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Background: Axenfeld-Rieger syndrome (ARS, OMIM:602482) is a genetic disease characterized by ocular and systemic features. Clinical features of ARS are highly variable among patients and associated with mutations of human PITX2 and FOXC1 genes. Herein, we present an ARS in two cases (proband and his mother) with a novel variant in the PITX2. Methods: A 3-month-old boy was admitted with an abnormal eye development at birth. Physical examination and ophthalmologic examination findings revealed an abnormal development of the anterior segments, ectropion of redundant skin in the umbilicus, single-sided deafness, teeth eruption failure, patent foramen ovale, and a mid-facial flattening. The proband's mother has been blind since the age of 12. We conducted genetic tests for the family via whole exome sequencing (WES) and quantitative PCR (qPCR) to identify the genetic etiology in the family. We also conducted a retrospective review of the ARS type I phenotype caused by the PITX2 mutations. Results: WES and qPCR results of the proband and his parents suggested that both the child and his mother carry a 1.31kbp deletion (chr4: g.111538559_111539864del [GRCh37]) spanned the exon 4 of PITX2, resulting in the typical and rare phenotype of ARS type I. It can conclude that truncating variants in the exon 3-4 of PITX2 are the more common mechanism to cause the malfunction of the gene with a broader phenotypic spectrum. Conclusion: The study has filled in a new clinical manifestation of the PITX2 and enriched the phenotype of ARS. The retrospective analysis of phenotype of PITX2 mutations provided a comprehensive understanding of the disease. [ABSTRACT FROM AUTHOR]

Background: The main features of Axenfeld–Rieger Syndrome (ARS) are ocular, auditory, neurological, and morphological brain abnormalities. Mutations in forkhead box protein C1 (FOXC1) are among the responsible genes causing ARS, but neuropsychiatric features have rarely been reported. The case of an ARS patient (a 77‐year‐old man) with delusions of jealousy and impairment of working memory, in addition to the main clinical features, glaucoma and leukoencephalopathy, is presented. Methods: The mutation in the patient's genome was found with whole exome sequencing and in silico analysis using PolyPhen‐2 and SIFT. Furthermore, AlphaFold2 and PyMOL were used to predict the protein structure based on the mutation. Results: A novel mutation at the forkhead domain of FOXC1 gene (c.408C>A, p.Phe136Leu) was found and confirmed in the patient's family, and it was predicted to cause protein damage; the SIFT score was 0, meaning deleterious, and the PolyPhen2 result also indicated damaging (score: 0.997). The predicted protein structure based on the novel mutation was different from that of the native structure. In the literature review, 6 of 95 (6.3%) cases showed neuropsychiatric features. Of them, 5 of 6 (83.3%) mutations were located in the forkhead domain. Conclusion: A novel mutation was found in the FOXC1 gene (c.408C>A, p.Phe136Leu), which possibly induces delusions of jealousy and impairment of working memory, as well as features of ARS, by changing the protein structure. Mutations in that domain of the FOXC1 gene may be important not only for ocular abnormalities but also for brain function. [ABSTRACT FROM AUTHOR]

Abstract Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld–Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes.

(1) Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, the symptoms of which include both ocular and systemic abnormalities. In the studied subjects, the cornea was significantly opacified with peripheral scarring neovascularization, which is not specific to this syndrome. A suspicion of incorrect diagnosis was raised despite an initial diagnosis of a bilateral Chandler syndrome. (2) In order to provide the proper diagnosis, a DNA sequencing genetic test was conducted with three sisters carrying the presence of a genome imbalance in the FOXC1 gene. The aim of this study is to report a case of a Polish family with a novel gene mutation and its relation with ARS. (3) Our findings implicate the novel deletion of the FOXC1 gene in the pathogenesis of ARS in the affected family. The phenotypic variability observed, including differences in corneal and systemic anomalies, underscores the importance of genetic testing and suggests the influence of non-genetic factors on ARS manifestation. [ABSTRACT FROM AUTHOR]

Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld–Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The main features of Axenfeld–Rieger Syndrome (ARS) are ocular, auditory, neurological, and morphological brain abnormalities. Mutations in forkhead box protein C1 (FOXC1) are among the responsible genes causing ARS, but neuropsychiatric features have rarely been reported. The case of an ARS patient (a 77‐year‐old man) with delusions of jealousy and impairment of working memory, in addition to the main clinical features, glaucoma and leukoencephalopathy, is presented. Methods The mutation in the patient's genome was found with whole exome sequencing and in silico analysis using PolyPhen‐2 and SIFT. Furthermore, AlphaFold2 and PyMOL were used to predict the protein structure based on the mutation. Results A novel mutation at the forkhead domain of FOXC1 gene (c.408C>A, p.Phe136Leu) was found and confirmed in the patient's family, and it was predicted to cause protein damage; the SIFT score was 0, meaning deleterious, and the PolyPhen2 result also indicated damaging (score: 0.997). The predicted protein structure based on the novel mutation was different from that of the native structure. In the literature review, 6 of 95 (6.3%) cases showed neuropsychiatric features. Of them, 5 of 6 (83.3%) mutations were located in the forkhead domain. Conclusion A novel mutation was found in the FOXC1 gene (c.408C>A, p.Phe136Leu), which possibly induces delusions of jealousy and impairment of working memory, as well as features of ARS, by changing the protein structure. Mutations in that domain of the FOXC1 gene may be important not only for ocular abnormalities but also for brain function.

Anterior segment dysgeneses are congenital ocular anomalies that involve the cornea, iris, anterior chamber, iridicorneal angle structures, and ciliary body. Management highly varies and often depends on the extent of cornea and lens involvement and glaucoma diagnosis. A coordinated approach between pediatric ophthalmology, cornea, retina, and glaucoma specialists may be required to minimize complications and optimize results. A review of the clinical findings of primary congenital glaucoma, congenital aniridia, Axenfeld-Rieger syndrome, Peters anomaly, sclerocornea, congenital ectropion uvea, and megalocornea/megalophthalmos will be followed by the current management of these diseases. For optimal outcomes, these diseases often require a multi-specialty approach incorporating glaucoma, cornea, and retina specialists with pediatric ophthalmologists. However, there is a critical shortage of pediatric ophthalmologists and few adult sub-specialists have an interest and desire to incorporate children into their practices. A greater emphasis on pediatric eye diseases during training and exposure to anterior segment dysgeneses is needed to provide the optimal care for these rare conditions. [ABSTRACT FROM AUTHOR]

Axenfeld‐Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes. [ABSTRACT FROM AUTHOR]

Background: AxenfeldRieger syndrome is a genetically heterogeneous group of morphogenesis disorders associated with abnormal development of the anterior segment of the eye, teeth, the organ of hearing, and abdominal region. Сongenital glaucoma, which is refractory to standard methods of treatment due to pronounced changes in the structures of the anterior segment of the eyeball and other comorbidities, is frequent manifestation of this syndrome. There are several methods for treating glaucoma in patients with AxenfeldRieger syndrome: sinus trabeculectomy, implantation of drainage devices and transscleral cyclocoagulation. Сlinical case description: A patient with congenital glaucoma associated with AxenfeldRieger syndrome underwent sinus trabeculectomy with posterior scleral trepanation in the right eye and valve drainage implantation in the left eye at the S. Fyodorov Eye Microsurgery Federal State Institution, Moscow due to the intraocular pressure decompensation. In the postoperative period, an encapsulated cyst around the body of the drainage was detected, and then a revision of the operation area was performed. After the anti-glaucoma operations, the intraocular pressure compensation was achieved in the follow-up period up to 9 months. Conclusion: Depending on the degree of the changes in the anterior chamber angle structures, sinus trabeculectomy or valve drainage implantation are the methods of choice for the surgical treatment aimed at the intraocular pressure compensation and visual function preservation in patients with Axenfeld-Rieger syndrome.

