Genetics of syndromic ocular coloboma: CHARGE and COACH syndromes.

Optic fissure closure defects result in uveal coloboma, a potentially blinding condition affecting between 0.5 and 2.6 per 10,000 births that may cause up to 10% of childhood blindness. Uveal coloboma is on a phenotypic continuum with microphthalmia (small eye) and anophthalmia (primordial/no ocular tissue), the so-called MAC spectrum. This review gives a brief overview of the developmental biology behind coloboma and its clinical presentation/spectrum. Special attention will be given to two prominent, syndromic forms of coloboma, namely, CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies/deafness) and COACH (Cerebellar vermis hypoplasia, Oligophrenia, Ataxia, Coloboma, and Hepatic fibrosis) syndromes. Approaches employed to identify genes involved in optic fissure closure in animal models and recent advances in live imaging of zebrafish eye development are also discussed.

Corneal Endothelial Cell Density in Uveal Coloboma Associated With Microcornea.

PURPOSE: To evaluate the relationship between endothelial cell density (ECD) and mean corneal diameter (MCD) in eyes with uveal coloboma associated with microcornea. METHODS: Corneal endothelial cell imaging was performed using specular microscopy on 22 eyes of 18 subjects diagnosed with uveal coloboma associated with microcornea. The MCD was noted as the average of horizontal and vertical corneal diameters, which were measured using the ruler tool of the slit-lamp biomicroscope and Castroviejo calipers. RESULTS: Mean age of the study subjects was 29.7 ± 10.4 years (range, 14-46 years). The MCD was 7.3 ± 1.1 mm (range, 4.9-9 mm). Mean ECD (3436 ± 316.2 cells/mm) of the study subjects was significantly (P < 0.0001) higher than the mean ECD (2761.8 ± 140.9 cells/mm) of age-matched (range, 10-40 years) normal eyes with no ocular pathology. The pleomorphism and polymegathism were comparable between the 2 groups. Regression analysis showed that MCD had a significant negative (R = -0.55; P = 0.02) relationship with ECD. CONCLUSIONS: Eyes with congenital uveal coloboma associated with microcornea have increased ECD. Increased ECD may be partly due to a reduced posterior corneal surface area in microcornea.

Uveal coloboma: about 3 cases at the University Teaching Hospital, Yaounde, Cameroon.

Uveal coloboma is a rare eye malformation caused by failure of the optic fissure to close during the fifth to seventh weeks of foetal life. The risk of retinal detachment increases with age in colobomatous eyes. Preventive measures such as early detection of the retinal break, prophylactic laser photocoagulation along the coloboma margin, confer a significant benefit in reducing this risk of retinal detachment. Difficulties linked to the diagnosis and management of uveal colobomas in developing countries setting are presented in this study.

A young Botswana patient with congenital iris ectropion uvea.

Congenital iris ectropion is a rare condition; non-progressive anomaly characterised by the presence of iris pigment epithelium on the anterior surface of the iris stroma and is frequently associated with anterior iris insertion, dysgenesis of the drainage angle and glaucoma. This paper describes unusual case of bilateral case of congenital iris ectropion in adult patient with pupillary abnormality, normal anterior chamber angle structure and with no evidence of glaucoma.

Congenital ectropion uveae presenting as acute glaucoma in a 3-year-old child.

Congenital ectropion uveae is a rare anomaly commonly associated with neurofibromatosis and occasionally with other ocular abnormalities. Glaucoma related with this condition may be present in infancy, or may develop later in life, and is thought to be due to an associated angle dysgenesis. Diagnosis is frequently delayed due to the subtle signs and the absence of symptoms and management is primarily surgical. We report an unusual case of unilateral congenital ectropion uveae in a 3-year-old child, with no evidence of neurofibromatosis, presenting as acute glaucoma, which was successfully managed by topical treatment only, avoiding surgical intervention.

Dysfunctional uveoscleral pathway in a rat model of congenital glaucoma.

UNLABELLED: The purpose of the study was to investigate the presence of the uveoscleral pathway in the normotensive rat (NR) and in a rat model of congenital glaucoma (CGR). We injected the fluorescent tracer 70-kDa dextran rhodamine B in the anterior chamber of four NRs and four CGRs. At 10 and 60 minutes after injection, rats were euthanized by CO2 inhalation and eyes were enucleated. Cryosections were prepared and analyzed using fluorescent microscopy. Hematoxylin-eosin staining and electron microscopy of the anterior chamber angle (ACA) were performed. At 10 minutes after injection, fluorescent tracer was detected in the iris root and ciliary processes of NRs and CGRs. At 60 minutes, NRs showed prominent signal in the suprachoroidal, whereas, in the CGRs, tracer was barely detectable. Histology of the anterior chamber revealed the presence of an open ACA and electron microscopy confirmed the normal structure of the ciliary body in CGRs. CONCLUSIONS: Our results document the presence of an uveoscleral pathway in the normotensive rat. The rat model of congenital glaucoma shows severe impairment of the uveoscleral pathway, suggesting that alterations of the uveoscleral outflow might play a role in the pathogenesis of CG.

