Primary Congenital Glaucoma Cases Research Articles

FOXC1 -associated phenotypes in humans may not always exhibit corneal neovascularization

The transcription factor gene FOXC1 has been implicated with Axenfeld–Rieger syndrome (ARS) in humans. Mutations in this gene have been suggested to contribute to the mechanism leading to developmental defects in the anterior chamber of the eye. In PNAS, Seo et al. (1) demonstrated that mutations in FOXC1 led to corneal angiogenesis in mice and in anterior segment anomalies like ARS in humans. Although the data on mice are very convincing, we provide a different perspective based on our observations in two different patient cohorts with FOXC1 mutations. Our screening of patients (n = 10) with Axenfeld–Rieger anomaly (ARA) for FOXC1 mutations did not reveal any form of corneal neovascularization among the heterozygous mutation carriers (2). We also screened the FOXC1 gene in a large cohort (n = 210) of another related disease, primary congenital glaucoma (PCG) without any anterior segment anomalies, and, similarly, the mutations carriers were devoid of any corneal neovascularization as observed in our ARA cohort (3). Interestingly, the results were consistent across PCG cases that harbored heterozygous alleles of FOXC1 alone or in combination with an accompanying allele of CYP1B1.

Central corneal thickness in Iranian congenital glaucoma patients

Purpose:To compare central corneal thickness (CCT) in subjects with controlled primary congenital glaucoma (PCG) and nonglaucomatous subjects and to investigate the correlation between CCT and intraocular pressure (IOP) in the study population.Materials and Methods:Twenty-three consecutive PCG cases with controlled IOP and no clinical evidence of corneal edema comprised the Study Group. There was an interval of at least 2 months between last intraocular surgery and inclusion in the study. Twenty-one subjects with strabismus or lacrimal drainage insufficiency who did not have glaucoma or any history of intraocular surgery or ocular trauma comprised the control group. The Control Group was age and sex-matched. Data from ultrasonic pachymetry and applanation tonometry were analyzed for differences between groups. Correlation of the study parameters was investigated. A P-value less than 0.05 was statistically significant.Results:Data from both eyes of subjects in the Study Group and Control Group were included in the original analysis. Mean CCT was statistically significantly higher in the Study Group compared to the Control Group (589.42 ± 53.44 μm vs. 556.14 ± 30.51 μm, respectively; P=0.001). There was a significant correlation between CCT and IOP (r=0.63; P<0.0001). Similar statistically significant outcomes were observed when only one eye per subject was used in a reanalysis of the data for the Study and Control Groups.Conclusion:Patients with PCG who had controlled IOP have statistically significantly thicker corneas than nonglaucomatous age and sex-matched subjects The thicker cornea could significantly alter IOP measurement with applanation tonometry. Pachymetry should be considered an essential part of the evaluation for PCG.

Primary congenital glaucoma and the involvement of CYP1B1

Primary congenital glaucoma (PCG) is an autosomal recessive disorder in children due to the abnormal development of the trabecular meshwork and the anterior chamber angle. With an onset at birth to early infancy, PCG is highly prevalent in inbred populations and consanguinity is strongly associated with the disease. Gene mapping of PCG-affected families has identified three chromosomal loci, GLC3A, GLC3B and GLC3C, of which, the CYP1B1 gene on GLC3A harbors mutations in PCG. The mutation spectra of CYP1B1 vary widely across different populations but are well structured based on geographic and haplotype backgrounds. Structural and functional studies on CYP1B1 have suggested its potential role in the development and onset of glaucomatous symptoms. A new locus (GLC3D) harboring the LTBP2 gene has been characterized in developmental glaucoma but its role in classical cases of PCG is yet to be understood. In this review, we provide insight into PCG pathogenesis and the potential role of CYP1B1 in the disease phenotype.

