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Frontiers in Cell and Developmental... 2020During vertebrate embryonic development, a population of dorsal neural tube-derived stem cells, termed the neural crest (NC), undergo a series of morphogenetic changes... (Review)
Review
During vertebrate embryonic development, a population of dorsal neural tube-derived stem cells, termed the neural crest (NC), undergo a series of morphogenetic changes and extensive migration to become a diverse array of cell types. Around the developing eye, this multipotent ocular NC cell population, called the periocular mesenchyme (POM), comprises migratory mesenchymal cells that eventually give rise to many of the elements in the anterior of the eye, such as the cornea, sclera, trabecular meshwork, and iris. Molecular cell biology and genetic analyses of congenital eye diseases have provided important information on the regulation of NC contributions to this area of the eye. Nevertheless, a complete understanding of the NC as a contributor to ocular development remains elusive. In addition, positional information during ocular NC migration and the molecular pathways that regulate end tissue differentiation have yet to be fully elucidated. Further, the clinical challenges of ocular diseases, such as Axenfeld-Rieger syndrome (ARS), Peters anomaly (PA) and primary congenital glaucoma (PCG), strongly suggest the need for better treatments. While several aspects of NC evolution have recently been reviewed, this discussion will consolidate the most recent current knowledge on the specification, migration, and contributions of the NC to ocular development, highlighting the anterior segment and the knowledge obtained from the clinical manifestations of its associated diseases. Ultimately, this knowledge can inform translational discoveries with potential for sorely needed regenerative therapies.
PubMed: 33425902
DOI: 10.3389/fcell.2020.595896 -
Korean Journal of Ophthalmology : KJO Aug 2015To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome.
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.
Topics: Aged, 80 and over; Anterior Eye Segment; DNA; DNA Mutational Analysis; Eye Abnormalities; Eye Diseases, Hereditary; Female; Forkhead Transcription Factors; Genetic Testing; Homeodomain Proteins; Humans; Male; Middle Aged; Mutation; Pedigree; Retrospective Studies; Transcription Factors; Young Adult; Homeobox Protein PITX2
PubMed: 26240509
DOI: 10.3341/kjo.2015.29.4.249 -
Transactions of the American... 1983Twenty-four patients with the diagnosis of Axenfeld's anomaly or Rieger's anomaly or syndrome were the subjects of a clinical study, which included specular microscopy...
Twenty-four patients with the diagnosis of Axenfeld's anomaly or Rieger's anomaly or syndrome were the subjects of a clinical study, which included specular microscopy of the corneal endothelium in 16 cases and fluorescein angiography of the iris in 5. Histopathologic material was obtained from ten eyes of eight of these patients (one enucleated eye and nine trabeculectomy specimens) and was studied by light and electron microscopy. The overlapping of ocular and nonocular defects in these patients prevented subclassification according to traditional criteria. Any attempted subdivision appears to have minimal clinical value, and a single classification for the disease spectrum is believed to be more practical. The collective term Axenfeld-Rieger (A-R) syndrome is proposed. A theory of mechanism for the ocular features of the A-R syndrome is postulated which involves a developmental arrest, late in gestation, of tissues derived from neural crest cells. This leads to retention of primordial endothelial tissue on the iris and across the anterior chamber angle, which produces the iridic changes and the peripheral tissue strands. Continued contraction of these membranes after birth explains the progressive changes noted in some patients. This primordial endothelium also produces excessive and atypical basement membrane, especially near the corneolimbal junction, which accounts for the prominent Schwalbe's line. The secondary glaucoma results from arrested development of the anterior chamber angle structures, characterized by incomplete maturation of the trabecular meshwork and Schlemm's canal and a high insertion of the iris. The ICE syndrome may be confused with the A-R syndrome on the basis of certain clinical and histopathologic similarities. Based on available evidence, however, it is postulated that the two entities are distinctly separate, in that the fundamental defect in the ICE syndrome is believed to be an abnormality of the corneal endothelium with secondary proliferation of a tissue layer over the anterior chamber angle and iris, while the A-R syndrome is thought to represent a developmental arrest with retention of a primordial membrane and other developmental defects.
Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Child, Preschool; Corneal Diseases; Corneal Opacity; Descemet Membrane; Diagnosis, Differential; Endothelium; Female; Fluorescein Angiography; Glaucoma; Gonioscopy; Humans; Infant; Iris; Iris Diseases; Male; Microscopy, Electron; Middle Aged; Syndrome; Trabecular Meshwork
PubMed: 6676983
DOI: No ID Found -
Biomedicines Feb 2022Mutations in cause Axenfeld-Rieger syndrome, with congenital glaucoma as an ocular feature. The mouse strain carries a chemically induced mutation and develops...
Mutations in cause Axenfeld-Rieger syndrome, with congenital glaucoma as an ocular feature. The mouse strain carries a chemically induced mutation and develops early-onset glaucoma. In this study, we characterized the glaucomatous features in mice. The eyes of and C57BL/6J control mice were assessed by slit lamp examination, total aqueous humor outflow facility, intraocular pressure (IOP) measurement, pattern electroretinography (PERG) recording, and histologic and immunohistochemistry assessment beginning at 3 weeks and up to 12 months of age. The mice developed elevated IOP as early as 4 weeks old. The IOP elevation was variable and asymmetric within and between the animals. The aqueous humor outflow facility was significantly reduced in 12-month-old animals. PERG detected a decreased response at 2 weeks after the development of IOP elevation. Retinal ganglion cell (RGC) loss was detected after 8 weeks of IOP elevation. Slit lamp and histologic evaluation revealed corneal opacity, iridocorneal adhesions (anterior synechiae), and ciliary body atrophy in mice. Immunohistochemistry assessment demonstrated glial cell activation and RGC axonal injury in response to IOP elevation. These results show that the eyes of mice exhibit anterior segment dysgenesis and early-onset glaucoma. The mouse strain may represent a useful model for the study of congenital glaucoma.
PubMed: 35327318
DOI: 10.3390/biomedicines10030516 -
Journal of Clinical Cases & Reports Oct 2023This is a descriptive summary of the case of a patient with Axenfeld-Rieger syndrome associated with a congenital malformation of the iris and consequent pupillary...
SUMMARY
This is a descriptive summary of the case of a patient with Axenfeld-Rieger syndrome associated with a congenital malformation of the iris and consequent pupillary morphological alteration of an atypical characteristic reported. This anomaly is unique in scientific literature and exhibits a peculiarity that we have called pseudoacorea: Hidden pupil. Other associated abnormal clinical findings were posterior embryotoxon, astigmatism, amblyopia, and exotropia. Diagnosis was achieved by instilling ocular mydriatics into the cul-de-sac that revealed this peculiarity. It is necessary to make a differential diagnosis with other pupillary pathologies such as corectopia, acorea and microcoria. Early detection of pathology and surgical management is necessary, since it would lead to a better visual prognosis for both amblyopia and strabismus.
BACKGROUND
Among the malformations of the pupil, we can find polycoria (more than one pupil), dyscoria (abnormal pupil shape), corectopia (abnormal pupil position) and acorea (absence of pupil). In addition, morphologically normal pupils can denote other anomalies such as the microcoria described by Holth in 1923. Acorea is a rare anomaly, congenital or acquired, characterized by an absolute absence of the pupil both at rest and in mydriasis. In our case we prefer to differentiate it and name it pseudoacorea, since although there is a total absence of the pupil at rest thanks to the application of ocular mydriatics, a micropupil with discoric and corectopic characteristics is achieved. It is worth noting that we have not detected in the scientific literature any case described as the one that we will develop here.
CONCLUSION
The case of a patient with Axenfeld-Rieger syndrome associated with a congenital malformation of the iris and consequent atypical pupillary morphological alteration is presented. This anomaly is unique in the scientific literature and presents a peculiarity that we have called pseudoacorea: Hidden pupil. Early detection of pathology and surgical management is necessary, since it would lead to a better visual prognosis for both amblyopia and strabismus.
PubMed: 37663013
DOI: 10.46619/joccr.2023.6-1145 -
Human Molecular Genetics May 2018The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital...
