Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation.

Background: Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes. Results: We find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype. Conclusion: These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant.

Linear Nevus Sebaceous Syndrome: Clinical Presentation and Management Considerations.

A relatively rare neurocutaneous condition known as linear nevus sebaceous syndrome (LNSS) is marked by a variety of symptoms as well as the unusual characteristics of developing mosaic RASopathies of phacomatoses. Mental retardation, seizures, and midline facial linear nevus sebaceous were the usual diagnostic triad. A hallmark of LNSS is the papillomatous growth of the epidermis, also known as nevus sebaceous. In this case report, we presented a case of a 13-year-old male with LNSS with a vascular conjunctival lesion and a coloboma of the optic disc.

Retinitis pigmentosa with iris coloboma due to miR-204 gene variant in a Chinese family.

PURPOSE: To characterize the phenotype and genotype of a Chinese family with autosomal-dominant retinitis pigmentosa (RP) accompanied by iris coloboma. METHODS: The proband, a 34-year-old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full-field electroretinography (ffERG). Genetic analyses were conducted through whole-exome sequencing (WES) to screen for variations. RESULTS: Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR-204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. CONCLUSIONS: In this third independent and the first Asian family, the existence of a miR-204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR-204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal-dominant pattern, including in Chinese patients, miR-204 aberrations should be considered.

Morning Glory Anomaly With Serous Macular Detachment.

The morning glory (MG) disc anomaly is a congenital excavation of the posterior globe involving the optic disc, with a distinct appearance reminiscent of the MG flower. Various intracranial and ocular associations with MG have been documented. Conditions such as trans-sphenoidal encephalocele and hypoplasia of the intracranial vasculature have been observed in association with this anomaly. In this report, we present a case of MG optic disc anomaly accompanied by serous macular detachment.

Cavitación coroidea asociada a coloboma macular. Estudio multimodal. Imagen en face / Choroid cavitation associated with macular coloboma. Multimodal study. Image en face

La cavitación intracoroidea es un hallazgo identificado con OCT descrito inicialmente en pacientes miopes, pero también aparece en pacientes no miopes. Puede presentarse tanto en el área peripapilar como en el polo posterior. El coloboma macular es un defecto del desarrollo embrionario del polo posterior, y en la OCT estructural es imprescindible la ausencia del epitelio pigmentario de la retina y de los vasos coroideos para su diagnóstico. Este caso presenta la cavitación intracoroidea circunscribiendo el coloboma macular, en ausencia de membrana intercalar. La imagen en face permite valorar la relación entre ambas estructuras, así como la magnitud de las mismas. (AU)

Intrachoroidal cavitation is a finding identified with OCT initially described in myopic patients, it also appears in non-myopic patients. It can occur in both the peripapillary area and the posterior pole. Macular coloboma is a defect of embryonic development of the posterior pole, in structural OCT the absence of the retinal pigment epithelium and choroidal vessels is essential. In this case, intrachoroidal cavitation circumscribes the macular coloboma, in the absence of an intercalary membrane. The face image allows us to assess the relationship between the two structures as well as their magnitude. (AU)

Ocular manifestations of CHARGE syndrome in a pediatric cohort with genotype/phenotype analysis.

CHARGE syndrome is a rare multi-system condition associated with CHD7 variants. However, ocular manifestations and particularly ophthalmic genotype-phenotype associations, are not well-studied. This study evaluated ocular manifestations and genotype-phenotype associations in pediatric patients with CHARGE syndrome. A retrospective chart review included pediatric patients under 20 years-old with clinical diagnosis of CHARGE syndrome and documented ophthalmic examination. Demographics, genetic testing, and ocular findings were collected. Comprehensive literature review enhanced the genotype-phenotype analysis. Forty-two patients (20 male) underwent eye examination at an average age of 9.45 ± 6.52 years-old. Thirty-nine (93%) had ophthalmic manifestations in at least one eye. Optic nerve/chorioretinal colobomas were most common (38 patients), followed by microphthalmia (13), cataract (6), and iris colobomas (4). Extraocular findings included strabismus (32 patients), nasolacrimal duct obstructions (11, 5 with punctal agenesis), and cranial nerve VII palsy (10). Genotype-phenotype analyses (27 patients) showed variability in ocular phenotypes without association to location or variant types. Splicing (10 patients) and frameshift (10) variants were most prevalent. Patients with CHARGE syndrome may present with a myriad of ophthalmic manifestations. There is limited data regarding genotype-phenotype correlations and additional studies are needed.

