Genetic dissection of marfan syndrome and related connective tissue disorders: an update 2012

Abstract

Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue characterized by early development of thoracic aortic aneurysms/dissections together with symptoms of the ocular and skeletal systems. While most patients/families with a classic phenotypic expression of MFS harbour mutations in the gene encoding fibrillin-1 (FBN1), genetic studies of the recent years revealed that the clinical features, as well as the mutated genes, show a high degree of overlap between MFS and other connective tissue diseases (e.g. Loeys-Dietz syndrome, Ehlers-Danlos syndrome, familial thoracic aneurysms and dissections and others). We summarize herein the current knowledge about the wide spectrum of differential diagnoses and their genetic background as well as novel therapeutic approaches in order to provide appropriate counselling and clinical follow-up for the patients.

Keywords: Connective tissue disorders; Ehlers-Danlos syndrome; Loeys-Dietz syndrome; Marfan syndrome.

Fig. 1

TGFβ signalling pathway. Fibrillin-1 (FBN1), as a major component of the extracellular matrix, interacts with large latent TGFβ-binding protein (LTBP) which sequesters TGFβ1 and thus prevents excessive TGFβ1 signalling. Binding of TGFβ1 to TGFBR2 leads to phosphorylation and activation of TGFBR1, resulting in activation of Smad2/3 transcription factors. After association with Smad4, these transcription factors enter the nucleus and increase the transcription of several target genes (canonical pathway). Additionally, TGFβ1 induces other (noncanonical) pathways, including for example the mitogen-activated protein kinase (MAPK), PP2A or RhoA cascades. Both defective FBN1 as well as heterozygous mutations in TGFBR1/TGFBR2 were shown to result in increased TGFβ1 signalling, promoting aneurysm formation. Angiotensin II (AngII) regulates TGFβ activation and signalling through the angiotensin II type 1 receptor (AT1R). The AT1R blocker Losartan was found to down-regulate TGFβ signalling and is currently evaluated as a therapeutic option for MFS.

Fig. 2

Differential diagnosis for Marfan syndrome and overlapping phenotypes. The cardinal symptoms of MFS, including thoracic aneurysm/dissection, ectopia lentis and skeletal features (sometimes called Marfanoid build) show a high degree of overlap with various other diseases that have to be considered for differential diagnosis. The discriminating features of the respective disorders are given in the text and summarized in table 2.