The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital phenotype is Axenfeld-Rieger syndrome, type 1, an autosomal dominant condition characterized by variable defects in the anterior segment of the eye, an increased risk of glaucoma, craniofacial dysmorphism and dental and umbilical anomalies; in addition to this, one report implicated PITX2 in ring dermoid of the cornea and a few others described cardiac phenotypes. We report three novel PITX2 mutations-c.271C > T, p.(Arg91Trp); c.259T > C, p.(Phe87Leu); and c.356delA, p.(Gln119Argfs*36)-identified in independent families with typical Axenfeld-Rieger syndrome characteristics and some unusual features such as corneal guttata, Wolf-Parkinson-White syndrome, and hyperextensibility. To gain further insight into the diverse roles of PITX2/pitx2 in vertebrate development, we generated various genetic lesions in the pitx2 gene via TALEN-mediated genome editing. Affected homozygous zebrafish demonstrated congenital defects consistent with the range of PITX2-associated human phenotypes: abnormal development of the cornea, iris and iridocorneal angle; corneal dermoids; and craniofacial dysmorphism. In addition, via comparison of pitx2M64* and wild-type embryonic ocular transcriptomes we defined molecular changes associated with pitx2 deficiency, thereby implicating processes potentially underlying disease pathology. This analysis identified numerous affected factors including several members of the Wnt pathway and collagen types I and V gene families. These data further support the link between PITX2 and the WNT pathway and suggest a new role in regulation of collagen gene expression during development.
Topics: Animals; Anterior Eye Segment; Collagen Type I; Collagen Type V; Eye Abnormalities; Eye Diseases, Hereditary; Gene Editing; Gene Expression Regulation, Developmental; Glaucoma; Homeodomain Proteins; Humans; Mutation; Pedigree; Transcription Factors; Wnt Signaling Pathway; Wolff-Parkinson-White Syndrome; Zebrafish; Zebrafish Proteins; Homeobox Protein PITX2
PubMed: 29506241
DOI: 10.1093/hmg/ddy074 -
Genes Jan 2023Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone...
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 (5) and four other histone lysine methyltransferases/demethylases (, , and ) 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.
Topics: Humans; Histones; Lysine; Histone-Lysine N-Methyltransferase; Eye Abnormalities; Histone Demethylases
PubMed: 36672956
DOI: 10.3390/genes14010216 -
International Journal of Ophthalmology 2017To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in in the family.
AIM
To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in in the family.
METHODS
Patients 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.
RESULTS
Genome-wide linkage and exome sequencing analyses showed 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 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family.
CONCLUSION
Our findings implicate the first intronic mutation of the 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 have been found.
PubMed: 28730073
DOI: 10.18240/ijo.2017.06.04 -
BMC Medical Genomics Nov 2021Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular...
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.
Topics: Anterior Eye Segment; Child, Preschool; Eye Abnormalities; Eye Diseases, Hereditary; Forkhead Transcription Factors; Humans; Male
PubMed: 34809627
DOI: 10.1186/s12920-021-01130-7 -
Eye (London, England) Oct 2022A Bitot spot is a conjunctival lesion, classically associated with severe vitamin A deficiency. In this paediatric series, we describe conjunctival lesions...
BACKGROUND/AIMS
A Bitot spot is a conjunctival lesion, classically associated with severe vitamin A deficiency. In this paediatric series, we describe conjunctival lesions indistinguishable from Bitot spots, seen in the presence of normal vitamin A levels.
METHODS
This descriptive case series was performed by retrospective review of case notes, including all patients with Bitot-like spots found to have normal serum vitamin A levels, seen at the Hospital for Sick Children, Toronto, between 2006 and 2016. Data collected included age at presentation, ophthalmic and systemic diagnoses, and the presence of recognised genetic mutations. Histopathology was reviewed in one case.
RESULTS
Ten patients with Bitot-like spots with laboratory-confirmed normal serum vitamin A levels were identified. The conjunctival lesions were indistinguishable clinically and histopathologically from classic Bitot spots and were noted to occur in a range of anterior segment pathologies, including aniridia, WAGR syndrome, Axenfeld-Rieger syndrome, and blepharokeratoconjunctivitis.
CONCLUSIONS
Bitot-like spots are found in children with a number of anterior segment pathologies in the absence of vitamin A deficiency.
Topics: Anterior Eye Segment; Child; Eye Abnormalities; Eye Diseases, Hereditary; Humans; Vitamin A; Vitamin A Deficiency
PubMed: 34531553
DOI: 10.1038/s41433-021-01569-z