FLACS (Femtosecond-Laser-Assisted Cataract Surgery) combined with pupiloplasty in iris-lens coloboma.

Purpose: To describe the use of FLACS (Femtosecond-Laser-Assisted Cataract Surgery) and pupiloplasty technique employed in a cataract surgery associated with iris-lens-zonule coloboma, as well as to report the advantages that FLACS can provide in this type of complicated surgery. Observations: During FLACS (Victus® - TECHNOLAS, Bausch and Lomb Incorporated, USA), after the docking procedure, the parameters of capsulotomy, fragmentation and incisions were manually adjusted. Iris retractors were anchored to the edge of the anterior lens capsule to provide stability to the bag during phacoemulsification maneuvers, and a capsular tension ring and intraocular lens (IOL) were implanted. Iris repair was approached using a modification of the slip-knot technique. For this purpose, a 10.0 Prolene on a straight needle was used and knotted extraocularly, over the conjunctiva. Finally, an anterior vitrectomy was performed as a precaution. Conclusions and importance: In spite of the existing controversy regarding FLACS technology compared to conventional surgery, it seems to be beneficial in complicated cases such as cataracts associated with iris and lens coloboma, since it allows the modification of different parameters that facilitate and ensure surgery safety. On the other hand, the iris repair technique described facilitates manipulation of the iris sutures. In addition, complementary techniques such as the use of a capsular tension ring and pupiloplasty help to center and stabilize the IOL, and to reduce the symptoms derived from iris coloboma, obtaining a better visual quality.

Congenital Optic Disc Anomalies: Insights from Multimodal Imaging.

In this comprehensive review, we delve into the significance of multimodal imaging in diagnosing and managing complications of congenital optic disc anomalies. While the fundus examination is the gold standard tool in the diagnosis of these pathologies, spectral domain (SD) optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) could shed light on the pathogenesis and treatment. Moreover, this review seeks to offer a comprehensive insight into the multimodal approach of these rare congenital pathologies. In conclusion, congenital anomalies of the optic nerve represent a major challenge for ophthalmologists. Further research could be useful to clarify the pathophysiology of these diseases and define a correct and more specific treatment approach.

Couching of cataractous lens in microphthalmic eyes with irido-fundal coloboma: revisiting the historical technique.

PURPOSE: Cataract surgery in microphthalmic eyes is challenging due to anatomical restraints, hard bulky nucleus. This series aims to evaluate the safety and efficacy of couching of intraocular lens in irido-fundal coloboma with microphthalmos. SETTING: Tertiary care centre in South India. DESIGN: Retrospective non-comparative study in eyes with irido-fundal coloboma, corneal diameter < 7 mm and brown cataract. Visual acuity less than 6/60 in other eye. METHODS: Anterior chamber entry made, zonules broken and lens dislocated into the vitreous cavity in a controlled manner. Baseline Clinico-demographic details, corrected distance visual acuity (CDVA), Intra-ocular pressure (IOP), corneal diameter, axial length, lens status and post-surgery CDVA, IOP and complications recorded and followed up for atleast 6 months. RESULTS: Fifteen eyes of 15 subjects were evaluated with a mean age 49.4 ± 10.9 years. At baseline, mean IOP 14.5 ± 3.8 mmHg, mean axial length 19.3 ± 0.5 mm, mean corneal diameter was 6.5 ± 0.34 mm and CDVA 2 logMAR which improved to 1.5 logMAR at 3 months (p value 0.002). Transient spike in IOP in 33.3% subjects was medically managed with no significant difference in IOP (p > 0.05) at baseline (14.5 ± 3.8 mmHg), 3 months post-surgery (16 ± 2.8 mmHg) and 6 months post-surgery (14.9 ± 2.5 mmHg). One patient underwent re-couching. No other major complications were noted. CONCLUSION: Couching of cataractous lens is an effective and safe method in microphthalmic eyes with irido-fundal coloboma as last resort procedure, where no other surgical procedure may work. It provides an ambulatory gain of visual acuity in previously non-ambulatory subjects. Corneal measurements help in determining the subset of patients where couching offers viable option.

