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Objectives : To present the clinical features of and diagnostic methods used for macular coloboma (MC), and to analyze the factors associated with best-corrected visual acuity (BCVA) in patients with MC. Methods : A systematic review using the MEDLINE (PubMed), EMBASE, LILACS, and Cochrane databases was performed. The factors associated with BCVA were analyzed. Results : A total of 21 patients (mean age at diagnosis, 18.1 ± 14.6 years) with 36 eyes affected by MC (5 unilateral, 16 bilateral) were included in the study. All 21 patients (100%) had undergone a good-quality fundus examination. The size of the MC lesions ranged from 1.0 × 1.2 to 4.0 × 4.0 disc diameters (DD). Twenty-seven (73%) eyes had pigmented MC, seven (19%) had non-pigmented MC, and one (3%) had an unspecific type. The diagnosis was confirmed using spectral-domain optical coherence tomography (SD-OCT) in 16 (43.2%) eyes. A positive correlation was found between BCVA and the type of MC (β = 0.876, p = .006) and abnormal eye movement (β = 0.087, p = .018), and a negative correlation was found between BCVA and a contributory medical history of ventricular septal defect (β = -0.327, p = .001). Conclusions : Pigmented MC was the most common type and had the highest possibility of causing impaired vision in the affected eyes. Additionally, joint examinations should be applied for diagnostic confirmation of MC. Furthermore, fundoscopy, electroretinogram, electrooculography, fundus fluorescein angiography, and SD-OCT are all critical for differential diagnosis of MC-like lesions.

Aims: To describe the clinical features, visual acuity and causes of ocular morbidity in children (0-18 years) with microphthalmos, anophthalmos, and coloboma (MAC) from North India., Methods: A retrospective study conducted between October 2017 and September 2018 in three tertiary eye institutes, part of the Bodhya Eye Consortium with consensus led common pro formas. Children with complete clinical data and without syndromic/systemic involvement were included. The clinical phenotype was divided into isolated ocular coloboma (CB), coloboma with microcornea (CBMC), colobomatous microphthalmos (CBMO), non-colobomatous microphthalmos (MO) and anophthalmos (AO)., Results: A total of 532 children with MAC were examined. Seventeen records were excluded due to incomplete data (0.2%). 515 children (845 eyes) were included: 54.4% males and 45.6% females. MAC was unilateral in 36% and bilateral in 64%. CB, CBMC, CBMO, MO and AO were seen in 26.4%, 31%, 22%, 8% and 12.5% of eyes, respectively. Nystagmus was found in 40%, strabismus in 23%, cataract in 18.7% and retinal detachment in 15%. Best-corrected visual acuity (BCVA) of <3/60 was seen in 62.4% eyes. Blindness (BCVA <3/60 in better eye) was seen in 42.8% of bilateral patients. Those with microcornea or microphthalmos with coloboma had worse BCVA (p<0.001). There were regional differences in the type of MAC phenotype presenting to the three institutes., Conclusion: The MAC group of disorders cause significant ocular morbidity. The presence of microcornea or microphthalmos with coloboma predicts worse BCVA. The variation of the MAC phenotype with the district of origin of the patient raises questions of aetiology and is subject to further studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype-ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype-phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment ( p -value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features. Animal studies indicate BRPF1 as an important mediator in brain development. However, only 5 of 22 previously reported patients show structural brain abnormalities. We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome., (Copyright © 2019. Published by Elsevier Masson SAS.)

