Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome.

Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all individuals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G > T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippocampal sclerosis.

Anesthesia management of laser photocoagulation for retinopathy of prematurity. A retrospective review of perioperative adverse events.

AIMS: The aim of this study was to report the incidence of perioperative adverse events occurring in infants undergoing diode laser photocoagulation of retinopathy of prematurity and to identify clinical risk factors that may affect the incidence. METHODS: This was a retrospective study of anesthetic and medical records of premature infants who were treated in the neonatal intensive care unit or an operating theater with laser photocoagulation in our institution between January 2014 and December 2019. Infants less than 38 weeks post-menstrual age or less than 2000 grams were considered high risk for complications. Electronic medical records were evaluated for clinical and demographic characteristics, comorbidities, and perioperative complications of anesthesia. RESULTS: Sixty-one infants (39 males, 22 females) underwent 72 laser treatments. The mean gestational age was 25.3 weeks (SD 1.6), and mean birth weight was 730 grams (SD 202). At treatment, the mean postmenstrual age was 37.5 weeks (SD 2.7) and weight was 2320 g (SD 610). Laser therapy was performed in an operating theater in 66 procedures (91.7%) and in the neonatal unit in 6 cases (8.3%). Twenty-nine (40.3%) laser surgeries occurred outside normal week-day daytime operating hours. Intraoperative hypotension occurred in 12 procedures (16.7%) but was not significantly different in high-risk infants (16.1% vs 16.7% OR 0.94 P = .94) or in procedures performed in-hours (16.3% vs 17.2% OR 0.93 P = .91). Post-extubation apnea occurred in 21 procedures (29%) but was not significantly different in high-risk infants (29.0% vs 27.3% OR 0.98 P = .34) or in procedures performed in-hours (27.9% vs 31.1% OR 0.86 P = .77). Infants remained intubated at the end of the procedure in 58 (80.5%) cases and 29 (40.3%) remained ventilated more than 24 hours after the procedure. CONCLUSION: The incidence of perioperative adverse events was not associated with patient's age, current weight, timing, or location of the procedure. Extubating infants at the end of the procedure is however associated with a high rate of apneas and bradycardia, and consideration should be given to keeping low weight infants undergoing prolonged procedures out-of-hours intubated.

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay.

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in ß-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however ß-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.

New trends in childhood vision impairment in a developed country.

BACKGROUND: The Education Vision Assessment Clinic (EVAC) is a unique statewide service that reviews school children 4-18 years of age with low vision in Victoria, Australia, to determine their eligibility for educational support. The purpose of this study was to identify causes of vision impairment in students in Victoria using data from the EVAC. METHODS: Data collected from students who attended the EVAC at the Royal Victorian Eye and Ear Hospital, Melbourne, between the years 2003 and 2012 inclusive, were analyzed retrospectively. Participants were identified through the EVAC schedule of medical appointments. Medical records were reviewed for clinical and demographic information, including diagnosis of vision impairment and best-corrected visual acuity and/or visual fields. RESULTS: Of 543 students, 355 (65%) were eligible for educational assistance. Of those, 249 (70%) had best-corrected visual acuity between 20/60 and 20/200 and/or a field of vision of <20° to 10°, and 106 (30%) had a best-corrected visual acuity worse than 20/200 and/or a field of vision of <10°. Common causes of vision impairment were retinal dystrophies (24%), optic nerve pathology (14%), albinism (14%), and infantile motor nystagmus (10%). CONCLUSIONS: Treatable and potentially preventable causes of vision impairment, such as retinopathy of prematurity and cataract, caused <10% of vision impairment cases in Victorian school children. Analysis of demographic trends is essential to supporting efforts to ensure that students with low vision, from any socioeconomic background, receive specialist teaching services.

Green-laser induced maculopathy in a 15-year-old boy.

We report the case a 15-year-old boy who presented with retinopathy caused by a green-diode (class IIIB) laser. The patient was followed over a period of 8 weeks. Visual acuity on day 1 was 6/7.5, with central scotoma in the right eye, and 6/5 in the left eye. Macular optical coherence tomography of the right eye day 1 showed focal subfoveal disruption of the photoreceptor ellipsoid and myoid zones extending through the external limiting membrane to the outer nuclear layer. At week 8, visual acuity was 6/6 right eye and 6/5 in the left eye. Disruption of the ellipsoid and myoid layers, though still present, had improved.

Solar retinopathy in children.

