Pituitary deficiencies related to optic nerve hypoplasia and visual acuity.

OBJECTIVE: Optic nerve hypoplasia (ONH), the congenital underdevelopment of the optic nerve, is an increasing cause of visual impairment and is associated with pituitary dysfunction. Past studies have focused on the relationship between ONH, pituitary deficiencies, and brain imaging. However, recent studies have demonstrated the true risk for hypopituitarism lies with the presence or absence of ONH, irrespective of midline brain findings. This study reviewed the relationship between the health of the optic nerve (visual acuity) and pituitary gland (number and age of development of pituitary deficiencies) as a way to stratify risk, regardless of imaging findings. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective chart review of 197 patients seen at a single center from 2013 to 2022. Visual assessment was defined by distance acuity, and the presence of nystagmus or afferent pupillary defect. Pituitary deficiencies were diagnosed per Endocrine Society guidelines. RESULTS: In children with bilateral ONH (bONH), profound visual impairment was associated with more pituitary deficiencies between 0 and 15 years of age. The odds of having any pituitary deficiency were 4.9 times higher (95% confidence interval [95% CI]: 2.4-10.1) for patients with bONH versus unilateral ONH (uONH). Central hypothyroidism was the most common first presenting pituitary deficiency followed by growth hormone across all patients. CONCLUSION: This study shows a significant association between severity of visual impairment and increased probability of pituitary deficiencies in children with bONH versus uONH. Children with ONH require urgent endocrine evaluation due to risk of pituitary deficiencies, but risk stratification may also be based on severity of visual impairment.

Gastroschisis and septo-optic-pituitary dysplasia: Is there an association?

AIM: There are several case reports describing patients with both optic nerve hypoplasia/septo-optic-pituitary dysplasia (ONH/SOD) and gastroschisis (GS). Our aim was to investigate whether ONH/SOD is associated with GS. METHODS: A retrospective population-based study was undertaken using the Population Research Data Repository at the Manitoba Center for Health Policy in Manitoba, Canada to investigate if any patient with ONH/SOD also had GS. In addition, Winnipeg's Surgical Database of Outcomes and Management (WiSDOM), a hospital-based paediatric surgical database, was searched to ascertain if any of the patients with GS also have ONH/SOD. RESULTS: Cases were 124 patients with ONH/SOD diagnosed during 1990-2019. None had GS. The surgical database had 188 patients from Manitoba with GS during 1991-2019. None had ONH/SOD. CONCLUSION: There does not appear to be an association between ONH/SOD and GS in our cohorts of patients with these two disorders.

Septo-Optic Dysplasia: A Case Series of 33 Patients.

The objective of this study was to record the clinical, neuro-radiological, and systemic features of patients with septo-optic dysplasia (SOD). A retrospective review of patients was conducted to identify patients with features consistent with SOD over a 6-year period, including optic nerve hypoplasia with agenesis of midline structures, along with an absent septum pellucidum and/or agenesis of the corpus callosum. Thirty-three patients were identified. The male to female ratio was 2:1, while the median age at diagnosis was 5 years (interquartile range = 10 years, range = 0-44 years). Optic nerve hypoplasia (ONH) was bilateral in 81.81% of cases (n = 27) and unilateral in 18.18% of cases (n = 6), with three cases in each eye. Developmental delay was documented in 24.2% (n = 8). The most frequent magnetic resonance imaging features that were consistent with SOD included: isolated absent septum pellucidum reported in 51.51% (n = 17); isolated corpus callosum agenesis in 33.33% (n = 11); and both absent septum pellucidum and corpus callosum agenesis in 15.15% (n = 5). Pituitary gland abnormalities, including pituitary hypoplasia in 9% (n = 3) or hypoplasia of pituitary infundibulum in 6% (n = 2) were less common. Pituitary hormonal abnormalities were present in 50% of the 10 tested patients (n = 5). Although bilateral ONH is more frequent, hypoplasia of just one optic nerve could be a presenting feature of SOD. Therefore, additional neuro-imaging is important for a diagnosis in cases of unilateral and bilateral ONH and a multidisciplinary approach is beneficial.