Purpose: The aim of the study was to report prevalence, ocular outcome, neurological characteristics, cognitive and behavioural problems in children with optic disc coloboma (ODC)., Methods: This was a population-based, cross-sectional study of 31 children between 2 and 18 years of age diagnosed with ODC. The children were part of a larger cohort of 184 children with congenital optic disc malformations. Clinical ophthalmological examinations, neurological assessments, behavioural and developmental screening were performed., Results: The prevalence of ODC was 8.9/100 000 children. Of the 31 patients, 18 had unilateral ODC (p = 0.21). The best-corrected visual acuity (BCVA) in the ODC eye ranged from blindness to 1.3 (median 0.3). BCVA was 0.82 in eyes with an isolated ODC (range 0.4-1.3) and 0.15 (range 0-0.5) in eyes with concurrent macular involvement (p < 0.0001). Nystagmus was observed more often in patients with bilateral ODC (9/13 versus 3/17, p = 0.004). Two patients had retinal detachment. Behavioural/psychological screening was performed in 21 patients with severe deficits identified in six cases. Intellectual disability was present in seven patients. Neurological dysfunction was diagnosed in 8/22 cases. All of the above children had already systemic diagnoses before the ODC diagnosis was made., Conclusions: ODC was the second most common optic disc malformation in this cohort after optic nerve hypoplasia. The children had a wide range of ocular comorbidity. An isolated ODC without macular involvement was not associated with profound vision loss. The ability of screening in the regular child care centres to diagnose extraocular comorbidities was very good and referral to a paediatrician appears redundant in cases of normal development., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Rationale: The case with congenital macular coloboma and cataract was rarely reported, and the pathogenic gene of the disease is still not clear. Moreover, it is difficult to improve the visual acuity of the eye with this disease., Patient Concerns: An 11-year-old boy presented low visual acuity and horizontal nystagmus in both eyes. Ophthalmologic examination showed the patient with bilateral congenital coloboma and cataract. The visual acuity of the patient improved slightly after cataract surgery. Heterozygous mutations of frizzled-4 (FZD4) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) were identified by next-generation sequencing in this case., Diagnosis: Congenital macular coloboma and cataract of both eyes., Interventions: We performed the standard phacoemulsification and intraocular lens implantation on both eyes of the patient for the treatment of congenital cataract, and then followed up the fundus lesions regularly., Outcomes: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, but the vision of this patient was still very poor postoperatively. Furthermore, the heterozygous mutations of FZD4 and NOD2 were found in this patient., Lessons: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, and heterozygous mutations of FZD4 and NOD2 may be involved in the occurrence of congenital macular coloboma and cataract.

Defects in choroid fissure (CF) formation and closure lead to coloboma, a major cause of childhood blindness. Despite genetic advances, the cellular defects underlying coloboma remain poorly elucidated due to our limited understanding of normal CF morphogenesis. We address this deficit by conducting high-resolution spatio-temporal analyses of CF formation and closure in the chick, mouse and fish. We show that a small ventral midline invagination initiates CF formation in the medial-proximal optic cup, subsequently extending it dorsally toward the lens, and proximally into the optic stalk. Unlike previously supposed, the optic disc does not form solely as a result of this invagination. Morphogenetic events that alter the shape of the proximal optic cup also direct clusters of outer layer and optic stalk cells to form dorsal optic disc. A cross-species comparison suggests that CF closure can be accomplished by breaking down basement membranes (BM) along the CF margins, and by establishing BM continuity along the dorsal and ventral surfaces of the CF. CF closure is subsequently accomplished via two distinct mechanisms: tissue fusion or the intercalation of various tissues into the inter-CF space. We identify several novel cell behaviors that underlie CF fusion, many of which involve remodeling of the retinal epithelium. In addition to BM disruption, these include NCAD downregulation along the SOX2 + retinal CF margin, and the protrusion or movement of partially polarized retinal cells into the inter-CF space to mediate fusion. Proximally, the inter-CF space does not fuse or narrow and is instead loosely packed with migrating SOX2 + /PAX2 + /Vimentin + astrocytes until it is closed by the outgoing optic nerve. Taken together, our results highlight distinct proximal-distal differences in CF morphogenesis and closure and establish detailed cellular models that can be utilized for understanding the genetic bases of coloboma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To determine the child's and parental perception of functional visual ability (FVA), vision-related and health-related quality of life (VR-QoL, HR-QoL) in children with microphthalmia/anophthalmia/coloboma (MAC)., Methods: Between June 25, 2014, and June 3, 2015, we carried out a cross-sectional observational study at Moorfields Eye Hospital, London, UK, enrolling 45 children 2-16 years of age with MAC attending our clinics, and their parents. To assess FVA, VR-QoL, and HR-QoL we asked participants to complete three validated tools, the Cardiff Visual Ability Questionnaire for Children (CVAQC), the Impact of Vision Impairment for Children (IVI-C) instrument, and the PedsQL V 4.0. The main outcome measures were the FVA, VR-QoL, and HR-QoL scores, reported by children and parents., Results: In children with MAC, FVA is moderately reduced, with a median CVAQC score of -1.4 (IQR, -2.4 to 0.4; range, -3.0 [higher FVA] to +2.8 [lower FVA]). VR-QoL and HR-QoL are greatly reduced, with an IVI-C median score of 63 (IQR, 52-66; normal VR-QoL, 96), a median self-reported PedsQL score of 77 (IQR, 71-90; normal HR-QoL, 100) and parental score of 79 (IQR, 61-93), and a family impact score of 81 (67-93). Psychosocial well-being scores are lower than physical well-being scores. Parents and children have a different perception of the impact of the condition on the child's HR-QoL., Conclusions: MAC has a significant impact on a child's FVA and QoL, similar to that described by children with acute lymphoblastic leukaemia and chronic systemic conditions. Children and families may benefit from psychosocial support., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Cryptophthalmos (CO, MIM: 123570) is rare congenital anomalies of eyelid formation, which can occur alone or in combination with multiple congenital anomalies as part of Fraser syndrome (FS) or Manitoba Oculotrichoanal syndrome. Causal mutations have been identified for these syndromes but not in the isolated cases. Here, we described two patients from two unrelated Chinese families: one with unilateral isolated CO, while the other with unilateral CO and renal agenesis. A novel homozygous mutation (c.6499C>T: p.Arg2167Trp) and compound heterozygote mutations (c.15delG; c.6499C>T: p.Arg2167Trp) in FREM2 (NM&#95;172862) were identified for the two patients, respectively. The deletion mutation c.15delG resulted in a frameshift and triggered the nonsense-mediated mRNA decay. For the shared missense mutation, p.Arg2167Trp altered a conserved residue and was predicted to affect protein structure by in silico analysis. Functional analysis revealed that Arg2167Trp mutant decreased its interaction with FRAS1 related extracellular matrix 1 (FREM1) and impaired the function of the FRAS1-FRAS1 related extracellular matrix 1 (FREM2)-FREM1 ternary complex required for normal embryogenesis. Furthermore, considering that mutation (c.5914C>T: p.Glu1972Lys) in FREM2 causes FS, a severe systemic disorder, we also compared these two different missense mutations. Our results showed that p.Arg2167Trp had a weaker effect in interrupting interactions between FREM2 and FREM1 than FS-associated missense mutation p.Glu1972Lys. Overall, our data demonstrate that the homozygous mutation p.Arg2167Trp in FREM2 causes isolated CO, which will facilitate our better understanding of the molecular mechanisms underlying the disease.

