Congenital Ocular Malformations Research Articles

A study to evaluate the cause of blindness/low vision among certified visually disabled individuals in Mandya district of Karnataka

Aim: To identify the demographic characteristics, degree and cause of visual disability among certified visually disabled individuals in Mandya district, Karnataka, India in patients attending Ophthalmology OPD. Materials and Methods: Retrospective record based observational study was carried out in teaching Hospital of Mandya district. Data was collected from visual disability certificates of patients who attended our OPD during the period May 2013 to May 2016. The cause of the visual loss was ascertained. Information from the history, clinical examination and investigations was compiled. Results: In our study, a total of 152 patients were enrolled out of 170 cases. Children and young adults up to age of 30 years constituted around (48, 31.57%) of cases. Among certified visually disabled individuals there were more males (105, 69.08%) compared to females (47, 30.92%). Amount of visual disability percentage of 100%, 75% and 40% was seen in 102(67.10%), 36(23.68%) and 14(9.21%) people respectively. Congenital ocular malformations (32, 21.05%), Retinitis pigmentosa (27, 17.76%) and Optic atrophy (21, 13.81%) were responsible for more than 50% of the cases. Conclusion: Children and young adults constitute around one third of disabled individuals. Men are more common beneficiaries when compared to women showing gender bias. Congenital ocular malformation and Retinitis pigmentosa were the most common causes of certified visual disability. Keywords: Certification, Congenital Ocular malformation, Retinitis pigmentosa, Visually disabled, Optic atrophy

Evaluation of Ocular Side Effects in the Patients on Topiramate Therapy for Control of Migrainous Headache.

Topiramate, a sulfa-derivative monosaccharide, is an antiepileptic drug which is administered in the control of migraine. It is reported to cause various ocular side effects such as visual field defect and myopic shift. To investigate the alterations in refractive error, properties of the cornea and changes in the anterior chamber in patients that receive Topiramate for migraine control. This is a hospital-based, non-interventional, observational study that is conducted at Imam Hossein Hospital, affiliated to Shahid Beheshti University of Medical Sciences, Department of Neurology, in collaboration with the department of Ophthalmology. Thirty three consecutive patients with the diagnosis of migraine that were candidate for Topiramate therapy were recruited. Patients with history of ocular trauma or surgery, keratoconus, glaucoma, congenital ocular malformations and any history of unexplained visual loss were excluded. After thorough ophthalmic examination, all the patients underwent central corneal thickness (CCT) measurement, and Pentacam imaging (Scheimpflug camera) at the baseline. Various parameters were extracted and used for analysis. Anterior chamber volume (ACV), anterior chamber depth (ACD), and anterior chamber angle (ACA) measurement was performed. These measurements were repeated on day 30(th) and 90(th) after the initiation of Topiramate therapy. According to the normality tests, parameters with normal distribution were analysed using the repeated measures test and the remaining parameters (with non-normal distribution) were analysed using the non-parametric k-sample test. A p-value< 0.05 was considered statistically significant, according to Bonferroni post hoc correction. There were 66 eyes of 33 patients under the diagnosis of migrainous headache, that Topiramate was initiated for headache control, included in the study. The mean value of refractive error had a statistically significant myopic change, from -0.23 diopters (D) at the baseline to -0.61 D at the 90(th) day of follow-up period (p-value < 0.001). Mean CCT was 531.43 μm at the baseline and increased to 534.72 μm at the 30(th) day, and 537.51 μm at the 90(th) day after the administration of Topiramate (p-value=0.001). Mean value of other parameters, ACV, ACD, and ACA, did not reveal statistically significant change. Myopic shift and gradually increasing CCT in the patients after Topiramate administration should be considered before any refractive surgery. We found no gradual change in the anterior chamber and angle parameters in our patients in the 90 days of follow up. More studies with a longer duration of follow-up are needed to elucidate dose-dependent ocular manifestations.

