Clinical course during 40-year follow-up of Axenfeld-Rieger syndrome in a Japanese family.
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ABSTRACT:
SUBMITTER: Yoshida S
PROVIDER: S-EPMC2886229 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
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Clinical course during 40-year follow-up of Axenfeld-Rieger syndrome in a Japanese family.
Yoshida Shigeo S Miyazaki Aki A Ishikawa Keijiro K Ikeda Yasuhiro Y Fujisawa Kimihiko K Ishibashi Tatsuro T
Oman journal of ophthalmology 20100101 1
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Project description:PurposeAxenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder characterized by extraocular anomalies and developmental defects of the anterior segment. PITX2 (paired-like homeodomain transcription factor 2) is considered the major causative gene. In this study, we characterized the molecular defect in PITX2 in a Chinese family with ARS.MethodsTwo generations of the family with ARS were enrolled in the present study. In addition to ophthalmologic examinations, polymerase chain reaction (PCR) amplification and nucleotide sequencing of all coding exons of PITX2 were performed. Exon 5 (region 1) was also sequenced in 100 healthy controls unrelated to the family for comparison.ResultsA novel PITX2 mutation, c.840G>T, was identified in all affected members of the family with ARS that causes an amino acid substitution from tryptophan to cysteine at codon 86.ConclusionsWe found a novel p.W86C mutation in PITX2 in a Chinese family with ARS. The tryptophan residue at position 86 is strictly conserved in PITX2a proteins from several species and in homeodomain proteins. We suggest that this mutation in PITX2 is the cause of typical ARS in patients. Our results may be useful for better understanding of the spectrum of PITX2 mutations and the role of PITX2 in the development and progression of ARS.
| S-EPMC2592999 | biostudies-literature
Project description:ObjeciveTo describe the clinical and genetic findings of an Axenfeld-Rieger syndrome (ARS) family with a new PITX2 splicing mutation.MethodsA Chinese ARS family with five affected individuals was recruited. Exome sequencing was performed on the proband and the variant (C.253-9C > A) in PITX2 gene was detected as a pathogenic mutation. Sanger sequencing was performed for verification and cosegregation analysis. Real-time polymerase chain reaction (RT- PCR) and Western blotting were performed to verify the expression of the pathogenic gene.ResultsAll the patients showed abnormalities in the anterior segment of both eyes including posterior embryotoxon, corectopia, iris dysplasia, and iridocorneal tissue adhesions. In addition, they all presented systemic features, including maxillary hypoplasia, underbite, hypodontia, conical teeth. Only III-7 showed obvious umbilical skin. In the PITX2 family, we identified a novel heterozygous splicing mutation (C.253-9C > A) which was confirmed by Sanger sequencing to be completely cosegregated with the ARS phenotype. Real-time quantitative PCR and Western results showed that PITX2 mRNA and protein expression were significantly lower in patients compared with unrelated normal controls.ConclusionIn the ARS pedigree, we summarized the variable phenotype, described a novel PITX2 splicing mutation which expand the genetic spectrum of ARS. We further confirmed the possibility of development of ARS induced by this PITX2 gene deficiency.
| S-EPMC9813731 | biostudies-literature
Project description:Abstract Axenfeld-Rieger syndrome (ARS) is a rare congenital disease that is primarily characterized by ocular anterior segment anomalies but is also associated with craniofacial, dental, cardiac, and neurologic abnormalities. Over half of cases are linked with autosomal dominant mutations in either FOXC1 or PITX2, which reflects the molecular role of these genes in regulating neural crest cell contributions to the eye, face, and heart. Within the eye, ARS is classically defined as the combination of posterior embryotoxon with iris bridging strands (Axenfeld anomaly) and iris hypoplasia causing corectopia and pseudopolycoria (Rieger anomaly). Glaucoma due to iridogoniodysgenesis is the main source of morbidity and is typically diagnosed during infancy or childhood in over half of affected individuals. Angle bypass surgery, such as glaucoma drainage devices and trabeculectomies, is often needed to obtain intraocular pressure control. A multi-disciplinary approach including glaucoma specialists and pediatric ophthalmologists produces optimal outcomes as vision is dependent on many factors including glaucoma, refractive error, amblyopia and strabismus. Further, since ophthalmologists often make the diagnosis, it is important to refer patients with ARS to other specialists including dentistry, cardiology, and neurology.