Purpose: To quantify the improvements in visual performance for both distance and near tasks attained by children with bilateral chorioretinal coloboma (CRC) with use of low-vision aids (LVAs)., Methods: This was a hospital-based, cross-sectional, interventional case series of children with bilateral CRC. Demographic data were collected through a structured questionnaire and review of medical records. Distance and near best-corrected visual acuity, contrast sensitivity, and reading speed were evaluated with refractive correction alone and with the use of LVAs (Keplerian telescopes for distance; handheld magnifiers and a tinted lens [400 nm filter] for near). Effects are presented as medians of differences with 95% binomial-exact confidence intervals., Results: Six children were included (median age, 11.5 years; range, 7-17 years), of whom 5 were already using LVAs on a daily basis. The use of a Keplerian telescope achieved a significant median improvement in distance best-corrected visual acuity of 0.75 logMAR (95% CI, 0.20-1.20). Contrast sensitivity was also improved across all tested spatial frequencies. Use of near LVAs resulted in a significant median improvement in near reading acuity of 0.47 logRAD (95% CI, 0.28-0.90). Critical print size and reading speed at N10 were also improved., Conclusions: LVAs enable meaningful improvements in the visual performance of children with bilateral CRC, allowing noteworthy increases in distance and near visual acuities as well as good reading speeds at small print sizes., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Objective: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD., Patients and Methods: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients., Results: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm., Conclusion: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

We describe a surgical technique for the correction of isolated congenital lenticular coloboma associated with high corneal astigmatism. Transscleral fixation of the capsular bag with a single eyelet Cionni capsular tension ring was followed by in-the-bag implantation of a toric intraocular lens (IOL). This lead to complete correction of the lenticular defect and perfect alignment of the toric lens. In this case, the child attained an unaided distance visual acuity of 20/30 following amblyopia therapy and a well-aligned toric IOL at 12 months of follow-up. This technique can be used in cases with concomitant lenticular coloboma and significant corneal astigmatism., Competing Interests: There are no conflicts of interest

The authors discuss the association of persistent fetal vasculature and ocular coloboma in three children. They explore the possibility of a cause-effect relationship between these disorders, and link them together as a broader posterior dysgenesis. [J Pediatr Ophthalmol Strabismus. 2017;54:e77-e80.]., (Copyright 2017, SLACK Incorporated.)