Neuroimaging Features in Children with Optic Nerve Hypoplasia and Septo-Optic-Pituitary Dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are common causes of congenital visual impairment. Our primary aim was to investigate the prevalence of abnormal neuroimaging features in patients with these disorders in Manitoba, Canada, and compare them with published reports. METHODS: A retrospective neuroimaging review was performed in patients resident in Manitoba with ONH/SOD. RESULTS: There were 128 patients (M = 70) with ONH/SOD who had neuroimaging. Their mean age (SD) at the end of the study was 13.2 (7.5) years. Males were significantly more likely to have bilateral ONH and a small optic chiasm size, while females were more likely to have a left ONH and a small left optic chiasm size on neuroimaging (p = 0.049). ONH and small optic chiasm size were seen in most patients on neuroimaging. Absent septum pellucidum was noted in 40%, small pituitary gland size in 28%, neuronal migration disorders (NMD) in 20% (>1 type and bilateral in 13 cases), corpus callosum abnormalities were present in 9%, while olfactory bulbs-tracts and olfactory sulci were absent in 8.6% of cases. Unilateral ONH was not significantly associated with other structural brain abnormalities, while NMD were significantly associated with other midline brain abnormalities including a symmetrically small optic chiasm size. CONCLUSION: The prevalence of structural neuroimaging abnormalities in our cohort with ONH/SOD was generally in the same range reported in other studies with corpus callosum abnormalities being relatively less common in our study. Bilateral NMD were relatively common among patients with NMD. The association between sex and ONH laterality requires further study.

Comparison of Cirrus spectral domain OCT with disc-macula distance to disc diameter ratio in diagnosing congenital optic nerve hypoplasia.

PURPOSE: Diagnosis of congenital optic nerve hypoplasia (CONH) can be challenging in children or uncooperative individuals. Misdiagnosis can lead to inappropriate treatment; thus, it is important to identify an objective and reliable measurement. The purpose of this study was to evaluate whether Cirrus spectral domain optical coherence tomography (SD-OCT) is a valid test for diagnosing CONH by comparing it to the disc-macula distance to disc diameter (DM:DD) ratio. METHODS: A total of 93 participants (64 controls and 29 CONH) underwent comprehensive eye examinations, fundus photography and Cirrus SD-OCT. Receiver operating characteristic (ROC) curves for the DM:DD ratio and OCT disc area were constructed for CONH and control eyes. RESULTS: Mean (±SD) OCT disc area was 1.46 (±0.42) mm2 and 1.89 (±0.38) mm2 for CONH and control eyes, respectively (p < 0.0001). The area under the curve for the DM:DD ratio was 0.97 (95% confidence interval: 0.91-0.99) and 0.79 for OCT disc area (95% confidence interval: 0.70-0.86), which were significantly different (p = 0.0005). The optimal cut-off value for OCT disc area was 1.66 mm2 (76% sensitivity, 70% specificity), while the optimal cut-off for DM:DD ratio was 3.10 (85% sensitivity and 95% specificity). The Cirrus SD-OCT showed a tendency to overestimate disc size, especially in cases with no light perception (NLP) or segmental CONH. CONCLUSIONS: Although the DM:DD ratio is superior to OCT in diagnosing CONH with a higher sensitivity and specificity, the ratio is subject to inter-examiner variability and can be challenging to obtain. We found the Cirrus SD-OCT to be a valid objective test for diagnosing CONH. Caution is advised when using SD-OCT in segmental CONH or in an eye with NLP. We suggest 1.66 mm2 as the optimal cut-off value for Cirrus SD-OCT disc area to differentiate a hypoplastic from a normal optic disc.

Porencephaly with an optic organ abnormality in a beagle dog.

