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Open access peer-reviewed chapter
By Cemşit Karakurt
Submitted: May 2nd 2012Reviewed: September 13th 2012Published: April 10th 2013
Aortic aneurysm involves the aorta which is one of the large arteries through which blood passes from the heart to the rest of the body. Aortic aneurysm is a relatively common finding in the elderly patients because of aging, hypertension, or atherosclerosis, but it is rarely seen in childhood. In the adult population, the incidence of aortic aneurysm has been estimated to be 5.9 cases per 100000 person-years. However, there are no real data about the incidence of aortic aneurysm in childhood . Aortic aneurysm is mostly seen in the ascending aorta, but it may also be seen in the descending aorta and /or aortic branches [2, 3]. Although it is rare, aortic aneurysm can be important cause of mortality in children and adolescents. Aortic aneurysm may be related to hereditary diseases (Marfan syndrome, Loeys –Dietz syndrome, Ehler-Danlos syndrome, Arterial Tortuosity Syndrome, Cutis laxa syndrome, Alagille syndrome, and Noonan Syndrome), or non genetic diseases (bicuspid aortic valve, coarctation of aorta, tetralogy of Fallot, and aortitis syndromes). In this review, causes, clinical findings, diagnostic methods, and treatment modalities of aortic aneurysm in children and adolescents have been discussed.
Marfan syndrome, characterized by otosomal dominant inheritance, I was first described in 1986. The syndrome is due to more than 500 mutations in the fibrillin 1 gene on chromosome 15q21. Expression of the disease is variable and 30% of cases represent new mutation. Although cardiovascular manifestations are variable, the incidence (35-80%) of aortic root dilatation, mitral regurgitation in Marfan patients depends on the patient’s age. In Marfan syndrome, fibrillin-1 gene mutation leads to elastic fiber fragmentation and cystic medial necrosis. Fibrillin-1 is a matrix glycoprotein and a constituent of fibrils. Apart from structural abnormalities, a defective subenthelial fibrillin leads to decreased distensibility, and increased aortic stiffness was showed in patients with Marfan syndrome. Excessive transforming growth factor β(TGFβ) activity, defect in gene encoding TGF β receptor and complex interaction between the fibrillin, microfibrils, TGFβ and its receptor have been proposed hypothesis of defective arterial wall matrix. Aortic dilatation may be related to arterial muscle cell apoptosis due to angiotensin-II receptor signalling pathways. Aortic stiffness has been showed to be an independent predictor for progressive aortic dilatation and dissection . Beta blocker and ACE inhibitor therapy have been showed to decrease aortic stiffness and delay aortic surgery .
Clinical findings of Marfan syndrome are variable. Although most of the patients are diagnosed after 10 years, physical findings may be present at birth. The height of the patient increases. An arm span exceeds the height. Marfan patients have hypermobile joints, chest deformities, long and thin fingers, kyphoscoliosis, high palates, inguinal hernias, and dental abnormalities. Figure 1 shows long and thin fingers; figure 2 shows increased arm length and height in a Marfan syndrome patient. Ocular abnormalities such as lens subluxation, and/or myopia may be present in nearly 75% of the patients. Cardiovascular manifestation including aortic aneurysm, mitral valvar prolapse less severe in children than adults. Ghent nosology has been developed for diagnosis of Marfan syndrome in 1996. The 1996 Ghent criteria were adopted worldwide, but diagnostic criteria were revised in 2010, highlighting aortic root aneurysm and lens subluxation more [6, 7].
According to Ghent’s criteria, positive family history of Marfan syndrome (known fibrillin 1 mutation in the parent(s) or siblings), cardiac findings including aortic root dilatation, aortic dissection, and lumbosacral dural ectasia are the major criteria. Mitral valvar prolapse, calcific mitral annulus (age< 40 years), other aortic dilatations or dissections (age <50 years), spontaneous pneumothorax, apical blebs, skin abnormalities including recurrent or incisional hernias, and stria atrophicae are considered minor criteria. Recently, diagnostic criteria were revised nosology established for adult Marfan population [8, 9, 10].
Cardiovascular manifestations, especially aortic aneurysm and dissection, are the most common causes of mortality. Aortic aneurysms are usually located in the ascending aorta but it may also be located in the abdominal aorta or aortic branches [11, 12, 13]. Figure 3 and 4 show an aneurysm in the right renal artery and multiple aneurysm in the hepatic artery in a 16-year-old Marfan patient. Figure 5 shows intraoperative appearance of an aneurysm in the ascending aorta in an 18-year-old patient with Marfan syndrome.
Elective root replacement should be seriously considered in any Marfan patient with significant root dilatation. Reoperation is required for half of Marfan syndrome patients . Risk of sudden death or aortic dissection remains low in patients with Marfan syndrome and aortic diameter between 45-49 mm. Aortic diameter of 50 mm appears to be reasonable threshold for prophylactic surgery [15, 16].
