Macular hypoplasia in congenital disorder of glycosylation type 1a

Congenital disorders of glycosylation are a rare group of metabolic disorders that can result in multiorgan disease. This article describes a novel finding of macular hypoplasia in congenital disorders of glycosylation type 1a

Orbital Subperiosteal Hematoma in the Newborn Causing Unilateral Proptosis: Ultrasound as First-Line Imaging Modality

This journal is published under the Creative Commons license CC BY-NC-ND (Attribution-NonCommercial-NoDerivatives)Proptosis in the neonatal period is relatively infrequent and has diverse underlying etiologies. One of the more common causes appears to be orbital subperiosteal hematoma. Early detection, differentiation from other causes, and regular follow-up are essential as loss of vision can occur. We describe two cases of neonatal proptosis caused by orbital subperiosteal hematoma highlighting different diagnostic and management approaches, and provide a summary of previously reported cases. Spontaneous resolution occurs in most cases; however, emergent surgical evacuation is warranted in cases of optic nerve compression. This is the first report to provide orbital ultrasound images of uncomplicated neonatal orbital subperiosteal hematoma. Orbital ultrasound followed by magnetic resonance imaging (MRI) is a valid nonradiation approach for assessing neonatal proptosis due to subperiosteal orbital hematoma

Mutations in the EPHA2 gene are a major contributor to inherited cataracts in South-Eastern Australia.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C.T in the EPHA2 gene and the previously reported splice mutation c.2826-9G.A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract

This author accepted manuscript is made available following 6 month embargo from date of publication (March 2017) in accordance with the publisher’s copyright policyCongenital cataract is a rare but severe paediatric visual impediment, often caused by variants in one of several crystallin genes that produce the bulk of structural proteins in the lens. Here we describe a pedigree with autosomal dominant isolated congenital cataract and linkage to the crystallin gene cluster on chromosome 22. No rare single nucleotide variants or short indels were identified by exome sequencing, yet copy number variant analysis revealed a duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, with the duplicated CRYBB1 product predicted to create a gain of function allele. This association suggests a new genetic mechanism for the development of isolated congenital cataract

High throughput genetic screening of 51 paediatric cataract genes identifies causative mutations in inherited paediatric cataract in South Eastern Australia

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Paediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of paediatric cataract in Australian families by screening known disease associated genes using massively parallel sequencing technology. We sequenced 51 previously reported paediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritised for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract causing mutations were screened in 326 unrelated Australian controls. We detected eleven novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA and MIP, three previously reported cataract causing mutations in GJA8, CRYAA and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of paediatric cataract associated mutations in our Australian cohort, known genes account for more than 60 % of familial paediatric cataract in Australia, indicating that still more causative genes remain to be identified

Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma

© 2019 American Medical Association. Reproduced in accordance with the publisher's Public Access policy. This author accepted manuscript is made available following 12 month embargo from date of publication (January 2019) in accordance with the publisher’s archiving policyImportance Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l’Azienda Socio–Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels

Ocular malformation in a newborn secondary to maternal hypovitaminosis A

We report a case of microphthalmia, inferior adherent leukoma, and optic nerve hypoplasia in an infant whose mother underwent biliopancreatic diversion surgery for obesity 7 years before his birth. The pregnancy was complicated by severe, maternal hypovitaminosis A despite oral supplementation. The infant was found to have undetectable serum vitamin A levels in the perinatal period. At 8 weeks of age, the infant underwent sector iridectomies. At 9 months of age, electroretinography suggested rod dysfunction. His visual performance is poor. © 2010 by the American Association for Pediatric Ophthalmology and Strabismus

Repeatability of corneal first-surface wavefront aberrations measured with Pentacam corneal topography [Post print]

PURPOSE: To assess the repeatability of corneal wavefront aberrations derived from Pentacam (Oculus) corneal topography. SETTING: Flinders Eye Centre, Flinders Medical Centre, Bedford Park, South Australia, Australia. METHODS: Forty-five normal participants and 10 participants with keratoconus were tested. Intraobserver and interobserver repeatability was determined using 4 observers within and between sessions. Topographical maps were exported to external software, and corneal first-surface wavefront aberrations were calculated using a 10th-order Zernike expansion over a 6.0 mm optical zone. Repeatability was determined with Bland-Altman limits of agreement and expressed as the coefficient of repeatability (COR). RESULTS: Initial data showed high wavefront aberrations in normal participants and poor repeatability. Topographical maps showed extrapolated topography in zones without data acquisition; maps with less than 6.0 mm of complete data were excluded in the final analysis. The mean wavefront aberrations for normal participants remained high, but repeatability improved. The COR relative to the magnitude of wavefront aberrations was high (average 100%) across all modal pairs and orders, although best for total higher-order root mean square. Participants with keratoconus had higher magnitude wavefront aberrations and poorer repeatability but similar COR to average wavefront aberration ratios. Examination of raw elevation data showed poor repeatability. CONCLUSIONS: Wavefront aberrations calculated from Pentacam corneal topography were large in magnitude, and reliability was poor, largely due to variability in corneal elevation data. Intraobserver and interobserver reliability within and between sessions was comparable. The Pentacam was not reliable in measuring corneal wavefront aberrations