Morning glory disc anomaly: characteristic MR imaging findings.

SUMMARY: Establishing the diagnosis of morning glory disc anomaly is crucial to appropriate patient treatment. Although typically made clinically, the diagnosis is not always straightforward, especially in circumstances where physical examination is limited. The goal of this study was to define the spectrum and frequency of orbital findings in a series of patients with funduscopically-confirmed morning glory disc anomaly by using MR imaging. MR imaging demonstrated 3 findings in all patients: 1) funnel-shaped morphologic pattern of the posterior optic disc with elevation of the adjacent retinal surface; 2) abnormal tissue associated with the distal intraorbital segment of the ipsilateral optic nerve, with effacement of the regional subarachnoid spaces; and 3) discontinuity of the uveoscleral coat. These findings were not observed in any of the unaffected globes of the study patients. In summary, these consistent and characteristic findings of morning glory disc anomaly should allow for accurate differentiation from other ocular anomalies and have the potential to guide appropriate management of this patient population.

Pigmented free-floating vitreous cyst in a patient with high myopia and uveal coloboma simulating choroidal melanoma.

A 60-year-old woman was referred for a pigmented fundus lesion in her right eye that was suspected to be a possible choroidal melanoma. She complained of an intermittent floater in the right eye. Funduscopy revealed peripapillary atrophy and posterior staphyloma due to degenerative myopia, large inferior choroidal coloboma, and a cystic pigmented lesion measuring 7 mm in diameter and 3 mm in thickness located inferiorly when the patient was in the upright position. Following supine positioning, the lesion floated to the macular region. Ultrasonography confirmed that the lesion is cystic and freely mobile. Magnetic resonance imaging showed a well-defined, nodular preretinal intraocular lesion that was hypointense in both T1- and T2-weighted, non-contrast axial images. Observation of the benign vitreous cyst was advised. A free-floating pigmented vitreous cyst can be associated with high myopia and uveal coloboma. Its location in the posterior vitreous can lead to a misdiagnosis of a choroidal melanoma.

Novel SOX2 mutation associated with ocular coloboma in a Chinese family.

OBJECTIVES: To report a novel SOX2 (OMIM 184429) mutation in a Chinese family and to describe its ocular and extraocular clinical features. METHODS: Ocular and systemic examinations were performed, and genomic DNA was prepared from peripheral leukocytes. The coding exons and the adjacent intronic sequence of SOX2 were analyzed by cycle sequencing. RESULTS: A novel heterozygous c.695C>A (p.Thr232Asn) mutation in SOX2 was identified in a Chinese family in which both the father and the son had iris and chorioretinal uveal colobomas. In addition, cataracts were noted in the father but not in the son. Other anomalies were not found in the father but were present in the son, including brain arachnoid cyst, microcornea, retrobulbar colobomatous orbital cyst, and penoscrotal hypospadias. This mutation was not detected in the unaffected mother and 103 unaffected control individuals. CONCLUSIONS: Mutation in SOX2 is associated with typical ocular coloboma and probably other anomalies in this Chinese family. Arachnoid cyst has not been reported in individuals with the SOX2 mutation. CLINICAL RELEVANCE: The results remind us that ocular coloboma may be accompanied by arachnoid cyst and may be associated with SOX2 mutation, which will be helpful for improving diagnosis and patient care.

Familial blepharophimosis-like syndrome with esotropia, uveal coloboma, and short stature.

BACKGROUND: Interstitial deletion of Hsa 3q involves FOXL2, the gene responsible for blepharophimosis-ptosis-telecanthus-epicanthus inversus (BPES). Thought to be due to a contiguous gene syndrome, the recognizable phenotype of 3q interstitial deletion includes BPES facies and has not been associated with other loci. OBJECTIVE: To describe a familial syndrome that resembles the interstitial deletion of 3q clinically, but does not map to the FOXL2 region. METHODS: Clinical evaluation of family members and linkage analysis. RESULTS: Three affected siblings with a phenotype resembling that seen in 3q interstitial deletion were studied in addition to their clinically unaffected parents. Linkage analysis excluded FOXL2 as underlying the distinct phenotype, observed with > 99% confidence. CONCLUSIONS: The relevant locus in the current family, although remote from FOXL2, is likely important to the FOXL2 functional pathway. The phenotype observed in 3q interstitial deletion may be due to severe disruption of FOXL2 rather than to a contiguous gene syndrome.