We report two cases of bilateral asymmetric optic disc coloboma (ODC) in siblings. The index patient is a 9-year-old Nigerian girl with severe cognitive deficit who presented with a poor vision of 3 years' duration. She had a history of childhood febrile convulsions and delayed developmental milestones. Her visual acuity could not be assessed because she had a cognitive deficit and expressive aphasia. Ocular examination revealed a very large excavated right optic disc with only a strip of remnant neuro-retinal rim superiorly, and a smaller left optic disc with inferior disc excavation, superior wedge of the pink neuro-retinal rim as well as a temporal optic disc pit. No systemic features of syndromes associated with ODCs and intellectual disability were present in both patients. The younger sibling an 8-year-old girl later presented to the eye clinic with a 5-month history of poor vision in the left eye. Ocular examination revealed visual acuity of 6/6 in the right eye and counting fingers in the left eye. Dilated binocular indirect ophthalmoscopy revealed a right large excavated colobomatous disc and a left small disc with infero-temporal disc coloboma.

CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease-causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL., (© 2017 Wiley Periodicals, Inc.)

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245&#95;6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non-syndromic forms of anophthalmia-microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968-2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males., (© 2016 Wiley Periodicals, Inc.)

A 27-year-old woman presented with a history of long-standing poor vision in both eyes. Ophthalmologic examination after pupillary dilatation revealed bilateral lens coloboma situated in the inferotemporal quadrant. No associated ocular abnormalities were seen, except amblyopia. A bicuspid aortic valve was observed during echocardiography during systemic evaluation. Lens coloboma usually occurs unilaterally; however, bilateral lens coloboma which is isolated or associated with other ocular malformations is also encountered. This is the first description of bilateral isolated lenticular coloboma associated with bicuspid aortic valve. Although the association between bicuspid aortic valve and lens coloboma may be an incidental finding, they may be components of an unknown syndrome.

Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examination revealed a well-demarcated circular paramacular lesion in both eyes. As macular coloboma and achondroplasia are developmental disorders, the funduscopic examination is required in patients with achondroplasia.

A 5-year-old boy was referred to our clinic due to an abnormal visual acuity test at school. His corrected visual acuity was counting fingers in the left eye. A nasal side deficiency of the lens substituted by a membrane was found. Lens coloboma was diagnosed. After making a 3 mm limbal incision, the colobomatous lens was removed by anterior continuous curvilinear capsulorhexis and lens aspiration. Posterior capsulorhexis and anterior vitrectomy on the side of the lens was performed to prevent posterior capsular or anterior hyaloid opacity. As the defect in the lens was very large, intracapsular placement of an intraocular lens was not feasible. A three-piece acrylic soft intraocular lens was placed in the ciliary sulcus. Since amblyopia was diagnosed by poor corrected visual acuity as 20/800 1 month after the operation, occlusion therapy with correcting eyeglasses was started at 6 h a day on the contralateral eye. The patient's corrected visual acuity improved to 20/125 7 months after the operation., (2015 BMJ Publishing Group Ltd.)

Purpose: We reported the clinical and echographic features of colobomas, prevalence of retinal detachment, and associated visual acuity in these patients., Methods: The study is a nonrandomized consecutive case series of 140 colobomatous eyes in 98 patients (age range, 0-83 years). Coloboma depth, width, volume, and relative coloboma excavation (coloboma depth/axial length) were measured using standardized echographic images. The presence of structural and other ocular abnormalities was noted. The clinical and echographic findings present were correlated with visual acuity of the patient. In addition, these features were correlated with the presence or absence of retinal detachment., Results: Increased relative coloboma excavation was significantly associated with an increased risk of retinal detachment. A relative coloboma excavation (ratio of coloboma depth to axial length) greater than 0.15 was associated with an increased risk of retinal detachment (52%), compared to those with a relative coloboma excavation less than 0.15 (23%, P = 0.014). The presence of any structural abnormality and the presence of a retrobulbar cyst were associated with increased risk of retinal detachment and severe visual impairment (worse than 20/200). Increased coloboma depth, width, volume, and relative coloboma excavation were not associated with increased risk of severe visual impairment., Conclusions: Clinical and echographic features of colobomas may be used in predicting the risk of retinal detachment. Measuring relative coloboma excavation upon presentation may alter follow-up and assist in the diagnosis of retinal detachment.

