Mutations in a TGF-ß ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

BACKGROUND: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-ß signaling. OBJECTIVES: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-ß signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-ß signaling in association with up-regulation of the expression of TGF-ß ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

Carcinoid heart disease: case and literature review.

We present the case of a 69-year-old woman with a metastatic neuroendocrine tumour of the ileum and severe tricuspid valve regurgitation due to carcinoid valvulopathy. Carcinoid heart disease arises in the context of metastatic serotonin-producing neuroendocrine tumours and typically presents as structural and functional abnormalities of tricuspid (TV) or pulmonary valve (PV). Carcinoid heart disease arises from a low-grade neuroendocrine tumour derived from serotonin-producing enterochromaffin cells that reduces the mobility of the leaflets. Following the development of this type of heart failure, the prognosis is unfavourable and patients usually die as a result of heart failure and not because of the metastatic disease. Our patient was not considered a candidate for valvular surgery because of the progressive nature of the malignancy. However, surgical valve replacement is a therapeutic option that, although it has a significant mortality, needs to be considered in selected patients and leads to improvement in functional capacity and survival.