L. Jay Katz
• A spectrum of developmental disorders resulting in bilateral iris and angle abnormalities frequently associated with secondary glaucoma and systemic anomalies including dental and facial bone abnormalities
• Nomenclature has changed through the years. Axenfeld anomaly, Rieger anomaly, and Axenfeld–Rieger syndrome have previously been classified separately but now are all considered to be a single entity representing a spectrum of related anterior segment developmental disorders collectively referred to as Axenfeld–Rieger syndrome.
• Autosomal dominant with high penetrance
• Mutations at the following loci have been linked to Axenfeld–Rieger syndrome (1).
– Paired-like homeodomain transcription factor 2 (PITX2, 4p25): A transcription factor that regulates the expression of other genes in anterior segment structures, dental lamina, and the umbilical cord during embryonic development
– Forkhead box C1 (FOXC1) – formerly called Forkhead Drosophila homologue-like transcription factor gene – (FKHL7, 6p25): Another transcription factor
– Gap junction protein, alpha 1 (GJA1, 6q21q23.2): Encodes connexin 43 protein which forms gap junctions
– Paired box gene 6 (PAX6, 11p13)
– V-MAF avian musculoaponeurotic fibrosarcoma oncogene (MAF, 16q24)
– 13q14 (gene unknown)
No known modes of prevention, other than genetic counseling.
• A neural crestopathy resulting from a genetically triggered arrest in anterior segment development during late gestation (2)
• Consequently, the aqueous outflow structures are incomplete and retained primordial endothelium covers the angle and iris (2)[C].
• A genetic developmental disorder
• See “Pathophysiology”
COMMONLY ASSOCIATED CONDITIONS
• The most common systemic anomalies associated with Axenfeld–Rieger syndrome are dental and facial bone abnormalities:
– Maxillary hypoplasia
– Broad, flat nose
• Other less common systemic associations include:
– Pituitary anomalies including empty sella syndrome and growth hormone deficiency
– Redundant periumbilical skin
– Heart defects
– Middle ear deafness
– Mental retardation
• Ocular abnormalities that are not identified as part of the Axenfeld–Rieger spectrum but have been infrequently associated with Axenfeld–Rieger syndrome include:
– Limbal dermoids
– Iris transillumination defects
– Retinal detachment
– Macular degeneration
– Chorioretinal colobomas
– Choroidal hypoplasia
– Optic nerve hypoplasia
• Most cases are identified in infancy or childhood during a routine exam, often prompted by a positive family history.
• Often asymptomatic, but may present with the symptoms of infantile glaucoma such as blepharospasm, epiphora, and/or photophobia
• Glaucoma develops in 50%.
• Typically bilateral
• Ocular findings include a range of the following corneal, angle, and iris anomalies (3)[C]:
– A prominent, anteriorly displaced Schwalbe’s line (posterior embryotoxon) noted 360° or limited to the temporal quadrant with adherent peripheral iris strands.
– The cornea is usually otherwise normal, although megalocornea, microcornea, and central opacities have rarely been described.
– On gonioscopy, the iris inserts into the posterior meshwork, obscuring the scleral spur.
– The iris may be normal or stromal thinning, pseudopolycoria, corectopia, and/or ectropion uvea may be present.
– Peripheral iris changes usually do not progress after birth, but central iris anomalies have progressed during childhood in a small number of individuals.
– Elevated intraocular pressure may be present.
– Optic nerve cupping may develop. When the onset is in childhood, cupping is usually concentric with healthy surrounding disk tissue until late stages.
• In children, exams under anesthesia are often required. However, all children should also be examined without sedation to screen for amblyopia and monitor ocular motility.
• In children <3 years of age, monitor for the following signs as they may be indicative of the onset of glaucoma:
– Progressive corneal enlargement
– Increasing axial length
– Progressive myopia or rapid loss of hyperopia
DIAGNOSTIC TESTS & INTERPRETATION
• Optic disc photos
• Consider optic nerve head imaging (optical coherence tomography, confocal scanning laser ophthalmoscopy, scanning laser polarimetry); hand-held optical coherence tomography (if available) may be used during exams under anesthesia.
Visual field (once the child is old enough to complete this test reliably, the age will vary depending on the child)
• Peripheral iris strands attached to (or sometimes anterior or posterior to) an anteriorly displaced, prominent Schwalbe’s line.
• A monolayer of spindle-shaped cells extends from the cornea to cover the angle and anterior surface of the iris.
• This layer of spindle-shaped cells is frequently seen covering the iris in areas toward which the pupil is displaced.
• The iris stroma may be thin or absent in areas away from the corectopia.
• Iris not adherent to the cornea typically inserts into the posterior aspect of the meshwork.
• The trabecular meshwork is composed of a reduced number of attenuated lamellae.
• Schlemm’s canal may be rudimentary or absent.
• Iridocorneal endothelial syndrome
• Posterior polymorphous dystrophy (PPMD)
• Posterior embryotoxon
• Peters anomaly
• Observation may be appropriate if no signs of ocular hypertension or glaucoma are present.
• Once elevated intraocular pressure develops, medical therapy should be initiated:
– Topical beta-blockers (in children, timolol 0.25%, levobunolol 0.25%, or betaxolol are reasonable options)
– Topical carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide)
– Prostaglandin analogs (e.g., latanoprost, travoprost, bimatoprost)
– Topical alpha2-agonists (e.g., brimonidine)
• Use of alpha2-agonists (e.g., iopidine, brimonidine) in children <1 year of age is not recommended due to potential central nervous system depression.