PRPS1-associated retinopathy: a diagnostic odyssey.

PURPOSE: This study describes how the diagnosis of Usher syndrome was revised to PRPS1-associated retinopathy and Charcot-Marie-Tooth disease type 5. CASE REPORT: A 38-year-old female with bilaterally subnormal vision and non-congenital hearing loss was initially diagnosed with Usher syndrome, based on finding variants in three genes (MYO7A, USH2A, and PCDH15), was re-evaluated at the inherited retinal disorders clinic. She had asymmetric retinopathy and right macular pseudocoloboma. She was also found to have myopathic facies, poor grip strength and atrophy of the calf muscles. Whole exome sequencing including variants in PRPS1 showed a variant (NM_002764.4:c.287 G > A; p.Arg96Gln), which was not detected by targeted Sanger sequencing of the DNA from her mother and sister. CONCLUSION: The constellation of asymmetric retinopathy and non-congenital hearing impairment should prompt the clinician to search for other diagnoses that may not be covered by an Usher syndrome next generation sequencing panel. Interpretation of genetic testing results should be correlated with a detailed clinical phenotype.

Renal coloboma syndrome/dominant optic atrophy with severe retinal atrophy and de novo digenic mutations in PAX2 and OPA1.

Renal coloboma syndrome (RCS) and dominant optic atrophy are mainly caused by heterozygous mutations in PAX2 and OPA1, respectively. We describe a patient with digenic mutations in PAX2 and OPA1. A female infant was born without perinatal abnormalities. Magnetic resonance imaging at 4 months of age showed bilateral microphthalmia and optic nerve hypoplasia. Appropriate body size was present at 2 years of age, and mental development was favorable. Color fundus photography revealed severe retinal atrophy in both eyes. Electroretinography showed slight responses in the right eye, but no responses in the left eye, suggesting a high risk of blindness. Urinalysis results were normal, creatinine-based estimated glomerular filtration rate was 63.5 mL/min/1.73 m2, and ultrasonography showed bilateral hypoplastic kidneys. Whole exome sequencing revealed de novo frameshift mutations in PAX2 and OPA1. Both variants were classified as pathogenic (PVS1, PS2, PM2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Genetic testing for ocular diseases should be considered for patients with suspected RCS and a high risk of total blindness.

Bilateral Iris Coloboma in an 11-Year-Old Child with Low Vision and High Intraocular Pressure: A Rare Case Report and Review of Literature.

Background: Coloboma means curtailed in Greek language. It is mainly used when normal tissue of the eye or another organ is not present since birth. Coloboma is a congenital abnormality mainly caused by incomplete closure of the embryonic fissure of the choroid part of eye. Purpose: The aim of this case report is to share the clinical findings in a patient with bilateral iris coloboma, low vision, and headache. Patients and Methods: Case report. Results: An eleven-year-old boy with low vision and headache visited the University Eye Hospital of Kabul University of Medical Science (UEHKUMS) for consultation. Ophthalmic examination revealed a bilateral iris coloboma without concomitant chorioretinal defect, refractive error, and high intraocular pressure in both eyes. The refractive error of the patient was corrected by advising proper glasses, and the high intraocular pressure was controlled by anti-glaucoma drops. After several follow-up visits, the patient no longer complained of headache and low vision. Conclusion: Visiting patients with iris coloboma should be considered for intraocular pressure (IOP) check, and screening of other family members is mandatory.

