Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder that encompasses anterior segment ocular dysgenesis in addition to systemic abnormalities such as dental, cardiac, craniofacial, and abdominal wall defects as well as other parts of the body. 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.[rx]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 embryotoxic) 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).
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 the Axenfeld anomaly.
Axenfeld syndrome and Rieger syndrome are defined as Axenfeld anomaly and Rieger anomaly accompanied by systemic effects, respectively. The 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.
Symptoms
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 embryotoxic). Other features include adhesions in the front of the eye, between the iris and the edge of the cornea.
A 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 is 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), the complete absence of teeth (anodontia) and/or cone-shaped teeth.
Other characteristics include craniofacial abnormalities resulting in a prominent forehead, a face that appears to be flattened, widely spaced eyes (hypertelorism), broad flat bridge of the nose, underdeveloped bones of the upper jaw, and 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 present with an umbilical hernia — a protrusion of the 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.
Causes
ARS is caused by changes (mutations) in several different genes and follows an autosomal dominant pattern of inheritance.
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.[rx]
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.[rx] Other cases have correlations with PITX2 mutations, in chromosome 4q25.[rx]
Approximately 40 to 70% of ARS cases correlate with mutations in FOXC1 and PITX2, on chromosomes 6p25 and 4q25, respectively.[rx]
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.[rx]
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 gain of function mutations or extra copies of genes. This might increase the activity of proteins involved in the development of the eyes.
Diagnosis
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. Other studies should include neurodevelopmental evaluation, screening echocardiogram, brain imaging, and hearing and vision tests, including auditory brainstem response evaluation.[rx]
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 the 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 (intraocular pressure). If eyedrops are not sufficient to control glaucoma, surgery could be considered.
Aqueous suppressants, including beta-blockers and carbonic anhydrase inhibitors, are safe and effective. These medications can have side effects, especially in children with a smaller volume of distribution for the drugs; therefore, these patients should be monitored closely. Prostaglandin analogs may be used to lower IOP. Alpha-2 agonists, especially brimonidine, are contraindicated in children less than 2 years of age secondary to their association with potentially serious apnea, bradycardia, hypotension, hypotonia, and CNS depression in this population. Apraclonidine should be used with caution for the same considerations but seems to be safer than brimonidine.
Surgical
As in congenital glaucoma, surgical intervention is more efficacious than medical management in ARS. However, achieving long-term surgical success in congenital and developmental glaucoma is also difficult and complications are common. Surgical options include goniotomy, trabeculectomy, trabeculectomy with or without antifibrotic agents, aqueous shunt procedures, or cyclodestructive procedures. In a retrospective review of pediatric glaucoma by Bussieres et al, 40% of patients with ARS had a craniotomy, 30% had trabeculectomy, and 2% required glaucoma drainage devices. Most of those patients required 1.5 surgeries per eye.
In general, goniotomy and trabeculectomy are less successful interventions in developmental glaucoma than other pediatric glaucomas, presumably because of the angle dysgenesis and other developmental abnormalities associated with this group of glaucomas.
Trabeculectomy with mitomycin C is associated with a successful IOP lowering effect in 82-95% of cases and long-term success in around 59% at 2-year follow-up. However, this intervention is associated with a risk of late postoperative endophthalmitis in 7-8% of cases.
Glaucoma drainage devices have been reported to have success rates of 70-90% with long-term success reported to be 58-63% at 2-year follow-up. The rate of endophthalmitis is low with this procedure, 2.9%, but surgical revision may have to be performed for other associated complications such as dislocation, tube-cornea touch, or erosion. In addition, concomitant medical therapy is often necessary to augment IOP control with glaucoma drainage devices, and re-operation may be necessary. In surgically refractory pediatric glaucomas, specifically developmental glaucomas, glaucoma drainage devices are likely to be successful whereas trabeculectomy has a relatively poor chance of success. Cyclodestructive procedures are usually reserved for refractory glaucomas after other options have been exhausted because of low reported success rates, frequent need for re-treatment, and high complication rates.
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.
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