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.

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.

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.

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.

Congenital upper eyelid coloboma: embryologic, nomenclatorial, nosologic, etiologic, pathogenetic, epidemiologic, clinical, and management perspectives.

PURPOSE: To review the recent literature and describe the authors' experience with congenital upper eyelid coloboma. METHODS: In this review, we will summarize the embryologic and etiopathogenetic bases of congenital upper eyelid coloboma, and study the published clinical reports. We will also attempt to briefly shed some light on the rarer syndromic curiosities associated with upper eyelid coloboma. RESULTS: Congenital upper eyelid colobomas are one of the few nontraumatic oculoplastic emergencies that may occasionally present in the first few days of life with a corneal ulcer and may even present with impending perforation. They can present with or without corneopalpebral adhesions, may be isolated findings or a part of a larger spectrum of congenital anomalies as in the case of Fraser syndrome or Goldenhar syndrome, or could be associated with other rare curiosities that could challenge the clinician with a huge diagnostic dilemma. CONCLUSIONS: Existing literature dealing with congenital colobomas of the upper eyelid is fraught with nosologic problems, confusing etiologies, and overlapping clinical features. We attempted to clarify the salient clinical features, outline the management principles, and until a time in the not-so-distant future where advances in molecular genetic testing would help redefine the etiology and the diverse clinical spectrum of genetic diseases associated with upper eyelid colobomas, we propose a simplified classification scheme based on the relation of the coloboma to the cornea, the presence or absence of systemic features, and all the syndromic and nonsyndromic associations of congenital coloboma of the upper eyelid known today.

Amniotic bands as a cause of congenital anterior staphyloma.

BACKGROUND: Congenital anterior staphyloma is a rare, complex malformation syndrome of the anterior segment. Only a few reports on associated systemic malformations have been published. We herein present a rare manifestation of congenital anterior staphyloma (CAS) combined with amniotic band disruption syndrome (ABS). PATIENT AND METHODS: Shortly after birth, a massive enlargement of the left eye was observed in a female child. Furthermore, an extensive bilateral congenital cleft lip and cleft alveolar ridge with oblique facial cleft extending into the left medial canthal region, coloboma(s) of the left eyelids, extensive adhesions between lids and eye bulb, as well as circumferential grooves, clubfeet, and terminal transverse defects in both hands and feet were present. Due to severe progression of eye bulb protrusion with thinning of the sclera, enucleation of the left eye was performed at the age of 3 years in order to prevent complications including perforation of the globe and with the aim of improving cosmetic aspects. RESULTS: Histopathological examination of the enucleated eye disclosed findings typical of congenital anterior staphyloma, including massive corneal staphylomatic deformation with superficial vascularization and elapsed corneoscleral margin, destruction of Bowman's layer, absence of Descemet's layer, corneal endothelium, and angle structures. The lens was only partially formed, and had mainly dissolved. The neural retina appeared normal. The optic nerve disc revealed a pronounced excavation. Facial clefts, lid colobomas, congenital constriction bands, and amputation of distal limbs match ABS. This malformation complex develops in early pregnancy, probably prior to 35 days post conception. CONCLUSION: This is the first report on an association of these two rare complex congenital malformations, congenital anterior staphyloma and amniotic band syndrome. The anterior staphyloma was unilateral, and related to facial clefts and lid coloboma in the area adjacent to the anterior staphyloma. Furthermore, the systemic deformities are clearly due to the amniotic bands, and the timing of the development of both complex malformations seems to be similar. All findings suggest that the presence of amniotic bands is a causative factor for all observed abnormalities including anterior staphyloma.

Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma.

In this review, we highlight recent literature concerning the signaling mechanisms underlying the development of two neural birth defects, holoprosencephaly and coloboma. Holoprosencephaly, the most common forebrain defect, occurs when the cerebral hemispheres fail to separate and is typically associated with mispatterning of embryonic midline tissue. Coloboma results when the choroid fissure in the eye fails to close. It is clear that Sonic hedgehog (Shh) signaling regulates both forebrain and eye development, with defects in Shh, or components of the Shh signaling cascade leading to the generation of both birth defects. In addition, other intercellular signaling pathways are known factors in the incidence of holoprosencephaly and coloboma. This review will outline recent advances in our understanding of forebrain and eye embryonic pattern formation, with a focus on zebrafish studies of Shh and retinoic acid pathways. Given the clear overlap in the mechanisms that generate both diseases, we propose that holoprosencephaly and coloboma can represent mild and severe aspects of single phenotypic spectrum resulting from aberrant forebrain development. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.

"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.

