Clinical features and genetic variations of Axenfeld-Rieger syndrome / 中华实验眼科杂志

Axenfeld-Rieger syndrome is a rare autosomal dominant hereditary disease characterized by anterior segment dysgenesis, which may be accompanied by various systemic defects, including craniofacial dysmorphism, hypodontia, microdontia, and redundant periumbilical skin.Its typical ocular manifestations include posterior embryotoxon, iris hypoplasia, peripheral anterior synechiae, corectopia and polycoria with a high prevalence of glaucoma.Patients can exhibit any combination of these features.However, family members with the same genotype may present different phenotypes due to phenotypic heterogeneity.Emerging evidence suggests that PITX2 and FOXC1 genes encoding transcription factors are primarily associated with genetic variants in ARS.Intragenic mutations and gene deletions are common types of genetic variations suspected to trigger changes in gene dosages and protein function.However, the underlying molecular mechanism remains unclear.Some patients with ARS carry mutations in the COL4A1, PRDM5, and CYP1B1 genes, but the pathogenicity of these variations has yet to be confirmed by further studies.This article provided an overview of the typical clinical features, potential correlations between phenotype and genotype, as well as gene function.

Axenfeld-Rieger syndrome � report of a rare case and review

A typical case of Axenfeld-Rieger syndrome (ARS), a rare autosomal dominant condition manifesting with ocular, craniofacial, and dental abnormalities, is presented. The patient showed dental features such as oligodontia, microdontia, abnormally shaped teeth, hyperplastic maxillary labial frenum, and maxillary retrognathism. Early diagnosis of the syndrome from its dentofacial manifestations and a multidisciplinary approach is required for the management of patients with ARS.

Axenfeld-Rieger Syndrome: Case Report

Aims:To describe a Axenfeld-Rieger Syndrome.Presentation of Case: MCL, 7 years old, female, brown, was taken to the ophthalmology outpatient clinic of the Hospital Universit醨io Ant鬾io Pedro, Brazil by her parents, complaining of low visual acuity and malformation of the pupil perceived since birth.Discussion: Axenfeld-Rieger Syndrome is a rare and hereditary disease. Clinically, Axenfeld's anomaly is characterized by the presence of posterior embryotoxon, and there may be adherence of iridian tissue in its periphery. In addition to Rieger's anomaly, posterior embryotoxon is added to iris hypoplasia and iris thickness defects, uveal ectropion and pupillary alterations, such as corectopia. Rieger's syndrome is associated with extraocular changes, of which hypodontia, myicrodontia, maxillary hypoplasia, telecanthus, hypertelorism and hypospadias stand out.Conclusions: Therefore, the importance of early diagnosis, follow-up and adequate treatment becomes evident in order to preserve the visual function of patients and thus avoid an unfavorable evolution.

Síndrome de Axenfeld-Rieger con glaucoma asociado / Axenfeld-Rieger syndrome associated with glaucoma

El síndrome de Axenfeld-Rieger es una enfermedad congénita que puede estar asociada a glaucoma en el 50 por ciento de los casos. Por esta razón se describen un caso clínico con síndrome de Axenfeld-Rieger y glaucoma bilateral. Se trata de un paciente masculino de 18 años con escleras azules, microcórnea, embriotoxon posterior, aniridia parcial, atrofia sectorial del iris y alteraciones sistémicas asociado a glaucoma, al que se decide realizar trabéculo-trabeculectomía en ambos ojos. Al mes de la cirugía se constata un aumento de las presiones intraoculares del ojo izquierdo y se realiza trabéculo-trabeculectomía con mitomicina C, posteriormente se hace necesario implantar válvula de Ahmed con mitomicina C en dicho ojo e implantar dispositivo de molteno en ojo derecho, el cual necesitó revisión con aguja y administración de mitomicina C para mantener presiones intraoculares dentro de límites normales con tratamiento médico asociado en ojo izquierdo(AU)

Axenfeld-Rieger syndrome is a congenital disease that can be associated with glaucoma in 50 percent of cases. For this reason, a clinical case with Axenfeld-Rieger syndrome and bilateral glaucoma is described. This is an 18-year-old male patient with blue sclera, microcornea, posterior embryotoxon, partial aniridia, sectorial atrophy of the iris, and systemic alterations associated with glaucoma, who decided to perform trabeculo-trabeculectomy in both eyes. One month after surgery, an increase in intraocular pressures in the left eye was observed and a trabeculo-trabeculectomy was performed with mitomycin C, subsequently it was necessary to implant Ahmed's valve with mitomycin C in said eye and implant a molteno device in the right eye, the which required revision with a needle and administration of mitomycin C to maintain intraocular pressures within normal limits with associated medical treatment in the left eye(AU)

