Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants.

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled-4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock-down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled-4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In-vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled-4 pathway. Our observations demonstrate that biallelic FZD4-variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non-penetrance is also a major feature in dominant FZD4-FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR.

Uveitis in Juvenile Idiopathic Arthritis: 18-Year Outcome in the Population-based Nordic Cohort Study.

PURPOSE: To assess the long-term outcome of uveitis in juvenile idiopathic arthritis (JIA). DESIGN: Population-based, multicenter, prospective JIA cohort, with a cross-sectional assessment of JIA-associated uveitis (JIA-U) 18 years after the onset of JIA. PARTICIPANTS: A total of 434 patients with JIA, of whom 96 had uveitis, from defined geographic areas of Denmark, Finland, Norway, and Sweden. METHODS: Patients with onset of JIA between January 1997 and June 2000 were prospectively followed for 18 years. Pediatric rheumatologists and ophthalmologists collected clinical and laboratory data. MAIN OUTCOME MEASURES: Cumulative incidence of uveitis and clinical characteristics, JIA and uveitis disease activity, ocular complications, visual outcome, and risk factors associated with the development of uveitis-related complications. RESULTS: Uveitis developed in 96 (22.1%) of 434 patients with JIA. In 12 patients (2.8%), uveitis was diagnosed between 8 and 18 years of follow-up. Systemic immunosuppressive medication was more common among patients with uveitis (47/96 [49.0%]) compared with patients without uveitis (78/338 [23.1%]). Active uveitis was present in 19 of 78 patients (24.4%) at the 18-year visit. Ocular complications occurred in 31 of 80 patients (38.8%). Short duration between the onset of JIA and the diagnosis of uveitis was a risk factor for developing ocular complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8). Patients with a diagnosis of uveitis before the onset of JIA all developed cataract and had an OR for development of glaucoma of 31.5 (95% CI, 3.6-274). Presence of antinuclear antibodies (ANAs) was also a risk factor for developing 1 or more ocular complications (OR, 3.0; 95% CI, 1.2-7.7). Decreased visual acuity (VA) <6/12 was found in 12 of 135 eyes (8.9%) with uveitis, and 4 of 80 patients (5.0%) with JIA-U had binocular decreased VA <6/12. CONCLUSIONS: Our results suggest that uveitis screening should start immediately when the diagnosis of JIA is suspected or confirmed and be continued for more than 8 years after the diagnosis of JIA. Timely systemic immunosuppressive treatment in patients with a high risk of developing ocular complications must be considered early in the disease course to gain rapid control of ocular inflammation.

Incidence and predictors of Uveitis in juvenile idiopathic arthritis in a Nordic long-term cohort study.

BACKGROUND: The incidence of uveitis associated with juvenile idiopathic arthritis (JIA) varies around the world. Our aim was to investigate the incidence and predictors of uveitis in a Nordic population-based cohort. METHODS: Consecutive JIA cases from defined geographical areas in Denmark, Finland, Sweden and Norway with disease onset between January 1997 to June 2000 were followed for median 98 months in this prospective longitudinal cohort study. Potential clinical and immunological predictors of uveitis were identified with logistic regression analysis. RESULTS: Uveitis occurred in 89 (20.5%) of the 435 children with regular ophtalmologic follow-up among the 500 included. Chronic asymptomatic uveitis developed in 80 and acute symptomatic uveitis in 9 children. Uveitis developed at a median interval of 0.8 (range - 4.7 to 9.4) years after onset of arthritis. Predictors of uveitis were age < 7 years at JIA onset (Odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3 to 3.5), presence of antihistone antibodies (AHA) > 15 U/ml (OR 4.8 (1.8 to 13.4)) and antinuclear antibodies (ANA) (OR 2.4 (1.5 to 4.0)). Mean combined IgM/IgG AHA was significantly higher in the uveitis group (19.2 U/ml) than in the non-uveitis group (10.2 U/ml) (p = 0.002). Young age at JIA onset predicted uveitis in girls (p < 0.001), but not in boys (p = 0.390). CONCLUSION: Early-onset arthritis and presence of AHA in girls, as well as presence of ANA in both genders, were significant predictors of chronic uveitis. The high incidence of uveitis in this long-term Nordic JIA cohort may have severe implications in a lifelong perspective.

