*Turner's syndrome*

It is a chromosomal abnormality in which the monosomy X is the most common (cariotipe 45, X0). The patients affected with Turner's syndrome present characteristic physical abnormalities such as short stature, webbed necks and sterility. There can be associated differents cardiovascular manifestations, as the coarctation of aorta, early ischemic cardiopathy, bicuspid aortic valve and TAA (up to 40 % of the cases). The incidence of aortic dissection in these patients is greater compared with the healthy population, six-times increased risk, with a median age of presentation of 31 years.

It is recommended to realize an initial imaging test to reject bicuspid aortic valve, coarctation of aorta and / or TAA. If the test is normal and there is no risk factors for aortic dissection it is enough to do an imaging test every 5-10 years. In the opposite case, annual controls are advised. Inthose patients with Turner´s syndrome who are planning the get pregnancy, an imaging test must be realized to determine the risk of aortic dissection.

#### *Autosomal dominant polycystic kidney disease*

Disease caused by a mutation in the genes PKD1 and PKD2. Its more frequent complication are the hemorrhages subaracnoideas due to the rupture of cerebral aneurysms. It is also associated with an increase in TAA and type-A aortic dissections.

#### *Beals's syndrome or congenital contractural arachnodactyly*

It is an autosomal dominantly inherited connective tissue disorder caused by a mutation in FBN2 gene. Although the clinical features can be similar to Marfan syndrome, multiple joint contractures (especially elbow, knee and finger joints), arachnodactyly, severe kyphoscoliosis, abnormal pinnae, muscular hypoplasia and crumpled ears in the absence of significant aortic root dilatation are characteristic of Beals syndrome and rarely found in Marfan syndrome.


syndrome.

*Turner's syndrome* 

Marfan syndrome.

*Ehlers-Danlos's syndrome vascular type or type IV Ehlers-Danlon´s syndrome* 

The majority of the deaths are due to vascular breaks.

increased risk, with a median age of presentation of 31 years.

associated with an increase in TAA and type-A aortic dissections.

*Beals's syndrome or congenital contractural arachnodactyly* 

*Autosomal dominant polycystic kidney disease* 

It is caused by mutations in the genes encoding the collagenous type 3 (COL3A1) with an autosomal dominant inheritance. It is characterized by vascular and visceral external fragility, which can lead to vascular and visceral spontaneous breaks or with minimal traumatisms. The cutaneous or articular hyperlaxity is less marked that in other subtypes.

It is recommended to carry out non invasive imaging tests because of the high risk of vascular break. It is unknown the usefulness of the aortic surgery in the repair of the not complicated TAA. In case of dissection or rupture, the urgent surgery is indicated, with specially attention to the vascular anastomosis because of the trend to the hemorrhage, vascular fragility and the difficulties in the tissue regeneration capacitiy in this

It is a chromosomal abnormality in which the monosomy X is the most common (cariotipe 45, X0). The patients affected with Turner's syndrome present characteristic physical abnormalities such as short stature, webbed necks and sterility. There can be associated differents cardiovascular manifestations, as the coarctation of aorta, early ischemic cardiopathy, bicuspid aortic valve and TAA (up to 40 % of the cases). The incidence of aortic dissection in these patients is greater compared with the healthy population, six-times

It is recommended to realize an initial imaging test to reject bicuspid aortic valve, coarctation of aorta and / or TAA. If the test is normal and there is no risk factors for aortic dissection it is enough to do an imaging test every 5-10 years. In the opposite case, annual controls are advised. Inthose patients with Turner´s syndrome who are planning the get

Disease caused by a mutation in the genes PKD1 and PKD2. Its more frequent complication are the hemorrhages subaracnoideas due to the rupture of cerebral aneurysms. It is also

It is an autosomal dominantly inherited connective tissue disorder caused by a mutation in FBN2 gene. Although the clinical features can be similar to Marfan syndrome, multiple joint contractures (especially elbow, knee and finger joints), arachnodactyly, severe kyphoscoliosis, abnormal pinnae, muscular hypoplasia and crumpled ears in the absence of significant aortic root dilatation are characteristic of Beals syndrome and rarely found in

pregnancy, an imaging test must be realized to determine the risk of aortic dissection.

**Table 6.** Familial non syndromic thoracic aortic aneurysm syndromes (*see text*)

The majority of the familial TAA and aortic dissections are produced in patients who cannot be fitted in any of the syndromes described before. The studies of family aggregation suggest that between 11 and 19 % of the patients with TAA or dissections present a first degree relative with this antecedent.

