Macular and optic nerve hypoplasia in chromosome 2p partial trisomy

This study evaluates, in patients with aniridia, the prevalence of optic nerve hypoplasia and its association with foveal hypoplasia. The medical records of 56 patients with aniridia (31 female, 25 male, mean age 33 years, range 2-74 years) were retrospectively evaluated for optic nerve and foveal hypoplasia. The difference in prevalence of foveal hypoplasia in patients with and without optic nerve hypoplasia was compared using Fisher's exact test. Six of 56 patients, 10.7% (95% CI: 4.8-21.5%), had optic nerve hypoplasia; hypoplasia was found in both eyes of five binocular patients and in one monocular patient. The prevalence of foveal hypoplasia was higher in aniridia patients with optic nerve hypoplasia than in those without (50.0 vs 6.0%); this difference did not achieve statistical significance (P=0.10). Clinically apparent optic nerve hypoplasia is found in roughly 10% of patients with aniridia and may occur independently or in association with foveal hypoplasia.

To describe visual function and ocular manifestations in patients with onset of cholestasis during the neonatal period. Patients with neonatal cholestasis, either transitory or chronic, who came for assessment to our tertiary referral centre were included in a cross-sectional study and underwent ophthalmological examinations including fundus photography. A total of 57 patients (24 girls and 33 boys), aged 0.4-18.0 years, were included. Of these, 28 patients had biliary atresia, 11 had Alagille's syndrome, five had progressive familiar intrahepatic cholestasis and nine had different disorders such as pituitary insufficiency, alpha-1-antitrypsin deficiency, mitochondriopathy, congenital infections or cholestasis caused by unknown reasons. Visual dysfunction and/or one or several ocular manifestations occurred in 39 out of 57 patients. Major ocular malformations occurred in five patients. Out of three patients with biliary atresia, one patient had severe visual impairment caused by microphthalmia and chorioretinal coloboma, one patient with Cat Eye syndrome had bilateral uveochorioretinal coloboma and one patient had Rieger's anomaly. Two patients, both with pituitary deficiency and transient cholestasis, had severe unilateral visual impairment caused by optic nerve hypoplasia. The majority (68%) of the patients with cholestasis had ocular manifestations. Although the severity of ocular complications varied with diagnosis, and was most apparent among patients with biliary atresia or pituitary deficiency, no conclusion can be drawn regarding the connections between these conditions from the present study. Nevertheless, ocular assessment is important for diagnostic purposes and for early intervention in patients with cholestasis.

Canine optic nerve hypoplasia (ONH) and aplasia (ONA) are significant neuro-ophthalmologic disorders that have been reported in several species. The purpose of this study was to describe the distinctive histopathologic features of ONH and ONA in canine patients identified from a collection of 20 000 ocular submissions at the comparative ocular pathology laboratory of Wisconsin from 1989 to 2006. The following information about ONH and ONA cases was collected: signalment, and clinical and gross findings, including unilateral vs. bilateral involvement. Microscopic evaluation was performed, with attention to optic nerve malformation, retinal ganglion cell (RGC) and nerve fiber layer (NFL) loss, and retinal disorganization. The distribution of retinal vasculature was recorded and a search for unusual findings of ONH and ONA was performed. Information and histologic documentation was available for 13 cases. Eight cases of ONH and five cases of ONA were identified. The average group age was 20.2 months and 16.1 months, respectively. The most common breed was the Shih Tzu (3/13). ONH usually presented bilaterally (7/8); all ONA cases presented as a unilateral disease (5/5). The morphologic findings in the optic nerve (ON) in ONH included variable degrees of ON hypoplasia and gliosis, as well as ectopic vestigial ON remnants within orbital nerves and connective tissues. The NFL was detected in the majority of the ONH cases; however, RGCs were rare or absent. Mild retinal disorganization was seen occasionally. Most cases of ONH were associated with regional peripheral retinal blood vessel extension into the vitreous, leaving the peripheral retina avascular. In ONA cases the retinal blood vessels, NFL and RGCs were totally absent and retinal disorganization was severe. Distinctive microscopic features encountered in ONA included anterior segment dysgenesis in some cases. The retina in these cases was stretched across the posterior lens capsule, never making contact with the posterior pole of the globe. The current study reviews the human and veterinary literature pertaining to ONH and ONA, compares ONH and ONA in dogs, and presents related ophthalmic histopathologic findings that have not been reported previously.

