"HOURGLASS COLOBOMA": A CASE REPORT AND REVIEW OF ETIOPATHOGENESIS.

PURPOSE: To report a rare case of multiple fundal colobomata and to review the possible etiopathogenic factors involved in its genesis. METHOD: Case report. RESULT: A 21-year-old myopic lady was noted to have 2 fundal colobomata-one in the inferior and the other in superior hemisphere of globe in a mirror-image fashion resembling an "hourglass" in the right eye and a typical Type 3 coloboma in the left eye. The iris was normal in both the eye. Multiple fundal colobomata have not been described in the literature. The presence of "accessory embryonic fissure" in the developing eyeball is the only probable mechanism that can explain this presentation. This case is an evidence for the possibility of presence of accessory embryonic fissure in developing eyeball in human. The eponym "hourglass coloboma" or "mirror-image colobomata" best describes this condition. CONCLUSION: This report of multiple fundal colobomata is the first of its kind. This case is an evidence for possibility of presence of accessory embryonic fissure in developing eyeball in human.

Atypical Ocular Coloboma in Tuberous Sclerosis-2: Report of Two Novel Cases.

ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by mutations in either TSC1 or TSC2 genes and is characterized by hamartomas in multiple organs. The most frequent and best-known ocular manifestation in TSC is the retinal hamartoma. Less frequent ocular manifestations include punched out areas of retinal depigmentation, eyelid angiofibromas, uveal colobomas, papilledema, and sector iris depigmentation. In this article, we report 2 patients carrying known pathogenic variants in the TSC2 gene who exhibited an atypical, unilateral, iris coloboma associated with localized areas of retinal dysembryogenesis.

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye.

Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (~1 in 5000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggests multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein Neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicate that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased retinal pigmented epithelium (RPE) proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F-actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF closure.

Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish.

Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Failure of this event leads to congenital vision impairment in the form of coloboma. Recent studies have suggested hyaloid vasculature to be involved in OF fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2a noi mutant line. We first determined that pax2a-/- embryos fail to accumulate F-actin in the OF prior to basement membrane (BM) degradation. Furthermore, using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a-/- embryos. When examining the connection between pax2a loss of function and hyaloid vasculature, we observed significant reduction of talin1 expression, a regulator of hyaloid vasculature. In addition, cranial VEGF expression was found to be reduced in pax2a-/- embryos. Pharmacological inhibition of VEGF signaling phenocopied the pax2a-/- vasculature, F-actin and BM degradation phenotypes. Lastly, we determined that OF associated hyaloid vasculature is a source of mmp2, mmp14a and mmp14b expression and showed that mmp2 is functionally necessary for degradation of OF BM. Taken together we propose a pax2a driven mechanism that ensures proper and timely hyaloid vasculature invasion of the OF in order to facilitate availability of the BM remodeler mmp2.

Ask-Upmark kidney in a girl with neurofibromatosis type 1.

Ask-Upmark kidney (AUK) is a scarred segment of the kidney, characterized by formation of primitive tubular and glomerular structures, and sporadically diagnosed as a cause of hypertension (HTN). A 6-year-old girl with neurofibromatosis type 1 (NF1) and moyamoya syndrome had severe HTN. Based on past history, she had HTN at the age of 1.5 years. Laboratory examination revealed slightly elevated plasma and renal venous renin activity without lateralization. No evidence of pheochromocytoma, or coarctation of the aorta was found. Contrast-enhanced computed tomography (CT) showed an area of hypoperfusion in the upper and middle poles with reduced size of the right kidney. The results of dimercaptosuccinic acid scintigraphy were in accordance with those of contrast-enhanced CT. Selected renal arteriography revealed a paucity of peripheral vascularity in the same parts of the right kidney. In the absence of a history of urinary tract infection and vesicoureteral reflux by cystography, we presumed that the severe HTN may be due to segmental hypoplasia of the kidney, AUK, with a possible contribution from NF1. Although renal artery stenosis and pheochromocytoma are well-known causes of HTN in NF1, this case demonstrates that HTN can be caused by AUK in patients with NF1.

Microphthalmos-anophthalmos-coloboma (MAC) spectrum in two brothers with Renpenning syndrome due to a truncating mutation in the polyglutamine tract binding protein 1 (PQBP1) gene.

