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The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients.

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Nine patients with severe Graves' ophthalmopathy were treated by intensive plasma exchange, followed by immunosuppression. Severity of ocular involvement and response to therapy were evaluated clinically by numerical scoring (ophthalmopathy index). Serum thyroid stimulating immunoglobulins (TSI) and urinary excretion of glycosaminoglycans (GAG) were measured immediately before and immediately after plasmapheresis.Plasma exchange was rapidly accompanied by marked clinical improvement in 8/9 patients. The most marked effects were on soft tissue involvement, proptosis, intraocular pressure, and visual acuity. The ophthalmopathy index decreased from 9.7 \ m=+-\ 4.1 to 5.7 \ m=+-\ 2.2 (P <0.001) after plasmapheresis. Serum TSI levels were initially elevated in 6 patients and remained positive in 3 patients after treatment. Urinary GAG excretion was initially 2-to 12-fold normal levels and was decreased by 60%. After plasmapheresis, patients received immunosuppressive drugs for 3\p=n-\6months. The follow-up period, after withdrawal of drugs, ranged from 5 to 38 months with a median of 17 months. The ocular condition remained stable in 6 patients. Three patients had a relapse 1 year after plasmapheresis: they were treated a second time by plasma exchange with subsequent improvement. In conclusion, intensive plasma exchange provided prompt and effective improvement in patients with severe progressive Graves' ophthalmopathy. This therapeutic procedure, followed by immunosuppression, gave long lasting results.

We have measured eye muscle antibodies, in immunoblotting, in the serum from five patients with severe ophthalmopathy associated with Graves' hyperthyroidism who underwent plasmapheresis, correlating their levels with clinical features of the eye disorder and response to treatment. Blood taken before each plasma exchange was tested in SDS-polyacrylamide gel electrophoresis and Western blotting for antibodies reactive with pig eye muscle membrane (PEMM) antigens and in a 51Cr release assay for antibodies which are cytotoxic to human eye muscle cells in antibody-dependent cell-mediated cytotoxicity (ADCC). Antibodies reactive with a 64 kDa PEMM antigen were detected in three patients who had eye disease of less than six months duration, but not in the two with more chronic disease. Antibodies against a 95 kDa PEMM antigen were detected in one patient in whom anti-64 kDa antibodies were also demonstrated. All five patients showed significant improvement in their eye disease following plasmapheresis exchange and titres of the anti-64 kDa protein antibody decreased in the three patients with detectable levels before treatment. TSH receptor stimulating antibodies were detected in all five patients before treatment, falling during plasmapheresis in four and becoming undetectable in three by the end of treatment. There was no close correlation between levels of TSH receptor antibodies and titres of anti-64 kDa protein antibodies although both tended to fall during and following plasmapheresis. ADCC tests were negative in all five patients before plasmapheresis but, surprisingly, transiently positive in three following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)