Screening of pathogenic mutation in a family with Axenfeld-Rieger syndrome by whole exome sequencing / 中华实验眼科杂志

Objective:To identify disease-causing variation in a Chinese family with Axenfeld-Rieger syndrome (ARS) through the analysis of clinical symptoms and hereditary information.Methods:The method of pedigree investigation was adopted.A Chinese ARS family including 15 family members of 3 generations was recruited in the Second Affiliated Hospital of Harbin Medical University in 2018.There were 3 patients in the family.The family history and clinical data were collected.Ophthalmic and general examinations were carried out in all the members included.DNA and RNA were extracted from collected peripheral venous blood samples of 2-5 ml from each member.Whole exome sequencing was used to screen the variations in the proband.Suspected variations screened through searching population databases and bioinformatics analysis were verified by Sanger sequencing and real-time quantitative PCR.Conservation analysis and deleteriousness prediction of suspected variations were conducted.The pathogenecity of candidate rare variations were evaluated according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.This study followed the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (No.KY2019-231).Written informed consent was obtained from each subject or custodian prior to entering the study cohort.Results:The 3 patients all had typical ARS clinical features in eyes, teeth and umbilicus, and carried the same heterozygous variant, c.525delC (p.Asp175Glufs *) in the PITX2 gene, which were not found in other members, indicating co-segregation.The relative expression of PITX2 mRNA was 0.672±0.063 in the patients, which was significantly lower than 1.015±0.179 in the healthy controls ( t=8.847, P<0.001).This variant was not recorded in dbSNP, 1000G, gnomeAD, ExAC, Korea1K and EVS databases, and it was labelled as deleterious by MutationTaster.The affected conservative amino acid sequences were found in 9 species.The variant was determined as pathogenic according to the ACMG standards and guidelines. Conclusions:The c.525delC (p.Asp175Glufs *) mutation of PITX2 gene is pathogenic in the pedigree.This is the first time that this mutation has been reported in Chinese family with ARS.

A clinical analysis on 15 cases of Axenfeld-Rieger syndrome associated with secondary glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the clinical features of Axenfeld-Rieger syndrome associated with secondary glaucoma and its surgical treatment. <p>METHODS: It was a retrospective case series study. The general clinical data and related ocular manifestations in 15 patients(26 eyes)with Axenfeld-Rieger syndrome associated with secondary glaucoma in our hospital from January 2003 to January 2016 were collected and analyzed retrospectively. <p>RESULTS: Age of the patients ranged from 3-month to 43 years old, and the median age was 11 years old. There were of all 11 patients(73%)had bilateral glaucoma and 4(27%)had unilateral glaucoma. In the aspect of clinical features, hypoplasia or deficiency of the iris was found in 20 eyes(77%), peripheral iridocorneal adhesions was found in 17 eyes(65%)in various extent, and pupil distortion or multiple-pupil was found in 14 eyes(54%); Also posterior embryotoxon was found in 14 eyes(54%)as well; And 11 eyes(42%)had anomalies in corneal size. That root of iris is located at a more anterior position than that of a normal eye was found in all affected eyes by gonioscopy, coupled with different extent of angle synechiae-closure. According to the data, in 15 patients only two had a family history of ARS, while 5 had systematic abnormalities, eyes excepted, in dental, maxillary, cardiovascular, <i>et al</i>. Anti-glaucoma surgeries including trabeculotomy, trabeculectomy, glaucoma valve implantation were performed in 20 eyes. Nine patients(11 eyes)were followed up for 59mo on average. Intraocular pressure was significantly lower than pre-operation(<i>t</i>=2.4185, <i>P</i>=0.0362), and intraocular pressure in 7 followed-up eyes was controlled ≤21mmHg. The long-term success rate of surgery was 64%. <p>CONCLUSION: The clinical features of Axenfeld-Rieger syndrome associated with secondary glaucoma were diverse. The patients might concomitant with other systematic dysplasia. Although it was tough to treat, surgery for glaucoma could reduce the intraocular pressure effectively.

