**2.1. Diagnostic criteria for Marfan´s syndrome**

The MFS was described by the first time in 1896 by Antoine-Bernard Marfan, and it was not until 1995 that it was included in the connective tissue diseases classification. In 1986 a group of experts established a set of clinical criteria for the diagnosis of MFS (Berlin nosology). Later, in 1996 [1], it suffered a modification, known as Ghent's nosology (table 1), in order to avoid the overdiagnosis and to facilitate the differentiation with other similar syndromes. These criteria have been used throughout the world for the diagnosis of the SM, with a high specificity, as mutations in the gene FBN1 had been detected in up to 97 % of the patients who assemble these criteria [2]. Nevertheless, it presents some limitations, such as not consider the dependence on the age for some clinical manifestations, preventing the diagnosis in children, or to include not specific clinical manifestations, or with a poorly established diagnostic value. These facts may involve the overdiagnosis of MFS in patients with ectopia lentis or mitral valve prolapse syndrome; or on the contrary they may restrict the diagnosis in patients with ectopia lentis and aortic dilatation without sufficient skeletal manifestations.



For the diagnosis of Marfan´s syndrome in patients without family history of the disease, there must be involved two organs / systems that assemble major criteria, and at least the affectation of a third organ / system. In patients with positive family history of this sybndrome, it is needed a major criteria, with information that suggest the affectation of a second system.

**Table 1.** Diagnostic criteria of Ghent´s nosology

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**2. Body** 

manifestations.

Skeletal

The Marfan syndrome (MFS) is an autosomal dominantly inherited disorder of connective tissue with multisystem involvement. It is caused by mutations in the *FBN1* gene on chromosome 15, which encodes a glycoprotein called fibrillin-1, a component of the extracellular matrix. Over 1700 mutations have been identified in the fibrillin-1 gene associated with MFS, other genes related with the disease have been discovered and other disease-related genes with phenotypes very similar to this clinical syndrome (which need a thorough differential diagnosis) have been also identified. Because connective tissue is found throughout the body, MS can affect many body systems, including the ocular, cardiovascular, skeletal, and pulmonary Systems, as well as the skin and dura mater. The most serious signs and symptoms associated with MS involve the cardiovascular system; the cardiac complications, particularly aortic dilatation, dissection and rupture and involvement

The MFS was described by the first time in 1896 by Antoine-Bernard Marfan, and it was not until 1995 that it was included in the connective tissue diseases classification. In 1986 a group of experts established a set of clinical criteria for the diagnosis of MFS (Berlin nosology). Later, in 1996 [1], it suffered a modification, known as Ghent's nosology (table 1), in order to avoid the overdiagnosis and to facilitate the differentiation with other similar syndromes. These criteria have been used throughout the world for the diagnosis of the SM, with a high specificity, as mutations in the gene FBN1 had been detected in up to 97 % of the patients who assemble these criteria [2]. Nevertheless, it presents some limitations, such as not consider the dependence on the age for some clinical manifestations, preventing the diagnosis in children, or to include not specific clinical manifestations, or with a poorly established diagnostic value. These facts may involve the overdiagnosis of MFS in patients with ectopia lentis or mitral valve prolapse syndrome; or on the contrary they may restrict the diagnosis in patients with ectopia lentis and aortic dilatation without sufficient skeletal

of the aortic and mitral valves, lead to a greatly reduced life expectancy.

**2.1. Diagnostic criteria for Marfan´s syndrome** 

Organ / System Requirements for the classification of

1. *Pectus carinatum* 

surgery

height

major criteria

At least four of the following ones:

3. Reduced upper segment / lower segment ratio, or increased armspan /

2. *Pectus excavatum* that needs

4. Thumb and wrist´s signs 5. Curvature of the spine (20◦) o

Requirements for the affectation of organs/systems

At least two findings for major criteria, or one of those and two of the following minor

1. Moderate severity pectus

2. Articular hypermobility 3. Marked arch palate, or dental agglomeration

criteria:

excavatum

In order to solve the limitations of Ghent's nosology, it has been proposed a review of this. A group of international experts in the diagnosis and the management of MFS summoned in Brussels by the National Marfan Foundation, published recently *"The revised Ghent nosology"* [3], based on the review of wide cohorts of patients, experts opinion and the available literature about the application of the classic criteria, the differential diagnosis of the MS and the solidity and limitations of the genetic study.

