Axenfeld Rieger Syndrome

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Introduction [edit | edit source]

Axenfeld-Rieger syndrome(ARS) refers to an autosomal dominant genetic condition characterized by anterior segment dysgenesis and systemic abnormalities. In 1920, Axenfeld characterized the anomaly which bears his name when he described posterior embryotoxon and iris strands adherent to the anteriorly displaced Schwalbe’s line.1(Figure 1)  Posterior embryotoxon is a clinical and histologic term referring to displacement of Schwalbe’s line anterior to the limbus in the cornea.  Rieger described patients with congenital iris abnormalities including iris hypoplasia, correctopia, and polycoria, now referred to as Rieger anomaly, in 1935.2(Figure 2)  Rieger anomaly, associated with systemic findings, such as dental, facial bone defects including maxillary hypoplasia, umbilical abnormalities, or pituitary involvement is known as Rieger syndrome.3,4 The combination of Axenfeld anomaly and Reiger syndrome is known collectively as Axenfeld-Rieger syndrome.


Posterior embryotoxon.JPG     Posterior embryotoxon1.JPG

Figures 1, 2. Note in 1 and 2 the posterior embryotoxon, a white line anterior to the limbus in the cornea which is the abrnormal premature termination of Descemet’s membrane with the trabecular meshwork. In figure 2, note the corectopia and area of atrophy commonly seen in ARS.


Genetics[edit | edit source]

Axenfled-Rieger syndrome is autosomal dominant in most cases, but it can also occur sporadically.5 It has complete penetrance with variable expressivity and is associated with a 50% risk of glaucoma.3,5,6 ARS is a genetically heterogeneous group of abnormalities as a result of mutations in at least 4 different gene loci. Mutations in PITX2 on ch 4q25, FOXC1 on 6p25, PAX6 on 11p13, and FOXO1A on 13q14 have been associated with formation of ARS.7-10 FOXC1 and PITX2 both encode for transcription factors which regulate expression of downstream genetic targets by binding to specific DNA sequences and activating transcription. In mouse models, both FOXC1 and PITX2 are expressed in the ocular structures affected in ARS during embryogenesis.11,12 Cases of ARS with mutations in CYP1B1 have also been reported.


Epidemiology/Pathophysiology
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This disorder is seen is approximately 1/200,000 live births.  There is no sex predilection.  Most cases are diagnosed during infancy or childhood; however, glaucoma typically occurs in late childhood or adulthood.3,4


Defects in differentiation, migration, or arrested development of neural crest cells in the anterior chamber, facial bones, teeth, cardiovascular system, and periumbilical skin are considered to be the etiological basis for the systemic and ocular findings characteristic of ARS.


Histologically, patients with ARS have been found to have a monolayer of endotheilial-like cells with a Descemet-like membrane extending from the cornea, across the anterior chamber and angle structures onto the surface of the iris. The membrane is typically found in the quadrant with associated the ectropion uveae/corectopia and the iris atrophy is found in the opposite quadrant.4


It is important to recognize that 8-15% of the normal population may have a subtle, mild form of posterior embryotoxon without other sequelae, including glaucoma.  The posterior embryotoxon in ARS may be more dramatic and associated with other anterior segment findings, as described above.13 In some cases, the posterior embryotoxon may not be visible with the slit lamp examination. Shields published a case series of 24 patients with ARS, in which 5 patients had posterior embryotoxon visible only with gonioscopy.3

Clinical Characteristics [edit | edit source]

As mentioned, Axenfeld-Rieger syndrome is a bilateral, heterogeneous condition and may include developmental abnormalities in the anterior chamber angle, iris, and trabecular meshwork. Correctopia, polycoria, ectropion uveae, posterior embryotoxon, and increased intraocular pressure are common ophthalmologic findings with ARS. Photophobia may be a symptom resulting from the pupillary and iris abnormalities.


The most commonly recognized clinical manifestations of ARS are the iris correctopia/atrophy, and posterior embryotoxon.(figures 1,2). Typically, the reminder of the cornea is clear. Occasional patients have megalocornea or microcornea.The posterior embryotoxon may not be visible with the slit lamp examination. Shields published a case series of 24 patients with ARS, in which 5 patients had posterior embryotoxon visible only with gonioscopy.3


The iris strands adherent to the posterior embryotoxon can range from fine threadlike strands to broad bands of iris tissue. Likewise, the iris stroma may be grossly abnormal including generalized atrophy with correctopia, ectropion uveae, and often is similar in clinical appearance to iridocorneal endothelial syndrome(ICE). 


