General criteria
Condition
In the absence of family history
(1) Ao (Z≥2) and EL = MFS
(2) Ao (Z≥2) and FBN1 = MFS
(3) Ao (Z≥2) and Syst (≥7pts) = MFSa
(4) EL and FBN1 with known Ao = MFS
In the presence of family history
(5) EL and FH of MFS (as defined above) = MFS
(6) Syst (≥7 pts) and FH of MFS (as defined above) = MFS*
(7) Ao (Z≥2 above 20 years old, ≥3 below 20 years old) + FH of MFS (as defined above) = MFS*
Others
EL with or without Syst and with an FBN1 not known with Ao or no FBN1= ELS
Ao (Z< 2) and Syst (≥5) without EL = MASS
MVP and Ao (Z<2) and Syst (<5) without EL = MVPS
Scoring of systemic features
Systemic features | Score |
|---|---|
Wrist and thumb sign (wrist or thumb sign) | 3 (1) |
Pectus carinatum deformity – (pectus excavatum or chest asymmetry ) | 3 (1) |
Hindfoot deformity (plain pes planus) | 2 (1) |
Pneumothorax | 2 |
Dural ectasia | 2 |
Protrusio acetabuli | 2 |
Reduced US/LS and increased arm/height and no severe scoliosis | 1 |
Scoliosis or thoracolumbar kyphosis | 1 |
Reduced elbow extension | 1 |
Facial features (3/5) (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) | 1 |
Skin striae | 1 |
Myopia >3 diopters | 1 |
Mitral valve prolapse (all types) | 1 |
Criteria for causal FBN1 mutation
Mutation | Conditions |
|---|---|
Segregation | Mutation previously shown to segregate in Marfan family |
De novo | De novo (with proven paternity and absence of disease in parents) mutation (one of the five following categories) |
Nonsense | Nonsense mutation |
Deletion/Insertion | In-frame and out-of-frame deletion/insertion |
Splice site mutation | Splice site mutations affecting canonical splice sequence or shown to alter splicing on mRNA/cDNA level |
Missense | Missense affecting/creating cysteine residues |
Missense affecting conserved residues of the EGF consensus sequence ((D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) with m and n representing variable number of residues; D aspartic acid, N asparagine, E glutamic acid, Q glutamine, Y tyrosine, F phenylalanine) | |
Other missense mutations: segregation in family if possible + absence in 400 ethnically matched control chromosomes, if no family history absence in 400 ethnically matched control chromosomes | |
Linkage | Linkage of haplotype for n ≥ 6 meioses to the FBN1 locus |
5.2.2 MFS: FBN1 and TGF-β Signaling Pathways (Fig. 5.1)
Fibrillin-1 regulates the TGF-β signaling pathway by interacting with latency-associated peptide (LAP), which is a protein derived from the N-terminal region of the TGF-β gene product and latent TGF-β-binding protein (LTBP) [10]. TGF-β interacts with LAP to form a complex termed small latent complex (SLC), which is bound by LTBP to form a larger complex called large latent complex (LLC) and then secreted to the extracellular matrix. Then, TGF-β remains in the extracellular matrix in an inactivated complex with LTBP and LAP, and this inactive complex regulates mediation of TGF-β signaling. Since fibrillin-1 interacts with LTBP and LAP to regulate the active level of TGF-β, its dysfunction results in activation of TGF-β signaling [11]. Therefore, it was initially thought that upregulation of TGF-β signaling occurred in canonical (SMAD-dependent) pathways. However, recent findings have shown changes in noncanonical (SMAD-independent) TGF-β pathways involving mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK)1/2, p38, and Jun N-terminal kinase (JNK). As a result, increased TGF-β signaling via both canonical and noncanonical pathways contributes to aortic lesion formation. As shown in the following sections, increased TGF-β signaling is also critical for pathogenic changes in other related genetic aortopathies.