Among the most importants changes, a major value is granted for two cardinal findings of the MFS, the aneurysm/dissection of the root of the aorta and the ectopia lentis, being sufficient the combination of both to establish the diagnosis. The rest of ocular and cardiovascular manifestations, as well as the findings of other organs/systems, contribute to a systemic score that facilitates the diagnosis when the aortic disease is present but not the ectopia lentis (table 2).

A more relevant role is assigned to the genetic study of the gene FBN1 and other related genes (TGFBR1 and TGFBR2). Some of the less specific manifestations lose importance in the diagnostic evaluation.

The new criteria emphasize the need of diagnostic considerations and additional tests if patients assemble sufficient criteria for MS but show unexpected findings, especially because of the possibility of an alternative specific diagnosis. It is emphasized specially in Sphrintzen-Goldberg and of Loeys-Dietz syndromes, and in the vascular form of Ehlers-Danlos's syndrome.

The new diagnostic criteria have been defined for a sporadic index patients, or for a patient with positive family history (table 3).


Wrist AND thumb sign: 3 (wrist OR thumb sign: 1) *Pectus carinatum deformity:* 2 (*pectus excavatum* o chest asymmetry: 1) Hindfoot deformity: 2 (plain flat foot: 1) Pneumothorax: 2 Dural ectasia: 2 Protrusio acetabulae: 2 Reduced upper segment/lower segment and increased armspan/height: 1 Scoliosis of thoracolumbar kyphosis: 1 Reduced elbow extension 1 3 of 5 facial features: 1 (dolichocephaly, enophthalmos, downward slanting palpebral fissures, malar hypoplasia, retrognathia) Skin striae: 1 Myopia >3 diopters: 1 Mitral valve prolapse: 1

Maximum total 20 points; *score* ≥7 indicates systemic affectation.

**Table 2.** Systemic findings score

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genetic study.

ectopia lentis (table 2).

the diagnostic evaluation.

Danlos's syndrome.

cases:

MS.

with positive family history (table 3).

vascular form of Ehlers-Danlos's syndrome

genetic aortic aneurisma syndromes.

In order to solve the limitations of Ghent's nosology, it has been proposed a review of this. A group of international experts in the diagnosis and the management of MFS summoned in Brussels by the National Marfan Foundation, published recently *"The revised Ghent nosology"* [3], based on the review of wide cohorts of patients, experts opinion and the available literature about the application of the classic criteria, the differential diagnosis of the MS and the solidity and limitations of the

Among the most importants changes, a major value is granted for two cardinal findings of the MFS, the aneurysm/dissection of the root of the aorta and the ectopia lentis, being sufficient the combination of both to establish the diagnosis. The rest of ocular and cardiovascular manifestations, as well as the findings of other organs/systems, contribute to a systemic score that facilitates the diagnosis when the aortic disease is present but not the

A more relevant role is assigned to the genetic study of the gene FBN1 and other related genes (TGFBR1 and TGFBR2). Some of the less specific manifestations lose importance in

The new criteria emphasize the need of diagnostic considerations and additional tests if patients assemble sufficient criteria for MS but show unexpected findings, especially because of the possibility of an alternative specific diagnosis. It is emphasized specially in Sphrintzen-Goldberg and of Loeys-Dietz syndromes, and in the vascular form of Ehlers-

The new diagnostic criteria have been defined for a sporadic index patients, or for a patient

**In absence of any family history**, the diagnosis can be established in the following

1. The presence of aortic root dilatation or dissection (Z score ≥2, adjusted to age and body surface area) and ectopia lentis establish the diagnosis, independently of the presence of other systemic findings, except when these are indicative of other genetic syndromes of aortic aneurysm, as Sphrintzen-Goldberg and of Loeys-Dietz syndromes, and the