Choroid cavitation associated with macular coloboma. Multimodal study. Image en face.

Intrachoroidal cavitation is a finding identified with OCT initially described in myopic patients, it also appears in non-myopic patients. It can occur in both the peripapillary area and the posterior pole. Macular coloboma is a defect of embryonic development of the posterior pole, in structural OCT the absence of the retinal pigment epithelium and choroidal vessels is essential. In this case, intrachoroidal cavitation circumscribes the macular coloboma, in the absence of an intercalary membrane. The en face image allows us to assess the relationship between the two structures as well as their magnitude.

Non-nasal, atypical retinochoroidal coloboma in pediatric patients: Case series and review.

Purpose: To report 2 cases of atypically located, non-nasal colobomas in the pediatric population. Observations: A 3-week-old female neonate with no known past ocular or medical history was diagnosed with temporal iris and chorioretinal coloboma with tractional membranes upon examination under anesthesia and imaging. A 9-year-old female with a history of bilateral sensorineural hearing loss and left mild hydronephrosis presented with a temporal chorioretinal coloboma associated with retinal detachment. Conclusions and importance: Very few cases of atypically located, non-nasal pediatric colobomas have been reported, and they lack a clear cause or mechanism of formation. Continued documentation of their occurrence and research into their formation at a molecular and embryological level are warranted to better understand their pathogenesis.

[Embryonic development and congenital diseases of the orbit]. / Embryologische Entwicklung und angeborene Erkrankungen des Auges.

Many neuroradiologists focus primarily on the central nervous system and give little attention to other regions like the eye/orbit. It is easy to be deceived by the pitfall called satisfaction of search (also abbreviated SOS), despite most congenital eye diseases being easily recognized if one is aware of them. In this article, the most common congenital orbital abnormalities are described, and their basic prenatal causes are summarized.

Ocular manifestations of congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common birth defects worldwide and a major cause of kidney failure in children. Extra-renal manifestations are also common. This study reviewed diseases associated with the Genomics England CAKUT-associated gene panel for ocular anomalies. In addition, each gene was examined for expression in the human retina and an ocular phenotype in mouse models using the Human Protein Atlas and Mouse Genome Informatics databases, respectively. Thirty-four (54%) of the 63 CAKUT-associated genes (55 'green' and 8 'amber') had a reported ocular phenotype. Five of the 6 most common CAKUT-associated genes (PAX2, EYA1, SALL1, GATA3, PBX1) that represent 30% of all diagnoses had ocular features. The ocular abnormalities found with most CAKUT-associated genes and with five of the six commonest were coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataract. Seven of the CAKUT-associated genes studied (11%) had no reported ocular features but were expressed in the human retina or had an ocular phenotype in a mouse model, which suggested further possibly-unrecognised abnormalities. About one third of CAKUT-associated genes (18, 29%) had no ocular associations and were not expressed in the retina, and the corresponding mouse models had no ocular phenotype. Ocular abnormalities in individuals with CAKUT suggest a genetic basis for the disease and sometimes indicate the affected gene. Individuals with CAKUT often have ocular abnormalities and may require an ophthalmic review, monitoring, and treatment to preserve vision.

Suspected Autosomal Recessive Polycystic Kidney Disease but Cerebellar Vermis Hypoplasia, Oligophrenia Ataxia, Coloboma, and Hepatic Fibrosis (COACH) Syndrome in Retrospect, A Delayed Diagnosis Aided by Genotyping and Reverse Phenotyping: A Case Report and A Review of the Literature.

The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.

Floating-Harbor syndrome with chorioretinal colobomas.