Objectives: To investigate the detailed ultrastructural patterns of dental abnormalities affected by Axenfeld‐Rieger syndrome (ARS) with a heterozygous microdeletion involving paired‐like homeodomain 2 (PITX2) and explored the underlying molecular mechanisms driving enamel defects. Subjects and methods: Sanger sequencing, genomic quantitative PCR analysis, and chromosomal microarray analysis (CMA) were used to screen the disease‐causing mutation in one ARS proband. An exfoliated tooth from an ARS patient was analyzed with scanning electron microscopy and micro–computerized tomography. A stable Pitx2 knockdown cell line was generated to simulate PITX2 haploinsufficiency. Cell proliferation and ameloblast differentiation were analyzed, and the role of the Wnt/β‐catenin pathway in proliferation of ameloblast precursor cells was investigated. Results: An approximately 0.216 Mb novel deletion encompassing PITX2 was identified. The affected tooth displayed a thinner and broken layer of enamel and abnormal enamel biomineralization. PITX2 downregulation inhibited the proliferation and differentiation of inner enamel epithelial cells, and LiCl stifmulation partially reversed the proliferation ability after Pitx2 knockdown. Conclusions: Enamel formation is disturbed in some patients with ARS. Pitx2 knockdown can influence the proliferation and ameloblast differentiation of inner enamel epithelial cells, and PITX2 may regulate cell proliferation via Wnt/β‐catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of Axenfeld-Rieger and Stickler Syndrome in a pediatric patient. Observations: A 3-month-old male was referred to the glaucoma clinic after he was noted to have elevated intraocular pressures in both eyes. His family history was notable for infantile glaucoma on his maternal side and retinal detachment on his paternal side. He was found to have anterior segment dysgenesis with iris strands, iridocorneal adhesions, and corectopia, as well as veil-like vitreous in both eyes. He required trabeculotomy, goniotomy, and multiple Baerveldt glaucoma implants in both eyes to achieve intraocular pressure control. Furthermore, the patient later developed macula-involving retinal detachments in both eyes, requiring pars plana vitrectomy with silicone oil tamponade. Genetic analysis confirmed heterozygous pathogenic variants in both the FOXC1 and COL2A1 genes, leading to the concurrent diagnoses of Axenfeld-Rieger and Stickler syndromes. Conclusions and importance: This is a rare case of a patient with concurrent Axenfeld-Rieger and Stickler syndromes. The severity of pathology in both the anterior and posterior segments required a collaborative multidisciplinary approach. In the diagnostic evaluation of congenital eye diseases, if there is strong family history of atypical findings for a given diagnosis, concurrent syndromes should be considered and ruled out. A comprehensive eye genetics panel may be a useful tool in these cases.

Axenfeld–Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld–Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. USP9X and JAG1 explained three families each. USP9X was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy–Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with FOXC1-ARS. Anterior segment anomalies are not currently associated with USP9X, yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in CDK13, BCOR, and an X chromosome deletion encompassing HCCS and AMELX (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for PITX2/FOXC1 sequencing and copy number analysis, with attention to the described genes/regions. [ABSTRACT FROM AUTHOR]

Axenfeld–Rieger syndrome (ARS) is a rare autosomal-dominant neurocristopathy that presents with a variety of classical ocular and systemic findings. The pathophysiology of the disease involves anterior segment dysgenesis, and patients may present with ophthalmic complications early in life, including secondary glaucoma, high refractive errors, amblyopia, and permanent visual damage. There are a limited number of studies in the literature that focus primarily on pediatric patients with ARS. The purpose of this article was to review the current literature on clinical presentation, genetic associations, diagnosis, secondary complications, and treatment of ARS in pediatric patients. Evaluating the essential clinical aspects of the disease in children may allow for earlier diagnosis and treatment and prevent visual morbidity from amblyopia and secondary glaucoma that may result in permanent visual damage. [ABSTRACT FROM AUTHOR]

Axenfeld-Rieger syndrome (ARS) is a rare disease characterized by anterior segment anomalies with or without glaucoma. A 28-year-old antenatal female diagnosed with ARS presented with uncontrolled intraocular pressures (IOPs) and advanced glaucoma despite maximal medical therapy and progressive vision loss during her third trimester. The refractory and progressive nature of the disease, with useful vision in one eye, necessitated immediate surgical intervention, following which there was successful control of IOP, lasting till the final follow-up at 18 months. We discuss the role of glaucoma surgery, for an ARS patient with refractory glaucoma during the third trimester with a comprehensive review of literature. [ABSTRACT FROM AUTHOR]