A 13-year-old male presented with decreased vision and squint from childhood. He had bilateral large colobomata at the macula in each eye, the one on the right being larger than the left. The disc was dragged temporally with straightening of the temporal retinal vessels. This is a case report of bilateral large macular coloboma and serves to report its association with a temporally dragged disc and straightened temporal retinal vessels. A dragged disc if present with a colobomatous defect at the macula may strengthen the case for diagnosis of macular coloboma and help exclude other differentials.

We report the case of a 46-year-old hypertensive Japanese female with renal insufficiency related to unilateral renal hypoplasia. The patient was found to have developed paraganglioma in the retroperitoneal space over a 5-year period. Catecholamine-producing tumors are not usually recognized as conditions associated with renal hypoplasia. Our long-term observation of the patient eventually led us to the diagnosis of paraganglioma. In hypertensive patients with chronic kidney disease, not only the renin-angiotensin-aldosterone system but also catecholamine activity may be involved, particularly in the patients whose cases are complicated with unilateral renal hypoplasia.

Background: Otodental syndrome is a rare condition characterised by globodontia, and sensorineural high frequency hearing loss. To date, only 20 cases of otodental syndrome have been reported., Case Report: A 6 year-old girl presented with a chief complaint of delay in the eruption of primary canines. Following clinical, radiographic and audiologic evaluations, the patient was diagnosed with otodental syndrome., Conclusion: Globodontia is a diagnostic feature of the otodental syndrome, which often provides the path to discovery of the associated hearing loss. Missing teeth, arch-size discrepancies, chewing problems and teething disturbances are the other major complications.

Renal hypoplasia is a congenital anomaly, the etiology of which is not yet fully known. Genetic studies have shown that certain genes, in utero environmental factors and molecular mechanisms have a role in the identification ofnephron formation and kidney size. The coexistence of bilateral renal hypoplasia and optic disc coloboma is observed in papillorenal syndrome, which caused by the mutation of the PAX2 gene. In the case presented in this article, bilateral renal hypoplasia and optic disc coloboma have been detected to coexist. The analysis of the PAX2 gene, which was carried out with an eye to the papillorenal syndrome, did not reveal any mutations. However, de novo t(2;15) (q31; q26) (reciprocal translocation) was detected in chromosome analysis. As far as we know, there are not any publications focusing on the clinical importance of this type of translocation. In cases with renal hypoplasia and optic disc coloboma, the possibility of a de novo translocation between chromosomes 2 and 15 should be considered.

During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via β-catenin mediated Pdgfrα and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Colobomas are the major ophthalmic manifestation of CHARGE syndrome. Ophthalmological advice may be sought for an infant diagnosed with CHARGE syndrome presenting with coloboma, and electrophysiology can be particularly useful in assessing retinal and cortical function at an early age. Here we describe electrophysiology findings in a four-week-old infant born with bilateral coloboma, more extensive in the right eye, as part of CHARGE syndrome. The left eye showed robust ERGs indicating near-normal rod and cone function. The right eye ERG amplitudes were relatively reduced being around one half to two-thirds that of the left eye ERGs. Flash VEPs were present from both left and right eyes, but the right eye VEP was smaller and delayed relative to that of the left eye. By 5 years of age, right eye acuity was approximately 6/1000 and left eye acuity was 6/12 (Cardiff cards). In cases such as this, it is helpful to give parents a reasonable prediction of visual outcome as soon as possible, allowing instigation of appropriate management and permitting parents to begin to come to terms with the diagnosis. Electrophysiology can provide valuable information on visual function when behavioural testing is limited by the child's ability to co-operate, such as during the early weeks of life.

Congenital abnormalities of the optic disc are not so rare. The etiology for the most of them is unknown. Visual acuity of affected eye may be minimally or severely affected, depending on the extent of lesion. All of these conditions can be unilateral or bilateral. Children who have unilateral optic disc abnormalities generally present during the preschool years with sensory esotropia. Visual acuity may be unaffected like in optic disc pit, optic disc drusen, fibre medullares, ect. However, during the evolution they may cause a decrease in visual acuity like serous retinal detachment in optic disc pit, atrophy or subretinal neovascularisation in optic disc drusen. Some of them like fibre medullares needs only a good diagnose and they do not have any evolution. Fluorescein angiography and ultrasonography may be crucial diagnostic procedures to discover some of them, like optic disc drusen. Optic disc abnormalities may be associated with other congenital disorders of the eye and often central nervous system malformations. Secondary they may be associated retinal detachment, retinochisis, macular edema, choroid neovascularisation and lipid exudation. Some of these conditions may be found on routine ophthalmologic exam such as optic disc drusen and fibre medullares and often are diagnostically problem. The aim of our study was to present some of our cases with different optic disc abnormalities such as fibre medullares, optic disc coloboma, hypoplasio disc, optic disc drusen and optic disc pit.

