Abstract

Marfan syndrome (MFS) and Loeys–Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable.

Highlights

  • Loeys–Dietz syndrome (LDS; MIM#609192) is a rare pleiotropic heritable connective tissue disorder (HCTD) displaying an autosomal dominant transmission

  • Marfan Syndrome: Marfan syndrome (MFS) is a rare multisystemic HCTD with autosomal dominant transmission and the following characterising features: thoracic aortic aneurysm (TAA) at the sinus of Valsalva, and/or thoracic aortic dissection (TAD), ectopia lentis, systemic features (SF) with a score indicating the presence of such manifestations =/> 7 to be positive for the clinical diagnosis, in addition to a positive family history (FH) among first relatives and the detection of a pathogenic fibrillin 1 gene (FBN1) mutation already described in patients with thoracic aorta aneurysm/dissection (TAAD) [2]

  • We report on a family with a chromosomal deletion involving TGFB2 detected in a father and in his two sons

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Summary

Introduction

Loeys–Dietz syndrome (LDS; MIM#609192) is a rare pleiotropic heritable connective tissue disorder (HCTD) displaying an autosomal dominant transmission This syndrome was first reported by Drs Bart Loeys and Harry Dietz in 2005, characterised by the following clinical features: hypertelorism, cleft palate and/or bifid uvula, multiple arterial tortuosity, and ascending aortic aneurysm. Marfan Syndrome: MFS is a rare multisystemic HCTD with autosomal dominant transmission and the following characterising features: thoracic aortic aneurysm (TAA) at the sinus of Valsalva, and/or thoracic aortic dissection (TAD), ectopia lentis, systemic features (SF) with a score indicating the presence of such manifestations =/> 7 to be positive for the clinical diagnosis, in addition to a positive family history (FH) among first relatives and the detection of a pathogenic fibrillin 1 gene (FBN1) mutation already described in patients with thoracic aorta aneurysm/dissection (TAAD) [2]. We can carry out diagnoses of MFS when one of the three clinical manifestations is present together with the presence of a positive FH or a pathogenic FBN1 mutation [2]

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