The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular disorders [17, 18]. For patients with Marfan syndrome, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to the status of distal aorta; they need multiple procedures for better quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for patients with Marfan syndrome [19, 20]. Prophylactic propranolol treatment delays progression of aortic root dilatation. Because the patogenetic role of angiotensin II receptor signaling pathway and TGFβ in Marfan syndrome is clearly understood, angiotensin converting enzyme inhibitors should be started in patients with Marfan syndrome. Timing of surgery including aortic root surgery and/or valve replacement must be determined according to the risk and benefit of the surgery. Because annual mortality rate is 5% in patients with an aortic root greater than 50 cm, elective surgery must be performed before aortic root reaches 55 mm. For patients with a family history of aortic dissection and likelihood of pregnancy, elective surgery should be performed while the aortic root is in a smaller size. Upon diagnosis of Marfan syndrome, echocardiographic evaluation should be done, and beta blocker treatment and angiotensin converting enzyme inhibitors should be started after aortic root measurement. Patients with this syndrome should be followed up with echocardiograph periodically, and if it is necessary, with magnetic resonance imaging. Patients with Marfan syndrome who remain undiagnosed until adulthood are more likely to require surgical intervention. Early diagnosis of Marfan syndrome can improve the long-term outcome .
Infantile form of Marfan syndrome is a rare condition in which the ocular and skeletal abnormalities are similar to those in the adult form. Myxomatous changes of mitral and tricuspid valves and chordaes with elongation of chordae tendineas are seen commonly in infantile form. Pulmonary emphysematous changes are also seen. Cardiovascular morbidity is commonly related to mitral and tricuspid valve disease rather than aortic aneurysm and dissection. Family history is rare and death commonly occurs in 2 years after diagnosis [22, 23].
Loeys-Dietz syndrome, which was first described in 2005, resembles Marfan syndrome, which is also inherited otosomal dominant, aortic aneurysm, and vascular pathology in Loeys-Dietz syndrome is more probable than in Marfan patients. It is caused by heterozygous mutations in the genes encoding type I and II transforming growth factor-β (TGFBR1, TGFBR2) and is characterized by hyperteleroism, bifid uvula, cleft palate, arterial tortuosity, aneurisms of the ascending aorta, and dissection. Despite phenotypical resemblance, Loeys-Dietz syndrome can be differentiated from Marfan syndrome by palatal involvement and hyperteleroism. Aneurysms may occur in young ages and lead to aortic dissection in Loeys-Dietz Syndrome. Elective surgery is recommended at an aortic root diameter of 40 mm. In Loeys-Dietz syndrome, defective microfibrils due to excessive activity of Transforming Growth Factor β activity lead to defective formation of matrix in the arterial wall and thus, aortic aneurysms [24, 25, 26].
Valve sparing operation of the aortic root is ideal in treating young patients with aortic root aneurysm with normal or minimally diseased aortic cusps to avoid the disadvantages of prosthetic valve replacements [27, 28].
Loeys-Dietz syndrome is an aggressive aortic aneurysm syndrome that can be addressed by prophylactic aortic root replacement with low operative risk. Valve-sparing procedures have encouraging early and midterm results, similar to Marfan syndrome, and are an attractive option for young patients [29, 30, 31].
The other genetic cause of aortic aneurysm is Ehler-Danlos syndrome. Ehler-Danlos syndrome is a genetically heterogeneous disorder of collagen and extracellular matrix and it is characterized by abnormal collagens. Although more than 10 subtypes have been described, 90% of patients with Ehler –Danlos Syndrome encompass six subtypes. Hyper extensibility of joints and skin, distinctive facial appearance, easy bruising, poor healing of wounds, smooth and rubbery palm and soles, blue sclera, epicanthal folds, lens subluxation, poor muscle tone are clinical findings of Ehler-Danlos. Premature death can occur in the most severe forms due to poor muscle tones. Cardiovascular findings are seen in subtype IV. In Ehler Danlos type IV collagen type III α-1 gene mutation leads to abnormal type III collagen in the vascular wall, skin and other organs. These patients carry aortic dissection risk and it does commonly occur after the 3rd decade. Aortic aneurysm can be seen in Ehler-Danlos type IV patients, but dissection is a rare condition in these patients [32, 33, 34, 35].
Arterial tortuosity syndrome is an autosomal recessive disorder characterized by tortuosity of the aorta and its major branches due to SLC2A 10 genes that encodes for the glucose transporter GLUT10. Coucke et al reported location of the arterial tortuosity syndrome locus to 20q13 to a 1.2 Mb region containing 7 genes. Aortic aneurysms can also be seen in Arterial tortuosity syndrome patients [36, 37, 38].
