Journal Article

Axenfeld-Rieger syndrome: more than meets the eye

Semina, Elena V., Vaneckova, Manuela, Costakos, Deborah, Reis, Linda M., Kremlikova Pourova, Radka, Shue, Ann, Levin, Alex V., Atilla, Huban, Lay-Son, Guillermo, Thompson, Samuel, Murray, Jeffrey C., Lowry, R. Brian, Jedlickova, Jana, Bachman, Kristine, Glaser, Thomas M, Skalicka, Pavlina, Trkova, Marie, Liskova, Petra, Black, Jennifer, Williams, Bradley, Maheshwari, Mohit, Seeley, Andrea H., Dudakova, Lubica, Lee, Joseph, Richard, Gabriele, Capasso, Jenina, Zitano, Lia

2023

Overview

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.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD
• Subject: Anterior Eye Segment - abnormalities / Brain diseases / congenital, hereditary, and neonatal diseases and abnormalities / Cysts / Dental enamel / Eye / Eye Abnormalities - diagnosis / Eye Abnormalities - genetics / eye diseases / Forkhead Transcription Factors - genetics / Genetic analysis / Genetic testing / genetics / genetics, medical / Genotype-phenotype correlations / Glaucoma / Hearing loss / Homeodomain Proteins - genetics / Humans / Hypoplasia / Localization / Mutation / Neuroimaging / Phenotypes / Substantia alba / Transcription factors / Transcription Factors - genetics