In our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657 .).

We describe a distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram. Heterozygous mutations in BEST1 have previously been found to cause the two dominantly inherited disorders, Best macular dystrophy and autosomal-dominant vitreoretinochoroidopathy. The transmembrane protein bestrophin-1, encoded by BEST1, is located at the basolateral membrane of the retinal pigment epithelium in which it probably functions as a Cl(-) channel. We sequenced BEST1 in five families, identifying DNA variants in each of ten alleles. These encoded six different missense variants and one nonsense variant. The alleles segregated appropriately for a recessive disorder in each family. No clinical or electrophysiological abnormalities were identified in any heterozygotes. We conducted whole-cell patch-clamping of HEK293 cells transfected with bestrophin-1 to measure the Cl(-) current. Two ARB missense isoforms severely reduced channel activity. However, unlike two other alleles previously associated with Best disease, cotransfection with wild-type bestrophin-1 did not impair the formation of active wild-type bestrophin-1 channels, consistent with the recessive nature of the condition. We propose that ARB is the null phenotype of bestrophin-1 in humans.

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.

Vernal keratoconjunctivitis (VKC) is a bilateral, usually seasonally recurrent, allergic inflammation of the conjunctiva, characterised by limbal gelatinous hypertrophy and/or upper tarsal giant conjunctival papillae. Although rare in temperate regions, it represents an important cause of hospital referral in many parts of Africa and Asia. Clinical and immunohistochemical studies suggest that IgE-dependent (type I allergic) and IgE-independent (type IV allergic) mechanisms are involved in the immunopathogenesis of VKC, in which various inflammatory cells, including different T cell subpopulations play an active role via a cascade of chemical mediators. Endocrine, genetic, neurogenic, environmental and socioeconomic risk factors have been identified. However, its aetiology and pathophysiology remain unclear. The clinical course of this disease is usually benign and self-limiting, but a minority of patients will face very debilitating and sight threatening complications. Topical corticosteroids are often used during flare-ups in combination with mast cell stabilizers as maintenance treatment for VKC. However this management is unsatisfactory in controlling severe cases and avoiding recurrences. Non-steroidal immune modulators such as ciclosporin A and tacrolimus are promising alternatives, but tolerance to these agents needs to be improved and production costs reduced. The purpose of this review is to give an update on its epidemiology, immunopathogenesis and management. EPIDEMIOLOGYVernal keratoconjunctivitis (VKC) is a bilateral, chronic, external ocular inflammatory disorder, mainly affecting patients in their first or second decade.1-3 Although it is a rare allergic disorder in temperate regions, in many parts of Africa, Latin America and Asia VKC represents an important cause for hospital attendance, ranging from 3% to 6% of patients of all ages, rising to 33% and 90% in children and adolescents.2 4-7 A population prevalence of 4% to 5% has been found among African children.3 8 In large European and Asian case series boys appear to be affected more than girls, but this sex distribution is not found uniformly in Africa, and becomes less obvious with age.

FOXC1 and PITX2 genetic defects explain 40% of our large ASD cohort. The current spectrum of intragenic FOXC1 and PITX2 mutations was extended considerably, the identified copy number changes were fine mapped, the smallest FOXC1 and PITX2 deletions reported so far were identified, and the need for dedicated copy number screening of the FOXC1 and PITX2 genomic landscape was emphasized. This study is unique in that sequence and copy number changes were screened simultaneously in both genes.