PURPOSE: To describe the visual acuity, fundus appearance, and spectral domain optical coherence tomography (SD-OCT) findings in 5 eyes of 3 children with foveal damage from solar retinopathy. METHODS: This was a prospective, observational case series of children who presented to the emergency department at the Royal Victorian Eye and Ear Hospital after having directly viewed the Sun during the transit of Venus on June 6, 2012, or the partial eclipse of the Sun on November 14, 2012. All patients underwent visual acuity testing, dilated fundus examination, and SD-OCT imaging. RESULTS: The 3 patients' ages at presentation were 8, 10, and 11 years. Best-corrected visual acuity in the affected eyes ranged from 20/20 to 20/40 on presentation. Significant foveal pathology was identified on SD-OCT in all 5 eyes, even when visual acuity was normal. At presentation, all eyes showed disruption of the photoreceptor ellipsoid zone and the interdigitation zone on SD-OCT. Additionally, in those eyes with decreased visual acuity, there was disruption of the outer nuclear layer and/or external limiting membrane. At 3-5 months' follow-up, the outer nuclear layer and external limiting membrane lesions had resolved; however, in some eyes the ellipsoid and interdigitation zone abnormalities persisted at 5 months' follow-up, even in the presence of best-corrected visual acuity as good as 20/12.5. CONCLUSIONS: Solar retinopathy in children can cause persistent damage to multiple retinal layers despite recovery of good visual acuity.

Paradoxical myopic shift following cycloplegia in retinopathy of prematurity patients: a case series.

INTRODUCTION: Spectacle non-compliance is a significant problem in pediatric patients, and may have a variety of consequences. Non-compliance with myopic refractive correction could be secondary to a variety of issues, including age, discomfort, gender, urban vs. rural residence, presenting visual acuity, and degree of refractive error. We observed a phenomenon in our pediatric patients with retinopathy of prematurity that may add another possible explanation: incorrect prescription due to measures of increased, rather than decreased, myopia after cycloplegia. CASE PRESENTATION: An unmasked, prospective study of 8 consecutive patients seen in a single practice. Retinoscopic refraction measurements were obtained before and after pharmacologic cycloplegia. In all 13 eyes, there was either no change (2 eyes) or a myopic shift (11 eyes) in the measured refractive error. The average change in refraction was -1.58 and -1.54 for the right and left eyes, respectively (range 0 to -3.00 OD and 0 to -3.00 OS). CONCLUSIONS: The contribution of ocular components to refractive status differs between ROP and non-ROP eyes. Unanticipated myopic shift following cycloplegia in ROP patients may result in inappropriate glasses prescription with poor correction of visual acuity. This may contribute to spectacle noncompliance in this group.

Analysis of the National Health and Nutrition Examination Survey. Comment on "Prevalence of visual impairment in the United States", by S Vitale, MF Cotch, and RD Sperduto. JAMA 295:2158-63, 2006.

CONTEXT: The prevalence of visual impairment in the U.S. public has not been surveyed nationally in several decades. OBJECTIVE: To estimate the number of U.S. individuals aged 12 years or older who have impaired distance vision due to uncorrected refractive error. DESIGN, SETTING, AND PARTICIPANTS: The National Health and Nutrition Examination Survey (NHANES), using a multistage probability sampling design, included a vision evaluation in a mobile examination center. Visual acuity data were obtained from 13,265 of 14,203 participants (93.4%) who visited the mobile examination center in 1999-2002. Visual impairment was defined as presenting distance visual acuity of 20/50 or worse in the better-seeing eye. Visual impairment due to uncorrected refractive error was defined as (presenting) visual impairment that improved, aided by automated refraction results, to 20/40 or better in the better-seeing eye. MAIN OUTCOME MEASURES: Presenting distance visual acuity (measured with usual corrective lenses, if any) and distance visual acuity after automated refraction. RESULTS: Overall, 1,190 study participants had visual impairment (weighted prevalence, 6.4%; 95% confidence interval [CI], 6.0-6.8%), and of these, 83.3% could achieve good visual acuity with correction (95% CI, 80.9-85.8%). Extrapolating these findings to the general U.S. population, approximately 14 million individuals aged 12 years or older have visual impairment (defined as distance visual acuity of 20/50 or worse), and of these, more than 11 million individuals could have their vision improved to 20/40 or better with refractive correction. CONCLUSIONS: Visual impairment due to uncorrected refractive error is a common condition in the United States. Providing appropriate refractive correction to those individuals whose vision can be improved is an important public health endeavor with implications for safety and quality of life.