Children with CHARGE syndrome frequently develop moderate to severe behavior difficulties and are often diagnosed with obsessive-compulsive disorder, attention deficit disorder, Tourette syndrome, and autism. Anecdotal reports have indicated that sleep is also affected. However, the prevalence and types of sleep disturbance have not been identified. This study investigated sleep disturbances in 87 children with CHARGE syndrome, aged 6 to 18 years (mean 11y, SD 3y 8mo). There were 52 males and 35 females represented. Instruments included measures of sleep (Sleep Disturbances Scale for Children [SDSC]), behavior (Developmental Behaviour Checklist [DBC]), and carer well-being (Malaise Inventory). On the SDSC, 57.5% received scores considered significant for sleep disturbances, with disorders of initiating and maintaining sleep, sleep breathing, and sleep-wake transition being the most common. The SDSC was significantly correlated with the DBC (p=0.010) and the Malaise Inventory (p=0.003). Regression analysis found that both problem behavior and sleep disturbances contributed to the prediction of scores on the Malaise Inventory. Being both deaf and blind (p=0.001), experiencing frequent middle-ear infections (p=0.015), and starting to walk at an older age (p=0.007) were associated with more sleep disturbance. Craniofacial anomalies were not. The study highlights the importance of addressing the sleep difficulties associated with CHARGE syndrome relating both to airway management and to disorders of initiating sleep.

Objective: To describe the features at the margin of the choroidal colobomas as evaluated clinically and by optical coherence tomography (OCT)., Design: Prospective observational case series., Participants: Seventeen patients (30 eyes) that presented to the outpatient department of a tertiary care center., Testing: Clinical examination and OCT testing of the 30 eyes., Main Outcome Measures: Description of OCT features of the margin of the choroidal colobomas., Results: Histologically, there is no normal choroid, retinal pigment epithelium, or retina overlying choroidal colobomas; rather, the overlying tissue is an extension of the retina called the intercalary membrane (ICM). In these patients, OCT showed that transition from normal retina to the ICM could be categorized as abrupt or gradual and also showed that the inner neurosensory retinal layers continued as the ICM, whereas the outer layers could not be traced beyond a point. In some cases with apparently attached retina, subclinical retinal detachments were identified along the margin of the coloboma. In cases with retinal detachment, OCT allowed for identification of the precise site of communication between the sub-ICM space and subretinal space at the locus minoris resistentiae. The margin of the choroidal coloboma, in some cases, showed the appearance of a hump owing to inward turning of the retinochoroidal layers with thickening of the layers at the margin. In small colobomas, OCT revealed the ICM thickness comparable to normal retina but showed structural alterations. Fundus lesions that were clinically labeled forme fruste of choroidal coloboma seemed to have normal retinal thickness and layering on OCT. In 1 patient, a temporal optic pit was associated with the forme fruste choroidal coloboma in 1 eye; the fellow eye had a typical choroidal coloboma., Conclusions: Optical coherence tomographic evaluation of the margins of choroidal colobomas helps in understanding the transition from retina to ICM, detects subclinical retinal detachments, and aids in identifying the site of communication between the sub-ICM space and the subretinal space in eyes with retinal detachment.

Attention deficit hyperactivity disorder (ADHD) is characterized by hyperactivity, inattention, and impulsivity. The coloboma mouse model of ADHD exhibits profound hyperactivity. To determine whether coloboma mice exhibit other signs of ADHD, we assessed latent inhibition as a test of attention, and impulsivity in a delayed reinforcement paradigm. Latent inhibition was present in control mice but was disrupted in coloboma mice. Coloboma mice also exhibited impaired performance on the delayed reinforcement task and were not able to wait as long as control mice to obtain the greater reinforcer. Because norepinephrine mediates hyperactivity in coloboma mice, we examined the role of norepinephrine in disrupted latent inhibition and impulsivity. Reduction of norepinephrine with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) restored latent inhibition but did not ameliorate impulsivity. In summary, coloboma mice exhibit hyperactivity, inattention as determined by latent inhibition, and impulsivity, and norepinephrine mediates hyperactivity and inattention but not impulsivity in these mice.