Background: Patients with intellectual disability syndromes frequently have coexisting abnormalities of ocular structures and the visual pathway system. The microphthalmos, anophthalmos, and coloboma (MAC) spectrum represent structural developmental eye defects that occur as part of a syndrome in one-third of cases. Ophthalmic examination may provide important diagnostic clues in identifying these syndromes.Purpose: To provide a detailed and comprehensive description of the microphthalmos, anophthalmos, and coloboma (MAC) spectrum in two brothers with intellectual disability and dysmorphism.Methods: The two brothers underwent a detailed ophthalmic and systemic evaluation. A family pedigree was obtained and exome sequencing was performed in the proband.Results: The two brothers aged 4 and 7 years had intellectual disability, microcephaly, short stature, and characteristic dysmorphic features. Ophthalmic evaluation revealed the presence of the MAC spectrum in both boys. Genetic testing led to the detection of an X-linked hemizygous truncating mutation in the nuclear polyglutamine-binding protein 1 (PQBP1) gene confirming the diagnosis of X-linked recessive Renpenning syndrome.Conclusion: The presence of X-linked intellectual disability and characteristic dysmorphism, in a patient with the MAC spectrum should raise the suspicion of Renpenning syndrome. PQBP1 mutation testing is confirmatory. A comprehensive systemic evaluation is mandatory in all patients with the MAC spectrum and intellectual disability.

Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors.

Polyglutamine (polyQ) expansion in Ataxin-7 (ATXN7) results in spinocerebellar ataxia type 7 (SCA7) and causes visual impairment. SCA7 photoreceptors progressively lose their outer segments (OSs), a structure essential for their visual function. ATXN7 is a subunit of the transcriptional coactivator Spt-Ada-Gcn5 Acetyltransferase complex, implicated in the development of the visual system in flies. To determine the function of ATXN7 in the vertebrate eye, we have inactivated ATXN7 in zebrafish. While ATXN7 depletion in flies led to gross retinal degeneration, in zebrafish, it primarily results in ocular coloboma, a structural malformation responsible for pediatric visual impairment in humans. ATXN7 inactivation leads to elevated Hedgehog signaling in the forebrain, causing an alteration of proximo-distal patterning of the optic vesicle during early eye development and coloboma. At later developmental stages, malformations of photoreceptors due to incomplete formation of their OSs are observed and correlate with altered expression of crx, a key transcription factor involved in the formation of photoreceptor OS. Therefore, we propose that a primary toxic effect of polyQ expansion is the alteration of ATXN7 function in the daily renewal of OS in SCA7. Together, our data indicate that ATXN7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation, and its loss of function may contribute to the development of human coloboma.

Meningocele de la vaina del nervio óptico asociado a coloboma / Optic nerve sheath meningocele associated with coloboma

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Three Cases of Associated Persistent Fetal Vasculature and Ocular Coloboma: Posterior Segment Dysgenesis.

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.].

A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole-exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband-only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra-ocular signs of Baraitser-Winter syndrome. We found this mutant protein to be incapable of incorporation into F-actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.

Isquemia retiniana y proliferación fibrovascular tardía asociada a coloboma de nervio óptico / Retinal ischaemia and delayed fibrovascular proliferation associated with an optic nerve coloboma

CASO CLÍNICO: Paciente con coloboma de nervio óptico izquierdo, que desarrolla tardíamente (a los 15 años de edad) proliferación fibrovascular vitreorretiniana y desprendimiento de retina traccional (DRT). Se realiza fotocoagulación retiniana sectorial con regresión del tejido proliferativo y la exudación asociada. DISCUSIÓN: Las anomalías congénitas del nervio óptico pueden asociar avascularidad e isquemia retiniana significativa y proliferación fibrovascular de aparición tardía. El tratamiento láser es efectivo para obtener la regresión del tejido neovascular y prevenir la progresión del DRT

CASE REPORT: A patient with a left optic nerve coloboma with late development (at 15 years of age) of vitreoretinal fibrovascular proliferation and tractional retinal detachment (TRD). Sectorial retinal photocoagulation was performed with regression of the proliferative tissue and exudation. DISCUSSION: Congenital optic nerve anomalies may be associated with significant retinal avascularity, ischaemia and late fibrovascular proliferation. Laser is effective for regression of the neovascular tissue and preventing TRD progression

BILATERAL OPTIC NERVE COLOBOMAS IN INFANT WITH TETRAPLOIDY.

PURPOSE: To describe the previously unreported ocular anomalies in the rare condition of tetraploidy. METHODS: This study is a retrospective case report of a 23-day-old male infant with tetraploidy. RetCam fundus photography and neuroimaging were performed. RESULTS: This 23-day-old male infant was born at full term and found to have tetraploidy with numerous congenital anomalies including bilateral optic nerve colobomas, left microphthalmia, vitreous hemorrhage, and septo-optic dysplasia. CONCLUSION: Infants with tetraploidy can present with ocular anomalies and while hospitalized should be examined by an ophthalmologist.