Primary Congenital Glaucoma Associated With Patau Syndrome With Long Survival

Ocular abnormalities are common in Patau syndrome (trisomy 13), but only a few cases with congenital glaucoma have been reported, some of which were associated with other ocular defects. This report describes a case of primary congenital glaucoma in an 11-year-old patient with full trisomy 13.

Congenital Glaucoma

To investigate CYP1B1 gene mutations in Arab-Bedouin Israeli patients with primary congenital glaucoma (PCG). Testing linkage to candidate genes using adjacent polymorphic markers and sequencing of genomic DNA samples by standard methods. In 9 of 11 unrelated affected Israeli Bedouin families, PCG was associated with homozygosity of 3 different CYP1B1 mutations. As in Saudi Arabian families, the 3987G>A CYP1B1 substitution accounted for approximately 50% of cases. A novel CYP1B1 mutation, 8405G>A, was found in 2 unrelated families. In 2 consanguineous families, there was no evidence of homozygosity or mutations in CYP1B1. CYP1B1 mutations account for the majority of cases of PCG in the Israeli Bedouin population. The most frequently found CYP1B1 mutation (3987G>A) in our study is also the commonest CYP1B1 mutation in the Saudi Arabian population, in line with the common genetic background of both populations. The absence of homozygosity in the CYP1B1 locus in the affected individuals in 2 consanguineous inbred families, suggests that other genes take part in the causation of congenital glaucomas. This is the first study describing the genetic basis of PCG among Israeli Arab-Bedouin individuals, in whom the frequency of the disease is the highest in the world. Further similar studies based on new diagnosed patients are needed to possibly prevent, screen, and treat (antenatal and postnatal) this sight-devastating childhood disease.

A novel mutation of CYP1B1 gene in primary congenital glaucoma

To investigate the distribution of the CYP1B1 (Cytochrome P450, family 1, subfamily B, polypeptide 1) gene mutations in primary congenital glaucoma (PCG) in Hunan Province. Case-control study. Thirteen cases of PCG from different districts of Hunan province were collected in this study. Direct sequencing was used to evaluate the coding and the promoter regions of the CYP1B1 gene in PCG patients. A novel pathogenic mutation (c.C319G, L107V) was identified in a PCG patient in our study and it was a missense mutation in exon 2. Additionally, four single nucleotide polymorphisms(SNPs) were found in PCG patients, including R48G, A119S, V432L and D449D. A novel CYP1B1 gene mutation (L107V) may be the cause for primary congenital glaucoma in Hunan Province.

Recognising congenital glaucoma

The Medical Journal of Australia ISSN: 0025-729X 19 October 2009 191 8 466-467©The Medical Journal of Australia 2009www.mja.com.auLessons from PracticeThis case of primary congenital glaucoma (PCG) illustrates thetypical clinical features of this condition, which, if untreated,results in blindness. In this case, the infant was referred to ourophthalmology service by a general paediatrician, who was review-ing her for thyroid and cardiac disease; neither of these conditionshas a known association with congenital glaucoma.The difficulty in recognising PCG lies partly in its rarity; PCG hasa reported incidence of 1 in 30000 live births in Australia.

The Transcription Factor GeneFOXC1Exhibits a Limited Role in Primary Congenital Glaucoma

