Novel compound heterozygous variants of tyrosinase gene in an isolated foveal hypoplasia patient without nystagmus.

Foveal hypoplasia is the major cause of visual loss. Here we report an isolated foveal hypoplasia patient without nystagmus. It is very rare, and its etiology is not completely understood. Using whole-exome sequencing and foveal hypoplasia-related gene filtering from a family with two generations, we identified a novel variant c.859T>C (p.S287P) and a rare non-frameshift variant c.229_230insGGG (p.Arg77_Glu78insGly) in the tyrosinase (TYR) gene that co-segregated in the affected member of this family. The compound heterozygous variants inherited in the proband were confirmed by Sanger sequencing and predicted from in silico studies to have an effect on protein function. In conclusion, our finding extends the spectrum of TYR variants and supports the important role of TYR in the development of eyes.

Optical Coherence Tomography Neuro-Toolbox for the Diagnosis and Management of Papilledema, Optic Disc Edema, and Pseudopapilledema.

BACKGROUND: Distinguishing optic disc edema from pseudopapilledema is a common, sometimes challenging clinical problem. Advances in spectral-domain optical coherence tomography (SD-OCT) of the optic nerve head (ONH) has proven to be a cost effective, noninvasive, outpatient procedure that may help. At its core are tools that quantify the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL). The SD-OCT also provides a set of tools that may be qualitatively interpreted in the same way that we read an MRI. They include the transverse axial, en face, and circular tomogram. Our goal is to describe a practical office-based set of tools using SD-OCT in the diagnosis and monitoring of papilledema, optic disc edema, and pseudopapilledema. EVIDENCE ACQUISITION: Searches on PubMed were performed using combinations of the following key words: OCT, papilledema, pseudopapilledema, optic disc drusen, retinal folds (RF), and choroidal folds (CF). RESULTS: The principal elements of SD-OCT analysis of the ONH are the RNFL and GC-IPL thickness; however, these metrics have limitations when swelling is severe. Qualitative interpretation of the transverse axial SD-OCT aids in assessing peripapillary shape that may help distinguish papilledema from pseudopapilledema, evaluate atypical optic neuropathies, diagnose shunt failures, and identify outer RF and CF. There is a consensus that the SD-OCT is the most sensitive way of identifying buried optic disc drusen. En face SD-OCT is especially effective at detecting peripapillary wrinkles and outer retinal creases, both of which are common and distinctive signs of optic disc edema that rule out pseudopapilledema. Mechanically stressing the ONH in the adducted eye position, in patients with papilledema, may expose folds and peripapillary deformations that may not be evident in primary position. We also discuss how to optimize the acquisition and registration of SD-OCT images. CONCLUSIONS: The SD-OCT is not a substitute for a complete history and a careful examination. It is, however, a convenient ancillary test that aids in the diagnosis and management of papilledema, optic disc edema, and pseudopapilledema. It is particularly helpful in monitoring changes over the course of time and distinguishing low-grade papilledema from buried drusen. The application of the SD-OCT toolbox depends on optimizing the acquisition of images, understanding its limitations, recognizing common artifacts, and accurately interpreting images in the context of both history and clinical findings.

BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure.

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.

The recurrent TUBB3 Gly98Ser substitution is the first described to inconsistently result in CFEOM3.

Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G>A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of TUBB3 syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype-specific to the TUBB3 Gly98Ser substitution.

Wide-field true-colour imaging and clinical characterization of a novel GRK1 mutation in Oguchi disease.

