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Axenfeld-Rieger syndrome: more than meets the eye
LM. Reis, M. Maheshwari, J. Capasso, H. Atilla, L. Dudakova, S. Thompson, L. Zitano, G. Lay-Son, RB. Lowry, J. Black, J. Lee, A. Shue, R. Kremlikova Pourova, M. Vaneckova, P. Skalicka, J. Jedlickova, M. Trkova, B. Williams, G. Richard, K....
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
Grant support
R01 EY015518
NEI NIH HHS - United States
R01 EY025718
NEI NIH HHS - United States
UL1 RR031973
NCRR NIH HHS - United States
NLK
ProQuest Central
from 1994-01-01 to 6 months ago
Health & Medicine (ProQuest)
from 1994-01-01 to 6 months ago
- MeSH
- Eye Abnormalities * genetics diagnosis MeSH
- Forkhead Transcription Factors genetics MeSH
- Homeodomain Proteins * genetics MeSH
- Humans MeSH
- Mutation MeSH
- Anterior Eye Segment abnormalities MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Center for Development Behavior and Genetics SUNY Upstate Medical University Syracuse New York USA
Department of Cell Biology and Human Anatomy UC Davis School of Medicine Davis California USA
Department of Clinical Genetics Alberta Children's Hospital Calgary Alberta Canada
Department of Family Medicine McMaster University Hamilton Ontario Canada
Department of Medical Genetics Spectrum Health Grand Rapids Michigan USA
Department of Ophthalmology Medical College of Wisconsin Milwaukee Wisconsin USA
Department of Ophthalmology School of Medicine Ankara University Ankara Turkey
Department of Pediatrics Geisinger Medical Center Danville Pennsylvania USA
Department of Pediatrics University of Iowa Iowa City Iowa USA
GeneDx Gaithersburg Maryland USA
Gennet Centre for Fetal Medicine and Reproductive Genetics Prague Czech Republic
References provided by Crossref.org
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