Authors: Linda M Reis, Mohit Maheshwari, Jenina Capasso...

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.

Topics: Humans; Homeodomain Proteins; Transcription Factors; Anterior Eye Segment; Eye Abnormalities; Forkhead Transcription Factors; Mutation

PubMed: 35882526
DOI: 10.1136/jmg-2022-108646

Meta-Analysis Review

Authors: Marije E C Meuwissen, Dicky J J Halley, Liesbeth S Smit...

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.

Topics: Alleles; Anterior Eye Segment; Brain; Cerebral Hemorrhage; Cohort Studies; Collagen Type IV; Eye Abnormalities; Eye Diseases, Hereditary; Family; Gene Order; Genetic Association Studies; Genetic Loci; Genotype; Humans; Leukomalacia, Periventricular; Magnetic Resonance Imaging; Mutation; Pedigree; Phenotype; Porencephaly

PubMed: 25719457
DOI: 10.1038/gim.2014.210

Review

Authors: Logan Muzyka, Emily Winterhalter, Melissa A LoPresti...

Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors or are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The gene was most commonly found, followed by , then . The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.

PubMed: 37539177
DOI: 10.1016/j.heliyon.2023.e18225

Review

Authors: Curtis R French

Axenfeld-Rieger syndrome (ARS) encompasses a group of developmental disorders that affect the anterior segment of the eye, as well as systemic developmental defects in some patients. Malformation of the ocular anterior segment often leads to secondary glaucoma, while some patients also present with cardiovascular malformations, craniofacial and dental abnormalities and additional periumbilical skin. Genes that encode two transcription factors, and , account for almost half of known cases, while the genetic lesions in the remaining cases remain unresolved. Given the genetic similarity between zebrafish and humans, as well as robust antisense inhibition and gene editing technologies available for use in these animals, loss of function zebrafish models for ARS have been created and shed light on the mechanism(s) whereby mutations in these two transcription factors cause such a wide array of developmental phenotypes. This review summarizes the published phenotypes in zebrafish and loss of function models and discusses possible mechanisms that may be used to target pharmaceutical development and therapeutic interventions.

Topics: Animals; Anterior Eye Segment; Eye Abnormalities; Eye Diseases, Hereditary; Forkhead Transcription Factors; Humans; Transcription Factors; Zebrafish; Zebrafish Proteins

PubMed: 34576164
DOI: 10.3390/ijms221810001

Review

Authors: Zeynep Tümer, Daniella Bach-Holm

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, which encompasses a range of congential malformations affecting the anterior segment of the eye. ARS shows genetic heterogeneity and mutations of the two genes, PITX2 and FOXC1, are known to be associated with the pathogenesis. There are several excellent reviews dealing with the complexity of the phenotype and genotype of ARS. In this study, we will attempt to give a brief review of the clinical features and the relevant diagnostic approaches, together with a detailed review of published PITX2 and FOXC1 mutations.

Topics: Abnormalities, Multiple; Animals; Anterior Eye Segment; Forkhead Transcription Factors; Homeodomain Proteins; Humans; Mutation; Syndrome; Transcription Factors; Homeobox Protein PITX2

PubMed: 19513095
DOI: 10.1038/ejhg.2009.93

Review

Authors: B A Amendt, E V Semina, W L Alward...

Rieger syndrome (RIEG 1; MIM 180500) is an autosomal dominant disorder of morphogenesis. It is a phenotypically heterogeneous disorder characterized by malformations of the eyes, teeth, and umbilicus. RIEG belongs to the Axenfeld-Rieger group of anomalies, which includes Axenfeld anomaly and Rieger anomaly (or Rieger eye malformation), which display ocular features only. Recently, mutations in the homeodomain transcription factor, PITX2, have been shown to be associated with Rieger syndrome. This review discusses the clinical manifestations of Rieger syndrome and how they correlate with the current molecular and biochemical studies on this human disorder.

Topics: Abnormalities, Multiple; Amino Acid Sequence; Animals; DNA-Binding Proteins; Eye Abnormalities; Glaucoma; Homeodomain Proteins; Humans; Molecular Sequence Data; Nuclear Proteins; Paired Box Transcription Factors; Point Mutation; Prolactin; Promoter Regions, Genetic; Syndrome; Tooth Abnormalities; Transcription Factor Pit-1; Transcription Factors; Transcriptional Activation; Homeobox Protein PITX2

PubMed: 11092457
DOI: 10.1007/pl00000647

Review

Authors: Lin Zhou, Xiaoli Wang, Jingqi An...

PITX2 and FOXC1 are the most common pathogenic genes associated with Axenfeld-Rieger syndrome (ARS). In this study, we aimed to explore the variation spectrum of PITX2 and FOXC1 and their associated phenotype based on data from our study and previously reported literatures. Whole exome sequencing was performed on eight probands in our study. Multistep bioinformatic and co-segregation analyses were performed to detect pathogenic variants. Genotype-phenotype correlations of PITX2 and FOXC1 and the differences between them were determined. We detected three variants of FOXC1 and two variants of PITX2 in five unrelated families with ARS. Macular retinoschisis had been observed in AR1 with variant in PITX2 and it is not reported before. Additionally, a review of published literature and our study led to the identification of 593 families with variants of PITX2 or FOXC1, including 316 families with heterozygous variants in FOXC1, 251 families with heterozygous variants in PITX2, 13 families with variants in double genes, seven families with homozygous or compound heterozygous variants in FOXC1, and six families with variants in ADAMTS17, PRDM5, COL4A1 or CYP1B1. Significant differences were observed between the prevalence of missense and in-frame, truncation, and large deletion variants in PITX2 (32.00%, 42.67%, and 25.33%, respectively) and FOXC1 (34.49%, 35.13%, 30.38%, respectively) (p = 1.16E-43). Enrichment and frequency analyses revealed that missense variants were concentrated in the forkhead domain of FOXC1 (76.14%) and homeodomain of PITX2 (87.50%). The percentage of Caucasians with variants in FOXC1 was significantly higher than that of PITX2 (p = 2.00E-2). Significant differences between PITX2 and FOXC1 were observed in glaucoma (p = 3.00E-2), corectopia (p = 3.050E-6), and polycoria (p = 5.21E-08). Additionally, we observed a significant difference in best-corrected visual acuity (BCVA) between FOXC1 and PITX2 (p = 3.80E-2). Among all the family members with PITX2 or FOXC1 variants, the prevalence of systemic abnormalities was significantly higher in PITX2 than in FOXC1 (89.16% vs. 58.77%, p = 5.44E-17). In conclusion, macular retinoschisis as a novel phenotype had been observed in patient with variant in PITX2. Significant differences were detected in phenotypes and genotypes between PITX2 and FOXC1.

Topics: Eye Abnormalities; Eye Diseases, Hereditary; Genetic Association Studies; Pedigree; Humans; Anterior Eye Segment; Homeobox Protein PITX2; Homeodomain Proteins; Retinoschisis; Mutation; Forkhead Transcription Factors

PubMed: 36442680
DOI: 10.1016/j.exer.2022.109307

Authors: Ryan C Higgins, Christopher M Bingcang, Jayme R Dowdall...

PubMed: 38321760
DOI: 10.1177/01455613241229955