Systemically, patients with ARS will commonly have mild craniofacial dysmorphism, dental abnormalities, and redundant umbilical skin. The facial abnormalities include hypertelorism, telecanthus, maxillary hypoplasia, and a broad, flat nasal bridge. Dental abnormalities include microdontia, oligodontia, or hypodontia. In addition, patients may have hypospadias, anal stenosis, pituitary abnormalities, growth retardation, and cardiac valvular abnormalities.5,14-17 Abnormalities of the pituitary gland and other surrounding areas are less common, but more serious findings. Cases of empty sella syndrome and arachnoid cysts have been reported. Growth hormone deficiency and short stature have also been described.

Glaucoma[edit | edit source]

Glaucoma is seen in approximately 50% of the cases with ARS. Development arrest of the neural crest cells with their retention in the anterior chamber angle during gestation results in incomplete development of the trabecular meshwork or Schlemm canal. The extent of iris defects and iris stands in the angle do not correlate well with the severity of glaucoma.  However, the high iris insertion appears to be more pronounced in eyes with glaucoma.3  Although glaucoma may present in early infancy, most cases occur during adolescence or early adulthood.

Medical Management[edit | edit source]

Medical management of congenital and childhood glaucoma is generally used as an adjunct to surgical interventions. Aqueous suppressants, including beta-blockers18,19 and carbonic anhidrase inhibitors20 have been shown to be safe and effective. These medications can have side-effects, especially in children with smaller volume of distribution for the drugs;therefore, these patients should be monitored closely. Prostaglandin analogues may be used to lower IOP.21,22 Alpha-2 agonists, especially brimonidine, is 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.23 Apraclonidine should be used with caution for the same considerations, but seems to be safer than brimonidine.24 For further discussion see: Congenital_Or_Infantile_Glaucoma


Surgical Management[edit | edit source]

As in congenital glaucoma, surgical intervention is more efficacious than medical management in ARS.25 However, achieving long term surgical success in congenital and developmental glaucoma is also difficult and complications are common.26, 29-34 Surgical options include, goniotomy, trabeculotomy, trabeculectomy with or without anitfibrotic agents, aqueous shunt procedures, or cyclodestructive procedures. In a retrospective review of pediatric glaucoma by Bussieres et al, 40% of patients with ARS had goniotomy, 30% had trabeculotomy, and 2% required glaucoma drainage devices.26 Most of those patients required 1.5 surgeries per eye.26

In general, goniotomy and trabeculotomy 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.27,28


Trabeculectomy with mitomycin C is associated with successful IOP lowering effect in 82-95% of cases and long term success around 59% at 2-year follow-up.29,30 However, this intervention is associated with risk of late post-operative endophthalmitis in 7-8% of cases.29,30


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.31-35 The rate of endophthalmitis is low with this procedure, 2.9%,34 but surgical revision may have to be performed for other associated complications such as dislocation, tube-cornea touch, or erosion.31-33 In addition, concomitant medical therapy is often necessary to augment IOP control with glaucoma drainage devices, and re-operation may be necessary.25,32,33 In surgically refractory pediatric glaucomas, specifically developmental glaucomas, glaucoma drainage devices are likely to be successful where trabeculectomy has a relatively poor chance of success.29,33


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.25

Other Considerations[edit | edit source]

As patients with ARS age, they may experience significant and debilitating glare or photophobia resulting from the sometimes progressive iris atrophy, polycoria, and corectopia. In these circumstances painted or tinted contact lenses may be beneficial in reducing these symptoms.


Differential Diagnosis
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ICE(Iridocorneal Endothelial) Syndrome[edit | edit source]

Spectrum of disorders characterized by varying degrees of corneal edema, glaucoma, and iris abnormalities. Encompassed by three variations (1) Chandler’s Syndrome, (2) essential iris atrophy, (3) Cogan-Reese(iris nevus). ICE is typically unilateral, female predominance, manifest in early adulthood. Pathologically appears to be an acquired disease where endothelial cells acquire features of epithelial cells.  Chandler’s syndrome is produced when the pathologic changes are confined to the inner corneal surface with dysfunction of the endothelial pump resulting in corneal edema. Essential iris atrophy is produced when the abnormal endothelium proliferates onto the iris surface with subsequent contractile membranes resulting in pupil correctopia, iris atrophy, polycoria. If the malformed and dysfunctional endothelium spreads across the anterior chamber angle, peripheral anterior synechiae develop and result in glaucoma. Cogan-Reese(iris nevus) is manifested by multiple pigmented iris nodules caused by contraction of the endothelial membranes on the surface of the iris.  The unilateral nature, corneal endothelial changes, manifestation in middle age, female predominance, and lack of systemic abnormalities differentiate ICE from ARS.4, 36 

Peter’s Anomaly[edit | edit source]

Characterized by a central corneal opacity associated with an absence of Descemet’s membrane and endothelial layers as well as variable degrees of iridocorneal adhesions from the border of the corneal opacity.