Fig. 5.1
FBN1 and TGF-β signaling pathways. Fibrillin-1 regulates the TGF-β signaling pathway by associating with LLC, consisting of LTBP and SLC. Active, free TGF-β molecules (TGF-β1, TGF-β2, TGF-β3) will be released by protease cleavage of inactive SLC molecules bound to LAP. LLC large latent complex, SLC small latent complex, LAP latency-associated peptide, LTBP latent TGF-β-binding protein
5.2.3 FBN1 Mutations in MFS
In 1990, the genetic locus for MFS was mapped to chromosome 15 by linkage analysis [12]. Thereafter, the first fibrillin gene mutation was found in an MFS patient in 1991, and it was confirmed that mutations in the FBN1 gene on chromosome 15 are responsible for MFS [13]. Since then, more than 1500 FBN1 mutations have been identified in MFS patients. Several lines of evidence were also shown that many FBN1 mutant alleles cause MFS phenotypes through a dominant-negative effect [14], though there is a considerable number of patients with mutations resulting in haploinsufficiency due to gene deletion, splicing mutations, or nonsense mutations causing nonsense-mediated mRNA decay (NMD) [15] (Fig. 5.2). Therefore, decreased protein synthesis as well as the dominant-negative effect by the mutant protein is thought to be a pathogenic mechanism for MFS [16]. In addition, the function of fibrillin-1 was shown to be closely related to regulation of TGF-β signaling pathways, as noted in the previous section.
Fig. 5.2
NMD and haploinsufficiency. About 30 % of FBN1 mutations resulted in haploinsufficiency, while about 60 % of mutations resulted in qualitative changes of fibrillin-1 molecules and about 10 % of mutations resulted in splicing defect [4]
5.3 Loeys-Dietz Syndrome (LDS)
5.3.1 LDS and Related Disorders
Loeys-Dietz syndrome (LDS: OMIM #609192, #610168) is an autosomal dominant disorder with an aortic disease and widespread systemic involvement that shows both similarities and differences as compared with MFS [17]. LDS was originally described as a disorder with the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate, though a wide range of variable phenotypes associated with this disorder were recognized [18]. The syndrome was originally reported as that caused by mutations in the TGF-β receptor 1 and 2 genes (TGFBR1, TGFBR2), and diagnosis is confirmed by genotyping. Some patients have craniofacial involvement consisting of cleft palate, craniosynostosis, or hypertelorism, though those features do not appear in all. Bifid uvula may also be present in some, but not in all patients. Some reports have indicated that the natural history is characterized by aggressive arterial aneurysms, while some patients show milder aortic phenotypes.
Mutations in the TGFBR2 gene in patients with the type 2 variant of MFS, MFS without ocular involvement, were also reported [19]. Most LDS patients develop aortic root aneurysms, while a previous study showed that the mean age at death was 26 years old (range 0.5–47 years) and caused by such factors as thoracic aortic dissection, abdominal aortic dissection, and intracerebral bleeding [17]. Based on this, it is recognized that LDS patients tend to experience more aggressive vascular events. However, it is also known that LDS has a large variability of phenotypes including vascular lesions, since some affected patients show severe and rapid aortic events with typical craniofacial features, while others show mild aortic lesions without craniofacial or skeletal features.
5.3.2 LDS and Related Disorders: TGF-β Signalopathies (Fig. 5.3)
Most LDS patients demonstrate missense mutations in the serine/threonine kinase domain of the TGF-β receptors, suggesting loss of function in these molecules as the pathogenic mechanism. Also, there were several reports of dysregulation of TGF-β signaling. In histochemical studies, increased TGF-β and MAPK signaling in aortic lesions of affected patients as well as in Tgfbr2 knockout mice was found [20].
Fig. 5.3
TGF-β signalopathies. Several genes (FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3, and SKI) associated with Marfan and related disorders are indeed closely connected with the TGF-β signaling pathways. Changes in the signal regulatory function promote pathological progress of vessels. Also, genes for smooth muscle contractile proteins (ACTA2, MYH11, MYLK) were depicted
Recently, three additional genes were identified as responsible for LDS-like syndromic aortopathy: SMAD3, TGFB2, and TGFB3. SMAD3 mutations were initially described in relation to aneurysm-osteoarthritis syndrome [21], though some patients with an SMAD3 mutation do not show such prominent osteoarthritis. TGFB2 mutations have also been described in patients with mild systemic features of MFS or LDS [22, 23]. Very recently, TGFB3 mutations were also reported in patients with syndromic types of thoracic aortic aneurysms similar to those seen in MFS and LDS [24], though one patient with a de novo TGFB3 mutation showed MFS and LDS features with no evidence of vascular disease [25].