Context: Vitreous surgery has been advocated as an alternative treatment of selected retinal detachments with choroidal colobomas., Aim: To study the long term anatomical and visual outcome of choroidal coloboma with retinal detachment managed by pars plana vitrectomy with silicone oil tamponade., Setting and Design: Retrospective study conducted in a tertiary eye care hospital., Materials and Methods: Fourty two eyes of 40 patients with retinal detachments related to coloboma of the choroid without any peripheral breaks were analyzed. All eyes underwent pars plana vitrectomy with internal tamponade using silicone oil. Endolaser was performed along the coloboma border. Silicone oil was removed in 50% of patients. The main outcome measures were retinal reattachment and visual recovery. SPSS (Statistical Package for the Social Science), version 10.0 was used for analysis., Results: The retina in all cases (100%) undergoing vitrectomy were completely reattached intra-operatively. After a mean follow-up of 14 months, 37 (88.1%) eyes had attached retina. The best corrected visual acuity was 10/200 or better in 33 (78.4%) eyes. The best corrected visual acuity improved from a preoperative median of counting fingers (range 20/40 to perception of light) to median best corrected visual acuity of 20/200 (range 20/40 to perception of light) at the end of 6 months. Of the 50% (21) cases that underwent silicone oil removal, two eyes had re-detachment of retina., Conclusion: Pars plana vitrectomy along with silicone oil tamponade for retinal detachment related to choroidal coloboma improves the long-term anatomical and visual outcome.

The behaviors and medical problems in 27 persons with CHARGE syndrome were studied, because it was hypothesized that their behavior might be partly dependent on the heterogeneous medical status. With the exception of more tics, cardiac surgery was associated with positive behaviors: less withdrawn behavior, better mood, and a more easy temperament. Tube feeding was also related to positive behavior, since participants with a history of tube feeding showed less intense behavior. Cerebral deficits were associated with three problem behaviors: more intense and withdrawn behavior and a worse mood. Deaf-blindness was associated with developmental delays in expressive and overall communication level, and recurrent middle ear infections correlated with delays in written language. Of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the participants with regard to the number of behavioral problems. Participants with heart surgery especially, had less behavior problems. The number of operations and hospitalizations was not associated with behavior, but the total length of the hospitalizations was. Long hospital stays were associated with less problem behavior, especially internalizing behaviors. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. Age effects were reflected in older participants, who showed more internalizing problems. Heart surgery and hospitalization may be protective factors, but the protection might not be the actual surgery or hospital stay, as there may be other variables that are the actual cause, such as reduced vitality or altered parent child interactions after heart surgery. The study could not confirm a significant association between medical conditions and autism found in previous studies., (Copyright 2006 Wiley-Liss, Inc.)

Purpose: Macular schisis or detachment is frequently observed in eyes with optic pits or colobomas. Although spontaneous resolution of the maculopathy has been reported, concurrent changes in the optic nerve coloboma have not. We report three cases of atypical optic nerve colobomas in which dynamic optic nerve changes coincide with the development and subsequent resolution of the associated maculopathy., Methods: We reviewed the records of three patients with dynamic optic nerve changes associated with maculopathy. All patients were observed for at least 6 months. Fundus photography and fluorescein angiography were used to document the optic nerve and macular changes., Results: Three patients were noted to have macular detachments without apparent optic nerve excavation. With observation, the maculopathy spontaneously resolved in each case. We documented concurrent optic nerve changes whereby atypical optic nerve colobomas became apparent over several months in all cases. In one case, we noted the simultaneous development of maculopathy in association with obscuration of a prior disc anomaly. None of the eyes had a posterior vitreous detachment. We could not identify any associated systemic conditions or reproduce the findings with external stimulation. Initial Snellen acuity ranged from 20/60 to 20/200. Final Snellen acuity ranged from 20/20 to 20/40., Conclusions: Fluctuating optic nerve changes may occur in the setting of atypical optic nerve coloboma and associated maculopathy. In cases of macular schisis or detachment where an optic nerve coloboma is not readily apparent, and no other causes are identified, consideration of a period of observation prior to therapeutic intervention seems appropriate.