PURPOSE: The available literature regarding Oguchi disease is limited, with around 50 cases described to date. Caused by mutations to either the SAG gene coding for arrestin (Hayashi et al. in Ophthalmic Res 46:175-180, 2011) or the GRK1 gene coding for rhodopsin kinase (Yamamoto et al. in Nat Genet 15:175-178. https://doi.org/10.1038/ng0297-175 , 1997), Oguchi disease is an autosomal recessive condition with a good visual prognosis. The clinical diagnosis of the condition is based on the presence of night blindness (nyctalopia), as well as fundoscopic observation of the Mizuo-Nakamura phenomenon. The Mizuo-Nakamura phenomenon refers to a fundus discolouration described as a golden-brown colour with a yellow-grey metallic sheen most prominent in the peripheral retina; after prolonged dark adaptation, the fundus appears normal. The prevalence of Oguchi disease is highest in Japan, particularly with SAG mutations (Nakazawa et al. in Retina 17:17-22, 1997), although patients from Europe, Pakistan and India have also been described. Formal diagnosis requires genetic testing. METHODS: Wide-field fundus images were obtained in both dark-adapted and light-adapted retina. Optical coherence tomography and dark-adapted electroretinography responses were used to further characterize the clinical phenotype. RESULTS: Existing descriptions of Oguchi disease have been limited by available technology. The flashes required for 45°-montage photographs in a dark-adapted eye quickly cause light adaptation. Recent advances in technology enable the capture of larger retinal areas in a single image. Wide-field 133° images were obtained of the native and dark-adapted fundus in natural colour. To our knowledge, these represent the first reported single-wide-field images of Oguchi disease, showing the characteristic Mizuo-Nakamura phenomenon in true colour. Genetic testing revealed a novel homozygous mutation in GRK1. CONCLUSIONS: Here, we demonstrate how characterizing this condition with single-shot true-colour wide-field imaging has distinct advantages over scanning laser technology, which applies artificial colouration, or stitched true-colour images. Images captured with wide-field systems create a much better representation of the native and dark-adapted fundus than can be observed by the ophthalmologist using direct fundoscopy and are essential in the clinical characterization of new mutations.

CHANGES OF CONE PHOTORECEPTOR MOSAIC IN AUTOSOMAL RECESSIVE BESTROPHINOPATHY.

PURPOSE: To assess the morphological changes of cone photoreceptors in eyes with autosomal recessive bestrophinopathy. METHODS: Both eyes of five patients with autosomal recessive bestrophinopathyunderwent spectral domain optical coherence tomography and adaptive optics fundus imaging. The cone photoreceptor densities were measured at intervals of 100 µm between 500 µm nasal and temporal eccentricities from the foveal center. RESULTS: The median age of the patients was 30 years (range, 23-45 years), and the best-corrected visual acuity ranged from 20/20 to 20/80. Adaptive optics fundus images showed reduced cone photoreceptor densities corresponding to the damages of the photoreceptor layer in the spectral domain optical coherence tomography images in four patients with relatively good best-corrected visual acuity. The cone photoreceptor densities at the center of the fovea were less than one-third of the normal cone densities (range 11,600-30,400 cells/mm). Cone photoreceptor mosaics were visible over the lesions with serous retinal detachment and retinal edema, although they were partially hyporeflective. CONCLUSION: There is a significant cone photoreceptor loss in the macular region of patients with autosomal recessive bestrophinopathy, although they had relatively good visual acuity. Monitoring cone photoreceptors by adaptive optics fundus imaging should provide accurate assessments of the disease status and indications for future therapeutic interventions.

High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report.

BACKGROUND: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. In this report, high-resolution ocular imaging reveals unexpected findings that reject previous hypotheses. CASE PRESENTATION: The proband is a 37-year-old female with a history of neonatal patent ductus arteriosus (PDA) ligation, left-sided choreiform movements at the age of 11 and a transient aphasia with right-sided weakness at the age of 30. Her older sister also had PDA ligation and congenital mydriasis but no neurological deficit up to age 41. Magnetic resonance angiogram demonstrated cerebrovascular lesions resembling but distinct from Moyamoya disease, characterised by internal carotid artery dilatation, terminal segment stenosis and absent basal collaterals. Their mother had poorly reactive pupils with asymptomatic cerebral arteriopathy resembling her daughters. All three had prominent retinal arteriolar tortuosity. The daughters were heterozygous and the mother was a somatic mosaic for a novel c.351C > G (p.Asn117Lys) transversion in ACTA2. Iris optical coherence tomography (OCT) showed a hyporeflective band anterior to the pigment epithelium indicating the presence of dysfunctional sphincter muscle. Adaptive optics retinal imaging showed no thickening of the arteriolar vessel wall whilst OCT angiography showed extreme corkscrew course of arterioles suggesting vessel elongation. CONCLUSIONS: In addition to the known association between Met46, Arg179 and Arg258 substitutions and ACTA2-related arteriopathy, this case illustrates the possibility that Asn117 also plays an important role in α-SMA function within the cerebrovascular smooth muscle cell. MSMDS-related congenital mydriasis is due to reduced iris sphincter contractility rather than its absence. Retinal arteriolar tortuosity might be due to longitudinal proliferation of arteriolar smooth muscle cells. The described cerebrovascular and ocular signs are consistent with predicted effects of the novel Asn117Lys substitution in ACTA2.

Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene.

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.

Long-term follow-up of retinal function and structure in TRPM1-associated complete congenital stationary night blindness.

Purpose: TRPM1-associated congenital stationary night blindness (CSNB) is characterized by nystagmus and high myopia. We assessed retinal function and structure over long-term follow-up up to 10 years in two siblings from a family with the homozygous deletion c.2394delC in exon 18 that we previously identified. In addition, we describe retinal function and structure in two other siblings with the novel homozygous c.1394T>A (p.Met465Lys) missense mutation. Methods: Clinical examination included full-field electroretinography, axial length measurements, and multimodal retinal imaging. Molecular genetic tests included next-generation sequencing and Sanger sequencing. Results: All patients had non-recordable rod responses and electronegative configuration of the rod-cone responses at presentation. There was a median of 26% reduction in the dark- and light-adapted electroretinographic (ERG) amplitudes over 4 years. Myopia progressed rapidly in childhood but showed only a mild progression after the teenage years. Visual acuities were stable over time, and there was no sign of progressive retinal thinning. All patients had axial myopia. A novel homozygous c.1394T>A (p.Met465Lys) missense mutation in TRPM1 was identified in two siblings. Conclusions: Further prospective study in larger samples is needed to establish whether there is progressive retinal degeneration in TRPM1-associated CSNB. The associated myopia was found to be mainly axial, which has not been described previously. The mechanism of myopia development in this condition remains incompletely understood; however, it may be related to altered retinal dopamine signaling and amacrine cell dysfunction.

Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy.

Purpose: To identify novel mutations in FZD4 and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR). Methods: Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in FZD4 on its biologic activity in the Norrin/ß-catenin signaling pathway was analyzed with the luciferase reporter assay. Results: Four novel mutations in FZD4 (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably. Conclusions: Four novel mutations in FZD4 were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.

Diagnosis of complicated FEVR preoperatively and intra-/post-operatively: characteristics and risk factors for diagnostic timing.

BACKGROUND: To delineate the characteristics of complicated familial exudative vitreoretinopathy (FEVR) patients diagnosed before surgery or intra-/post-operatively and to analyze the risk factors for the diagnostic timing. METHODS: Forty-eight patients who underwent surgery and were diagnosed as FEVR in our department were retrospectively reviewed. Data were collected including the demographic and clinical characteristics of these patients. FEVR patients were divided into 2 groups according to the diagnostic timing: FEVR diagnosed pre-operatively (23 patients), FEVR diagnosed intra-/post-operatively (25 patients). Multivariable analysis was applied for analyzing the risk factors for diagnostic timing. RESULTS: The clinical characteristics of the FEVR patients were of great variability, including retinal detachment (RD), disappear of anterior chamber, retrolental membrane, epiretinal membrane (ERM), vitreous hemorrhage (VH), myopic foveoschisis (MF), lamellar macular hole (LMH), high myopia (HM). And the referral diagnosis or pre-operative diagnosis were always non-specific. The majority of the referral or preoperative diagnosis were unilateral RD (52.1%), bilateral RD (8.3%), unilateral persistent fetal vasculature (PFV) (8.3%), bilateral PFV (4.2%). There are two risk factors for the complicated FEVR cases diagnosed as FEVR preoperatively: pre-operative ocular manifestations with RD only (OR, 0.104; p-value, 0.022), positive parent's fluorescein angiography (FA) (OR, 0.105; p-value, 0.035). CONCLUSIONS: The phenotypes of FEVR were greatly variable, they can mimic many non-specific vitreoretinal disorders. The most non-specific referral diagnosis/pre-operative diagnosis was unilateral RD, bilateral RD, unilateral PFV, bilateral PFV. A positive family history or a simple ocular presentation with RD only could contribute to diagnose FEVR preoperatively.

