Axenfeld-Rieger syndrome/anomaly (ARS) is a rare genetic disorder with an autosomal dominant inheritance pattern, characterized by dysgenesis of the anterior segment of the eye. It may present with systemic anomalies (Axenfeld-Rieger syndrome) or without (Axenfeld anomaly) and may sometimes be associated with multiple congenital malformations. The estimated prevalence ranges from 1 in 50,000 to 1 in 200,000 live births, with an approximate rate of 1 in 100,000, but no epidemiological studies have been conducted to date. A clinical diagnosis of Axenfeld-Rieger syndrome requires the presence of both Axenfeld and Rieger ocular anomalies, accompanied by extraocular systemic features. Ocular manifestations include iris abnormalities, posterior embryotoxon, juvenile-onset glaucoma (a common complication), and dysgenesis of the iridocorneal angle with iridocorneal adhesions. The most commonly observed systemic anomalies include: umbilical defects; craniofacial dysmorphism; dentofacial abnormalities, such as Class III malocclusion due to maxillary hypoplasia, oligodontia, dental malformations (taurodontism, root dysplasia), microdontia, hypodontia, and anodontia; hearing impairment (partial or complete sensorineural hearing loss); and cardiac anomalies, including non-congenital heart disease and mitral valve insufficiency. Additional anomalies may include hypospadias in males, anal stenosis, endocrine disorders (notably growth retardation) secondary to pituitary dysfunction, psychomotor delay, and various neurological malformations such as Dandy-Walker malformation, mega cisterna magna, posterior fossa cysts, cerebellar vermis hypoplasia, ventriculomegaly, aprosencephaly, cerebral atrophy, microcephaly, arteriovenous malformations (AVM), and digital anomalies such as camptodactyly. Diagnosis is typically made in infancy, based on iris anomalies such as corectopia (displacement of the pupil), polycoria (multiple pupils), and iris hypoplasia. Posterior embryotoxon is frequently observed upon slit-lamp examination. Given the clinical variability, a comprehensive pediatric assessment is essential to identify systemic anomalies and distinguish Axenfeld-Rieger syndrome from the isolated Axenfeld anomaly.

Alagille syndrome is a multisystem disorder inherited in an autosomal dominant manner with a variable phenotypic presentation. Typical features include intrahepatic bile duct paucity, butterfly-shaped vertebrae, typical facies, axenfeld anomaly (posterior embryotoxon) and cardiac abnormalities. Since this syndrome has typical ocular associations, ophthalmologists also have an important role in diagnosing the condition. Ocular features include posterior embryotoxon, corneal pannus, chorioretinal abnormalities and posterior subcapsular cataract. We report a toddler, diagnosed with Alagille syndrome who presented to us with a visually significant lamellar cataract in both eyes. To the best of our knowledge, this is the first case reporting lamellar cataract in a toddler with Alagille syndrome. In 920, the German ophthalmologist Theodor Axenfeld made an important contribution to the field by describing a prominent and anteriorly displaced Schwalbe line (posterior embryotoxon) with the adhesion of peripheral iris strands. Later, these observations became known as the Axenfeld anomaly. Another significant advancement came from the Austrian ophthalmologist Herwigh Rieger, who described a distinct set of ocular abnormalities known as the "Rieger anomaly." This anomaly encompasses posterior embryotoxon, iris hypoplasia, polycoria, and corectopia.  The constellation of systemic findings in conjunction with Rieger anomaly, such as dental abnormalities, facial bone changes, umbilical abnormalities, hypospadias, and pituitary abnormalities, was called Rieger syndrome. In current medical terminology, the terms Axenfeld anomaly, Rieger anomaly, and Rieger syndrome are no longer used. Instead, these ocular findings and associated systemic manifestations are now recognized under a spectrum of disorders called Axenfeld-Riger syndrome (ARS).  ARS is a disease that encompasses anterior segment ocular dysgenesis and systemic abnormalities such as dental, cardiac, craniofacial, and abdominal wall defects. The mutations associated with ARS include PITX2 (chromosome 4q25), FOXC1 (chromosome 6p25), PAX6 (chromosome 11p13), FOXO1A (chromosome 13q14), and CYP1B1 (chromosome 2p22.2).

Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors FOXC1 or PITX2 are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The FOXC1 gene was most commonly found, followed by COL4A1, then PITX2. The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.

Axenfeld-Rieger syndrome (ARS) is a rare congenital disease that is primarily characterized by ocular anterior segment anomalies but is also associated with craniofacial, dental, cardiac, and neurologic abnormalities. Over half of cases are linked with autosomal dominant mutations in either FOXC1 or PITX2, which reflects the molecular role of these genes in regulating neural crest cell contributions to the eye, face, and heart. Within the eye, ARS is classically defined as the combination of posterior embryotoxon with iris bridging strands (Axenfeld anomaly) and iris hypoplasia causing corectopia and pseudopolycoria (Rieger anomaly). Glaucoma due to iridogoniodysgenesis is the main source of morbidity and is typically diagnosed during infancy or childhood in over half of affected individuals. Angle bypass surgery, such as glaucoma drainage devices and trabeculectomies, is often needed to obtain intraocular pressure control. A multi-disciplinary approach including glaucoma specialists and pediatric ophthalmologists produces optimal outcomes as vision is dependent on many factors including glaucoma, refractive error, amblyopia and strabismus. Further, since ophthalmologists often make the diagnosis, it is important to refer patients with ARS to other specialists including dentistry, cardiology, and neurology.

The purpose of this study was to compare the corneal endothelial characteristics in Axenfeld anomaly (AXA), Rieger anomaly (RGA), and Axenfeld-Rieger anomaly/syndrome with age-matched healthy controls. This is a retrospective, comparative case-control study of 52 eyes of 30 patients with AXA/RGA and AXA/S and 36 controls. Median age at endothelial imaging was 21.5 years (interquartile range, 13.8-33.3 years). In the study group, the mean endothelial cell density (ECD) was 2112.4 ± 78.5 cells/mm 2 , the mean cell area (MCA) was 526.9 ± 28.5 μm 2 , and the coefficient of variation of cell size was 41.2 ± 1.8%. The ECD was significantly (all, P < 0.0001) lower than controls, while MCA ( P < 0.0001), SD of cell size ( P < 0.0001), and maximum cell area ( P = 0.0007) were significantly higher than controls. Four eyes of 3 patients had guttae on slitlamp evaluation and endothelial imaging. There were no differences in the corneal endothelial characteristics among the clinical subtypes. Patients with AXA, RGA, and Axenfeld-Rieger anomaly/syndrome have lower ECD and increased MCA compared with normal eyes. The reduced ECD associated with inherent anterior segment alterations can predispose to the risk of postcataract surgery endothelial decompensation in these eyes. The association of guttae in some eyes needs further investigational studies.