L. Jay Katz

BASICS

DESCRIPTION

• 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.

EPIDEMIOLOGY

Incidence

Rare

Prevalence

Unknown

RISK FACTORS

Family history

Genetics

• 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)

GENERAL PREVENTION

No known modes of prevention, other than genetic counseling.

PATHOPHYSIOLOGY

• 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].

ETIOLOGY

• 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:

– Microdontia

– Hypodontia

– Oligodontia

– Anodontia

– Maxillary hypoplasia

– Hypertelorism

– Telecanthus

– Broad, flat nose

• Other less common systemic associations include:

– Pituitary anomalies including empty sella syndrome and growth hormone deficiency

– Redundant periumbilical skin

– Hypospadias

– 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:

– Strabismus

– Limbal dermoids

– Cataracts

– Iris transillumination defects

– Retinal detachment

– Macular degeneration

– Chorioretinal colobomas

– Choroidal hypoplasia

– Optic nerve hypoplasia

DIAGNOSIS

HISTORY

• 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%.

PHYSICAL EXAM

• 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.

Pediatric Considerations

• 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

Imaging

• 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.

Diagnostic Procedures/Other

Visual field (once the child is old enough to complete this test reliably, the age will vary depending on the child)

Pathological Findings

• 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.

DIFFERENTIAL DIAGNOSIS

• Iridocorneal endothelial syndrome

• Posterior polymorphous dystrophy (PPMD)

• Posterior embryotoxon

• Peters anomaly

TREATMENT

MEDICATION

First Line

• 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)