A female TOYO beagle dog showed porencephaly and visual organ abnormalities. At necropsy, there was a cavity filled with cerebrospinal fluid in the right cerebral hemisphere and an adhesion area between the cerebral cortex and the skull, which was partially thickened. Additionally, the right optic nerve showed a slight decrease in diameter. Histopathological examination revealed increased glial fibers and collagen fibers, hemosiderin deposition, and an increased number of microglia in the adhesion area, along with a marked reduction of the cerebral parenchyma. In the right eyeball, the retina and optic nerve showed focal atrophy in the nerve fiber layer and inner granular layer to full retinal atrophy and hypoplasia of the myelinated nerve fibers, respectively. Electron microscopic examination revealed hypoplasia of the myelin sheath of nerve fibers in the right optic nerve. This is an extremely rare case of porencephaly and congenital optic nerve hypoplasia, along with independent retinal thinning.

Ocular findings of congenital Zika virus infection with microcephaly.

PURPOSE: To describe ocular findings in infants with signs of congenital Zika virus syndrome (CZS) in Paraíba, Brazil, as well as to conduct a literature review and report correlations with published clinical cases. METHODS: In the Paraíba sample, infants with microcephaly suggestive of CZS were classified as Z (confirmed), PZ (probable), or SZ (suspected) according to serological testing and/or clinical findings of CZS. The patients underwent a clinical eye examination, and the results were correlated with published clinical cases. RESULTS: Ocular findings were present in 24 (42.9%) of 56 patients, consisting of gross retinal pigmentation in 11 (45.8%), macular chorioretinal atrophy in 11 (45.8%), optic nerve hypoplasia in 1 (4.2%), optic nerve pallor in 14 (58.3%), and increased cup-to-disk ratio in 2 (8.3%). The study revealed retina and optic nerve findings consistent with previous reports of ophthalmic involvement in CZS. However, external ocular changes observed in other studies were not detected. CONCLUSION: Ocular findings similar and consistent with the literature on CZS were observed with considerable frequency and severity, regardless of the patients' serological confirmation or classification. Infants with signs of CZS should undergo ocular examination.

Selected Ophthalmological Features in Children with Septo-Optic Dysplasia and Optic Nerve Hypoplasia.

Septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH) cause congenital visual impairment. Their aetiology is mostly unknown. Our aim was to investigate the prevalence of selected ophthalmological features in patients with these disorders. A chart review was performed on patients with SOD/ONH. Ophthalmological data were extracted. There were 102 patients (56 males). The median age at the end of the study was 12.7 years. Best-corrected visual acuity ranged from normal to no light perception. Bilateral ONH was more common than unilateral ONH. Strabismus (85%) and to a lesser extent nystagmus (52%) were both very common in our cohort. Patients with esotropia had worse visual acuity than those who had exotropia. The presence of nystagmus was more likely in cases with bilateral ONH. Therefore, patients with SOD/ONH may have normal visual acuity. Many have strabismus, which may cause amblyopia thereby further decreasing visual acuity. Nystagmus occurs commonly and its presence typically indicates bilateral ONH.

Repeated measurements of ERGs and VEPs using chloral hydrate sedation and propofol anesthesia in young children.

PURPOSE: Sedation with chloral hydrate or anesthesia using propofol allow ocular examination and testing in young children, but these drugs may affect electrophysiologic recordings. We compared the flash and pattern ERGs and VEPs recorded with each drug in a cohort of young children enrolled in a prospective study of optic nerve hypoplasia (ONH) syndrome. METHODS: ERGs and VEPs to light-adapted, standard, full-field flashes, to standard and steady-state pattern-reversal (PR) were recorded with cycloplegia in 9 participants. Age range at the first session, with chloral hydrate was 8-23 mo; at the second session with propofol it was 20-29 mo. Examiners masked to the drug and clinical conditions measured the waveforms for longitudinal, paired comparisons between the sessions. RESULTS: Flash ERG amplitudes did not differ between sessions; peak times were longer at the second session (propofol) by clinically insignificant amounts (< 2 ms, p = 0.002). Standard PERGs had larger amplitudes and later peaks in the second session (propofol) than with chloral hydrate (P50 2.9 vs 4.7 µV, p = 0.016 and 43 vs 52 ms, p < 0.001; N95 4.0 vs 6.1 µV, p = 0.003 and 91 vs 98.5 ms p = 0.034.). These differences were present for those with an interval of  > 10 mo between sessions (n = 5, 10 eyes) but not for those with a shorter inter-test interval (< 8 mo, p > 0.05, n = 4). Magnitudes of the steady-state PERGs did not differ between tests but the waveforms had earlier peaks at the second test with propofol. Flash VEP waveforms were present in 10/18 eyes and showed 72% agreement for recordability between sessions. Standard pattern VEPs were recordable in only a few eyes in this cohort with ONH. CONCLUSIONS: Light-adapted flash ERG waveforms were generally similar with chloral hydrate and with propofol. Larger PERGs with later peaks, found in the second session (propofol) could reflect maturation of the PERG generators, as the differences found were associated with a greater age difference between the sessions, but we do not rule out that small differences in the waveforms may be drug-related. There are insufficient VEP data from these children with ONH to identify drug-related or maturational effects on VEPs.

ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings.

BACKGROUND: ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene. Patients manifest with severe neurologic, cardiac, musculoskeletal and ophthalmic phenotype in combination with dysmorphic features, and almost half of them die before or during the neonatal period. CASE PRESENTATION: A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment. Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth. Transferrin isoelectric focusing revealed a type 1 pattern. Funduscopy showed hypopigmentation and optic disc pallor. Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging. The presence of optic nerve hypoplasia was also supported by magnetic resonance imaging. A gene panel based next-generation sequencing and subsequent Sanger sequencing identified compound heterozygosity for two novel variants c.116del p.(Pro39Argfs*40) and c.1060 C > T p.(Arg354Cys) in ALG3. CONCLUSIONS: Our study expands the spectrum of pathogenic variants identified in ALG3. Thirty-three variants in 43 subjects with ALG3-CDG have been reported. Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

The Prevalence of Brain Abnormalities in Japanese Patients with Optic Nerve Hypoplasia.

The purpose of this study was to investigate the clinical characteristics of Japanese patients with optic nerve hypoplasia (ONH), with particular attention to the prevalence of brain abnormalities. We retrospectively analysed the medical charts of 16 patients who were diagnosed with ONH and who underwent magnetic resonance imaging (MRI) at Niigata University Medical and Dental Hospital. We recorded the age, sex, laterality, initial eye and visual symptoms, best-corrected visual acuity, and brain abnormalities on MRI (excluding ONH). The median age at the first visit to the Ophthalmology Clinic was 2.4 years old. Four patients were male and 12 were female. ONH was bilateral in 11 patients and unilateral in five. Best-corrected visual acuity ranged from no light perception to 20/20. Seven patients (43.8%) had brain abnormalities including agenesis of the septum pellucidum, pituitary gland hypofunction, cerebral dysplasia, and West syndrome. Five of these seven patients had general manifestations since the neonatal or infantile period. Our study revealed the prevalence of brain abnormalities associated with optic nerve hypoplasia in Japanese patients at a single institute. Because two of 11 patients had no general manifestations since the neonatal or infantile period but demonstrated brain abnormalities, MRI should be performed to investigate all patients with ONH.

Fetal Ultrasound and Magnetic Resonance Imaging Findings in Suspected Septo-Optic Dysplasia: A Diagnostic Dilemma.

