Axenfeld-Rieger syndrome: more than meets the eye

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

doi:10.1136/jmg-2022-108646

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Axenfeld-Rieger syndrome: more than meets the eye

Journal article

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Axenfeld-Rieger syndrome: more than meets the eye

Linda M. Reis, Mohit Maheshwari, Jenina Capasso, Huban Atilla, Lubica Dudakova, Samuel Thompson, Lia Zitano, Guillermo Lay-Son, R. Brian Lowry, Jennifer Black, …

Journal of medical genetics, Vol.60(4), pp.368-379

04/01/2023

DOI: 10.1136/jmg-2022-108646

PMCID: PMC9912354

PMID: 35882526

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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.

congenital, hereditary, and neonatal diseases and abnormalities

eye diseases

genetics

genetics, medical

Genotype-phenotype correlations

Details

Title: Subtitle: Axenfeld-Rieger syndrome: more than meets the eye
Creators: Linda M. Reis - Children's Hospital of Wisconsin
Mohit Maheshwari - Children's Hospital of Wisconsin
Jenina Capasso - Golisano Children's Hospital
Huban Atilla - Ankara University
Lubica Dudakova - Charles University
Samuel Thompson - Children's Hospital of Wisconsin
Lia Zitano - Spectrum Health
Guillermo Lay-Son - Pontificia Universidad Católica de Chile
R. Brian Lowry - Alberta Children's Hospital
Jennifer Black - SUNY Upstate Medical University
Joseph Lee - McMaster University
Ann Shue - Stanford University
Radka Kremlikova Pourova - General University Hospital in Prague
Manuela Vaneckova - Charles University
Pavlina Skalicka - Charles University
Jana Jedlickova - Charles University
Marie Trkova - Czech Academy of Sciences, Institute of Molecular Genetics
Bradley Williams - GeneDx, Gaithersburg, Maryland, USA
Gabriele Richard - GeneDx, Gaithersburg, Maryland, USA
Kristine Bachman - Geisinger Medical Center
Andrea H. Seeley - Geisinger Medical Center
Deborah Costakos - Medical College of Wisconsin
Thomas M Glaser - University of California, Davis
Alex V. Levin - Golisano Children's Hospital
Petra Liskova - Charles University
Jeffrey C. Murray - University of Iowa
Elena V. Semina - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: Journal of medical genetics, Vol.60(4), pp.368-379
DOI: 10.1136/jmg-2022-108646
PMID: 35882526
PMCID: PMC9912354
NLM abbreviation: J Med Genet
ISSN: 0022-2593
eISSN: 1468-6244
Publisher: BMJ Publishing Group Ltd
Number of pages: 12
Grant note: 1UL1RR031973 / National Institutes of Health (http://dx.doi.org/10.13039/100000002) EY015518; EY025718 / National Eye Institute (http://dx.doi.org/10.13039/100000053)
Language: English
Date published: 04/01/2023
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9985034985602771

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