Primary congenital glaucoma (PCG) is an autosomal recessive disorder that has been linked to CYP1B1 mutations. This study was conducted to explore the role of FOXC1, which is involved in anterior segment dysgenesis, in PCG. An earlier screening for CYP1B1 in a clinically well-characterized PCG cohort (n = 301) revealed cases that were either homozygous (n = 73), compound heterozygous (n = 18), or heterozygous (n = 41) for the mutant allele, whereas the remaining (n = 169) did not harbor any mutation. Hence, FOXC1 was screened in 210 PCG cases who were either heterozygous (n = 41) or did not harbor any CYP1B1 mutation (n = 169), along with ethnically matched normal control subjects (n = 157) by resequencing the entire coding region. Two heterozygous missense (H128R and C135Y) and three frame shift mutations (g.1086delC, g.1155del9bp, and g.1947dup25bp) were observed in FOXC1 in 5 (2.38%) of 210 cases. The missense mutations had a de novo origin in two sporadic cases, whereas the FOXC1 deletions were seen in two cases that were also heterozygous for the CYP1B1 allele (R368H). The parents of the proband with g.1086delC were heterozygous for either the FOXC1 or CYP1B1 alleles. The unaffected mother of the proband with the g.1155del9bp was heterozygous for both the FOXC1 and CYP1B1 alleles; the father harbored only the FOXC1 allele. Familial segregation of the g.1947dup25bp could not be performed because of the unavailability of DNA from one parent. Except for the g.1155del9bp (0.95% normal chromosomes), all the other variations were absent in the control subjects. The present study indicates a limited role of FOXC1 in PCG pathogenesis.

Antimetabolite and releasable suture augmented filtration surgery in refractory pediatric glaucomas

To evaluate childhood filtration surgery when using releasable sutures, antimetabolites, and bleb-needling with 5-fluorouracil (5FU). Retrospective case note review of 30 patients (38 eyes) with childhood glaucoma presenting between 1999 and 2004 to a tertiary pediatric ophthalmology center. Either trabeculectomy or combined trabeculotomy-trabeculectomy using antimetabolites, releasable sutures, and bleb modification was performed. Successful outcomes for survival analysis were measured intraocular pressures < or =21 mmHg, with two or less topical medications. Patients under 1 year old had trabeculotomy-trabeculectomy; the remainder had trabeculectomy alone. One case of primary congenital glaucoma had trabeculotomy-trabeculectomy at 24 months. Eighty-nine percent had previous failed glaucoma surgery. Twenty-five patients (33 eyes) had primary congenital glaucoma; 5 patients (5 eyes) had secondary glaucoma (aphakia or pseudophakia). Mean follow-up was 22.9 months (5.2-68.5). Sixty-six percent of all eyes had suture-release and 68% had bleb-needling (mean, 1.9 times). Five eyes (13%) needed further drainage tube surgery. Complications were early postoperative hypotony in three cases, requiring anterior chamber reinflation (mean age, 7.4 months at the time of surgery), two cases of transient wound leak, but no bleb-related complications or endophthalmitis. No blebs were avascular, or thin and cystic. Cumulative success was 75% for primary, but only 21% for secondary glaucoma at final follow-up. Antimetabolite and releasable augmentation of filtration surgery appear to give favorable outcomes in the treatment of refractory primary pediatric glaucomas. Secondary glaucomas after cataract surgery do not show good long-term success. There were no major or sight-threatening complications in our series; no eyes developed cystic avascular blebs or bleb-related infections.

Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma

Analysis of CYP1B1 in primary congenital glaucoma (PCG) patients from various ethnic populations indicates that allelic heterogeneity is high, and some mutations are population specific. No study has previously reported the rate or spectrum of CYP1B1 mutations in Australian PCG patients. The aim of this study is to determine the frequency of CYP1B1 mutations in our predominately Caucasian, Australian cohort of PCG cases. Thirty-seven probands were recruited from South-Eastern Australia, along with 100 normal control subjects. Genomic DNA was extracted and the coding regions of CYP1B1 analysed by direct sequencing. Sequence analysis identified 10 different CYP1B1 disease-causing variants in eight probands (21.6%). Five subjects were compound heterozygotes, two subjects heterozygous and one homozygous for CYP1B1 mutations. Three missense mutations are novel (D192Y, G329D, and P400S). None of the novel mutations identified were found in normal controls. One normal control subject was heterozygous for the previously reported CYP1B1 R368H mutation. Six previously described probable polymorphisms were also identified. Mutations in CYP1B1 account for approximately one in five PCG cases from Australia. Our data also supported the high degree of allelic heterogeneity seen in similar studies from other ethnic populations, thereby underscoring the fact that other PCG-related genes remain to be identified.

