Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.

Presumed non-accidental injury with retinal haemorrhages--findings from a tertiary referral centre in the United Kingdom.

AIM: To describe the clinical and demographic features of patients with retinal haemorrhages from presumed non-accidental injury (NAI) at a tertiary referral centre in Leeds over a 2-year period. METHODS: All patients with retinal haemorrhages from presumed NAI between 1 January 2007 and 31 December 2008 were retrospectively identified from the hospital RetCam® (Clarity Medical System, Pleasanton, CA, USA) database. Case-notes, fundus photographs and radiological studies were retrieved for all patients and examined. RESULTS: Over the study period, 14 infants had retinal haemorrhages secondary to presumed NAI. All were male with a mean age of 18 ± 15 weeks (range 2-47) and came from areas with a mean Index of Multiple Deprivation (IMD 2007) rank of 34 ± 27% (range 0.97-68). Seizure/collapse was the reason for presentation in 71% (10/14). Retinal haemorrhages were bilateral in 64% (9/14) and unilateral in 36% (5/14). They were single-layered in 71% (10/14) and multi-layered in 29% (4/14). Subdural haemorrhages were found in 93% (13/14) and were symmetrical in 77% (10/13). Skeletal survey was positive in 28% (4/14). CONCLUSIONS: In the context of presumed NAI, there is a strong association between presence of retinal haemorrhages and the likelihood of underlying subdural haemorrhage. In this region, male infants under 12 months, from deprived areas, appear to constitute a vulnerable group.

Unilateral retinal hemorrhages with subarachnoid hemorrhage in a 5-week-old infant: is this nonaccidental injury?

PURPOSE: Retinal hemorrhages are an important sign in the setting of nonaccidental injury (NAI) (abusive head injury) in young infants and form a very important part of the evidence in support of the diagnosis. The diagnosis of NAI has serious social and legal implications. Other causes of retinal hemorrhages in an infant, such as birth trauma, accidental head injury, subarachnoid hemorrhage, other less common disorders of clotting, leukemia, and infections such as endocarditis, need to be considered and ruled out in making a diagnosis of NAI. METHODS: Descriptive case report. RESULTS: A 5-week-old child presented with rapid onset of symptoms of drowsiness and hypotonia, unilateral retinal hemorrhages, and an intracranial hemorrhage in the posterior fossa. NAI was high on the list of differential diagnosis, which caused considerable anxiety in the parents. The cause of the intracranial hemorrhage only became apparent at repeat neuroimaging several weeks later. CONCLUSIONS: The case is presented to point out arteriovenous malformation as a possible cause of retinal hemorrhages in this age group where an early diagnosis of the etiology is often not possible. A diagnosis of NAI, commonly associated with a similar clinical presentation, can have serious social and legal implications.

Paediatric case of peripapillary choroidal neovascularisation associated with optic disc drusen treated with aflibercept.

Peripapillary choroidal neovascularisation (PPCNV) associated with optic disc drusen is a rare complication that can result in severe vision impairment in children. We report the first case of paediatric PPCNV secondary to optic disc drusen successfully treated with intravitreal aflibercept. A 6-year-old girl presented with a one week history of reduced vision in her right eye with best-corrected visual acuity of 20/500. Fundus examination revealed bilateral elevated discs with a peripapillary pigmentary lesion in the right eye. Optical coherence tomography of the right eye showed marked subfoveal fluid. Both B-scan ultrasonography and fundus autofluorescence demonstrated findings consistent with optic disc drusen. Diagnosis of PPCNV was further confirmed on fluorescein fundus angiography. The child received three intravitreal aflibercept injections with complete resolution of the subfoveal fluid. Her visual acuity improved to 20/25 with no recurrence at a 16-month follow-up. No adverse side effects were reported.

Bilateral retinal phototoxic injury during cataract surgery in a child.

The intense illumination of the operating microscope has been implicated in photic retinopathy in patients and in animal studies. We report a case of bilateral macular phototoxicity occurring in an eleven-year-old child who underwent bilateral cataract surgery for radiation cataracts. We are unaware of other reports of retinal toxicity occurring during pediatric cataract surgery. We hypothesize that this child may have been predisposed to macular injury because of previous chemotherapy and radiotherapy exposure. Ophthalmic surgeons should be aware that light toxicity from the operating microscope might also occur in the pediatric population.

Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR).

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder that disrupts the development of the retinal vasculature and can result in blindness. FEVR is genetically heterogeneous and mutations in four genes, NDP, FZD4, LRP5, and TSPAN12, encoding components of a novel ligand-receptor complex that activates the Norrin-ß-catenin signaling pathway, account for approximately 50% of cases. We recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to identify recessive TSPAN12 mutations in FEVR patients. METHODS: Mutation screening was performed by directly sequencing PCR products generated from genomic DNA with primers designed to amplify the coding sequence of TSPAN12. Splicing defects were verified by reverse transcriptase PCR of leukocyte cDNA. RESULTS: TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of 10 retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harboring two TSPAN12 mutations. CONCLUSIONS: We report for the first time recessive mutations in TSPAN12 and describe the first genetic cause for the clinical variation seen in FEVR families. Our data raise the possibility that patients with severe FEVR actually may harbor two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-ß-catenin signaling pathway.

Outcome of zone 1 retinopathy of prematurity.

PURPOSE: To describe the outcome in a series of patients with pre-threshold and threshold zone 1 retinopathy of prematurity. METHODS: We performed a retrospective analysis of 12 babies, 24 eyes, with zone 1 retinopathy of prematurity, treated between 1992 and 2002 with diode laser treatment. RESULTS: Ten out of the 12 babies had an unfavourable outcome. The only patients with successful anatomical outcomes were those treated before threshold disease occurred. All babies had developmental delay or neurological disability. CONCLUSION: Zone 1 retinopathy of prematurity has a poor anatomical and visual prognosis and many of the babies in our study had developmental delay and neurological disability. Earlier treatment may improve the visual outcome.