Turner syndrome is an aneuploidy syndrome [45, XO) characterized by short stature, webbed neck, and infertility. Bicuspid aortic valve, coarctation of the aorta, aortic dilatation, pseudocoarctation, aortic aneurysm, and dissection are common in Turner patients. Histological evidence of cystic medial necrosis has been reported in Turner syndrome. The prevalence of aortic dilation and aneurysm is lower in the young girls and women with Turner syndrome than in older Turner syndrome population [39, 40].
Noonan syndrome is characterized by hypertelorism, a downward eyeslant, and low-set posterior rotated ears, short stature, short neck with webbing, cardiac anomalies, epicanthic folds, deafness, motor delay, and bleeding diathesis. Noonan syndrome is similar to Turner syndrome but a genetically heterogeneous disease (PTPN11, RAS-MAPK mutations) characterized by dysplastic pulmonary valve, pulmonary stenosis [41,42]. Aortic aneurysm and dissection are rarely seen in Noonan syndrome .
Alagille syndrome is an autosomal dominant syndrome that has been defined as paucity of intrahepatic bile ducts, cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial appearance, ocular and renal abnormalities caused by heterozygous mutation in the Jagged -1 gene on chromosome 20p12. Another form of Alagille syndrome is caused by mutation in the NOTCH2 gene. Basillary artery aneurysm, middle cerebral artery aneurysm, aortic coarctation and aortic aneurysms have been reported in Alagille patients [44, 45, 46].
Cutis laxa is rare genetically heterogeneous disorder characterized by loose, sagging disease from early age. Autosomal dominant and recessive forms of cutis laxa have been described. In patients with cutis laxa, skin is loose and appears to be larger for the body . Cutis laxa phenotypically resembles Ehler –Danlos syndrome due to hypermobile joints, fragility of skin, and easy bruising. However, the skin slowly recoils after it is stretched. Inguinal hernias and rectal prolapses may be seen . Pulmonary stenosis, pulmonary emphysema, cor pulmonale, mitral regurgitation, dysplastic valvar disease and aortic aneurysm have also been reported in cutis laxa syndrome.
Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins predominantly expressed in medial layers of large veins and arteries. Fibulin-4 deficiency has been showed in autosomal recessive cutis laxa patients .
Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections caused by mutations SMAD3 gene, characterized by the presence of arterial aneurysms and tortuosity, mild skeletal, craniofacial and cutaneous anomalies, and early onset osteoarthritis . Smooth muscle alpha-actin (ACTA2] mutations have been determined to be associated with aortic aneurysm and dissection in some families .
Non genetic causes of aortic aneurysm are bicuspid aorta, coarctation of aorta, aortitis syndromes, systemic hypertension, and vasculitis.
Congenitally bicuspid aortic valve is the most common congenital anomaly, with a prevalence of 0.5 to 2 in 100 individuals. A bicuspid aortic valve with a fused commisure and an eccentric orifice accounts for the most common form of aortic stenosis. Bicuspid aortic valve patients have also variable degrees of aortic insufficiency and aortic aneurysm in addition to aortic stenosis (figure 6). Cystic medial necrosis has been reported in the aortic wall. Thereby, aortic aneurysm may lead to aortic dissection [52, 53]. Hope et al determined that four-dimensional flow MR imaging showed helical systolic flow in the ascending aorta of patients with bicuspid aortic, including those without aneurysm or aortic stenosis. They stated that identification and characterization of eccentric flow jets in these patients may help identify those at risk for development of ascending aortic aneurysm .
Coarctation of aorta occurs in 8% to 10% of all congenital heart defects. As many as 85% of patients with aortic coarctation patients have a bicuspid aortic valve. Aortic aneurysm can be seen in untreated coarctation of aorta patients, after balloon dilatation and after surgical treatment or infective endocarditis. Aneurysm formation at the site of the dilatation with balloon angioplasty markedly in different series, but in generally rare. In the earlier era of balloon angioplasty, the incidence of aneurysm was high due to over dilatation with balloon catheter but recent series showed that aneurysm incidence decreased after balloon angioplasty. The pathology in the aneurysms that were operated was tears through the intima and media of the aorta. Aneurysm of the aorta is rare but can be seen after surgical repair especially with patch aortoplasty. When discrete aneurysm was determined after surgical repair or balloon angioplasty, it should be followed closely with CT, MRI, or angiographic imaging. A discrete aneurysm can be treated by using a covered stent . Aortic aneurysms are less reported but may be rarely seen after bare stent implantation . Aortic aneurysm formation complicating aortic coarctation carries a risk of rupture with high mortality. Covered stents are a safe and effective treatment with low risk of complications for the treatment of coarctation associated with aortic wall aneurysm [57, 58, 59].