Congenital bony fusion of the maxilla and mandible is a rare condition. Two classifications were previously proposed dealing exclusively with craniofacial malformations. Most of the reported cases to date represent either aglossia-adactylia or hemifacial microsomia syndromes. We report a young girl with bony syngnathia associated with multiple defects (severe microcephaly, coloboma, vertebral segmentation defects), growth and mental delay. This patient is very similar to the patient described by Dobrow in 1983 and confirms the existence of this extremely rare disorder.

Background: In eyes with severe organic defects the question arises if amblyopia therapy makes sense., Patients and Methods: Three children are presented in whom despite severe organic eye diseases amblyopia therapy was tried. The first child had a unilateral large macular scar secondary to retinoblastoma treatment, the second a unilateral severe optic nerve atrophy secondary to an orbital hemangioma, and the third a unilateral large optic nerve coloboma., Results: In the first case a reading visual acuity of 0.9 was achieved by occlusion therapy and in the second a reading visual acuity of 0.5. In the third case occlusion lead to alternation of the divergent strabismus (child too strongly retarded for reliable visual acuity measurements)., Conclusions: During the sensitive phase, amblyopia therapy is also indicated in eyes with severe organic defects since good visual acuities can be achieved.

Described in the paper are the results of ophthalmologic, ultrasound and radiological examinations of 3 girls with the Aicardi syndrome. It was for the first time, that an expansion of the optic-nerve disk excavation was described in patients with the above syndrome; such expansion was conditioned by trans-synaptic neuron degeneration induced by lesions to optic radiation in view of prenatal of encephaloplastic processes. The changing brain white substance as projected by optic radiation was detected in all children by computer and magnetic resonance tomography. Besides, other anomalies of the optic nerve (bindweed syndrome, coloboma) and of the retina are elucidated. Finally, the pathogenesis and differential diagnostics of the Aicardi syndrome are under discussion.

Purpose: To determine the ocular and systemic anomalies associated with optic disc colobomas., Patients and Methods: The records of patients with a diagnosis of isolated optic disc coloboma and chorioretinal coloboma with optic disc involvement were retrospectively reviewed., Results: Fifteen patients were included in the study. Of the 30 eyes, the optic disc and choroid were involved in 18, an isolated disc coloboma was present in 5, a normal optic disc was present in 4, and the optic disc could not be identified because of extreme microphthalmia in 1. Of the optic discs outside the fundus colobomas, 1 had an abnormal shape and 1 had optic atrophy and hypoplasia. Eight patients had bilateral but asymmetric involvement of the optic nerve with the coloboma. Fourteen eyes of 9 patients were microphthalmic. Nine eyes of 6 patients had microcornea. One patient had a nonrhegmatogenous retinal detachment at the time of diagnosis. One eye had a retrobulbar cyst with microphthalmia. Eight (53%) of the patients had sensory strabismus. Two patients had unilateral cortical lens opacities. Associated systemic findings were present in 6 (40%) of the 15 patients., Conclusions: Optic disc colobomas have a wide variety of presentations. Poor visual acuity was observed mostly in eyes with macular involvement and microphthalmia.

Background: Paramacular coloboma (plural: colobomata) is a solitary oval football or torpedo-shaped chorioretinal lesion located temporal to the fovea in one or both eyes. Previous case reports have speculated varying etiology, but few have justified its pathognomonic shape and location. We believe it to be congenital in nature and caused by incomplete differentiation of the arcuate bundles along the horizontal raphe in development of the macular architecture. Associated ocular findings may include blepharophimosis, situs inversus, or other anomalous retinal vascular patterns., Case Reports: Three cases of asymptomatic unilateral paramacular colobomata are presented. In each case, a single oval chorioretinal lesion temporal to the macula was found during routine examination. Visual acuity and Humphrey threshold visual field testing were normal with no other associated congenital, systemic, or ocular abnormalities. Because the lesion is nonprogressive, these patients can be followed on an annual basis., Conclusion: Due to their anatomical origin, paramacular colobomata are always located temporal to the macula and have an oval football-shaped appearance. Visual acuity and visual field testing are usually normal, although highly observant patients may be aware of a mild scotoma. Differential diagnosis is important because the clinical appearance can be similar to acquired conditions, most notably age-related macular degeneration and presumed ocular histoplasmosis syndrome.