Genotype-phenotype analysis in Peters' anomaly patients with PITX2 and PAX6 genes / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To analyze the clinical characteristics of patients with Peters' anomaly(PA)in Chinese, and to study the variation of PITX2 and PAX6 genes in patients with PA, so as to provide basis for clinical diagnosis and pathogenesis of this rare ophthalmopathy.<p>METHODS: Fifteen patients with PA were selected from 2016 to 2019 in Changzhou No. 2 People's Hospital and Changzhou No. 3 People's Hospital, and the detailed clinical data were collected. Genomic DNA was prepared from venous leukocytes after obtaining the consent of the patients and their family members. The coding regions and the flanking exon-intron junctions of the PITX2 and PAX6 genes were amplified by polymerase-chain reaction(PCR)and subsequently analyzed by direct sequencing. Variations detected were further evaluated in any unaffected member and 80 normal controls by HA-SSCP. Analyzing and comparing the mutation of PITX2 and PAX6 genes and the related phenotypes in Chinese patients with PA.<p>RESULTS:Sequence analysis of the PITX2 gene revealed one novel mutation c.296delG(P.R99fsx56)in fifteen patients with PA. Nucleotide sequence analysis showed that this mutation led to the functional abnormal of this gene. The clinical characteristics of the mutant patient were analyzed, the right eye of the patient was diagnosed as Axenfeld-Rieger syndrome(ARS), and the left eye was diagnosed as Peters'anomaly. However, the mutation was not found in the family members of the patient's parents and unrelated normal controls, and therefore it was a de novo mutation. No mutation was found in PAX6 gene mutation screening.<p>CONCLUSION: A novel PITX2 gene mutation was detected in 15 patients with PA, which was the first report of PITX2 gene mutation in a patient with Peters'anomaly complicated with ARS in China. The results enrich the mutation spectrum of PITX2 gene and further clarify the clinical characteristics of PA complicated with ARS. All these will be useful foundations for clinical diagnosis and pathogenesis. Furthermore, it enriches our knowledge of genotype-phenotype relationship of PA. In addition, our results may provide basis for the functional and genomic study of the pathogenesis of the disease in the future.

Insuficiencia mitral moderada progresiva en un niño con síndrome de Axenfeld-Rieger: Importancia del seguimiento cardiológico / Progressive moderate mitral regurgitation in a children with Axenfeld-Rieger syndrome: The importance of cardiologic follow up

El síndrome de Axenfeld-Rieger es una enfermedad congénita con una prevalencia estimada de 1 cada 200 000 individuos. La afectación oftálmica con la disgenesia del segmento anterior es la que define la enfermedad. Se puede presentar desde el período neonatal. Se asocia con afectaciones extraoculares, como dismorfismo craneal y anomalías maxilofaciales o dentarias; otras manifestaciones menos frecuentes son las cardiológicas o hipofisarias. La aparición de cardiopatia no congénita en el síndrome de Axenfeld-Rieger ha sido descrita en muy pocos casos en la literatura. Presentamos un paciente de 7 años de edad que presentó síndrome de Axenfeld-Rieger, con insuficiencia mitral ligera desde los 3 años que progresó a insuficiencia mitral moderada en la actualidad. El seguimiento cardiológico estaría indicado en pacientes con síndrome de Axenfeld-Rieger.

Axenfeld-Rieger syndrome is a congenital disease with an estimated prevalence of one in 200,000 individuals. This is an ophthalmic disorder related to anterior segment dysgenesis, which may be present from the neonatal period. It is associated with extraocular affectations such as cranial dimorphism, maxillofacial or dental anomalies. Cardiological or pituitary manifestations are less common. The congenital heart disease in Axenfeld-Rieger syndrome has been described in very few cases in the literature. We report a 7-year-old patient with Axenfeld-Rieger syndrome and mild mitral insufficiency since the age of 3 years, which is progressing to moderate mitral regurgitation at the present time. The cardiologic follow up may be indicated in patients with Axenfeld-Rieger syndrome.

A Family with Axenfeld-Rieger Syndrome: Report of the Clinical and Genetic Findings

PURPOSE: To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. METHODS: A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. RESULTS: The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. CONCLUSIONS: This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome.