Microcornea, posterior megalolenticonus, persistent fetal vasculature, and coloboma: a new syndrome.

PURPOSE: To report a newly identified syndrome of bilateral microcornea, posterior megalolenticonus, persistent fetal vasculature, and chorioretinal coloboma (MPPC). DESIGN: Noncomparative case series. PARTICIPANTS: Eight patients with MPPC syndrome. METHODS: Clinical data collected retrospectively included visual acuity, findings on office examination as well as examination under anesthesia, and, in some cases, fluorescein angiography. Intraoperative findings and postoperative visual acuity and clinical findings were recorded when surgical intervention was performed. MAIN OUTCOME MEASURES: Clinical description, intraoperative findings, and surgical outcomes. RESULTS: All patients were found to have microcornea with corneal diameters of less than 8 mm. In all cases, the crystalline lens was found to be retrodisplaced with massive enlargement and a dramatic posterior lenticonus (posterior megalolenticonus), and the ciliary processes frequently were drawn to the lens capsule. A stalk of persistent fetal vascular tissue extended from the posterior pole of the lens to the optic disc. Posterior chorioretinal coloboma was present in all cases. Some cases also exhibited grossly dysplastic retina. Presentation frequently was asymmetric. Eight eyes of 6 patients underwent lensectomy, vitrectomy, membrane peeling, and fluid-Healon exchange (Healon OVD [sodium hyaluronate]; Advanced Medical Optics, Santa Ana, CA) with functional vision in at least 4 of the 5 patients with postsurgical follow-up. CONCLUSIONS: Bilateral microcornea, posterior megalolenticonus, persistent fetal vasculature, and chorioretinal coloboma syndrome is a distinct syndrome previously unreported, to the authors' knowledge, and appropriate surgical intervention may result in significantly improved visual function.

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.

Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the sonic hedgehog-patched-GLI pathway.

Curry-Jones syndrome (OMIM #601707) is a rare multiple malformation disorder of unknown etiology, associated with brain and skull abnormalities, polysyndactyly, and defects of the eyes, skin and gastrointestinal tract. We report on two new cases of Curry-Jones syndrome with previously unreported features, including benign and malignant neoplasms. The first patient had typical features of Curry-Jones syndrome as well as multiple intra-abdominal smooth muscle hamartomas and trichoblastoma of the skin. The second patient was born with occipital meningoceles and developed a desmoplastic medulloblastoma. Routine lymphocyte karyotype, GLI3 gene analysis and Patched (PTCH) gene analysis on both patients and chromosome microarray analysis on the first patient were normal. We review the previously reported cases of Curry-Jones syndrome and compare our patients' findings. In view of the association of trichoblastoma with basal cell carcinoma and desmoplastic medulloblastoma with nevoid basal cell carcinoma syndrome (NBCCS) and PTCH mutations, we hypothesize that Curry-Jones syndrome is caused by malfunction of an element in the sonic hedgehog pathway.

'My pupil has gone black!' Subluxation of a total cataractous lens.

A patient with a history of longstanding opaque cataract and a white pupil reported a return to a black pupil, which was the result of lens subluxation. The case was complicated by optic nerve coloboma of the Morning Glory syndrome type and a total retinal detachment.

Morning glory anomaly with bilateral choroidal colobomas in a patient with Goldenhar's syndrome.

A child with Goldenhar's syndrome, bilateral choroidal colobomas, and a morning glory anomaly of the optic disk in one eye is described. Bilateral posterior segment anomalies associated with Goldenhar's syndrome are rare. An association between the morning glory anomaly and Goldenhar's syndrome has not been previously reported.

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.].

Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.

BACKGROUND: Abetalipoproteinemia (ABL) is a metabolic disorder resulting in poor absorption of fat-soluble vitamins. CASE: Two pregnancies in a woman with ABL are reported, contrasting outcomes with subtherapeutic and normal vitamin levels. CONCLUSION: Fat-soluble vitamin levels in pregnancy are critical for many aspects of fetal development. This report details a congenital ophthalmologic finding that may be associated with vitamin A deficiency.

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.

Ocular coloboma: a reassessment in the age of molecular neuroscience.

Congenital colobomata of the eye are important causes of childhood visual impairment and blindness. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes, where the eye phenotype is often seen in association with severe neurological or craniofacial anomalies or other systemic developmental defects. Several studies have shown that, in addition to inheritance, environmental influences may be causative factors. Through work to identify genes underlying inherited coloboma, significant inroads are being made into understanding the molecular events controlling closure of the optic fissure. In general, severity of disease can be linked to the temporal expression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.