High-Resolution Imaging of the Optic Nerve and Retina in Optic Nerve Hypoplasia

Autism is a developmental disorder characterized by impaired social interaction, problems in verbal and nonverbal communication, and stereotyped or repetitive activities and interests. Rather than a single condition, autism is today generally regarded as consisting of a spectrum of pervasive developmental disorders that together are known as autism spectrum disorders (ASDs). Optic nerve hypoplasia (ONH) is a congenital condition characterized by underdeveloped optic nerves and neurological impairment involving endocrine dysfunction and developmental delay, with or without brain malformations that are visible by way of neuroimaging tools. Increasing in prevalence, ONH is now the leading single ocular cause of blindness in children in the developed world, affecting 10.9 per 100,000 births (Patel, McNally, Harrison, Lloyd, & Clayton, 2006; Hatton, Schwietz, Boyer, & Rychwalski, 2007). Clinical observations and recent reports indicate a high frequency of ASDs in children with ONH (Ek, Fernell, & Jacobson, 2005; Parr, Dale, Shaffer, & Salt, 2010). In children with ONH, there are additional characteristics of ASD beyond those attributable to visual impairment alone, such as echolalia and stereotypic motor movements. We argue that ONH, like ASDs, should be considered a spectrum disorder to account for the range of severity in outcomes and symptoms associated with this condition. In addition, we believe the similarities in the two conditions illustrate the possibility of a shared neurodevelopmental origin. Comparing the similarities in these conditions may lead to a greater understanding of the risk factors contributing to either condition, as well as potential clinical outcomes, as the relationship is further explored. ASD AND BLINDNESS It is not surprising that ASDs are prevalent in children with ONH when one considers that published data indicate ASDs are overrepresented in the visually impaired population, with prevalence estimates as high as 1 case of autism in every 4 visually impaired persons (Brown, Hobson, Lee, & Stevenson, 1997), compared to 1 out of 110 in the general population (Rice, 2009). The behaviors and characteristics of children with vision impairment that resemble those of children with ASDs, including echolalia, pronoun reversal, stereotypic motor movements, and delays in developing pretend play, are often attributed to the vision impairment itself (Andrews & Wyver, 2005). These behaviors may be termed blindisms, since they are explainable in the context of vision impairment. (For example, rocking or spinning may provide needed vestibular stimulation in a child with limited mobility due to lack of vision; language development and social interactions may be impaired in congenitally blind children due to their lack of concrete experiences and visual models.) The similarity of these blindisms to autistic-like behaviors, coupled with the absence of autism diagnostic measures designed for use with people who are blind or visually impaired, complicates the diagnosis of ASDs in children who are visually impaired. Thus, the debate concerning whether true autism is prevalent in children who are visually impaired remains unresolved. ASDs AND ONH Most reports of ASDs in children with vision impairment (ASDVI) are limited to children who have severe congenital blindness regardless of any cause (Brown, Hobson, Lee, & Stevenson 1977; Ek, Fernell, Jacobson, & Gillberg, 1998). There are a few reports focused specifically on children with ONH. In a group of 13 Swedish children with ONH and blindness, 6 had ASDs and 3 had autistic-like conditions. The remaining 4 children did not fall on the autism spectrum (Ek, Fernell, & Jacobson, 2005). Parr and colleagues reported in a sample of 83 children with ONH and severe vision impairment (with acuities of worse than 6/30), 31 (37%) had social, communicative, and repetitive or restricted behavioral difficulties. …

The optic nerve and retinal vasculature in albinism: Normal or abnormal?

To quantify optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) morbidities and comorbidities. A retrospective population-based study with a case-control design was undertaken using administrative health data from Manitoba, Canada. Cases were 124 patients with ONH or SOD (70 males, 54 females; age range 6 months-36 years 8 months [mean 13 years, SD 7 years 2 months]) diagnosed from 1990 to 2019, matched to 620 unrelated population-based controls (350 males, 270 females; age range 0-36 years 8 months [mean 12 years 5 months, SD 7 years 2 months]) on birth year, sex, and area of residence. Additionally, 76 cases with ONH or SOD (46 males, 30 females; age range 2 years 5 months-36 years 8 months [mean 13 years 11 months, SD 7 years 3 months]) were matched one-to-one with sibling controls (40 males, 36 females; age range 7 months-33 years 1 month [mean 11 years 8 months, SD 7 years 3 months]). We used χ2 or Fisher's exact tests to test for differences in prevalence in morbidities and comorbidities between cases and controls; odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Cox proportional hazards models were used to test for differences in subgroups of cases; hazard ratios and 95% CIs were estimated. Visual impairment and visual impairment with hypopituitarism were core morbidities associated with ONH and SOD cases respectively compared to unrelated controls (OR = 58.6, 95% CI = 22.5-152.5; OR = 243.4, 95% CI = 32.9-1799.0 respectively). Developmental delay or intellectual disability (OR = 6.9, 95% CI = 3.3-14.4), autism spectrum disorder (OR = 4.0, 95% CI = 2.0-8.3), epilepsy (OR = 14.9, 95% CI = 6.1-36.5), cerebral palsy (OR = 40.9, 95% CI = 14.0-119.6), and mood or anxiety disorders (OR = 1.7, 95% CI = 1.0-2.8) were the comorbidities more common among cases with ONH and SOD. Cases matched to siblings showed similar results except for mood and anxiety disorders. Visual impairment and visual impairment with hypopituitarism are the main morbidities in patients with ONH and SOD respectively, while developmental delay or intellectual disability, autism spectrum disorder, epilepsy, cerebral palsy, and mood or anxiety disorders are important comorbidities.

Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7–18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.

High-resolution magnetic resonance images of the intracranial optic nerves and chiasm were obtained in 15 patients with severe optic nerve hypoplasia. These were compared, in a double-blind manner, with similar images from 30 age-matched controls. On both coronal and sagittal images, hypoplastic optic nerves were thin and demonstrated signal attenuation when compared with normal optic nerves. All patients with severe bilateral optic nerve hypoplasia also had diffuse chiasmal hypoplasia, which was seen best on coronal images. Patients with unilateral or asymmetrical optic nerve hypoplasia had variable chiasmal abnormalities. The degree to which the magnetic resonance diagnosis of optic nerve hypoplasia matched the clinical diagnosis was highly significant (P less than .001, Fisher's Exact Test) for both coronal and sagittal views of the intracranial optic nerves. Oblique axial and coronal views of the orbital optic nerves did not reliably distinguish optic nerve hypoplasia from normal optic nerves. High-resolution magnetic resonance imaging is a useful diagnostic modality to identify small optic nerves neuroradiologically.

Background Costello syndrome (CS) is a multisystem developmental disorder caused by germline pathogenic variants in HRAS resulting in dysregulation of the Ras pathway. A systematic characterization of ophthalmic manifestations provides a unique opportunity to understand the role of Ras signal transduction in ocular development and guide optimal ophthalmic care in CS individuals. Methods Visual function, ocular features and genotype/phenotype correlations were evaluated in CS individuals harboring HRAS pathogenic variants, by cross-sectional and retrospective studies, and were recruited through the Costello Syndrome Family Network (CSFN) between 2007 and 2020. Results Fifty-six molecularly diagnosed CS individuals including 34 females and 22 males, ages ranging from 0.5 to 37 years were enrolled. The most common ophthalmic manifestations in the cross-sectional study were lack of stereopsis (96%), refractive errors (83%), strabismus (72%), nystagmus (69%), optic nerve hypoplasia or pallor (55%) and ptosis (13.7%) with higher prevalence than in the retrospective data (refractive errors (41%), strabismus (44%), nystagmus (26%), optic nerve hypoplasia or pallor (7%) and ptosis (11%)). Visual acuities were found to ranged from 20/25 to 20/800 and contrast sensitivity from 1.6% to 44%. HRAS pathogenic variants included p.G12S (84%), p.G13C (7%), p.G12A (5.4%), p.G12C (1.8%) and p.A146V (1.8%). Conclusion Majority of individuals with CS have refractive errors, strabismus, nystagmus, absent stereopsis, and optic nerve abnormalities suggesting that HRAS and the Ras pathway play a vital role in visual system development. Ptosis, refractive errors and strabismus are amenable to treatment and early ophthalmic evaluation is crucial to prevent long-term vision impairment and improve overall quality of life in CS.

Retinall and Optic Nerve Findings in Goldenhar-Gorlin Syndrome

Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature

53 - Congenital anomalies of the optic discs

Optic nerve hypoplasia (ONH) is a congenital ocular malformation that has been associated with neurodevelopmental disorders, but the prevalence in unilateral disease and less severe visual impairment is unknown. We studied intellectual disability and autism spectrum disorders (ASDs) in patients with ONH. This was a population-based cross-sectional cohort study of 65 patients (33 female) with ONH below 20 years of age, living in Stockholm in December 2009, with data analysed in January 2016. Of these 35 were bilateral and 30 were unilateral. Neurodevelopmental disorders were diagnosed or confirmed by neurological assessments, the Five to Fifteen parent questionnaire and reviewing previous neuropsychological investigations or conducting neuropsychological tests. Bilateral ONH patients had lower mean full scale intelligence quotient scores than unilateral patients (84.4 and 99.4, respectively, p = 0.049). We assessed intellectual disability in 55 eligible patients, and it was more common in patients with bilateral ONH (18 of 32, 56%) than unilateral ONH (two of 23, 9%, p < 0.001). ASDs were diagnosed in seven of 42 (17%) patients. Children with bilateral ONH had a high risk of neurodevelopmental disorders, especially intellectual disability. The risk was lower in unilateral ONH, but the levels of neurodevelopmental disorders warrant screening of both groups.

Peripheral Nonperfusion and Tractional Retinal Detachment Associated with Congenital Optic Nerve Anomalies