In most of these gene mutations, immunohistochemical staining reveals an increase of phosphorylated SMAD2 in aortic tissues, indicating that TGF-β signaling has been changed to increase the downstream molecules. Therefore, in addition to the receptors, intracellular signaling molecules as well as their ligands are now considered to be responsible for the common pathogenic changes toward MFS- or LDS-related phenotypic features. Nevertheless, it remains unknown how dysfunction or haploinsufficiency status of these molecules results in increased TGF-β signaling even if such a change causes loss of function. Although the precise mechanisms involved in these changes are uncertain, it is considered that negative feedback and noncanonical stimulus may lead to the increase in TGF-β signaling. Indeed, previous results showed that haploinsufficient Tgfbr2 mice as well as cranial neural crest cell-specific Tgfbr2-deficient mice recapitulate human phenotypes, such as aortic dilatations or craniofacial deformities, along with increased noncanonical (phosphorylated extracellular signal-regulated kinase) TGF-β signaling pathways [20, 26].
Shprintzen-Goldberg syndrome (SGS: OMIM 182212), which results in craniosynostosis, skeletal changes (arachnodactyly, camptodactyly, scoliosis, joint hypermobility), and aortic aneurysms, shows considerable phenotypic overlap with MFS and LDS, and affected patients have been found to have mutations in the v-ski avian sarcoma viral oncogene homolog gene, SKI [27]. The oncogene SKI encodes a protein that plays important roles in the negative feedback loop of the TGF-β signaling pathway. Therefore, not only signaling molecules but also molecules affecting the TGF-β signaling pathway, as well as possibly others, may play additional key roles in MFS- or LDS-like phenotypes including aortopathy.
Autosomal recessive cutis laxa type 1B and arterial tortuosity syndrome, two other rare recessive connective tissue disorders, were shown to have autosomal recessive gene mutations in EFEMP2 [28], which codes FBLN4 proteins. FBLN4 binds to LTBP1 and regulates the latency of TGF-β cytokine. Indeed, upregulated TGF-β signaling has been found in both fibroblasts of patients with FBLN4 mutations and of the aortic walls in Fbln-4 hypomorphic mice [28, 29].
5.4 Vascular Ehlers-Danlos Syndrome (vEDS)
5.4.1 vEDS and Gene
The vascular type of Ehlers-Danlos syndrome (vascular EDS, vEDS, type 4 EDS: OMIM #130050), caused by a defect of type III collagen (COL3A1) [30], is a disorder featuring cutaneous, skeletal, and vascular abnormalities, including vascular rupture and easy bruising, though affected individuals usually do not show skin hyperextensibility. Clinical features include rupture of the middle-sized arteries, the bowels, or the uterus. Therefore, general care and follow-up examinations are critical for management of vEDS patients upon the diagnosis, and determination of the COL3A1 mutation is critical for affected individuals and their family members. There is no evidence indicating that COL3A1 mutations change TGF-β pathway regulation, while it was reported that celiprolol can reduce the risk for vascular events in patients with vEDS [31].
5.4.2 EDS-Like Features and FLNA
It was also reported that EDS-like phenotypes are associated with FLNA mutations [32]. The FLNA gene encodes filamin A, an intermediate filament connecting the contractile apparatus of vascular smooth muscle cells to the cell membrane [33]. Also, filamin A has numerous interaction partners, including membrane receptors, signaling proteins, and transcription factors. FLNA mutations are well known to be associated with periventricular nodular heterotopias (OMIM #300049), though patients with those mutations may also exhibit aortic root dilatation, mitral valve disease, and joint hypermobility even without demonstrating periventricular nodular heterotopias.
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