Faculty Collaboration Database

Axenfeld-Rieger syndrome: more than meets the eye. J Med Genet 2023 Apr;60(4):368-379

Date

07/27/2022

Pubmed ID

35882526

Pubmed Central ID

PMC9912354

DOI

10.1136/jmg-2022-108646

Scopus ID

2-s2.0-85135137847 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

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 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.

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, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Author List

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 EV

Authors

Deborah M. Costakos MD Chair, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Mohit Maheshwari MD Professor in the Radiology department at Medical College of Wisconsin
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anterior Eye Segment
Eye Abnormalities
Forkhead Transcription Factors
Homeodomain Proteins
Humans
Mutation
Transcription Factors