Uveal coloboma: clinical and basic science update.

PURPOSE OF REVIEW: To integrate knowledge on the embryologic and molecular basis of optic fissure closure with clinical observations in patients with uveal coloboma. RECENT FINDINGS: Closure of the optic fissure has been well characterized and many genetic alterations have been associated with coloboma; however, molecular mechanisms leading to coloboma remain largely unknown. In the past decade, we have gained better understanding of genes critical to eye development; however, mutations in these genes have been found in few individuals with coloboma. CHD7 mutations have been identified in patients with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth, genital anomalies, and ear anomalies or deafness). Animal models are bringing us closer to a molecular understanding of optic fissure closure. SUMMARY: Optic fissure closure requires precise orchestration in timing and apposition of two poles of the optic cup. The relative roles of genetics and environment on this process remain elusive. While most cases of coloboma are sporadic, autosomal dominant, autosomal recessive, and X-linked inheritance patterns have been described. Genetically, colobomata demonstrate pleiotropy, heterogeneity, variable expressivity, and reduced penetrance. Coloboma is a complex disorder with a variable prognosis and requires regular examination to optimize visual acuity and to monitor for potential complications.

Maldevelopment of neural crest cells in patients with typical uveal coloboma.

PURPOSE: To clarify the pathogenesis of ocular and systemic anomalies associated with typical uveal coloboma. METHODS: The records of 72 patients with typical uveal coloboma (35 males and 37 females) treated at Nagoya City University Hospital during a 16-year period were reviewed. RESULTS: Typical uveal coloboma was bilateral in 33 patients and unilateral in 35 patients; 4 patients were unclassified because of severe contralateral microphthalmos. Uveal coloboma was an isolated defect in 23 (37%) patients. Other ocular anomalies were present in 19 (31%) patients, systemic anomalies were found in 7 (11%) patients, and both other ocular and systemic anomalies were noted in 13 patients (21%). The associated ocular anomalies included microphthalmos in 28 eyes of 23 patients, persistent pupillary membrane in 28 eyes of 18 patients, and posterior embryotoxon in 20 eyes of 15 patients. The accompanying systemic anomalies included ear anomalies, retarded growth, and retarded development in 18 patients; heart anomalies in 13 patients; genital hypoplasia in 12 patients; and congenital facial palsy in 10 patients. The collection of malformations known as the CHARGE association was diagnosed in 14 (19%) patients. CONCLUSION: Abnormal development of neural crest cells appeared to be responsible for the majority of associated ocular and systemic anomalies in patients in the present series, suggesting that typical uveal coloboma may be related to maldevelopment of the neural crest cells. The present findings indicated that ophthalmologists should be aware of the possible association of typical uveal coloboma with systemic anomalies.

[The Schmid-Fraccaro syndrome]. / Schmidov-Fraccarov syndróm.

The authors describe a female patient with bilateral colobomatous malformations of the uvea in conjunction with anorectal atresia and other symptoms suggesting Schmid-Fraccaro's syndrome called also cat eye syndrome. Using fluorescent hybridization in situ, the authors identified the supernumerous bisatellite marker chromosome derived from chromosome 22 which made it possible to confirm the suspected diagnosis.

Treacher Collins syndrome: phenotypic variability in a family including an infant with arhinia and uveal colobomas.

We report extreme expression of Treacher Collins syndrome in an infant with arhinia, anotia, absent zygomatic bones, hypoplastic mandibular rami, and bilateral coloboma of iris, choroid plexus, and optic nerves. The Treacher Collins phenotype was mildly expressed in the mother and moderately in the sister. The father had no signs and was not ruled out as the father by DNA fingerprinting, thus making homozygosity by descent in the severely affected son very unlikely.

[Unilateral duplication of the uveal tract in a cat. Coexistence of an excess failure of formation with ocular leukosis]. / Unilateral doppelt angelegter uvealer Trakt bei einer Katze. Koexistenz einer Exzessfehlbildung mit einer okularen Leukose.

A six year old domestic cat, blind in the right eye from birth, slowly lost sight in the left eye. An ophthalmological examination of the right eye revealed uveal leucosis and unilateral duplication of the uveal tract. The additional tissues were rotated through 90 degrees resulting in displacement of the lens. In the left eye evidence of a previous retinal detachment and consecutive traumatic cataract were noted. The etiology of these pathological findings is discussed.

A complex chromosome translocation resulting in deletion 11p and associated with uveal colobomata.

A boy with a complex chromosome rearrangement of chromosomes 3, 10, and 11 resulting in a deletion of the short arm of chromosome II is presented. The occurrence of uveal coloboma as an isolated congenital malformation might suggest a chromosomal site for this ocular anomaly in proximity to the aniridia locus.