BACKGROUND: We present a case of a child with Floating-Harbor Syndrome (FHS) with bilateral chorioretinal coloboma (CC). To the best of our knowledge, this is the first case report of this association. Floating- Harbor syndrome is an extremely rare autosomal dominant genetic disorder with approximately 100 cases reported. It is characterized by a series of atypical features that include short stature with delayed bone age, low birth weight, skeletal anomalies, delayed speech development, and dysmorphic facial characteristics that typically portray a triangular face, deep-set eyes, long eyelashes, and prominent nose. MATERIALS AND METHODS: Our patient was examined by a pediatric ophthalmologist for the time at age of 7. Visual acuity, optical coherence tomography (OCT) and Optos imaging were collected on every visit. The patient had whole genome sequencing ordered by a pediatric geneticist to confirm Floating-Harbor syndrome. RESULTS: We present the patient's OCT and Optos images that illustrate the location of the patient's inferior chorioretinal coloboma in both eyes. The whole genome sequencing report collected revealed a heterozygous de novo pathogenic variant in the SRCAP gene, consistent with a Floating-Harbor syndrome diagnosis in the literature. DISCUSSION: Both genetic and systemic findings are consistent with the diagnosis of Floating-Harbor syndrome in our patient. Rubenstein-Taybi and Floating-Harbor syndrome share a similarity in molecular and physical manifestations, but because of the prevalence in Rubenstein-Taybi diagnoses, it is a syndromic condition that includes coloboma and frequently associated with each other. Therefore, a retinal exam should become part of the standard protocol for those with FHS, as proper diagnosis, examination and treatment can prevent irreversible retinal damage.

Ocular manifestations of renal ciliopathies.

Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.proteinatlas.org/humanproteome/tissue ) and for an ocular phenotype in mouse models ( http://www.informatics.jax.org/ ). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment.

Síndrome de Morning Glory / Morning Glory Syndrome

Introducción: la anomalía congénita del disco óptico conocida como "morning glory" (MG) es un desarrollo anómalo del nervio óptico, caracterizado por una cavidad amplia en forma de embudo del disco en el punto donde salen las fibras del nervio de la retina. Su presentación más frecuente es unilateral. La mayoría de los casos son aislados y no se asocian con anomalías sistémicas. Objetivo: se presenta el caso de un niño de 1 año con MG y los hallazgos imagenológicos. Caso clínico: presentamos el caso de un paciente masculino de 1 año con sospecha de patología visual; en el estudio se realizó resonancia magnética cerebral (RM) en la que se identificó excavación en forma de embudo de la papila del globo ocular izquierdo, alteración en la morfología del quiasma óptico con desplazamiento inferior asimétrico y engrosamiento del infundíbulo y del tallo hipofisiario. Discusión: el diagnóstico de MG es clínico, las imágenes aportan información adicional sobre anomalías oculares, craneofaciales y vasculares asociadas. En este caso además de la lesión ocular había anomalías de estructuras de línea media como el infundíbulo y el tallo hipofisiario, además de engrosamiento quiasmático. Conclusión: la valoración por imágenes en fundamental, no solo para describir la alteración del nervio óptico, si no para identificar y describir anomalías asociadas para realizar manejo integral del paciente.

Introduction: the congenital optic disc anomaly known as morning glory disc anomaly (MGDA) is an alteration of normal optic nerve development, characterized by an enlarged funnel-shaped cavity of the optic disc, the point in the eye where the optic nerve fibers leave the retina. The anomaly is typically unilateral. Most are isolated cases with no associated systemic anomalies. Objective: a case is presented in a one-year-old boy with MGDA and the corresponding imaging findings. Case reports: we present the case of a one-year-old male patient with suspected visual impairment. Cerebral magnetic resonance imaging (MRI) revealed a papillary funnel-shaped excavation in the left eye, alteration in the morphology and inferior asymmetric displacement of the optic chiasm and thickening of the pituitary infundibular stalk. Discussion: MGDA is diagnosed clinically, however, imaging provides additional information regarding the associated ocular, craniofacial and vascular abnormalities. In this case, in addition to the ocular lesion there were abnormalities of midline structures, such as, the pituitary infundibular stalk, as well as, optic chiasm thickening. Conclusion: imaging is fundamental, not only to describe the anatomic alteration of the optic nerve, but also to identify related abnormalities in order to provide patients a comprehensive management