We aimed to characterize the genetic basis and craniofacial and dental features of Finnish patients with Axenfeld‐Rieger syndrome (ARS). Mutational analyses of seven patients in five families were performed by sequencing or comparative genomic hybridization. Phenotypic analysis was based on both clinical and radiographic examinations, as well as on medical data. Lateral cephalometric radiographs of five patients were analysed using Viewbox 3.1‐Cephalometric Software. The cephalometric values were compared to Finnish population‐standard values of the same age and gender. Two frameshift mutations and three whole gene deletions were detected in five families. Class III skeletal relationship with retrognathic maxilla and mildly retrognathic mandible were detected in all five patients studied. Significant differences compared with the control values were in SNA (P =.0014), ANB (P =.0043) and SNB angles (P =.013). Five patients had anterior crossbite. Six patients showed tooth agenesis. The average number of missing teeth (third molars excluded) was 9 (range 0‐15). The tooth agenesis rate was 52% in maxilla and 26% in mandible. Maxillary central and lateral permanent incisors were most often missing (rate 71% equally) while no one lacked canines or first molars in mandible. Two patients had a supernumerary mandibular permanent incisor. Six patients had either taurodontic and/or single‐rooted molars. Our results suggest that class III skeletal relationship with maxillary and mandibular retrognathism, anterior crossbite, maxillary incisor agenesis and taurodontic, even pyramidal, roots are common determinants of ARS caused by PITX2 mutations. [ABSTRACT FROM AUTHOR]

Kristi Michels,1 Brenda L Bohnsack2 1Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USACorrespondence: Brenda L Bohnsack, Email bbohnsack@luriechildrens.orgAbstract: 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.Keywords: Axenfeld-Rieger syndrome, Axenfeld anomaly, Rieger anomaly, glaucoma, posterior embryotoxon, iris hypoplasia

Axenfeld–Rieger syndrome (ARS) is a rare disease characterized by anterior segment anomalies with or without glaucoma. A 28-year-old antenatal female diagnosed with ARS presented with uncontrolled intraocular pressures (IOPs) and advanced glaucoma despite maximal medical therapy and progressive vision loss during her third trimester. The refractory and progressive nature of the disease, with useful vision in one eye, necessitated immediate surgical intervention, following which there was successful control of IOP, lasting till the final follow-up at 18 months. We discuss the role of glaucoma surgery, for an ARS patient with refractory glaucoma during the third trimester with a comprehensive review of literature.

Axenfeld–Rieger syndrome (ARS) is a rare autosomal-dominant neurocristopathy that presents with a variety of classical ocular and systemic findings. The pathophysiology of the disease involves anterior segment dysgenesis, and patients may present with ophthalmic complications early in life, including secondary glaucoma, high refractive errors, amblyopia, and permanent visual damage. There are a limited number of studies in the literature that focus primarily on pediatric patients with ARS. The purpose of this article was to review the current literature on clinical presentation, genetic associations, diagnosis, secondary complications, and treatment of ARS in pediatric patients. Evaluating the essential clinical aspects of the disease in children may allow for earlier diagnosis and treatment and prevent visual morbidity from amblyopia and secondary glaucoma that may result in permanent visual damage.

Abstract Background Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD). The most common ocular features of ARS are posterior embryotoxon and iris hypoplasia, while some patients may manifest as corneal opacity and edema. However, the current understanding of how ARS affects the cornea is still incomplete. This study reports a novel histopathological finding of ARS, complicating corneal abnormalities, including congenital corneal opacity and irreversible endothelial decompensation. Methods This retrospective study included 6 eyes of 3 ARS patients, 5 of which underwent keratoplasty for irreversible endothelial decompensation from May 2016 to January 2019. No eye had a history of surgery. We reviewed the data of epidemiology, clinical manifestations and histopathologic examinations. Results Five eyes developed irreversible endothelial decompensation, among which 4 were born with corneal opacity. One eye exhibited transparent cornea but showed a continuous loss of endothelial cells in the absence of surgery and elevated intraocular pressure thereafter. Anterior segment optical coherence tomography photographs showed that anterior synechia existed in the area with corneal opacities, where we found the interlayer splitting of the Descemet membrane inserted by hypoplastic iris and a basement membrane-like structure under a light microscope. Conclusion Anterior synechia might be associated with corneal abnormalities in ARS patients. The novel histopathologic finding revealed the internal relation between anterior segment dysgenesis and would help explore the inner mechanism of corneal abnormalities in ARS.

FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome. [ABSTRACT FROM AUTHOR]

The 6p25 deletion syndrome is a rare genetic disorder characterized by a wide spectrum of congenital anomalies. Ophthalmic abnormalities appear to be highly associated with the syndrome, although this relationship has not been well characterized to date. We conducted a systematic literature review to highlight the ocular features in patients with this deletion syndrome and describe a 7‐month‐old female who has a 6.07 MB 6p25.1p25.3 deletion and a 4.25 MB 17q25.3 duplication. Our patient presented with multiple congenital anomalies, including macrocephaly, frontal bossing, low set ears, tent‐shaped mouth, saddle nose, flat midface, and hearing impairment. Her ophthalmic features included proptosis, down‐slanting palpebral fissures, hypertelorism, nystagmus, bilateral posterior embryotoxon, and decentered and abnormally shaped pupils. A systematic review of the published cases with sufficient clinical eye descriptions included 63 cases with a confirmed 6p25 deletion. The most common eye findings observed were posterior embryotoxon, iris hypoplasia, corectopia, cornea opacity, and glaucoma. [ABSTRACT FROM AUTHOR]

FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.

Abstract Axenfeld–Rieger Syndrome (ARS) is a rare autosomal dominant genetic disease with considerable expressive variability, characterized by ocular and non-ocular manifestations, cardiovascular, mild craniofacial abnormalities and dental malformations. Current data report an incidence of Xenfeld-Rieger syndrome in the population of 1: 200,000. The case described is that of a 14-year-old female patient whose ARS is suspected and investigated following a dental specialist visit for orthodontic reasons, acquired the patient’s family and clinical data following a medical approach multidisciplinary, we proceed to the orthodontic involved the use of the Rapid Palatal Expander (RPE) and a fixed orthodontic treatment. The aim of this study is to report the case of the orthopaedic and orthodontic treatment in a patient affected by ARS and with facial dysmorphism and teeth anomalies associated to ocular anomalies.

Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis. [ABSTRACT FROM AUTHOR]

Background: Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD). The most common ocular features of ARS are posterior embryotoxon and iris hypoplasia, while some patients may manifest as corneal opacity and edema. However, the current understanding of how ARS affects the cornea is still incomplete. This study reports a novel histopathological finding of ARS, complicating corneal abnormalities, including congenital corneal opacity and irreversible endothelial decompensation. Methods: This retrospective study included 6 eyes of 3 ARS patients, 5 of which underwent keratoplasty for irreversible endothelial decompensation from May 2016 to January 2019. No eye had a history of surgery. We reviewed the data of epidemiology, clinical manifestations and histopathologic examinations. Results: Five eyes developed irreversible endothelial decompensation, among which 4 were born with corneal opacity. One eye exhibited transparent cornea but showed a continuous loss of endothelial cells in the absence of surgery and elevated intraocular pressure thereafter. Anterior segment optical coherence tomography photographs showed that anterior synechia existed in the area with corneal opacities, where we found the interlayer splitting of the Descemet membrane inserted by hypoplastic iris and a basement membrane-like structure under a light microscope. Conclusion: Anterior synechia might be associated with corneal abnormalities in ARS patients. The novel histopathologic finding revealed the internal relation between anterior segment dysgenesis and would help explore the inner mechanism of corneal abnormalities in ARS. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical outcomes of penetrating keratoplasty (PK) and Descemet's stripping automated endothelial keratoplasty (DSAEK) in eyes with irreversible corneal decompensation secondary to Axenfeld–Rieger syndrome (ARS). Methods: In this retrospective case series, a total of four eyes undergoing PK and seven eyes undergoing DSAEK, including one eye requiring one repeat DSAEK, between 2014 and 2021 were enrolled. Postoperative complications, graft survival, glaucoma treatment before and after keratoplasty, visual outcomes, and endothelial cell density were recorded. Results: The mean follow-up duration was 34.4 ± 16.8 months. Before keratoplasty, the mean BCVA was 2.0 ± 0.4 LogMAR, and the mean IOP was 21.7 ± 8.1 mmHg. A total of 63.6% of eyes (7/11) received glaucoma treatment, including five eyes with glaucoma surgeries. After keratoplasty, 27.3% of eyes (3/11) exhibited secondary graft failure. The mean BCVA reached a maximum of 0.7 ± 0.5 LogMAR at 8.9 ± 7.5 months, with no significant difference between the PK and DSAEK groups (P1 = 1.00, P2 = 0.12). Four eyes with previous glaucoma surgeries exhibited markedly high IOP. A total of 72.7% of eyes (8/11) required additional glaucoma treatments. The mean endothelial cell loss (ECL) rates at 1, 6, 12 and 24 months were 43%, 49%, 63% and 54%, respectively, with no significant difference between the PK and DSAEK groups (P1 = 0.64, P2 = 1.00, P3 = 0.57, and P4 = 0.44). Conclusion: Both PK and DSAEK can successfully treat corneal decompensation secondary to ARS, resulting in similar outcomes with regard to IOP control, BCVA and ECL. IOP control is essential for postoperative management, especially for eyes with previous glaucoma surgeries. [ABSTRACT FROM AUTHOR]

Abstract Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

Objecive: To describe the clinical and genetic findings of an Axenfeld-Rieger syndrome (ARS) family with a new PITX2 splicing mutation. Methods: A 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. Results: All 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. Conclusion: In 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.

