960030390 Accessed Feb 10, 2022.
JOURNAL ARTICLES
Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017;93(6):1123-1130. doi:10.1111/cge.13148
Song W, Hu X. The rare Axenfeld–Rieger syndrome with systemic anomalies. Medicine (Baltimore). 2017;96(33). doi:10.1097/MD.0000000000007791
Rao A, Padhy D, Sarangi S, Das G. Unclassified Axenfeld-Rieger syndrome: a case series and review of literature. Semin Ophthalmol. 2016;33(3):300-307. doi:10.1080/08820538.2016.1208767
Dunbar AC, McIntyre GT, Laverick S, Stevenson B. Axenfeld–Rieger syndrome: a case report. J Orthod. 2015;42(4):324-330. doi:10.1179/1465313315Y.0000000017
Bender CA, Koudstaal MJ, Van Elswijk JFA, Prahl C, Wolvius EB. Two cases of Axenfeld-Rieger syndrome, report of the complex pathology and treatment. Cleft Palate Craniofac J. 2014;51(3):354-360. doi:10.1597/12-295
INTERNET
Zamora EA, Salini B. Axenfeld-Rieger Syndrome. In: StatPearls. Last Update: October 30, 2021.https://www.ncbi.nlm.nih.gov/books/NBK538504/ Accessed Feb 10, 2022.
Schultz SK. Axenfeld Rieger Syndrome. EyeWiki. Oct 7, 2021. https://eyewiki.aao.org/Axenfeld_Rieger_Syndrome Accessed Feb 10, 2022.
Axenfeld-Rieger syndrome. Genetic and Rare Diseases Information Center (GARD).12/9/2016. https://rarediseases.info.nih.gov/diseases/5701/axenfeld-rieger-syndrome Accessed Feb 10, 2022.
Axenfeld-Rieger syndrome: MedlinePlus Genetics. 18 August 2020. https://medlineplus.gov/genetics/condition/axenfeld-rieger-syndrome/ Accessed Feb 10, 2022.
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