OBJECTIVES: To investigate prenatal imaging findings supporting a diagnosis of suspected septo-optic dysplasia (SOD) by fetal ultrasound (US), magnetic resonance imaging (MRI), or both. METHODS: A retrospective review identified 11 patients with SOD: 9 had a clinical diagnosis of SOD postnatally, and 2 were terminated on the basis of suspicious prenatal imaging. Prenatal and neonatal imaging of the cavum septi pellucidi (CSP), frontal horns (FHs), and lateral ventricles was evaluated. RESULTS: The appearance of the CSP varied on US and MRI. Complete ("fused") FHs or partial absence of the CSP was reported in 6 of 11 patients by fetal US and 7 of 8 patients by fetal MRI. The diagnosis of SOD was prospectively suspected prenatally in 6 of 11 and in an additional 5 of 11 cases retrospectively. Fetal MRI incorrectly initially reported normal morphologic abnormalities for 2 cases with partial absence of the CSP, whereas US accurately identified the morphologic abnormalities in 1 of these cases before MRI. Imaging features were first suggested at anatomic US (4 patients) and follow-up prenatal US (2 patients). Neonatal imaging was concordant in all 9 live births: 5 completely absent CSP, 3 partially absent CSP, and 1 completely present CSP. Clinical manifestations included optic nerve hypoplasia (9 of 9), panhypopituitarism (5 of 9), and neurodevelopmental delays. CONCLUSIONS: Primary imaging features of SOD are "continuous" FHs with complete or partial absence of the CSP. Septo-optic dysplasia can be suspected in utero and can appear isolated but has substantial associated central nervous system anomalies identified on fetal MRI or after birth. Partial absence of the CSP can be a prenatal sign of suspected SOD, although fetal MRI lacked the spatial resolution to identify it accurately in all cases.

Optic nerve hypoplasia in miniature poodle dogs: A preliminary genetic and candidate gene association study.

OBJECTIVE: To conduct a genetic and candidate gene association study with samples from phenotype-ascertained dogs to identify putative disease-associated gene/mutation for optic nerve hypoplasia (ONH) in the miniature poodle. ANIMALS STUDIED: A total of 43 miniature poodles from the United States and Europe, nine affected bilaterally with ONH, were included in the study. Pedigree information was recorded. PROCEDURES: A pedigree including all animals studied was assembled. Twenty-one genes typically expressed in ganglion cells or that are associated with ocular malformations and have a critical function in eye and neural retina development were selected. Exons and exon-intron boundaries of eight genes were sequenced in four ONH cases and four controls. Furthermore, cases and controls were genotyped with the Illumina CanineHD BeadChip to obtain genotypes for 13 additional candidate genes for haplotype association. RESULTS: The assembled pedigree connected all ONH-affected dogs to a possible common founder. Identified variants and haplotypes of the tested candidate genes did not segregate with the phenotype using Identity by Descent approach assuming autosomal recessive inheritance with variable but yet unknown penetrance. CONCLUSIONS: Pedigree analysis did not reveal the inheritance pattern. There is no evidence of association of the evaluated candidate genes with ONH; therefore, the screened candidate genes can provisionally be ruled out as causally associated with the disease.

Non-Arteritic Anterior Ischaemic Optic Neuropathy Associated with Optic Nerve Hypoplasia and Elevated Intraocular Pressure.

A 46-year-old woman with no known past medical history presented with sudden painless visual impairment in the left eye. Ocular examination showed a swollen and hyperaemic left optic disc with a small and crowded right optic disc. Intraocular pressures were moderately elevated. Investigations for underlying ischaemic and inflammatory markers were normal. A diagnosis of left non-arteritic anterior ischaemic optic neuropathy (NAAION) was made, with associated ocular hypertension. On follow-up, NAAION resolved with anti-glaucoma medication and repeat fundus examination confirmed the presence of an underlying hypoplastic disc. The coexistence of optic disc hypoplasia and elevated intraocular pressure may further augment the risk of developing NAAION.

An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.

Heterozygous loss-of-function mutations in the X-linked gene CASK are associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and ophthalmological disorders including optic nerve atrophy (ONA) and optic nerve hypoplasia (ONH). Recently, we have demonstrated that CASK(+/-) mice display ONH with 100% penetrance but exhibit no change in retinal lamination or structure. It is not clear if CASK loss-of-function predominantly affects retinal ganglion cells, or if other retinal cells like photoreceptors are also involved. Here, we report a heterozygous missense mutation in the N-terminal calcium/calmodulin-dependent kinase (CaMK) domain of the CASK protein in which a highly conserved leucine is mutated to the cyclic amino acid proline. In silico analysis suggests that the mutation may produce destabilizing structural changes. Experimentally, we observe pronounced misfolding and insolubility of the CASKL209P protein. Interestingly, the remaining soluble mutant protein fails to interact with Mint1, which specifically binds to CASK's CaMK domain, suggesting a mechanism for the phenotypes observed with the CASKL209P mutation. In addition to microcephaly, cerebellar hypoplasia and delayed development, the subject with the L209P mutation also presented with bilateral retinal dystrophy and ONA. Electroretinography indicated that rod photoreceptors are the most prominently affected cells. Our data suggest that the CASK interactions mediated by the CaMK domain may play a crucial role in retinal function, and thus, in addition to ONH, individuals with mutations in the CASK gene may exhibit other retinal disorders, depending on the nature of mutation.