Abstract Background Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant hereditary disease characterized primarily by maldevelopment of the anterior segment of both eyes, accompanied by developmental glaucoma, and other congenital anomalies. FOXC1 and PITX2 genes play important roles in the development of ARS. Case presentation The present report describes a 7-year-old boy with iris dysplasia, displaced pupils, and congenital glaucoma in both eyes. The patient presented with a congenital atrial septal defect and sublingual cyst. The patient’s family has no clinical manifestations. Next generation sequencing identified a pathogenic heterozygous missense variant in FOXC1 gene (NM_001453:c. 246C>A, p. S82R) in the patient. Sanger sequencing confirmed this result, and this mutation was not detected in the other three family members. Conclusion To the best of our knowledge, the results of our study reveal a novel mutation in the FOXC1 gene associated with ARS.

Axenfeld–Rieger Syndrome (ARS) is a rare autosomal dominant genetic disease with considerable expressive variability, characterized by ocular and non-ocular manifestations, cardiovascular, mild craniofacial abnormalities and dental malformations. Current data report an incidence of Xenfeld-Rieger syndrome in the population of 1: 200,000. The case described is that of a 14-year-old female patient whose ARS is suspected and investigated following a dental specialist visit for orthodontic reasons, acquired the patient's family and clinical data following a medical approach multidisciplinary, we proceed to the orthodontic involved the use of the Rapid Palatal Expander (RPE) and a fixed orthodontic treatment. The aim of this study is to report the case of the orthopaedic and orthodontic treatment in a patient affected by ARS and with facial dysmorphism and teeth anomalies associated to ocular anomalies. [ABSTRACT FROM AUTHOR]

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than one person in every 2000 and many HCAs and nurses will encounter some of these conditions given the high number of them. This 58th article will briefly explore five of these conditions: amniotic band syndrome; Axenfeld-Rieger syndrome; adult neuronal ceroid lipofuscinosis; Hashimoto's syndrome; and pseudomyxoma peritonei. [ABSTRACT FROM AUTHOR]

Abstract Background Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant eye disorder that can also affect other organs of the human body. The condition is primarily characterized by the anterior segmental abnormalities of the eye. Here, we present an observational case series of a three-generation family with ARS and unexpected foveal anomaly. Case presentation A 33-year-old woman was admitted to an Ophthalmology Clinic in Bialystok for left eye congenital cataract surgery. The patient (proband) was diagnosed with visual deterioration, multiple defects of iris, corectopia, displacement of the Schwalbe’s line, and phenotypic characteristics of ARS. A perimetric examination indicated peripheral visual field loss and signs typical for glaucoma. Based on the phenotypic symptoms and genetic test, the patient was diagnosed with Axenfeld Rieger Syndrome. However, the optical coherence tomography of the macula showed foveal anomaly (absence of the physiological pit), which is not typically associated with this genetic disorder. The patient’s family history revealed that her two daughters were undergoing treatment for congenital glaucoma, and one of the daughters also had foveal anomaly the same as her mother. Interestingly, an examination of the patient’s mother showed typical phenotypic features of ARS such as a defect of the iris, posterior embryotoxon, and coloboma, as well as foveal anomaly. A genetic test confirmed PITX2 mutation in both, proband’s two daughters and mother. Conclusions This study highlights the occurrence of ARS with unusual ophthalmic features such as foveal anomaly (absence of the physiological pit) in a three-generation family. Although ARS is known to represent the developmental defects of the anterior segment of the eye, it is very important to perform fundus evaluation to identify associated posterior segment anomalies that may affect visual acuity. The presence of ocular defects not typically associated with ARS suggests a wide spectrum of mutations within PITX2 gene which are required to identify in order to determine genotype- phenotype correlation in ARS affected individuals.

