Bicuspid aortic valve disease (BAVD)
Isolated bicuspid aortic valve disease is a relatively frequent cause of aortic dissection (Homme et al. 2006). Aortic dissection associated with the bicuspid aortic valve usually affects relatively young patients with no other cardiovascular risk factors. Bicuspid aortic valve disease is one of the most frequent forms of cardiovascular malformation, with a prevalence of around 1–2%. There is an increased risk of aortic stenosis and aortic insufficiency, infectious endocarditis and aortic dissection. NOTCH1 mutations are only identified as the cause of the disease in a small proportion of the families affected. Aortic phenotype: in contrast to Marfan syndrome, a bicuspid aortic valve with stenosis leads to dilation of the ascending aorta above the sinotubular junction. In cases of insufficiency, Marfan-like dilation of the aortic root may occur, and in rare cases aneurysm formation is possible even without stenosis or insufficiency in the aortic valve (Aydin et al. 2011a). Aortic changes distal to the proximal aorta are typical, particularly when there is a simultaneous aortic isthmus stenosis. Aneurysms can also form after successful replacement of the aortic valve or aortic coarctation repair (Aydin et al. 2011b, 2002; Cotrufo and Della Corte 2009).
Fig. 2.1–22a, b Typical manifestations of Marfan syndrome per person according to the Ghent-1 classification (De Paepe et al. 1996). As discussed in detail by Sheikzadeh et al. (2011a), 300 adults with suspected Marfan syndrome were examined. (a) It was found that a considerable proportion of the patients in whom Marfan syndrome was excluded had a large number of typical Marfan manifestations. (b) The range of final diagnoses in these 300 adults.
Fig. 2.1–23a-c Typical findings in Loeys-Dietz syndrome that should raise doubts regarding a diagnosis of “Marfan syndrome.” (a) Contrast magnetic resonance angiography shows a typical Loeys-Dietz aorta. Although the pear-shaped distension of the aortic root is indistinguishable from aortic pathology in Marfan patients, a patient ductus arteriosus is also visible here, which is atypical in Marfan syndrome. In addition, the abdominal aorta has been replaced with a tubular prosthesis from the renal arteries downward. The development of aneurysms in the abdominal aorta is atypical in Marfan patients. (b) The CT angiography in a patient with confirmed Loeys-Dietz syndrome shows noticeable elongation and contortion in the cerebral vessels. (c) The discretely bifid uvula shown here was noticed during the clinical examination and raised a suspicion of Loeys-Dietz syndrome, which was confirmed by evidence of a mutation in the TGFBR2 gene.
Extremely rare hereditary thoracic aortic aneurysms and dissections (TAADs)
There is no established definition of what TAADs should include. We would use it to cover all of the very rare (prevalence in the general population ≥ 1 per 100,000) monogenic aortic diseases that occur with or without syndromally defined extra-aortic manifestations (von Kodolitsch et al. 2010; Milewicz et al. 2008). The syndromal aortic diseases include dermatochalasis (cutis laxa), caused by mutations in the FBLN4 gene; arterial tortuosity syndrome, caused by mutations in the GLUT10 gene and TAAD with patent ductus arteriosus, caused by mutations in the MYH11 gene. TAAD due to mutations in the ACTA2 gene is associated with marked livedo reticularis and early occurrence of coronary heart disease. Aortic phenotype: depending on the gene involved, this may vary widely. In TAAD associated with ACTA2 gene mutations, dissections occur in both the proximal and distal aorta, but the overall aortic prognosis is similar to that in Marfan syndrome.
2.1.9.4 Diagnosis
Diagnosis of Marfan syndrome
A revised version of the classification, intended to allow easier diagnosis, has been available since 2010 (Table 2.1-4) (Sheikhzadeh et al. 2011a; Loeys et al. 2010). In patients who do not have a confirmed family history of Marfan syndrome, the syndrome is diagnosed if there is evidence of aortic dilation with ectopia lentis or with a causative FBN1 mutation, or with a systemic score ≥ 7 points (Loeys et al. 2010). Evidence of ectopia lentis with an FBN1 mutation known to be the cause of aortic disease is not sufficient to confirm a diagnosis of Marfan syndrome. If there is a family history including confirmed Marfan syndrome, the diagnosis of Marfan is confirmed if there is evidence of aortic dilation or a systemic score ≥ 7 points or ectopia lentis. The systemic score and criteria for a causative FBN1 mutation are specified in the revised Ghent classification (Loeys et al. 2010). Marfan syndrome should not be diagnosed without excluding the clinical signs of alternative diagnoses. The revised Ghent classification provides a list of the criteria (Table 1.2-5).
Diagnosis of alternative aortic syndromes
From our point of view, three diagnostic rules need to be observed. Since Marfan syndrome is by far the most frequent cause of genetically determined aortic syndromes and many of its extra-aortic manifestations also occur in other aortic syndromes, the first rule is, when there is a suspicion of a genetically caused aortic disease, that one must always evaluate whether the clinical criteria for Marfan syndrome are present. If extra-aortic signs of Marfan syndrome are present in addition to thoracic aortic disease, sequencing of the FBN1 gene should be carried out primarily. If the evaluation shows typical manifestations of alternative aortic syndromes, then—particularly if they are typical of Loeys–Dietz syndrome—sequencing of the TGFBR1/2 genes or SMAD3 gene should be carried out first, or other alternatives should be considered if there are relevant clinical signs (see Table 2.1-5 and Fig. 2.1-24). The introduction of next-generation sequencing technology is likely to lead to the establishment of a sequencing strategy that allows diagnosis of all the typical genes responsible for aortic diseases (Baetens et al. 2011).
Another diagnostic rule is that a specific aortic syndrome should not be diagnosed, even if there is evidence of a gene sequence change in one of the potentially causative genes, unless the relevant phenotypic criteria are met. This has been firmly established for Marfan syndrome for a long time and is regulated by internationally recognized classifications (Loeys et al. 2010; De Paepe et al. 1996). The current Ghent classification also defines diagnostic criteria for MASS syndrome, ectopia lentis syndrome and mitral valve prolapse syndrome (Loeys et al. 2010). By contrast, vascular Ehlers–Danlos