Ectopia lentis

Abstract: Marfan syndrome is an autosomal dominant, multisystem disease characterized by long bone overgrowth and other skeletal abnormalities, dislocation of the ocular lens, pneumothorax, decreased skeletal muscle mass, mitral valve prolapse, and dilatation of the aortic root. Antoine BernardJean Marfan first described the syndrome in 1896 in a young patient with peculiarly long and thin digits (subsequently termed arachnodactyly), elongated limbs (which he termed dolichostenomelia), and congenital contractures of multiple joints. Because of the latter feature, this patient may really have had congenital contractural arachnodactyly, a connective tissue disorder not described until 1968. For the half century subsequent to Marfan’s report, features in other systems were described in patients with thin, elongated limbs: mitral valve disease in 1912; dislocation of the ocular lens in 1914; ruptured aortic aneurysm in 1918; aortic root dilatation and dissection in 1943; and autosomal dominant inheritance in 1949. Manifestations occur in many other tissues and organs and are increasingly being recognized as patients survive to older ages. 1 An accurate incidence has been impossible to define because of the age dependency of many of the features, the common occurrence of some features in the general population (such as scoliosis; lean, tall habitus; mitral valve prolapse; myopia), and shifting diagnostic criteria. Several conditions that were once classified as Marfan (eg, homocystinuria, Loeys-Dietz syndrome) are recognized now as clearly distinct. However, Marfan syndrome is clearly one of the more common, potentially lethal Mendelian conditions with an estimated prevalence of 1 case per 3000 to 5000 individuals. This figure does not appear to vary with ethnicity or geography.2 Mutations in the gene (FBN1) that encodes the extracellular matrix protein, fibrillin-1, cause classic Marfan syndrome. 3 Up to one third of cases have neither parent affected and represent de novo mutations in either the gamete from their mother or father. Heterozygosity for a mutation in FBN1 can also produce a variety of overlapping phenotypes with Marfan syndrome. No robust genotype-phenotype correlations have emerged, despite 1000 mutations being analyzed. 4 Mutations in the middle region of the gene, exons 24 to 32, tend to predict more severe cardiovascular problems at all ages. Other families or sporadic patients in which some of the features of Marfan syndrome occur, but typically without ectopia lentis, have mutations in 1 of 2 genes (TGFBR1 and TGFBR2) that encode receptors for the cytokine transforming growth factor- (TGF-). 5–7

Abstract: Mutations in the gene coding for fibrillin on chromosome 15 (FBN1) are known to cause Marfan syndrome (MFS). A related disorder, dominant ectopia lentis (EL), has also been linked genetically to this locus. We now describe ten novel mutations of FBN1 resulting in strikingly different phenotypes. In addition to classic MFS, FBN1 mutations also give rise to EL and a severe neonatal form of MFS. Interestingly, the neonatal MFS mutations are clustered in one particular region of FBN1, possibly providing new insights into genotype-phenotype comparisons.

Abstract: Mainly through the screening of cases of ectopia lentis or presumed Marfan syndrome, or both, 38 cases of homocystinuria distributed in 20 families were ascertained and studied. About 5% of cases of nontraumatic ectopia lentis have homocystinuria. Ocular, skeletal, and vascular changes in homocystinuria simulate those of the Marfan syndrome, but osteoporosis and thrombosis are distinguishing features of homocystinuria. Furthermore, mental retardation and cutaneous flushing are found in homocystinuria and not in the Marfan syndrome. Elucidation of the biochemical defect in homocystinuria opens up possibilities of successful therapy.

Abstract: Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.