Myocilin gene implicated in primary congenital glaucoma

Primary congenital glaucoma (PCG) has been associated with CYP1B1 gene (2p21), with a predominantly autosomal recessive mode of inheritance. Our earlier studies attributed CYP1B1 mutations to only 40% of Indian PCG cases. In this study, we included 72 such PCG cases where CYP1B1 mutations were detected in only 12 patients in heterozygous condition, implying involvement of other gene(s). On screening these patients for mutations in myocilin (MYOC), another glaucoma-associated gene, using denaturing high-performance liquid chromatography followed by sequencing, we identified a patient who was double heterozygous at CYP1B1 (c.1103G>A; Arg368His) and MYOC (c.144G>T; Gln48His) loci, suggesting a digenic mode of inheritance of PCG. In addition, we identified the same MYOC mutation, implicated for primary open angle glaucoma, in three additional PCG patients who did not harbor any mutation in CYP1B1. These observations suggest a possible role of MYOC in PCG, which might be mediated via digenic interaction with CYP1B1 and/or an yet unidentified locus associated with the disease.

Results of the Susanna implant in patients with refractory primary congenital glaucoma

To evaluate the results of the Susanna implant in children with primary congenital glaucoma. The authors report a retrospective noncomparative interventional case series of data from 24 eyes from 24 pediatric patients who underwent Susanna implant surgery for primary congenital glaucoma. All the patients were operated by the same surgeon. The postoperative follow-up time was 24 months for all patients. Success was defined by an IOP higher than 6 mm Hg and less than or equal to 15 mm Hg, with the concomitant use of a single medication if necessary. The age range of the patients was 1 to 15 years and the mean age was 5.04 +/- 4.12 years. At 12 months, 87.5% of the patients were considered as success, and at 24 months, the proportion dropped to 79.16%. Mean preoperative and postoperative intraocular pressure were 26.17 +/- 5.16 and 14.04 +/- 4.19 mm Hg ( p < 0.001), respectively. All 24 children had undergone previous glaucoma surgeries. Cataract was the only complication found during follow-up, occurring in three patients. Cox's regression model did not show influence of gender ( P = 0.740) and previous surgery ( P = 0.262) on the outcome through time. Age at the time of surgery was the only variable which was statistically associated with success through time, younger patients presenting higher probability of failure ( P = 0.05). The results of the present study reinforce the role of drainage implants as a safe alternative in difficult cases of primary congenital glaucoma, after failure of the initial approach.

Primary Congenital Glaucoma and Erupted Teeth (Natal Teeth) in the Newborn: A Report of Two Cases

Primary congenital glaucoma may be associated with several ocular, adnexal, and systemic abnormalities. Presented are two cases of primary congenital glaucoma that were associated with natal teeth; ie, the teeth were present in the oral cavity at the time of birth. To the knowledge of the author, this is the first report on the association of primary congenital glaucoma and natal teeth.

Molecular genetics of primary congenital glaucoma.

Molecular genetic studies conducted during the last several years have thrown some light on the basic molecular defects in primary congenital glaucoma (PCG) and the rationale behind the clinical and genetic presentation of this paediatric eye condition. The existence of a hereditary form of PCG segregating as an autosomal recessive trait with high penetrance is now confirmed. The primary molecular defect underlying the majority of PCG cases has been identified as mutations in the cytochrome P4501B1 (CYP1B1) gene. This gene is expressed in tissues of the anterior chamber angle of the eye. Molecular modelling experiments suggest that mutations observed in PCG patients interfere with the integrity of the CYP1B1 molecule as well as its ability to adopt a normal conformation and bind haem. On the basis of these observations, we hypothesised that CYP1B1 participates in the normal development and function of the eye by metabolising essential molecules that are perhaps used in a signalling pathway. Revealing the identity of this molecule is our major objective since it can lead to as yet unknown biochemical cascades controlling the terminal stages of anterior chamber angle development.