Retinoblastoma (RB) is the most common ocular cancer, and it typically presents before the age of 5 years in over 90% of cases. In high resource countries, RB patients tend to survive and retain ...their sight. This is not the case in low-resource countries because of late presentation and delayed intervention arising mostly from sociocultural and socioeconomic challenges. RB has no gender or racial predilection; the incidence is estimated as 1:16,000–1:18,000 live-births or 11/1 million children under 5 years. Most of the world's RB cases are found in Asia and Africa while most RB treatment centres are in America and Europe. RB is easy to detect by caregivers as a glowing white 'cat eye reflex' at night or when captured on camera. Health workers at primary care level can detect RB in early life if red reflex test and/or squint (Hirschberg) tests are deployed as part of wellness checks done especially during routine immunisation and well-baby clinics in the first 24 months of life. In most cases of RB, biopsies for histological confirmation are not required for diagnosis and treatment decisions to be made. Clinical information, ophthalmic evaluation and imaging modalities are typically used. There have been significant changes in the management of RB using various treatment modalities such as enucleation with orbital implant, use of chemotherapy delivered through intravenous, intravitreal, periocular and intra-arterial routes and targeted treatment with laser, cryotherapy and brachytherapy. Algorithm for management and development of the national RB program within the context of a low-resource country is presented from review of data extracted from Mendeley library, PubMed library, Google Scholar and One Network; full-text articles were mostly retrieved through the American Academy of Ophthalmology.
Retinoblastoma is a rare disease. Saving the lives of the children affected requires early detection, good referral systems and expert care by a multidisciplinary team. Setting up a national and ...joined-up service is an essential first step.
To explore the molecular mechanisms deregulated by high mobility group protein A2 (HMGA2) gene silencing in retinoblastoma (RB) cells.
Synthetic anti-HMGA2 short interfering RNA (siRNA) was used to ...silence the HMGA2 gene in cultured Y79 RB cells that were subjected to whole genome microarray analysis. The expression of differentially regulated key genes was confirmed with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in post-silenced RB cell lines (Y79 and WERI Rb1). These deregulated genes were compared for their constitutive expression in primary RB tumors (n=10). Zymographic determination of matrix metalloproteinase (MMP) activity was performed in RB cells. A cell cycle assay and a proliferation assay were performed in post-transfected RB cells.
HMGA2 gene silencing in cultured RB cells results in reduced cell proliferation and transition in the G1/S phase. The whole genome microarray analysis of HMGA2 silenced Y79 cells revealed overall upregulation of 1,132 genes (≥ 1.0 fold) and downregulation of 1,562 genes (≤ -1.0 fold). Specific quantitative pathway analysis of the deregulated genes (using Biointerpreter) revealed 150 upregulated genes and 77 downregulated genes (≥ 1.0 fold) involved in vital pathways, namely, mitogen-activated protein kinase, Janus kinase/signal transducers and activators of transcription, Ras pathway, Ras-induced extracellular signal-regulated protein kinases 1 and 2, and tumor protein p53. The differential expression of genes obtained from microarray analysis (Homo sapiens ELK1, member of ETS oncogene family ELK1, Homo sapiens cyclin-dependent kinase 6 CDK6, Homo sapiens E2F transcription factor 4, p107/p130-binding E2F4, Homo sapiens G-2 and S-phase expressed 1 GTSE1, Damage-regulated autophagy modulator DRAM, Homo sapiens cadherin 1, type 1,E-cadherin (epithelial) CDH1, Homo sapiens snail homolog 1 (Drosophila) SNAI1, Homo sapiens matrix metallopeptidase 2 MMP2, and Homo sapiens matrix metallopeptidase 9 MMP9) was confirmed with quantitative reverse-transcriptase polymerase chain reaction in post-silenced RB cells. Zymographic analysis revealed that the increase in MMP mRNA expression in the post-silenced RB cells did not correlate with corresponding enzyme activity.
Our study revealed molecular regulatory changes induced by HMGA2 silencing in RB cancer cells, offering mechanistic insights into the anticancer potential. HMGA2 may be considered a promising candidate for gene silencing therapy in RB.
Pediatric uveitis is rare and has been reported to cause increased rates of visual loss compared with adult patients. The reasons for this are unclear. Only one study has been population–based, so ...the effect of referral bias is not known. We examined the pattern of disease in primary and referral centers to establish the unique characteristics of uveitis in children.
Case control study.
Retrospective, multicenter, observational study of uveitis starting before the age of 20 years. Two hundred forty-nine patients were recruited from three primary and two referral ophthalmic units. Age-related differences in types of uveitis and systemic disease between hospitals were characterized, as were associations with visual loss.