Purpose: To present the first report of a XEN45 gel stent implantation in a female with Axenfeld-Rieger syndrome (ARS), a rare congenital anomaly caused by abnormal neural crest migration during early embryogenesis. This shows promise as new minimally invasive therapeutic option in the treatment of secondary glaucoma in ARS. Observations: A 31-year-old female with known sporadic ARS was evaluated and treated at the Edith Wolfson Medical Center in Holon, Israel. The vision in her right eye was hand motion and 20/25 in the left eye. In the left eye the intraocular pressure (IOP) was up to 31 mmHg under maximal tolerated treatment. She refused Trabeculectomy or Glaucoma Drainage Device (GDD) surgery, but agreed to Minimally Invasive Glaucoma Surgery (MIGS). A Xen device was implanted in uneventful surgery. 15 months post operatively her IOP is 8 mmHg. Conclusions: XEN implantation, when technically feasible, is a suitable procedure in ARS. This shows promise as new minimally invasive therapeutic option in the treatment of secondary glaucoma in ARS. This has particular significance as these patients often require surgery at a young age.

This study aimed to identify the disease‐causing gene of three Chinese families with glaucoma. Whole exome sequencing was performed on the probands and detected three different variants (c.405C>A (p.Cys135Ter), c.851G>T (p.Ser284Ile), and c.392C>T (p.Ser131Leu)) in FOXC1 as a causative gene of glaucoma, and Sanger sequencing was performed for verification and cosegregation analysis. Three in silico tools all predicted these two missense variants to be probably disease‐causing. Western blot analysis, immunofluorescence, and dual‐luciferase assay were further used to evaluate the effect of FOXC1 missense variants, and demonstrated that the two variants resulted in decreased transactivation activity of FOXC1 although the variants had no effect on the protein amount and the nucleus subcellar localization of FOXC1 compared with the wild type, which implies that both of two variants may be probably pathogenic. In this study, we reported two novel FOXC1 variants as well as a reported variant and the phenotypes associated to these variants, which expands the spectrum and relevant phenotypes of FOXC1 variants. Additionally, the functional analysis of FOXC1 variants provides further insight into the possible pathogenesis of anterior segment anomaly related to FOXC1. [ABSTRACT FROM AUTHOR]

Abstract 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

Abstract Background Axenfeld-Rieger syndrome (ARS) is a congenital disease with a series of developmental abnormalities, and no case of ARS with cataract and small cornea has been reported in previous studies. In the present report, we aimed to describe the diagnosis and phacoemulsification of an ARS patient with small cornea. Case presentation A 58-year-old Han Chinese male patient who was referred to Eye Center of the Second Affiliated Hospital of Zhejiang University Medical College was diagnosed with ARS. Systemic and ophthalmic examination and genetic testing were performed. The slit-lamp microscopic examination of anterior segment showed obvious nuclear cataract, iris lesions, and the abnormal cornea of both eyes with small transversal and longitudinal diameters. ARS with bilateral complicated cataract and small cornea was diagnosed. Microincision-phacoemulsification in combination with intraocular lens implantation was performed on his left eye. After successful surgery of his left eye, the best-corrected visual acuity (BCVA) was obviously improved from 2 to 0.5 (LogMAR). A transient elevation of intraocular pressure (IOP) was controlled with medication. Conclusions Through genetic testing, a known pathogenic mutation NM_153427.2:c.272G > A was detected on the PITX2 gene; and an unknown mutation NM_001453.2:c.1063C > T was detected on FOXC1 gene. For the ARS patient with complicated cataract, the visual acuity was increased by phacoemulsificasion in combination with microincision.

AIM: To investigate the clinical features of Axenfeld-Rieger syndrome associated with secondary glaucoma and its surgical treatment. 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. 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, et al. 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(t=2.4185, P=0.0362), and intraocular pressure in 7 followed-up eyes was controlled ≤21mmHg. The long-term success rate of surgery was 64%. 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.