High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia.

AIM: This study examined the prevalence of neurological impairment and pituitary hormone deficiency (PHD) in patients with unilateral and bilateral optic nerve hypoplasia (ONH). METHODS: A population-based cross-sectional cohort study of 65 patients (51% female) with ONH was conducted in Stockholm. Of these were 35 bilateral and 30 unilateral. The patients were below 20 years of age, living in Stockholm in December 2009 and found through database searching. The median age at the analysis of the results in January 2018 was 16.1 years (range 8.1-27.5 years). Neurological assessments and blood sampling were conducted, neuroradiology was reviewed and growth curves were analysed. Diagnoses of PHDs were based on clinical and biochemical evidence of hormone deficiency. RESULTS: Neurological impairments were identified in 47% of the patients and impairments in gross and fine motor function were more prevalent in bilateral ONH (p < 0.001). In addition, 9% had cerebral palsy and 14% had epilepsy. The prevalence of PHD was 29 and 19% had multiple PHD. CONCLUSION: Children with ONH had a high risk of neurological impairment, especially in bilateral disease. Both unilateral and bilateral ONH signified an increased prevalence of PHD and all these children should be endocrinologically followed up until completed puberty.

Ocular findings in Noonan syndrome: a retrospective cohort study of 105 patients.

The aim of this retrospective study is to describe ocular findings in a large Noonan syndrome cohort and to detect associations between ocular features and genetic mutations that were not found in earlier studies. We collected ophthalmological and genetic data of 105 patients (median age, 12 years; range, 0-60 years) clinically diagnosed as Noonan syndrome. The ocular findings were linked to the genotypes. All patients with Noonan syndrome showed multiple abnormalities in the categories of vision and refraction, external ocular features, ocular alignment and motility, anterior ocular segment, and posterior ocular segment. In total, 50 patients have NS due to a mutation in PTPN11. Permanent visual impairment (bilateral best-corrected visual acuity < 0.3) was found in 7 patients, including patients with a mutation in RAF1, SHOC2, and KRAS. Keratoconus was found in 2 PTPN11 positive patients, and prominent corneal nerves were observed in a patient with a SOS1 mutation. CONCLUSIONS: This study shows an overview of ocular abnormalities in Noonan syndrome, including permanent visual impairment caused by binocular optic nerve abnormalities and nystagmus. Delay in ophthalmological diagnosis is still present, also in patients with visual impairment. All Noonan syndrome patients should have a complete ophthalmological examination at the time of diagnosis. What is Known: • Although we discover more pathogenic mutations in patients with Noonan syndrome, Noonan syndrome still is a clinical diagnosis • Ocular features of Noonan syndrome are characterized by developmental anomalies of the eyelids and associated with other ocular abnormalities in childhood (including refractive errors, strabismus and amblyopia). What is New: • There seems to be a delay in the ophthalmological diagnosis and awareness of the broad variety ofophthalmological features including refractive errors and visual impairment in Noonan syndrome is needed. All children should have a full ophthalmological examination at the time of diagnosis. • Permanent visual impairment (best-corrected visual acuity < 0.3) is found in patients with mutations in RAF1, SHOC2, and KRAS and the cause is probably a developmental disorder of the optic nerves.

Children with optic nerve hypoplasia face a high risk of neurodevelopmental disorders.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Septo-optic dysplasia.

A seven-month-old child with congenital poor vision was referred for evaluation. Fundus examination revealed bilateral optic nerve hypoplasia with disc macula distance of approximately ten disc diameters. Neuroimaging revealed finding consistent with septo-optic dysplasia.