Validation of the existing modified screening criteria for detection of all cases of Retinopathy of Prematurity in preterm babies – 11 year study from a governorate referral hospital in Oman

PurposeTo study appropriateness of our modified screening criteria for detection of all cases of Retinopathy of Prematurity (ROP) among preterm babies. MethodRetrospective observational cohort study among preterm neonates who underwent ROP screening as per set protocol for 11years at Nizwa Hospital, Al Dhakilya Governorate, Oman. We screened all babies with gestational age ⩽32weeks or BW⩽1500g. Preterm babies >32weeks of GA or BW>1500g with unstable clinical course believed to be at high risk by the attending neonatologist also were screened. ResultsDuring the study period 528 babies were screened for ROP of which 76 babies were excluded due to death, associated congenital ocular malformation and loss for follow-up either due to transfer to other institution or defaulting. Thus 452 babies were included in the final analysis. Incidence of ROP was 46.4% of which 27.9% had mild ROP, 11.3% had severe ROP which regressed and 7.3% had severe ROP who were treated. The incidence of ROP among infants with GA<26wks, 26–28wks, 29–30wks, 31–32wks and above 32weeks was 100.0%, 80.0%, 59.3%, 34.4% and 19.4% respectively.56 babies of this cohort belonged to Extended (modified) criteria group. Among these 12 babies had ROP out of which 9 had mild ROP and 3 had severe ROP. Among cases with severe ROP, two cases regressed spontaneously and one case needed treatment.Multivariate analysis using stepwise regression model showed statistically significant association of GA and BW to development of ROP.We would have missed few babies with ROP if we had followed other criteria. ConclusionOur modified screening criteria seem to be appropriate as no infant with severe ROP was missed during the study period. Incidence of severe ROP among babies in the extended criteria group (5.4%) is low but significant compared to lower gestational age. We plan to formulate a scoring system following all risk factor analysis to enable us to optimize the number of infants screened. Detection of all babies with ROP is important as they need long-term follow-up for the timely detection and management of associated ocular comorbidities.

Genetics of strabismus and lid diseases.

The prevalence of congenital ocular malformations has been described to vary from 0.04 to 6.8 per 10,000 live births. The nuclear mutations identified in chronic progressive external ophthalmoplegia harbor multiple mtDNA deletions that include POLG mutations, PEO1 mutations, OPA1 mutations and RRM2B mutations. In Kearns-Sayre syndrome, the spontaneous mitochondrial deletions vary from 1.3 to 8.0 kb subunits of the oxidative phosphorylation enzymes and several t-RNA genes are affected. Oculopharyngeal muscle dystrophy is both autosomal dominant and recessive form. Congenital fibrosis of extraocular muscles (CFEOM) 1 has mutations in KIF21A on chromosome 12 with TUBB3 mutation also being seen. CFEOM 2 is an autosomal recessive, genetically distinct entity with homozygous mutations in PHOX2A. CFEOM 3 is autosomal dominant heterozygous missense mutations in TUBB3. Most cases of Mobius syndrome are sporadic with familial cases being autosomal dominant, autosomal recessive or X-linked recessive inheritance. Genetic testing has shown abnormalities involving chromosome 1 and 13. Presynaptic congenital myasthenic syndrome is caused by ChAT (choline acetyltransferase) mutation. Two loci have been found for myotonic dystrophy (DM). DM1, which is associated with trinucleotide expansion on chromosome 19q13.3 and DM2 which is associated with CCTG tetranucleotide expansion at 3q21. Blepharophimosis is caused by mutations in the FOXL2 gene 49 located at chromosome 3q23. Lymphedema-distichiasis is an autosomal dominant disorder caused by mutations in the FOXC2 gene.

Aldh7a1 regulates eye and limb development in zebrafish.

Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish.

Causes of visual handicap amongst patients attending outpatient department of a medical college for visual handicap certification in central India