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families.

BACKGROUND: Epidemiological studies of hereditary eye diseases allowed us to identify two Tunisian families suffering from macular dystrophies: Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The purpose of the current study was to investigate the clinical characteristics and the underlying genetics of these two forms of macular dystrophy. METHODS: Complete ophthalmic examination was performed including optical coherence tomography, electroretinography, electrooculography and autofluoresence imaging in all patients. Genomic DNA was extracted from peripheral blood collected from patients and family members. RESULTS: Sanger sequencing of all exons of the BEST1 gene in both families identified two new mutations: a missense mutation c.C91A [p.L31 M] at the N-terminal transmembrane domain within the ARB family and a nonsense mutation C1550G (p.S517X) in the C-terminal domain segregating in the BVMD family. CONCLUSIONS: Several mutations of the BEST1 gene have been reported which are responsible for numerous ocular pathologies. To the best of our knowledge, it is the first time we report mutations in this gene in Tunisian families presenting different forms of macular dystrophy. Our report also expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Intracranial hypertension: a current review.

PURPOSE OF REVIEW: To provide a current review of recent publications with regards to intracranial hypertension. RECENT FINDINGS: Attempts were made to provide pediatric data; however, the recent completion of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) has provided a wealth of data with regards to adult intracranial hypertension.The pediatric incidence of intracranial hypertension ranges between 0.63 and 0.71 per 100 000 children. A majority of pediatric cases responded to acetazolamide, with resolution of headache averaging 3.8 weeks. Most patients require less than 1 year of treatment with male sex, older age at diagnosis, primary intracranial hypertension, and lack of headache being predictors of good response. Fluorescein angiography has the highest accuracy in distinguishing true papilledema from pseudopapilledema. The IIHTT found Frisen grade of papilledema was within 1 grade in 92.8% of patients. Monitoring of potassium levels is not required and aplastic anemia was not seen in patients taking acetazolamide. SUMMARY: Although the newer pediatric studies report incidence rates in pediatric intracranial hypertension are lower than seen in adults, intracranial hypertension is still a concern in pediatrics. There has been a wealth of information with regards to symptomatology, treatment, and outcomes from the IIHTT that will hopefully assist with management in the pediatric population.

[Analysis on the clinical and retinal imaging characteristics of autosomal recessive bestrophinopathy].

Objective: To study the clinical and imaging features of autosomal recessive bestrophinopathy (ARB). Methods: Retrospective study. The clinical and imaging data of 14 participants were analyzed in using autofluorescence (AF), fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT). Ten patients were screened for mutations in BEST1 gene. Results: Retinopathy of ARB were shown as bilaterally and circularly distributed yellow subretinal deposits in the mid-peripheral and posterior retina, which was observed more clearly by AF and FA. The abnormalities were observed as hyperreflection between the sub-retinal pigment epithelium space as well as the subretinal space by SD-OCT imaging. All of the patients showed serous retinal detachment, and 4 of them were found to have intraretinal schisis. Other ocular complications include choroidal neovascularization (CNV) and angle closure glaucoma (ACG) were also found in the patients. Genetic examinations showed that the mutations are compound heterozygous in five patients, homozygous in one patient and heterozygous in only one of the rest 4 patients. Conclusions: The combination of clinical and retinal imaging data may facilitate the diagnosis of ARB. Physicians should be cautious of the vision-threatening complications of the disease. (Chin J Ophthalmol, 2018, 54: 263-269).

Accuracy of Diagnostic Imaging Modalities for Classifying Pediatric Eyes as Papilledema Versus Pseudopapilledema.