Vitamin D and intraocular pressure--results from a case-control and an intervention study.

PURPOSE: To study the associations between serum 25-hydroxy-vitamin D (25(OH)D) levels, vitamin D administration and intraocular pressure (IOP). METHODS: The design of the study included a nested case-control study and a randomized controlled intervention trial. In the first part, healthy Caucasians with high or low serum 25(OH)D levels were recruited from a population-based study. IOP of the right eye was measured by the use of a rebound tonometer. In the second part, those with low serum 25(OH)D levels were randomized to receive either capsules of vitamin D3 20,000 IU twice per week or placebo for 6 months before IOP was measured again. RESULTS: Intraocular pressure in the 87 participants with low serum 25(OH)D levels (mean 40.1±12.9 nm) did not differ from IOP in the 42 participants with high serum 25(OH)D levels (mean 85.1±14.0 nm) (15.9±3.3 mmHg versus 15.6±3.1 mmHg, p= 0.56, independent t-test). After intervention, IOP decreased by -0.8± 2.1 mmHg (p = 0.017, paired t-test) in the vitamin D group (n= 39) and -0.8±2.5 mmHg (p= 0.059) in the placebo group (n= 39), but the change was not significantly different between the groups (p= 0.92, independent t-test). CONCLUSION: This study in healthy participants revealed no associations between serum 25(OH)D levels and IOP, and administration of vitamin D3 to participants with low levels of 25(OH)D did not affect IOP. These results do not support a role of vitamin D in the regulation of IOP.

The potential of digital monochrome images versus colour slides in telescreening for diabetic retinopathy.

We explored the potential of digital monochrome images as an alternative to colour slides in screening for diabetic retinopathy. Twenty-eight patients with diabetes were recruited for the study and 20 actually participated. Using a fundus camera (Nikon 505AF) one set of three digital images and one set of three colour slides were taken per eye. Two independent ophthalmologists graded the colour slides and the digital images for diabetic retinopathy. The ophthalmologists spent about two minutes grading each set of images, suggesting that specialists could potentially screen a large number of patients. The agreement between the two screening methods was 0.95 and 0.89, with respect to disease or no disease. The agreement (kappa) between the two ophthalmologists for grade of retinopathy was 0.47 when colour slides were employed and 0.61 when digital monochrome images were employed. The results indicate that digital red-free monochrome images represent a superior screening tool for diabetic retinopathy. Tele-screening may be beneficial when patients have to travel substantial distances to visit an ophthalmologist.

Autosomal dominant retinitis pigmentosa in Norway: a 20-year clinical follow-up study with molecular genetic analysis. Two novel rhodopsin mutations: 1003delG and I179F.

PURPOSE: To examine the clinical picture and molecular genetics of 12 Norwegian families with autosomal dominant retinitis pigmentosa (adRP) in order to achieve a genotype-phenotype correlation. METHODS: In addition to a clinical ophthalmological examination, fundus photography, dark adaptometry and electroretinography were performed. Four genes were analysed: rhodopsin (RHO); retinitis pigmentosa 1 (RP1); retinal degeneration slow/peripherin (RDS/peripherin), and inosine monophosphate dehydrogenase 1 (IMPDH1). Seven of the families had been examined about 20 years previously. A total of 63 patients or first-degree relatives (aged 18-79 years) were examined. RESULTS: Mutations were found only in the RHO gene. Seven families were given a diagnosis of classical RP. Two of them had novel mutation 1003delG, and one family had the mutation V345M. Four families had pericentral retinal dystrophy (PRD), two families with the mutation A164V and one with novel mutation I179F. One family was given a diagnosis of central and pericentral retinal dystrophy (CPRD), a special type of cone/rod dystrophy, and no mutation was found. CONCLUSIONS: Six of 12 families had an RHO mutation. The mutation V345M and the novel mutation 1003delG both caused classical RP, the former indicating the most unfavourable prognosis. Two of the families with PRD had the A164V mutation with a favourable prognosis, whereas the novel mutation I179F caused PRD with extremely variable expressivity.