Novel occurrence of Axenfeld: Rieger syndrome in a patient with blepharophimosis ptosis epicanthus inversus syndrome.

is a complex eyelid malformation characterized by the classical tetrad of blepharophimosis, telecanthus, ptosis, and epicanthus inversus. It has been reported to be associated with other ocular anomalies such as euryblepharon, strabismus, nystagmus, amblyopia, microphthalmos, lacrimal drainage apparatus abnormality, extra ocular muscle abnormalities, microcornea, trabecular dysgenesis, optic nerve hypoplasias, and colobomas of the optic disk. We describe a case of BPES with Axenfeld–Rieger syndrome, a neurocristopathy characterized by maldevelopment of the anterior segment with predisposition to development of glaucoma. Interestingly, both syndromes are caused by mutations in the same class of genes, namely the winged‑helix/ forked transcription factors (FOX) involved in a variety of developmental processes.

Glaucoma en anomalía de Rieger / Glaucoma in Rieger's anomaly

Se describe un caso clínico con diagnóstico de anomalía de Rieger con embriotoxon posterior, adherencias iridocorneales, corectopia, atrofia sectorial del iris, goniodisgenesia y glaucoma bilateral no asociado a alteraciones sistémicas. Se decide realizar trabeculo-trabeculectomía con Mitomicina C. en ambos ojos manteniéndose compensado hasta el año de la cirugía con posterior adelgazamiento de la bula de filtración y salida de humor acuoso de ojo izquierdo con notable disminución de la presión intraocular, decidiéndose realizar reconstrucción de bula de filtración. Al mes de la cirugía las presiones intraoculares comenzaron a elevarse, encontrándose en estos momentos compensadas con dorzolamida colirio

A clinical case, who was diagnosed with Rieger's anomaly with later embriotoxon, iridocorneal adhesions, corectopia, sectoral atrophy of the iris, goniodysgenesis and bilateral glaucoma unrelated to systemic alterations, was described. The performance of trabeculo-trabeculectomy with Mitomycin C was decided for both eyes. The case remained compensated till one year after surgery, when there occurs thinning of the filtration bulla and aqueous humor discharge from the left eye in addition to remarkable decrease of intraocular pressure. It was then decided to reconstruct the filtering bulla. One month after surgery, the intraocular pressure began rising and they are presently compensated with the use of dorzolamide drops

Novel c.300_301delinsT Mutation in PITX2 in a Korean Family with Axenfeld-Rieger Syndrome

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.

Unusual presentation in Axenfeld-Rieger syndrome.

We report an unusual presentation of a case of Axenfeld-Rieger (A-R) syndrome. A 14-year-old male presented with gradual dimness of vision for 1 year and redness of left eye for 3 days. The patient had megalocornea with Haab's striae in the right eye and posterior embryotoxon in both the eyes. In the left eye, there was a white cord-like structure traversing the anterior chamber with adhesions to iris tissue along its course. On two antiglaucoma medications, his intraocular pressure (IOP) was 22 mm Hg in the right eye and 18 mm Hg in the left eye. Gonioscopy revealed a cord-like structure originating at the level of Schwalbe's line. He underwent right eye trabeculectomy with mitomycin-C. This case highlights a rare presentation of a strange cord-like structure, a rare presentation of A-R syndrome.

Anomalous Scleral Insertion of Superior Oblique in Axenfeld-Rieger Syndrome

Axenfeld-Rieger syndrome (ARS) is associated with ocular and systemic anomalies. PITX2 is known to be a major controlling gene in the pathogenesis of ARS and is associated with differentiation in both the neural crest and mesoderm during eye development. A 4-year-old girl with bilateral ARS had 20 prism diopters (PD) of exotropia with 30PD of A- pattern deviation, more than 20PD of dissociated vertical deviation (DVD), and severe superior oblique overaction (SOOA). During surgery we observed that the SO inserted more posteriorly than normal. We believe this finding is one of the abnormal manifestations of the development of the extraocular muscles in ARS.

A Case of Axenfeld-Rieger Syndrome with Severe Mitral Regurgitation

Axenfeld-Rieger syndrome is a rare autosomal dominant inherited developmental disorder characterized by ocular and systemic abnormalities. In ocular anomaly, it includes a prominent and anteriorly displaced Schwalbe line and an iridocorneal synechiae, iris hypoplasia, corectopia and secondary glaucoma. Extraocular developmental abnormalities of the syndrome are hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. We herein reported a familial case of Axenfeld-Rieger syndrome that had a mitral valve prolapse with severe mitral regurgitation finally requiring mitral valve replacement.