| S-EPMC10013571 | biostudies-literature
Project description: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.
| S-EPMC9912354 | biostudies-literature
Project description:Axenfeld-Rieger syndrome (ARS) is an extremely rare autosomal dominant disorder characterized by ocular, craniofacial, dental and periumbilical abnormalities. We present a case of a 10-year-old boy. Its awareness among oral surgeons is essential for timely diagnosis and subsequent prevention of ophthalmic and systemic complications as craniofacial and dental features constitute the early recognizable symptoms of this syndrome. Systematic ophthalmic surgeries aid in relieving vision abnormalities, while symptomatic dental treatment should be provided for masticatory and esthetic rehabilitation.
| S-EPMC7410934 | biostudies-literature
Project description:Axenfeld-Rieger syndrome (ARS) is characterized by anomalies of the anterior segment of the eye and systemic abnormalities. Mutations in the FOXC1 and PITX2 genes are underlying causes of ARS, but there has been few reports on genetically confirmed ARS in Korea. We identified a novel PITX2 mutation (c.300_301delinsT) in 2 Korean patients from a family with ARS. We expand the spectrum of PITX2 mutations and, to the best of our knowledge, this is the first confirmed family of PITX2-related ARS in Korea.
| S-EPMC3756242 | biostudies-literature
Project description:AimTo describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family.MethodsPatients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene.ResultsGenome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family.ConclusionOur findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.
| S-EPMC5515146 | biostudies-literature
Project description:To describe a Chinese family with Axenfeld-Rieger syndrome (ARS) and report our novel genetic findings.Nine members of the same family underwent complete ophthalmologic examinations and genetic analysis. Genomic DNA was isolated from veinal blood and amplifed using PCR; the products of PCR were sequenced and compared with FOXC1 and PITX2 genes, from which the mutations were found.Through the ophthalmologic examinations, 8 subjects were diagnosed as ARS and 1 subject was normal. A homozygous mutation c.1139_1141dupGCG(p.Gly380_Ala381insGly) and a heterozygous mutation c.1359_1361dupCGG(p.Gly456_Gln457insGly) in FOXC1 were identified in all subjects. The mutation (c.-10-30T>C) was identified in PITX2 in subjects III-1 and III-3.We found novel gene mutations in a Chinese family with ARS, which provides us with a better understanding of the gene mutation spectrum of ARS and the assistance for the genetic counseling and gene-specific therapy in the future.
| S-EPMC5485333 | biostudies-other
Project description:BACKGROUND:The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS:Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1?year. The number of eyes with glaucoma (IOP???21?mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20?mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS:In 32 patients identified with ARS (median age at presentation 6.9?years, 0-58.7?years; median follow-up 5.4?years, 1.1-43.7?years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3?years (0-57.9?years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8?±?9.3?mmHg (median 20?mmHg, 4-45?mmHg) on 1.0?±?1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2?±?1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3?±?3.9?years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8?±?12.7?years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5?±?13.5?years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7?±?1.9?years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9?±?2.3?years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7?±?3.5?years of IOP control. At final follow-up, mean IOP (12.6?±?3.8?mmHg, median 11.8?mmHg, 7-19?mmHg) in glaucomatous eyes was significantly decreased (p?<?0.0001), but there was no difference in number of glaucoma medications (1.6?±?1.5, p?=?0.1). CONCLUSIONS:In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.
| S-EPMC7193416 | biostudies-literature
Project description:We encountered a case with congenital iris coloboma, omphalocele, and developmental delay with a 2.5 Mb deletion on chromosome 4q25 encompassing PITX2, leading to Axenfeld-Rieger syndrome (ARS), NEUROG2, and ANK2. ARS is characterized by the aplasia of the anterior eye, odontogenesis, and abdominal wall aplasia. In our case, iris coloboma and omphalocele were thought to be caused by PITX2 haploinsufficiency. However, these symptoms are nonspecific, and clinical symptoms alone can make it difficult to make a correct diagnosis. In addition, the genes responsible for developmental delay, among others, are not well understood. Developmental delay, in this case, might be caused due to NEUROG2 haploinsufficiency. In spite of the partial deletion of ANK2, the causative gene of long QT syndrome type 4, the electrocardiogram was normal. Genetic testing can lead to a correct diagnosis, and it may be effective in detecting complications.
| S-EPMC9935865 | biostudies-literature