In general, the presentation of aoritc complications (rupture and/or dissection) in patients with familial non syndromics TAA occur at earlier ages in comparison with the sporadic aneurysms (median age of 56,8 years opposite to 64,3 years), though without reaching the precociousness of the syndromics TAA. The aortic dilatation can concern both the tubular portion of the ascending aorta and sinus of Valsalva. The age of appearance and the growth rate are very changeable, event inside the components of a same family.

From a genetic point of view, the familial non syndromic TAA are very heterogeneous, having been located up to 7 different loci, that can explain only 20% of the cases: TAAD1, TAAD2, TAAD3, TAAD4, TAAD5, FAA1 and TAAD-partner to persistent arterial ductus (table 6). The way of inheritance is autosomal dominant with incomplete penetrance, minor in the female sex.

In patients with familial non syndromic TAA it is necessary to realize an individualized genetic advine to the relatives. It is necessary to realize a genetic analysis to the first degree relatives in case of a known mutation in the index case. In the first degree relatives with a negative genetic study, it is recommended an unique imaging test to reject aortic pathology. In case of presenting any of the genetic mutations described mutations, periodic reviews must be made every 2 years approximately.

#### **2.3. Genetics of Marfan's syndrome**

Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1 and, occasionally, by mutations in *TGFβR1* or *TGFβR2* genes (transforming growth factor-β receptor 1 and 2) located on chromosome 9 and on chromosome 3p24.2-p25, respectively [5]. More than 500 fibrillin gene mutations have been identified. Almost all of these mutations are unique to an affected individual or family. Different fibrillin mutations are responsible for genetic heterogeneity. Phenotypic variability in the presence of the same fibrillin mutation suggests the importance of other, yet-to-beidentified factors that affect the phenotype.

#### *Fibrillin-1 (FBN1) gene*

The fibrillin-1 gene consists of 65 exones and it is located in the chromosome 15q-21.1. It encodes for the glycoprotein fibrillin, which is a major building block of microfibrils that constitute the structural components of the suspensory ligament of the lens and serve as substrates for elastina in the aorta and other connective tissues.

The FBN1 gene is characterized for having several rich sequences in cysteine, comparable to the factor of epidermal growth (EGF). 47 exones codify a complete domain EGF and 43 of these include the sequence consensus for the union to the calcium *Asp/Asn-x-Asp/Asn-* *Glu/Gln-xm-Asp/Asn\*-xn-Tyr/Phe* (where x represents any amino acid, \* it represents possible beta-hydroxylation of this residue and "m" y "n" represent a variable number of residues). Each of the EGF-similar contains six residues highly preserved of cysteine that form three disulfide bonds between C1 and C3, between C2 and C4 and between C5 and C6, resulting in a structure of βeta strand what is involved in the union to the calcium. Calcium plays a very important role in the stability of the domain and awards a major resistance to the proteolytic degradation.

436 Aneurysm

degree relative with this antecedent.

must be made every 2 years approximately.

**2.3. Genetics of Marfan's syndrome** 

identified factors that affect the phenotype.

substrates for elastina in the aorta and other connective tissues.

*Fibrillin-1 (FBN1) gene*

in the female sex.

The majority of the familial TAA and aortic dissections are produced in patients who cannot be fitted in any of the syndromes described before. The studies of family aggregation suggest that between 11 and 19 % of the patients with TAA or dissections present a first

In general, the presentation of aoritc complications (rupture and/or dissection) in patients with familial non syndromics TAA occur at earlier ages in comparison with the sporadic aneurysms (median age of 56,8 years opposite to 64,3 years), though without reaching the precociousness of the syndromics TAA. The aortic dilatation can concern both the tubular portion of the ascending aorta and sinus of Valsalva. The age of appearance and the growth

From a genetic point of view, the familial non syndromic TAA are very heterogeneous, having been located up to 7 different loci, that can explain only 20% of the cases: TAAD1, TAAD2, TAAD3, TAAD4, TAAD5, FAA1 and TAAD-partner to persistent arterial ductus (table 6). The way of inheritance is autosomal dominant with incomplete penetrance, minor

In patients with familial non syndromic TAA it is necessary to realize an individualized genetic advine to the relatives. It is necessary to realize a genetic analysis to the first degree relatives in case of a known mutation in the index case. In the first degree relatives with a negative genetic study, it is recommended an unique imaging test to reject aortic pathology. In case of presenting any of the genetic mutations described mutations, periodic reviews

Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1 and, occasionally, by mutations in *TGFβR1* or *TGFβR2* genes (transforming growth factor-β receptor 1 and 2) located on chromosome 9 and on chromosome 3p24.2-p25, respectively [5]. More than 500 fibrillin gene mutations have been identified. Almost all of these mutations are unique to an affected individual or family. Different fibrillin mutations are responsible for genetic heterogeneity. Phenotypic variability in the presence of the same fibrillin mutation suggests the importance of other, yet-to-be-

The fibrillin-1 gene consists of 65 exones and it is located in the chromosome 15q-21.1. It encodes for the glycoprotein fibrillin, which is a major building block of microfibrils that constitute the structural components of the suspensory ligament of the lens and serve as

The FBN1 gene is characterized for having several rich sequences in cysteine, comparable to the factor of epidermal growth (EGF). 47 exones codify a complete domain EGF and 43 of these include the sequence consensus for the union to the calcium *Asp/Asn-x-Asp/Asn-*

rate are very changeable, event inside the components of a same family.

Nowadays, several strategies can be used in the genetic study of the FBN1 gene, being the reference the direct sequentiation of the exones and the border intron regions. Another method is the high-performance denaturing liquid chromatography liquid, with later confirmation for direct sequentiation. When a mutation is not identified and there is a high clinical suspicion of the presence of the disease, there can be looked big deletion/duplication, impossible to detect for the previous methods, using MLPA (multiplex ligation-dependent probe amplification). Finally, the analysis of genetic linkage can be used to determine if an individual has inherited an allele of the FBN1 gene that is associated with the syndrome in several members of the family, nevertheless its cost and efficiency are limited compared by the sequencing technique.

In order to consider the identified mutation as responsible, the following criteria must be evaluated:

	- a. Certain mutations have a high probability of being pathogenic:
		- *Nonsense mutation*, that creates a premature stop codon
		- Insertion/deletion that concerns a number of bases that is not multiple of three, and consistently alters the reading, usually creating a premature stop codon
		- Mutation that affects the *splicing* of the sequence of reference or that alters to level of the cDNA/mRNA ("splice site mutations"); mechanism that forms a part of the mRNA maturation consisting of the elimination of the introns so that a codificant and without interruptions sequence is obtained, and it can be translated into protein.
		- *Missense* mutation that creates or replaces cysteine
		- *Missense* mutation that concerns a preserved residue of the consensus EGF sequence.
	- b. The mutation must concern a preserved residue in the evolution. It is considered that the amino acids that have not suffered changes along the evolutionary scale are important for the function of the same one.
	- c. For the demonstration of the pathogenic of a mutation, bioninformatic models can be used so that they can predict if the change that induces the mutation can carry deleterious effects or not in the protein.

The sensibility to find a mutation in a patient with MFS is high, varying between 76 and 93% in recent studies. It depends on several factors, as the age, the familial history or the method used for the genetic study.

Marfan syndrome is known as an autosomal dominant connective tissue disorder. Hereby, the risk that a son of an affected father has the disease is 50%. Approximately, 75% of the patients with MFS has one of his parents affected, and only in 25% the affected one presents a de novo mutation.

The penetration of the mutations in FBN1 is in general high, being considered to be near to 100%. It has been communicated exceptional cases of incomplete penetration. It is necessary to consider that many of the manifestations appear with the age.

Those patients with severe and progressive forms of the disease (called "The neonatal Marfan Syndrome") usually have mutations in the central part of the gene, between exons 24 and 32 of FBN1. Affected individuals are generally diagnosed at birth or shortly thereafter. Congestive heart failure associated with mitral and tricuspid regurgitation is the main cause of death, whereas aortic diseection is uncommon; survival beyond 24 months is rare. As a general rule, the mutations that produce insertions or deletions with change or displacement of the frame of reading or *splice site mutations*, are usually associated to severer forms of the disease. The patients with mutations that alter the terminal-C-propeptide procesate have been related to predominantly skeletal affectations of the disease. It is evident that it is necessary to compile information about the clinical consequences and the phenotype associated with different mutations, since mutations with the same mechanism can have very different clinical consequences, as it is demonstrated in other genetic pathologies.

The diagnosis of the MFS can be realized without needing a genetic study. Nevertheless, it has a great importance in the following suppositions:


clearly demonstrated, and avoiding the pollution by mother DNA of the studied sample, in the cases in which the mother is affected.

5. In the preimplantational diagnosis in in-vitro fertilization treatments. The use for the prenatal and preimplantational diagnosis is controversial in many countries, with ethical and legal aspects that must be have in mind.
