Axenfeld-Rieger syndrome: more than meets the eye

Abstract

BackgroundAxenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition.MethodsGenetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses.Results128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS.ConclusionSince clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Design and Outcomes of a Novel Multidisciplinary Ophthalmic Genetics Clinic

“…This did not reveal any additional pathogenic variants, suggesting the FOXC1 variant was the sole genetic cause of the patient’s disorder. The family was counseled that FOXC1 can be associated with hearing loss, brain anomalies, hypotonia, and failure to thrive in addition to ocular anomalies that would require continuous monitoring [ 15 ]. Heterozygous variants such as the one identified in both the patient and the patient’s mother have been associated with a spectrum of anterior-eye-segment defects, including Axenfeld–Rieger syndrome [ 15 ].…”

“…Genetic testing approaches, uptake, and results were evaluated for all patients with ocular findings who had been evaluated in the clinic (n = 71). Diagnostic rate was evaluated using established American College of Medical Genetics criteria, and compared to other published panel-based testing utilized by other practices, including the Oculome test, Cat-Map testing for cataracts, and anterior segment dysgenesis panel testing [ 14 , 15 , 16 , 17 ].…”

Snail Track Lesion with Flat Keratometry in Anterior Segment Dysgenesis Caused by a Novel FOXC1 Variant

“…We describe a patient with features of ASD caused by a novel de novo FOXC1 variant classified as pathogenic and predicted to cause loss of function. Given the frequency of whole FOXC1 gene deletions, haploinsufficiency is a clear mechanism for a FOXC1 -associated disease [ 4 ].…”

“…Dominantly inherited mutations in FOXC1 are associated with ASD type 3 (OMIM #601631) and Axenfeld-Rieger syndrome type 3 (OMIM #602482), characterized by additional systemic features of dental abnormalities, craniofacial dysmorphism, and hearing loss [ 3 , 4 ]. FOXC1 encodes Forkhead Box C1, which belongs to the human Forkhead-box (FOX) family, many of which play a vital role in neural crest differentiation [ 5 ].…”

CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements

“…Later, FOXC1 mutations were discovered in patients with aniridia, Peters anomaly and primary congenital glaucoma (PCG) [4][5][6]. Patients with mutations in FOXC1 often have additional nonocular anomalies, such as heart defects, craniofacial dysmorphisms, hearing loss, skeletal anomalies (hip dysplasia or scoliosis), feeding issues, dental enamel hypoplasia, hypotonia/delay, and white matter lesions in the brain [7][8][9][10][11]. Mutations in FOXC1 explain a high proportion of cases affected with ARS and related…”