Aim: To analyze various ocular diseases leading to permanent visual handicap in a district situated in central India based on visual handicap certification issued by the district ophthalmic surgeon after verification of the domicile of the person. Materials and Methods: Records of patients obtaining visual handicap certificate for complete blindness (visual acuity < 3/60 or central visual field less than 10 degree in the better eye) during 1 st January 2008 to 31 st December 2008 were identified. Information was retrieved and analyzed. Result: Two hundred and seventy nine people were blind (visual acuity <3/60 in the better eye) out of two thousand one hundred and ninety patients came for visual handicap certification. The causes of blindness were avoidable in 49.5% (diabetic retinopathy 12.9%, glaucoma 12.6%, corneal scar 14.0%, Steven Johnson syndrome 9.0%, retinopathy of prematurity 1.1%) and not preventable in 50.5% (retinitis pigmentosa 15.1%, congenital ocular malformations 13.6%, optic atrophy 12.5%, hereditary diseases 8.3%, and age-related macular degeneration 1.1%) patients. Conclusion: High prevalence of retinitis pigmentosa in the population warrants genetic counseling to be taken urgently. Early diagnosis and management is required to prevent blindness arising out of diabetic retinopathy and glaucoma. Newer challenges like congenital ocular malformations and retinopathy of pre-maturity were also seen. Screening for the retinopathy of prematurity should be made mandatory, as it is an increasing problem in countries with improving neonatal care services. Presence of bilateral corneal scar and Steven Johnson syndrome can be avoided by proper health education and inadvertent use of systemic medications.

Peters’ Anomaly

While conducting medical aid in Mozambique, a 41 year old African male presented to our eye clinic complaining of visual impairment. The male was found to have Peters’ anomaly type 2, a rare congenital ocular malformation leading to sensory amblyopia and glaucoma.

Mutation analysis of PAX6 gene in three Chinese families with aniridia

Background Human paired box gene 6 (PAX6) encodes a transcriptional regulator.It is essential for eye and brain morphogenesis.Mutation of PAX6 gene is responsible for many congenital ocular malformations,such as aniridia.Aniridia is a autosomal dominant inheritance mode. Objective In this study,PAX6 gene mutation was analyzed in three Chinese families with aniridia through polymerase chain reaction (PCR) and sequencing. Methods The blood specimens were collected from 5 suffers and normal individuals of 3 aniridia families to extract DNA.The sequences of extron 4-13 were designed based on PAX6 gene.The primer was amplified by PCR and sequenced and compared with the known PAX6 gene sequence.This study complied with Declaration of Helsinki and approved by ethic committee of Sichuan University.Written informed consent was obtained from each individual before any medial examination. Results There were 5 suffers in the 3 families.A heterozygous mutation (c.718 C＞T) in PAX6 gene was identified in 2 patients of family A.This mutation caused an amino acid substitution of arginine to termination codon at position 240 ( p.Arg240X) of PAX6 protein.No similar change in the normal families.No any the alteration of PAX6 gene was detected in family B whatever suffers and normal individuals.In family C,a deletion mutation of c.331 delG ( p.Val111 SerfsX13 ) in PAX6 gene was found.The deletion of one base caused frame shift mutation of PAX6 protein,and no such mutation was seen in other families. Conclusions Mutation of PAX6 gene appeares to be causative mutations of the disease in family A and C. Key words: Human paired box gene; Aniridia; Polymerase chain reaction; Gene mutation

This issue of Acta, printed and electronic

This issue of Acta, printed and electronic

High Frequency Of Submicroscopic Chromosomal Deletions in Patients with Idiopathic Congenital Eye Malformations

The purpose of this study was to evaluate the clinical usefulness of the array comparative genomic hybridization technique for the genetic analysis of patients with congenital ocular malformations. Laboratory investigation. This was a multicenter study. Samples were collected from 37 patients with negative results for the routine diagnostic work-up, including normal karyotype and mutation analysis of appropriate genes. Samples from both parents also were tested. High-resolution genome-wide Agilent 244K oligoarray (Agilent Technologies) was applied. Confirmation of the results was obtained with independent techniques. Causal deletions were identified in 5 (13%) patients, affecting OTX2, FOXC1 and VPS13B (COH1), the downstream regulatory region of PAX6, and a 1,5 Megabases de novo deletion on chromosome 16. This high frequency of causal submicroscopic chromosomal aberrations in patients with congenital ocular malformation warrants implementation of array comparative genomic hybridization in the diagnostic work-up of these patients. Moreover, this screening technique broadens the phenotypic and mutational spectrum associated with genes known to cause congenital ocular malformation.

