Fig. 2.1–20a-d Typical imaging findings in Marfan syndrome. (a) The slit-lamp examination shows the left eye in a Marfan patient in whom the lens has dislocated in an upper temporal direction. Dilated zonular fibers of the suspensory ligament of the lens are visible at the lower edge of the lens. (b) The magnetic resonance image (MRI) of the lumbosacral joint in a patient with classic Marfan syndrome shows marked dural ectasia, which in an erect posture is usually particularly clear in the distal region of the dural sac, due to hydrostatc pressure in the cerebrospinal fluid (Sheikhzadeh et al. 2011b; Habermann et al. 2005). (c) The contrast MRI of the entire aorta shows typical Marfan aortic pathology with a clear, pear-shaped distension of the aortic root but a normal-caliber aorta in the arch and descending thoracic and abdominal parts of the vessel. (d) The contrast computed tomogram taken due to acute chest pain shows acute intramural hemorrhage marked by acute bleeding into the middle layer of the aortic wall, seen here in both the ascending and descending aorta and often leading to progression of the classic aortic dissection and development of a false lumen in the aortic wall. When there is intramural hemorrhage with involvement of the ascending aorta, emergency surgery is indicated in the same way as in a classic aortic dissection (Hiratzka et al. 2010; von Kodolitsch et al. 2003).
2.1.9.3 Differential diagnoses
Typical reasons for a suspicion of Marfan syndrome include an aortic aneurysm or aortic dissection in young adults, manifestations of Marfan in a patient’s family, connective-tissue weakness or hyper-mobility in the extremities and Marfan-like skeletal manifestations (Fig. 2.1-21). Interestingly, Marfan syndrome is only actually confirmed in 28% of individuals with skeletal changes, while the confirmation rate in patients with suspicious eye manifestations is 70% and in those with a positive family history it is 44% (Fig. 2.1-21). Overall, the tentative diagnosis is only confirmed in approximately half of patients with suspected Marfan syndrome. Despite this, Marfan-like changes may also be seen in patients in whom the syndrome has been “excluded” (Fig. 2.1-22). It is extremely important to be unsatisfied with a diagnosis of “Marfan syndrome excluded” in these patients and to conduct a search for other differential diagnoses. Figure 2.1-22 shows the alternative syndromes which are diagnosed and their relative frequency. These syndromes are described below.
Other FBN1-associated diseases
The range of diseases that can be caused by mutations in the area of the FBN1 gene is very wide, ranging from neonatal Marfan syndrome, with an average life expectancy of less than 1 year, to a Marfan-like appearance that is not associated with aortic disease or with any reduction in life expectancy. Only a few forms of isolated thoracic aneurysms and dissections (i.e., with no other extra-aortic manifestations) are associated with FBN1. The mitral valve, aorta, skin and skeletal features (MASS) phenotype is a mild form of manifestation of Marfan syndrome. Mitral valve prolapse syndrome is associated with Marfan-like skeletal manifestations, but mutations in the FBN1 gene and aortic disease have not yet been reported with it. Particularly in pediatric groups of patients, Shprintzen–Goldberg syndrome and Weill–Marchesani syndrome are diagnosed in association with FNB1 gene mutations. Aortic phenotype: the MASS phenotype should not show any progression in the dilation of the aortic bulb, while in neonatal Marfan syndrome aortic dissections are already noted at the intrauterine stage.
Loeys–Dietz syndrome (LDS)
Loeys and Dietz have described a Marfan-like syndrome caused by mutations in the TGFBR1/2 genes, showing aortic disease with syndromal changes that differ clearly from Marfan syndrome in both the aortic and extra-aortic findings (Fig. 2.1-23). Type 1 Loeys – Dietz syndrome is characterized by cardiovascular, craniofacial, neurocognitive and skeletal manifestations (Mizuguchi et al. 2004). The cardinal craniofacial symptoms consist of hypertelorism, cleft palate, cleft or wide uvula, blue sclera and craniosynostosis. Rare manifestations include atrial septal defect, patent ductus arteriosus, type 1 Arnold–Chiari malformation, hydrocephalus, developmental retardation and club foot (Loeys et al. 2005). Type 2 Loeys–Dietz syndrome was first described in 2006 in patients with mutations in the TGFBR1 and TGFBR2 genes who met the clinical criteria for vascular Ehlers–Danlos syndrome, but without having the changes in type III collagen typical of that syndrome. Type 2 Loeys–Dietz syndrome is characterized by the development of arterial aneurysms, hypermobility and at least two additional symptoms that are typical for vascular Ehlers–Danlos syndrome such as intestinal rupture in the viscera, uterine rupture particularly during pregnancy, translucent, silky, brittle, or hyperelastic skin, and atrophic cicatricial tissue. Aortic phenotype: although more than 80% of the affected patients develop aneurysms in the proximal aorta in type 1 and 2 Loeys– Dietz syndrome, there are also often aneurysms in the distal aorta, in side branches of the aorta, in the cervical arteries or head—in contrast to Marfan syndromes. An additional feature of Loeys–Dietz syndrome is pathological elongation and tortuosity in the arteries. Furthermore, the age of manifestation of Loeys–Dietz syndromes is lower, acute vascular complications are located in multiple vascular regions and the risk of rupture and dissection does not depend on the diameter of the aorta.
Aneurysm–osteoarthritis syndrome (AOS)
The clinical presentation of this aortic syndrome is similar to that of Loeys–Dietz syndrome, and it is caused by mutations in the SMAD3 gene. There are mild signs of craniofacial dysmorphia bifid uvula, skeletal changes resembling those in Marfan syndrome, dural ectasia, involvement of the inner organs and skin changes (van de Laar et al. 2011). Osteoarthritides are typical in this syndrome and are not observed in the other aortic syndromes. In addition to vascular complications, mitral valve diseases, pulmonary valve stenoses, septal defects, and patent ductus arteriosus may occur. Aortic phenotype: aneurysms and dissection mainly occur in the aortic root, but can also develop in all of the other vascular segments of the aorta and extra-aortic arteries. The arteries also often have a severely tortuous course.
Fig. 2.1–21a, b Analysis of reasons for the referral of 300 consecutive adults in Hamburg for diagnostic clarification in cases of suspected Marfan syndrome. The methods with which these data were obtained are described in Sheikhzadeh et al. (2011a). (a) The reasons why the referring physicians raised a suspicion of Marfan syndrome. (b) The relative frequency with which the diagnosis was actually confirmed in patients with a specific reason for suspected Marfan syndrome. It is notable that “signs of connective-tissue weakness or joint hypermobility” and patients with “typical Marfan skeletal manifestations” were rarely in fact found to have Marfan syndrome.
Vascular Ehlers–Danlos syndrome (VEDS)
The Ehlers–Danlos syndromes are diseases of connective tissue that are characterized by increased elasticity in the skin, hypermobility in the joints and involvement of internal organs (Beighton