Objective: Axenfeld-Rieger syndrome (ARS) type 3 is a rare autosomal dominant disease, characterized by anterior segment dysgenesis of the eye, hearing loss, and cardiac defects. ARS type 3 is highly associated with FOXC1 mutations, which induces developmental disorders of neural crest cells. Most studies about ARS patients focused on ophthalmologic findings, but details in their hearing loss have not yet been revealed. In this report, we investigated audiological and otological manifestations in the ARS type 3 patient who had the novel heterozygous FOXC1 mutation leading deletion at the forkhead DNA-binding domain.Methods and Results: Pure tone audiometry showed bilateral sensorineural hearing loss (SNHL) and audiological examinations confirmed that major dysfunctions existed in the cochlea, rather than the spiral ganglion neurons and the cochlear nerve. CT and MRI revealed the hypoplastic cochlea at both sides. Given that the 6p25 deletion syndrome, lacking one allele of the FOXC1 gene, shows similar, but more severe cochlear malformations than the present case, the FOXC1 mutations might contribute to the hypoplasia and dysfunctions in the cochlea.Conclusion: To our knowledge, this is the first report demonstrating that the ARS type 3 patient with the FOXC1 mutation has the hypoplasia and dysfunctions in the cochlea, which results in bilateral SNHL. [ABSTRACT FROM AUTHOR]

Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant hereditary disease characterized primarily by maldevelopment of the anterior segment of both eyes, accompanied by developmental glaucoma, and other congenital anomalies. FOXC1 and PITX2 genes play important roles in the development of ARS. Case presentation: The present report describes a 7-year-old boy with iris dysplasia, displaced pupils, and congenital glaucoma in both eyes. The patient presented with a congenital atrial septal defect and sublingual cyst. The patient's family has no clinical manifestations. Next generation sequencing identified a pathogenic heterozygous missense variant in FOXC1 gene (NM_001453:c. 246C>A, p. S82R) in the patient. Sanger sequencing confirmed this result, and this mutation was not detected in the other three family members. Conclusion: To the best of our knowledge, the results of our study reveal a novel mutation in the FOXC1 gene associated with ARS. [ABSTRACT FROM AUTHOR]

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.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.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.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.

Abstract Background Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. Methods An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. Results All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. Conclusions PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.

Aim: The congenital oligodontia impeding the development of the alveolar process resulting in disproportionate jaw growth has been previously reported. This case report describes the interdisciplinary management of an 11-year-old girl with Axenfeld-Rieger syndrome exhibiting oligodontia and maxillary hypoplasia.Methods and Results: An adjunctive orthodontic therapy was performed by taking advantage of bone-anchored maxillary protraction (BAMP) therapy using miniplates and 24-hour traction by intermaxillary Class III elastics. After 6 months of active treatment, the maxilla advanced by approximately 5 mm and upper lip relation improved by 3 mm without any significant changes in vertical relations. All the changes were maintained at 15th-month follow-up. A temporary removable prosthesis was given for immediate esthetics, and the definitive management is discussed.Conclusion: The BAMP therapy can be a befitting alternative in cases exhibiting complex presentation involving skeletal and dentoalveolar components. An appreciable profile improvement without any dentoalveolar side effects can be achieved with BAMP therapy. [ABSTRACT FROM AUTHOR]

Keywords: Axenfeld-Rieger Syndrome; glaucoma; retinal detachment EN Axenfeld-Rieger Syndrome glaucoma retinal detachment 2650 2652 3 07/15/22 20220701 NES 220701 Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder and encompasses anterior segment dysgenesis, along with dental, cardiac, craniofacial, and abdominal wall defects.[[1]],[[2]] Although glaucoma[[3]] and retinal detachment (RD)[[4]] have been reported, little is known about the postoperative course after RD surgery in ARS patients. Examination revealed abnormal morphological [Figure 1]a, [Figure 1]b, [Figure 1]c and ophthalmological features corroborative of ARS [Figure 2]a, [Figure 2]b, [Figure 2]c. Early silicone oil removal along with continued antiglaucoma medication failed to control the IOP and staphylomatous protrusions [Figure 4]b and [Figure 4]c. [Extracted from the article]

Axenfeld-Rieger syndrome (ARS) is a genetic disease affecting multiple organ systems. In the eye, it is associated with anterior segment dysgenesis with a high risk for glaucoma. Dental anomalies, cardiovascular malformations, hypospadias, and craniofacial abnormalities are other associated systemic conditions. Five years old monozygotic twin brothers with ARS were referred to Umraniye Training and Research Hospital, ophthalmology clinic for iris abnormalities. At presentation, pathognomonic components of ARS were found in both patients, including iris anomaly (corectopia, iris hypoplasia, and iris strands in Scwalbe’s ring), oligodontia, hypodontia, hypospadias, and periumbilical skin fold. Intraocular pressure was within normal ranges in both of the patients. Patients were followed up in the glaucoma unit. [ABSTRACT FROM AUTHOR]