Anomalies oculaires fœtales : apport de l’imagerie anténatale en résonance magnétique

Congenital ocular malformations are uncommon and require prenatal diagnosis. Severe anomalies are more often detected by trained teams and minor anomalies are more difficult to identify and must be systematically sought, particularly when multiple malformations or a family and maternal history is known. The prenatal diagnosis-imaging tool most commonly used is ultrasound but it can be completed by magnetic resonance imaging (MRI), which contributes crucial information. Fetal dysmorphism can occur in various types of dysfunction and prenatal diagnosis must recognize fetal ocular anomalies. After systematic morphologic ultrasound imaging, different abnormalities detected by MRI are studied. Classical parameters such as binocular and interorbital measurements are used to detect hypotelorism and hypertelorism. Prenatal ocular anomalies such as cataract microphthalmia, anophthalmia, and coloboma have been described. Fetal MRI added to prenatal sonography is essential in detecting cerebral and general anomalies and can give more information on the size and morphology of the eyeball. Fetal abnormality detection includes a detailed family and maternal history, an amniotic fluid sample for karyotype, and other analyses for a better understanding of the images. Each pregnancy must be discussed with all specialists for genetic counseling. With severe malformations, termination of pregnancy is proposed because of risk of blindness and associated cerebral or systemic anomalies. Early prenatal diagnosis of ocular malformations can also detect associated abnormalities, taking congenital cataracts that need surgical treatment into account as early as possible. Finally, various associated syndromes need a pediatric check-up that could lead to emergency treatment.

Clinical and molecular aspects of aniridia

Aniridia is a severe, congenital ocular malformation inherited in an autosomal-dominant fashion with high penetrance and variable expression. Eye morphogenesis in humans involves a molecular genetic cascade in which a number of developmental genes interact in a highly organized process during the embryonic period to produce functional ocular structures. Among these genes, paired box gene 6 (PAX6) has an essential role as it encodes a phylogenetically conserved transcription factor almost universally employed for eye formation in animals with bilateral symmetry, despite widely different embryological origins. To direct eye development, PAX6 regulates the tissue-specific expression of diverse molecules, hormones, and structural proteins. In humans, PAX6 is located in chromosome 11p13, and its mutations lead to a variety of hereditary ocular malformations of the anterior and posterior segment, among which aniridia and most probably foveal hypoplasia are the major signs. Aniridia occurs due to decreased dosage of the PAX6 gene and exists in both sporadic and familial forms. The mutations are scattered throughout the gene and the vast majority of those reported so far are nonsense mutations, frameshift mutations, or splicing errors that are predicted to cause pre-mature truncation of the PAX6 protein, causing haploinsufficiency. Here we review the data regarding the mechanisms and the mutations that relate to aniridia.

Congenital ocular malformations (lens subluxation, pupillary displacement, cataract, myopia) and classic galactosaemia associated with Q188R and /or G1391A mutations

Observations of multiple ocular malformations together with heterozygosity for galactosaemia in siblings and homozygosity in one child are highly unusual. In these case histories, a series of investigations in one family are reported. Members of a family of two brothers and one sister and their children were pre- and post-surgically examined over several years. Blood examination was carried out in a laboratory specializing in investigation into genetic diseases (Dr Podskarbi, Munich). Two brothers and one sister suffered from cataract-induced visual deterioration at 38, 34 and 35 years of age, respectively. All three siblings reported having had bilateral poor vision since early childhood. The three siblings' parents had no congenital ocular malformations, nor was there any parental consanguinity. One child, the 10-year-old son of the 35-year-old sister, exhibited classic galactosaemia and normal ocular findings. This sister's other child was healthy. All three siblings presented congenital lens luxation, axial myopia, cataract and iridodonesis. In addition, the 34-year-old brother showed unilateral right corectopia and left coloboma adjacent to the optic disc. The 38-year-old brother revealed myopic fundus changes, but no coloboma. The three siblings experienced a distinct increase in visual acuity after cataract surgery. Both eyes of the patients were partially or distinctly amblyopic, respectively. We assume an autosomal-recessive transmission. Molecular genetic examination of the 10-year-old child with classic galactosaemia showed homozygosity for the mutation Q188R with a complete galactose-1-phosphate-uridyltransferase (GALT) deficiency. Because of his galactose-free diet, the child showed normal values for galactose-1-phosphate. The 35-year-old mother showed compound heterozygosity for Q188R and G1391A (D2/G). The 10-year-old boy's father also revealed heterozygosity for galactosaemia caused by GALT deficiency. The two children of the 38-year-old brother were heterozygous for G1391A. They did not show any clinical abnormality. None of the family members had clinical signs of Marfan's syndrome or homocysteinuria. The three siblings' parents were not consanguineous. Patients with worsening cataracts occurring at a pre-senile age should be examined for galactosaemia. We describe for the first time the molecular genetic findings in congenital ectopia lentis et pupillae. Early treatment in conjunction with a galactose-free diet is mandatory in patients with galactosaemia. Members of a family with heterozygosity for galactosaemia should be advised to attend a human genetic consultation.

Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome

Background:We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin β2 subunit...

Authors’ response

We read with interest the letter by Decock et al regarding the rare congenital ocular malformation (orbital cyst and bilateral colobomatous microphthalmos).1 The female child reported was the product of...

Ethnically diverse causes of Walker-Warburg syndrome (WWS):FCMDmutations are a more common cause of WWS outside of the Middle East

Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.

Oculocerebrocutaneous Syndrome: A Case Report

There are many congenital ocular malformations associated with systemic findings. In cases such as oculocerebrocutaneous syndrome, the severity of systemic findings makes diagnosis particularly important. This case report presents a case of this uncommon syndrome and demonstrates the common findings.

Bilateral ocular involvement in encephalocraniocutaneous lipomatosis

We report a case of encephalocraniocutaneous lipomatosis (ECCL), a rare congenital neurocutaneous syndrome, with cutaneous, ocular and neurologic malformations. The key features of ECCL are epibulbar choristomas, nevus psiloliparus, and intracranial lipomas. A full-term newborn presented at birth bilateral conjunctival tumours, right facial papulonodular lesions and an alopecic lesion consistent with lipoma on the right frontoparietal area. Brain imaging studies showed arachnoid cyst, enlarged lateral ventricle, cortical dysplasia, lipoma and leptomeningeal angiomatosis in the right hemisphere. The results were consistent with ECCL. Since ocular and skin involvement is a hallmark of the condition, children with epibulbar congenital lesions and skin lesions suggestive for ECCL should undergo a brain imaging study.

Matthew‐Wood syndrome: Report of two new cases supporting autosomal recessive inheritance and exclusion of FGF10 and FGFR2

We describe two fetal cases of microphthalmia/anophthalmia, pulmonary agenesis, and diaphragmatic defect. This rare association is known as Matthew-Wood syndrome (MWS; MIM 601186) or by the acronym "PMD" (Pulmonary agenesis, Microphthalmia, Diaphragmatic defect). Fewer than ten pre- and perinatal diagnoses of Matthew-Wood syndrome have been described to date. The cause is unknown, and the mode of transmission remains unclear. Most cases have been reported as isolated and sporadic, although recurrence among sibs has been observed once. Our two cases both occurred in consanguineous families, further supporting autosomal recessive transmission. In addition, in one family at least one of the elder sibs presented an evocatively similar phenotype. The spatiotemporal expression pattern of the FGF10 and FGFR2 genes in human embryos and the reported phenotypes of knockout mice for these genes spurred us to examine their coding sequences in our two cases of MWS. While in our patients, no causative sequence variations were identified in FGF10 or FGFR2, this cognate ligand-receptor pair and its downstream effectors remain functional candidates for MWS and similar associations of congenital ocular, diaphragmatic and pulmonary malformations.

Concordant familial segregation of atrial septal defect and Axenfeld–Rieger anomaly in father and son

The association of congenital heart defect and ocular malformations is involved in several genetic syndromes, metabolic diseases and environmental entities. We report here on father and son, both presenting with the combination of atrial septal defect and congenital ocular anomalies in Axenfeld-Rieger anomaly. The son had anterior iridotrabecular dysgenesis and posterior embryotoxon bilaterally, corneal leucoma and marked iridial vascularization at right. The father had bilateral anterior iridotrabecular dysgenesis, posterior embryotoxon and nystagmus, and corneal leucoma at left. No additional malformations were noted in these patients. The Axenfeld-Rieger syndrome seems to be a spectrum of developmental disorders. The present report confirms the existence of a specific Axenfeld-Rieger phenotype associated with congenital heart defect. Atrial septal defect is the anatomic type of congenital heart defect linked to this condition.