MFS is an autosomal dominant disorder of the connective tissue and has a frequency of 1:5,000–10,000. The molecular cause of the classic MFS are mutations in fibrillin-1, which is why MFS is also known as fibrillinopathy. Fibrillin is secreted by fibroblasts and is, apart from collagen and elastin, the most important structural component of the extracellular matrix of the connective tissue. Due to the extensive microfibrillar system in the organism, fibril-1 mutations can cause a broad spectrum of clinical manifestations in various organ systems. The cardiovascular and the skeletal system as well as the eyes (lens luxation) are predominantly affected. The characteristic primary and secondary criteria (skeletal and cardiovascular system, eyes and integumentary system) for a clinical diagnosis were summarized in the Ghent Nosology in 1996. Since certain signs and symptoms are age-dependant, establishing a diagnosis in children and adolescents has frequently been difficult. In 2010, the Ghent Nosology was revised; from then, more emphasis was placed on the cardinal signs of aortic root aneurysm or dissection and ectopia lentis. These signs alone suffice to establish the clinical diagnosis. All other organ manifestations are considered systemic involvement if a certain score is achieved; however, in contrast to 1996, unspecific signs and symptoms have been removed. An isolated aortic root dilation or dissection combined with systemic involvement also confirms the diagnosis MFS. The molecular genetic result has gained significance as well: isolated aortic root dilation or dissection or isolated lens luxation combined with a mutation in the FBN1 gene also confirms the diagnosis of Marfan syndrome.
The FBN1 gene extends over 230 kilobases of genomic DNA and consists of 65 coding exons. The protein fibrillin-1 consists of 2871 amino acids and has a molecular weight of approximately 350 kilodaltons. So far, over 1,300 different mutations, which are spread over the entire gene, have been described in the FBN1 gene. About 2/3 of all FBN1 mutations are causing amino acid substitutions; approximately 3/4 are affecting one of the 43 calcium binding (cb), epidermal growth factor (EGF)-like motifs. Missense mutations within various domains of the fibrillin-1 protein may lead to the classic MFS or may be associated with mild phenotypes with pure skeletal manifestations or mitral valve prolapse. 20% of all FBN1 mutations result in a translational stop, i.e. in degradation of mutant transcripts and lead to a reduction of the fibrillin-1 protein biosynthesis to 50%. These mutations have been described in both patients with classic MFS and in patients diagnosed with MASS phenotype (myopia, mitral valve prolapse, borderline dilated aortic root, striae and affected skeleton), ectopia lentis syndrome (ELS) and mitral valve prolapse syndrome (MVPS). Splice mutations (12%) or deletions have been associated with a very severe phenotype if they lead to the loss of entire exons with maintaining the reading frame. Intragenous deletions affecting one or several exons account for approximately 2% of all mutations in the FBN1 gene and can be detected by MLPA (multiplex ligation-dependent probe amplification). Type and location of the mutation allow a genotype phenotype correlation to a limited extent. The association between mutations in the region between the exons 24-32 and the severe progressive neonatal MFS is the most clear.
Mutations in the FBN1 gene are found in 95% of all patients with classic MFS who fulfill the Ghent criteria from 1996. In 5-25% of all patients who display some of the signs and symptoms of MFS with additional characteristics (patients with Marfan-like syndrome, MFS2 or incomplete Marfan signs and symptoms) and who do not have a mutation in the FBN1 gene, mutations in the genes for receptors of the transforming growth factor beta (TGFBR1 or TGFBR2) can be identified.