Tetralogy of Fallot occurs in 10 % of all congenital heart defects. Although tetralogy of Fallot include ventricular septal defect, overriding of aorta, and right ventricular outflow tract obstruction, it can present with a pulmonary atresia, absent pulmonary valve. Tetralogy of Fallot patients also have variable degrees of aortic dilatation; it sometimes leads to aortic aneurysm and dissection due to volume overload, abnormalities of tunica media, elastic fibers and collagen in the aortic wall . Histological abnormalities of aortic wall characterized by medial necrosis, fibrosis, and elastic fragmentation of the aortic root and ascending aorta lead to subsequent aortic root dilatation and aneurysm in patients with tetralogy of Fallot . Aortic aneurysm has also been described after aortic arch repair .
Aortic aneurysm can be seen in aortitis syndromes related to syphilis, inflammatory bowel disease, and vasculitic syndromes. The primary systemic vasculitis is a group of autoimmune conditions characterized by occlusion, stenosis or aneurysmal dilations secondary to inflammation [63, 64, 65]. Aortic aneurysm may also be related to infective endocarditis (figure 8) or septicemia [66, 67, 68, 69, 70, 71].
Aortic aneurysm has also been rarely described with Wiskott-Aldrich syndrome but real cause is not known .
Homosystinuria is an autosomal recessive metabolic disorder due to deficiency of cystathionin synthase which phenothpically resembles Marfan syndrome. Major cardiovascular complication of homosystinuria is premature atherosclerotic changes in the vascular system. Vitamin B6 and folic acid treatment helps reduce homocystein levels [73, 74].
Clinical presentation of aortic aneurysm depends on underlying disease, size, and location of aneurysm as well as presence of aortic dissection. Patients with aortic aneurysm related to genetic cause have specific phenotypical appearance such as having hypermobile joints, chest deformities, long and thin fingers, kyphoscoliosis, high palate, inguinal hernias, and/or aracnodactilia (Figure 1, 2). If patients have Marfan like appearance, family history should be sought. Decreased femoral pulsus, systolic ejection murmur in the aortic area can be detected during cardiac examination in patients with aortic aneurysm related to coarctation of the aorta or bicuspid aortic valve. Diastolic murmur can be heard secondary to aortic insufficiency or apical pansystolic murmur can be heard secondary to mitral valve insufficiency related to mitral valve prolapse. It is important to evaluate aortic dissection if presence of sharp chest and abdominal pain in patients who have aortic aneurysm.
Transthorasic and transesophageal echocardiographic evaluation is the first step evaluation for the aortic aneurysm. On transtorasic echocardiography, proximal ascending, thoracic aorta and proximal abdominal aorta can be visualized by using parasternal long axis, suprasternal views, and subcostal views. Echocardiographic evaluation can show mitral valve proplapse, aortic aneurysm, left ventricular and/or left atrial enlargement secondary to the mitral valve or aortic insufficiency, bicuspid aortic valve or coarctation of the aorta. 2D and colour-coded echocardiographic pictures from the parasternal long axis and apical four chamber view show mild aortic enlargement at the sinotubular junction, mitral valve prolapsus and mitral insufficiency in a 13-year-old patient with Marfan syndrome (figures 9, 10, 11, 12). Aortic aneurysm patients are also evaluated by transesopagheal echocardiography.
The other imaging modalities are cardiac catheterization, magnetic resonance imaging and computed tomography (figure 3, 4, 6, 7, 8). With the increasing availability of whole body imaging, the role of magnetic resonance imaging and multidetector computed tomography are increasing diagnostic modalities in patients with aortic aneurysm/dissection [75, 76, 77, 78].
Treatment of the cell cultures with dexamethasone induced remarkable up-regulation in the expression of tropoelastin, fibulin 1 and fibulin 4 encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFβ-R1 mutations .
Among children who have aortic aneurysm, timing of surgical treatment should be weighed against life expectancy, underlying disease, the size and location of aneurysm and presence of dissection. It has been showed that beta blocker and ACE inhibitor therapy delay aortic surgery in patients with aortic aneurysm related Marfan syndrome.
The indications of surgical treatment are aortic size over 5 cm, aneurysm growth rate exceeding 1 cm per year, progressive aortic insufficiency, and familial history of early aortic dissection for most of aortic aneurysm patients. However, since the risk of dissection is higher in Loeyz-Dietz syndrome, surgery is indicated even at lower diameters of the aorta.
In conclusion, aortic aneurysm is a rare but a lifethreatening condition in childhood. It is generally related to genetic hereditary syndromes. The patients who have predisposition to aortic aneurysm should be followed-up closely.
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