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Abstract #104742 Published in IGR 23-2
Axenfeld-Rieger syndrome: more than meets the eye
Reis LM; Maheshwari M; Capasso J; Atilla H; Dudakova L; Thompson S; Zitano L; Lay-Son G; Lowry RB; Black J; Lee J; Shue A; Kremlikova Pourova R; Vaneckova M; Skalicka P; Jedlickova J; Trkova M; Williams B; Richard G; Bachman K; Seeley AH; Costakos D; Glaser TM; Levin AV; Liskova P; Murray JC; Semina EVJournal of Medical Genetics 2023; 60: 368-379
BACKGROUND: Axenfeld-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. METHODS: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses. RESULTS: 128 individuals with causative variants in or , including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for -related ARS. Systemic anomalies were seen in all individuals with -related ARS and the majority of those with -related ARS. -related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. -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 -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. CONCLUSION: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, -related ARS or -related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.
Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, Wisconsin, USA.
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