SummaryBackgroundIrbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome.MethodsWe did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6–40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794.FindingsBetween March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12–28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of −0·22 mm per year (−0·41 to −0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means −0·10 per year, 95% CI −0·19 to −0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events.InterpretationIrbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications.FundingBritish Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders. Starting with genomic DNA, we analysed the FBN1 gene using PCR, SSCP and/or dHPLC analysis, and automatic sequencing of abnormal bands/peaks, in a consecutive series of 508 patients, of which 22 were children less than 5 years old. Our results are comparable with those reported by other groups. In this study we observed 193 mutations, 126 of which previously unreported. A total of 331 relatives (including 51 infants) of 120 probands for whom a family mutation had been identified here or elsewhere, were tested for the presence of that particular mutation. In addition, 4 prenatal tests were carried out. The identification of a mutation allows for early diagnosis, prognosis, genetic counselling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. © 2007 Wiley-Liss, Inc. KEY WORDS: Marfan, MFS, fibrillin-1, FBN1, ectopia lentis, ascending aortic aneurysm INTRODUCTIONMarfan syndrome (MFS; MIM# 154700) is an autosomal dominantly inherited disorder, characterised by highly variable phenotypic manifestations, mainly in skeletal, ocular, cardiovascular and central nervous systems. Other systems can be involved, mainly lungs and skin, but usually with less specific manifestations (De Paepe et al., 1996;Pyeritz and Dietz, 2002).According to the current Gent nosology, a clinical diagnosis of Marfan syndrome requires major criteria (more severe clinical signs) affecting at least two systems and the involvement of a third system with minor criteria (milder clinical signs) (De Paepe et al., 1996).Between 20% and 30% of cases are sporadic, representing new mutations. The incidence of this pleiotropic disease has been reported at 1 in 9,802 in the UK, with a prevalence of 1 in 14,217 (Gray et al., 1994). It is suggested that figures are not influenced by ethnicity or gender (Pyeritz and Dietz, 2002).MFS results from mutations in the FBN1 gene (MIM# 134797), which is more than 200 kb long, made up of 652 Comeglio et al.exons, and has a transcript of approximately 9.7 kb, with a coding region of about 8.6 kb Corson et al., 1993;Biery et al., 1999). FBN1 encodes for a ubiquitous connective tissue microfibrillar protein named fibrillin-1, and is located on chromosome 15q21.1 (Lee et al., 1991;Magenis et al., 1991). Fibrillin-1 is mainly composed of cysteine-rich EGF-like domains, most of them with a consensus sequence for calcium binding (cbEGF-like). Interspersed among these domains are TGFBP domains and other fibrillin-1 specific cysteine-rich hybrid motifs (Pereira et al., 1993). To date, identified mutations are distributed throughout the FBN1 gene, with limited evidence of correlation between the regions of the mutations and the clinical phenotype, reflecting sequence-specific roles in secretion, assembly and extra c...

ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term ‘IEL’ should be avoided in such cases.

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