The incidence of uveitis in district hospitals at less than 16 years of age was 4.9/100,000: the most frequent diagnosis was idiopathic uveitis (78%). In referral cohorts the most frequent diagnosis was juvenile idiopathic arthritis-associated uveitis (67%). Other systemic diseases were rare. The most frequent type of uveitis at 0 to 7 years of age was chronic anterior uveitis, posterior uveitis in 8- to 15-year-olds, and acute anterior uveitis in 16- to 19-year-olds. Visual loss (any eye < 6/12) occurred in 17% and was not associated with age, sex, or hospital cohort. It was most frequent in posterior uveitis (25%). Treatment variables were independent predictors of visual loss: systemic treatment 2.2 (1.1– 4.6), surgical intervention 8.2 (3.8–17.6).
Idiopathic uveitis was three times more common in district hospitals. Visual loss was similar to adult uveitis in this study. The increased frequency of severe chronic anterior uveitis in children aged 0 to 7 years and posterior uveitis in older children aged 8 to 15 years accounts for the rate of visual loss seen in previous studies.
Purpose: The study aimed to assess the incidence of and risk factors leading to visual impairment and legal blindness in children with retinoblastoma. Procedures: This is a single-center, ...retrospective case series of all patients with bilateral retinoblastoma presenting from 2010 to 2014. Results: A total of 44 patients were included in the study. Visual impairment was present in 14 (38%) children, legal blindness was present in 7 (19%) children. Bilateral macular tumors (BMT) were associated with visual impairment (12 of 18 patients with BMT, 2 of 19 patients without BMT, p = 0.0006) and legal blindness (7 of 18 patients with BMT, 0 of 19 patients without BMT, p = 0.003).The International Intraocular Retinoblastoma Classification (IIRC) of the better eye also predicted visual impairment (16% in IIRC Group A–C, 75% in IIRC Group D, E, p = 0.004) and blindness (3% eye in IIRC Group A–C, 50% in Group D, E, p = 0.005). Various non-Snellen visual acuity measures were able to predict visual impairment in pre-verbal children, providing them with early assistance. Conclusions: The rates of visual impairment and blindness reported in this paper can be used to counsel families regarding the risk of binocular visual impairment. Early detection and support for visually impaired infants are essential as development can be affected by severe visual impairment.
An 11-month-old girl was referred to the London Retinoblastoma Unit with a 2-month history of a unilateral, dull red reflex, strabismus, and an intraocular mass suspicious for retinoblastoma. There ...was no family history of note, and she was otherwise a normal developing child.
Classifying and staging retinoblastoma is an essential first step when planning how to manage a child with the condition; it also gives important information about prognosis.
BackgroundThe relationship between the ethnic background or socioeconomic status (SES) and late retinoblastoma (Rb) presentation in the UK is unclear. We aimed to investigate if such correlations ...exist in a cohort of non-familial Rb cases.MethodsA cross-sectional study based at the two centres providing Rb care in the UK. Included were non-familial Rb cases that presented from January 2006 to December 2011. Epidemiological and clinical data were retrieved from medical charts, as well as patients’ postcodes used to obtain the Index of Multiple Deprivation (IMD) score. A postal questionnaire was sent to participants’ parents to collect further, person-level, information on languages spoken and household socioeconomic position. Statistical correlations to advanced Rb at presentation as well as to treatment by enucleation and need for adjuvant chemotherapy were investigated.ResultsThe cohort included 189 cases, 98 (51.8%) of which were males. The median age at diagnosis was 16 months (IQR 8–34 months). Of the study patients, 153 (81%) presented with advanced Rb; 78 (41%) with group D and 75 (40%) with group E Rb. A total of 134 (72%) patients were treated with enucleation. South Asian ethnicity and being in the most deprived IMD quintile were associated with a higher likelihood of presentation with advanced disease, but these estimates did not reach statistical significance. Older age at presentation was associated with enucleation and bilateral disease with adjuvant chemotherapy.ConclusionsIn this national UK study of patients with non-familial Rb, there was no evidence of an association of ethnicity or SES and the risk of presenting with advanced disease. These findings may reflect equality in access of healthcare in the UK.
To investigate the genetic basis of autosomal dominant vitreoretinochoroidopathy (ADVIRC), a rare, inherited retinal dystrophy that may be associated with defects of ocular development, including ...nanophthalmos.
A combination of linkage analysis and DNA sequencing in five families was used to identify disease-causing mutations in VMD2. The effect of these mutations on splicing was assessed using a minigene system.
Three pathogenic sequence alterations in VMD2 were identified in five families with nanophthalmos associated with ADVIRC. All sequences showed simultaneous missense substitutions and exon skipping.
VMD2 encodes bestrophin, a transmembrane protein located at the basolateral membrane of the RPE, that is also mutated in Best macular dystrophy. We support that each heterozygous affected individual produces three bestrophin isoforms consisting of the wild type and two abnormal forms: one containing a missense substitution and the other an in-frame deletion. The data showed that VMD2 mutations caused defects of ocular patterning, supporting the hypothesized role for the RPE, and specifically VMD2, in the normal growth and development of the eye.