2. The presence of dilatation or dissection (Z-score ≥2) and the identification of a mutation

3. In presence of dilatation or dissection (Z-score ≥2) without ectopia lentis and ignorance of mutations of the FBN1 gene, diagnosis can be established when sufficient systemic findings exist (≥ 7 points); in this case, there must be excluded the possibility of other

4. In presence of ectopia lentis without aortic dilatation / dissection, the identification of mutations of the FBN1 gene associated with aortic disease allows the diagnosis of the

of the FBN1 gene is sufficient to establish the diagnosis of the MS.

 I**n the presence of family history**, the diagnosis can be established in the presence of ectopia lentis plus a systemic score ≥ 7 points, or the presence of aortic dilatation (Z ≥2 in adults ≥20 years, or Z ≥3 in individuals <20 years).

#### **In absence of family history for Marfan´s syndrome**

1. Ao (Z ≥2) and EL = MFSa

```
2. Ao (Z ≥2) and FBN1 mutation = SMF
```
3. Ao (Z ≥2) and systemic *score* (≥7 points) = SMFa

4. EL and FBN1 mutation identified in individuals with aortic aneurysm = SMF

• EL with or withour systemic score, without FBN1 mutation, or with FBN1 mutation not related to aortic aneurysm/dissection = ELS


#### **In the presence of family history**

5. EL and FH of MFS = MFS

6. Systemic score ≥7 points and FH of MFS = SMFa

7. Ao (Z ≥2 in > 20 years, Z ≥3 in < 20 years) and FH of MFS = MFSa

Ao: aortic diameter in Valsalva sinus (indicated by Z-score) or dissection; FBN1 mutation*:*  mutation in fibrillin 1 gene; EL: ectopia lentis; MASS: phenotype with myopia, mitral valve prolapse, bordering expansion of aortic root (Z<2), skin striae and skeletal findings; PVM: mitral valve prolapse; ELS: ectopia lentis syndrome; MFS: Marfan´s syndrome; VMPS: mitral valve prolapse syndrome; Z: Z-score.

a Warning: reject Shprintzen-Goldberg, Loeys-Dietz o vascular type Ehlers-Danlos syndromes, study of TGFBR1/2, COL3A1 mutations, and collagen biochemistry.

**Table 3.** The revised Ghent nosology for the Marfan Syndrome

In addition, there are considered two new situations in patients younger than 20-year-old. The first of them, the **"unspecific disorder of the connective tissue"** for the cases with insufficient systemic findings (<7 points) and/or bordering dimensions of the aortic root (Z <3), without mutation of the FBN1 gene. The second one, the **"MFS potential"** for the sporadic or family history cases with mutation of the FBN1 gene and aortic dimensions with Z<3 score.

In adults, three alternatives categories are defined: ecopia lentis syndrome (ELS), mitral valve prolapse syndrome (MVPS) and the phenotype MASS.

Finally, the experts' panel recognizes the difficulty for establishing MFS's diagnosis in certain patients due to the overlapping phenotype of diverse entities.

#### **2.2. Hereditary syndromes related to thoracic aorta aneurysms**

The thoracic aortic aneurysms (TAA) are a relatively frequent entity, being responsible for approximately 15,000 annual deaths in USA. Up to 20 % of the patients with TAA, a genetic substratum is detected [4].

The familial TAA are classified in syndromics (they appear with phenotypics manifestations to other levels) and non syndromics (they appear as an isolated manifestation but with family aggregation, suggesting a genetic substratum).

The MFS is the most important entity inside the familial syndromics TAA. It is necessary to establish the differential diagnosis between this one and others mixed connective tissue diseases with clinical manifestations and similar phenotypics features. The majority of these diseases (table 4) are monogenics and with a dominant autosomal inheritance.