PURPOSE: To identify the most accurate diagnostic imaging modality for classifying pediatric eyes as papilledema (PE) or pseudopapilledema (PPE). DESIGN: Prospective observational study. SUBJECTS: Nineteen children between the ages of 5 and 18 years were recruited. Five children (10 eyes) with PE, 11 children (19 eyes) with PPE owing to suspected buried optic disc drusen (ODD), and 3 children (6 eyes) with PPE owing to superficial ODD were included. METHODS: All subjects underwent imaging with B-scan ultrasonography, fundus photography, autofluorescence, fluorescein angiography (FA), optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL), and volumetric OCT scans through the optic nerve head with standard spectral-domain (SD OCT) and enhanced depth imaging (EDI OCT) settings. Images were read by 3 masked neuro-ophthalmologists, and the final image interpretation was based on 2 of 3 reads. Image interpretations were compared with clinical diagnosis to calculate accuracy and misinterpretation rates of each imaging modality. MAIN OUTCOME MEASURES: Accuracy of each imaging technique for classifying eyes as PE or PPE, and misinterpretation rates of each imaging modality for PE and PPE. RESULTS: Fluorescein angiography had the highest accuracy (97%, 34 of 35 eyes, 95% confidence interval 92%-100%) for classifying an eye as PE or PPE. FA of eyes with PE showed leakage of the optic nerve, whereas eyes with suspected buried ODD demonstrated no hyperfluorescence, and eyes with superficial ODD showed nodular staining. Other modalities had substantial likelihood (30%-70%) of misinterpretation of PE as PPE. CONCLUSIONS: The best imaging technique for correctly classifying pediatric eyes as PPE or PE is FA. Other imaging modalities, if used in isolation, are more likely to lead to misinterpretation of PE as PPE, which could potentially result in failure to identify a life-threatening disorder causing elevated intracranial pressure and papilledema.

Two novel mutations in XYLT2 cause spondyloocular syndrome.

We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.

Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome.

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc.

Optical Coherence Tomography to Differentiate Papilledema from Pseudopapilledema.

PURPOSE OF REVIEW: Mild papilledema may be difficult to distinguish by clinical observation from pseudopapilledema. An accurate diagnosis is critical to avoid invasive workup and unwarranted treatment. In this review, we focus on the development and subsequent role of optical coherence tomography (OCT) in detecting and differentiating optic nerve head drusen (ONHD) from papilledema and other causes of acquired swelling of the optic disc. RECENT FINDINGS: Newer OCT technologies which permit deeper penetration to improve detection of ONHD were also reviewed. Enhanced depth imaging (EDI) spectral-domain OCT and swept-source (SS) OCT are currently recognized as the most reliable and sensitive tools to diagnose ONHD. OCT devices currently available provide a means to quantify drusen dimensions, to evaluate the integrity of neighboring structures and to monitor axonal and neuronal damage, yielding additional information to better understand the relationship between the morphological features of drusen, and their effects on the structure and function of the optic nerve.

The efficacy of orbital ultrasonography and magnetic resonance imaging findings with direct measurement of intracranial pressure in distinguishing papilledema from pseudopapilledema.

INTRODUCTION: The goal of this study was to evaluate the utility of orbital ultrasonography and magnetic resonance imaging in the diagnosis of idiopathic intracranial hypertension (IIH). METHOD: We reviewed the medical records of patients referred to our department for suspected IIH. RESULTS: Seven children were diagnosed with IIH. Nine children revealed pseudopapilledema by optic coherence tomography and/or orbital ultrasonography. When the axial sequences were reexamined, patients with papilledema had optic nerve sheath (ONS) enlargement (6.62 ± 0.70 mm); patients with pseudopapilledema had ONS diameter as 4.62 ± 0.64 mm. There was a significant correlation between the CSF opening pressure and ONS diameter (p < 0.005, r = 0.661). In the papilledema group, the presence of proposed subtle markers as increased tortuosity in the optic nerve was found in six patients. Five of seven patients had a target sign, intraocular protrusion of the optic nerve, and posterior globe flattening. DISCUSSION: Ophthalmological review is important to avoid unnecessary procedures for detection of true papilledema. ONS diameter is a reliable neuroimaging marker as other subtle markers.