**Table 4.** Differential diagnosis of Marfan's syndrome

Among the genetic syndromes that can be accompanied of TAA, we can emphasize:

### *MAAS phenotype (mitral valve, aorta, skin, skeletal)*

It is included inside the fibrilinopathies group, that is to say, diseases results from mutations in the FBN1 gene. It is characterized by the presence of myopathy, mitral valve prolapse, aortic dilatation (slight and not progressive) and alterations of the cutaneous and musculoskeletal system. At least two systems must be affected.

#### *Loeys-Dietz's syndrome*

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Z<3 score.

substratum is detected [4].

**Familial Syndromic Thoracic Aortic Aneurysm Syndromes**

**Familial Non Syndromic Thoracic Aortic Aneurysm** 

**Table 4.** Differential diagnosis of Marfan's syndrome

**Syndromes** 

In addition, there are considered two new situations in patients younger than 20-year-old. The first of them, the **"unspecific disorder of the connective tissue"** for the cases with insufficient systemic findings (<7 points) and/or bordering dimensions of the aortic root (Z <3), without mutation of the FBN1 gene. The second one, the **"MFS potential"** for the sporadic or family history cases with mutation of the FBN1 gene and aortic dimensions with

In adults, three alternatives categories are defined: ecopia lentis syndrome (ELS), mitral

Finally, the experts' panel recognizes the difficulty for establishing MFS's diagnosis in

The thoracic aortic aneurysms (TAA) are a relatively frequent entity, being responsible for approximately 15,000 annual deaths in USA. Up to 20 % of the patients with TAA, a genetic

The familial TAA are classified in syndromics (they appear with phenotypics manifestations to other levels) and non syndromics (they appear as an isolated manifestation but with

The MFS is the most important entity inside the familial syndromics TAA. It is necessary to establish the differential diagnosis between this one and others mixed connective tissue diseases with clinical manifestations and similar phenotypics features. The majority of these

**Non fibrilinopathies**

**Turner's syndrome Beals's syndrome Noonan's syndrome Alagille's syndrome** 

**Fibrinilopathies** 

**MASS phenotype** 

Bicuspid aortic valve

**Loeys-Dietz's syndrome** 

**Type IV Ehler-Danlos's syndrome** 

**Shprintzen-Goldberg's syndrome Weill-Marchesani's syndrome** 

**Autosomal dominant polycystic kidney disease** 

TAAD1, TAAD2, TAAD3, TAAD4, TAAD5, FAA1 and TAAD associated to ductus arterial persistent

diseases (table 4) are monogenics and with a dominant autosomal inheritance.

valve prolapse syndrome (MVPS) and the phenotype MASS.

family aggregation, suggesting a genetic substratum).

certain patients due to the overlapping phenotype of diverse entities.

**2.2. Hereditary syndromes related to thoracic aorta aneurysms** 

Autosomal dominant genetic syndrome caused by mutations in the genes encoding transforming growth factor β1 (TGFBR1) or 2 (TGFBR2). Two phenotypic variants can be currently distinguished (table 5).

The aortic aneurysms are very frequent, appearing in 98 % of the cases, at early ages, and they are characterized by a high risk of dissection and / or rupture, even with diameters <5 cm. Up to 53 % of the patients may develop aneurysms in other locations. In general way, it is accepted that those patients with more severe craniofacial manifestations present the most aggressive vascular disease.

Patients with this syndrome are recommended to realize a complete imaging study to evaluate the aorta in the moment of the diagnosis and every 6 months, to check the growth rate of the TAA. An annual craniothoracoabdominal magnetic resonance must be fullfilled for the detection of systemics vascular aneurysms.


**Table 5.** Variants of Loeys-Dietz's syndrome

The surgical repair of the TAA in patients with Loeys-Dietz's syndrome must be realized when the internal diameter overcomes 4,2 cm for transesophageal echocardiogram or the external diameter is major than 4,5 cm in a computerized tomography or magnetic resonance.

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

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. The majority of the deaths are due to vascular breaks.

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 syndrome.
