Marfan syndrome and related connective tissue disorders in the current era in Switzerland in 103 patients: medical and surgical management and impact of genetic testing

DOI: https://doi.org/10.4414/smw.2020.20189

Introduction

Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene [1]. Over 1000 different mutations causing MFS and related disorders have been described so far [2, 3]. About 25% of the mutations are de-novo.

The mutations lead to a qualitative or quantitative lack of FBN1 protein, a 350 kDa glycoprotein that is a major component of elastin associated microfibrils in the extracellular matrix [4]. The structural change of FBN1 protein in MFS explains the resulting changes in elastin-containing tissue such as abnormalities of the eye (ectopia lentis), aorta, heart valves and, although partially, skeleton (dolichostenomelia, arachnodactyly, pectus deformity and joint laxity) [5].

There is a wide spectrum of clinical expression, ranging from severe neonatal MFS or fatal aortic dissection to milder forms without cardiovascular involvement. Cardiac problems include aortic dilatation, aortic dissection, aortic regurgitation, mitral valve prolapse and sudden cardiac death. Nowadays, MFS is diagnosed using the revised Ghent criteria of 2010 [6]. The most important differential diagnoses of MFS are shown in table 1. Frequently, other CTDs, including more aggressive Loeys-Dietz syndrome (LDS) and ACTA2 mutations can be identified by genetic testing only.

Before genetic testing became widely available, MFS was diagnosed solely on the basis of clinical findings (Ghent criteria). However, these clinical diagnostic criteria are imperfect. Genetic testing has much improved the diagnostic process over the last two decades. In this retrospective cohort study, we summarise clinical characteristics and findings from genetic testing in a multicentre cohort.

Materials and methods

Setting

The study was based on a retrospective chart review and data analysis between 2001 and 2013 at five large hospitals in the Canton of Zurich: University Hospital of Zurich (Department of Cardiology), University Children Hospital of Zurich (Divisions of Metabolism and Cardiology), Stadtspital Triemli (Department of Cardiology), Klinik Im Park (Cardiovascular Centre) and Kantonsspital Winterthur (Department of Cardiology).

The study was approved by the ethics review committee of the Canton of Zurich (KEK-ZH-Nr. 2013-0241).

Patients

Within the participating institutions all patients followed up in their dedicated programmes for Marfan syndrome, suspected Marfan syndrome or Marfan-like conditions were identified from their clinical databases. For the purpose of this study, the charts of all patients with a diagnosis of MFS were carefully reviewed. All patients had at least one echocardiographic examination or other imaging of the aorta, and at least one consultation at one of the study centres between 2001 and 2013.

Definitions

The aortic root was measured at the sinuses of Valsalva. In children and adolescents (2–18 years old), the root was measured in mm from inner edge to inner edge during diastole, thus excluding the thickness of aortic wall. In adults, the aortic root was measured in mm from leading edge to leading edge at end-diastole.

Aortic root ectasia is defined as a Z-score ≥2 in adults or ≥3 in children. The Z-scores were calculated using the nomograms for aortic root diameters by Gautier for the group aged <15 years and by Devereux for adults (age >15 years) [8, 9]. For the calculation of the Z-scores for the ascending aorta the formula according to Campens was used [8, 9].

In patients who underwent aortic root surgery, the preoperative diameters of the aorta were used as baseline, if available.

Diagnosis of Marfan syndrome

The diagnosis of MFS was defined as fulfilment the 2010 Ghent criteria [6]. These criteria include aortic dilatation, ocular involvement, systemic findings and results from genetic testing. Molecular genetic testing included analysis of FBN1 and MFS-related genes (see table 1) [6]. In the absence of a positive family history of MFS, a diagnosis of MFS can be confirmed in the following situations: (a) presence of aortic root aneurysm (aortic Z-score ≥2 above 20 years old or a Z-score ≥3 below 20 years) and ectopia lentis; (b) aortic root Z-score ≥2 above 20 years old or a Z-score ≥3 below 20 years and FBN1 mutation; (c) aortic root Z-score ≥2 above 20 years old or a Z-score ≥3 below 20 years and systemic involvement (systemic score ≥7); or (d) ectopia lentis and the presence of an FBN1 mutation known to cause an aortic phenotype [6].

In the presence of a positive family history for MFS (diagnosed in the index patients with the criteria mentioned above), the presence of only one of the following features confirms MFS: ectopia lentis OR aortic root aneurysm (aortic Z-score ≥2 above 20 years old or a Z-score ≥3 below 20 years) or aortic dissection OR a systemic involvement (systemic score ≥7) [6].

Genetic testing

DNA extraction from fibroblasts or ethylenediamine tetraacetic acid (EDTA)-anticoagulated whole blood samples, as well as exon-by-exon polymerase chain-reaction testing, denaturing high performance liquid chromatography (DHPLC) screening, and/or direct Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed as previously described [10–12].

Statistical analysis

Continuous variables are presented as mean and standard deviation or median with interquartilce range (IQR) as appropriate. Categorical variables are presented as percentages. For the analysis of Z-scores, average absolute deviation was used. Statistical comparisons of distribution between groups were made using the student t-tests. The analysis was performed using the SPSS standard statistical software.

Results

Patients

We identified a total of 103 patients from 62 distinct families. Of these, 96 (93%) had MFS, 7 (7%) LDS or another MFS-related CTD. Sixty-two patients (60%) of the cohort were newly diagnosed index patients, whereas 41 (40%) had a family member with an established diagnosis. Baseline patient characteristics are summarised in table 2.

Results of genetic testing

Genetic testing was performed in a total of 80/103 (78%) patients. In most of these patients, disease causing mutations in the FBN1 gene were found (69/80, 86%). One patient had a TGFBR1 (LDS1), three a TGFBR2 (LDS2), two a SMAD3 (LDS3) and one a TGFB2 mutation (LDS4) mutation. In four patients, three of whom fulfilled the Ghent criteria for MFS, no disease-causing mutations could be identified.

Clinical findings

The clinical findings are shown in tables 2 and 3 . Median age was 23 years (range 1–75) and 43/103 patients (42%) were under the age of 18 years.

In 40 patients (40/103, 39%) a systemic score of ≥7 was documented. Of the 96 patients with a definitive diagnosis of MFS, 38 (40%) had a systemic score of ≥7, 44 (46%) a systemic score of ≥6, 50 (52%) a systemic score of ≥5 and 59 (61%) a systemic score of ≥4.

Other features commonly seen included hypermobility of the joints in 28 (27%), leg length discrepancy in 10 (10%), arthralgia in 12 (12%) and varicose veins in 8 (8%) patients. Hypertelorism and a cleft palate were present in only one patient with LDS; a bifid uvula was present in four (4%) patients, three of them with LDS (LDS1 and LDS3) and one with MFS and a disease-causing mutation in the FBN1 gene. Twelve (12%) patients had a history of scoliosis surgery and prior foot surgery was reported by 7 (7%) patient; 12 (12%) patients had previous lensectomy.

Cardiovascular findings

The echocardiographic findings are summarised in table 4. Aortic root enlargement was found in 49 patients (49/103, 48%). Mitral valve prolapse was common (64/103 patients, 62%); however, severe mitral regurgitation was rare. Left ventricular ejection fraction was <50% in nine patients (9/103, 9%). There was no difference in echocardiographic findings between FBN1-positive patients and those with other CTDs (for each p-value see table 4).

Cardiac surgery

Cardiac surgery was performed in 34 patients (33%): 28 patients (27%) underwent aortic root surgery, 2 (2%) mitral valve surgery, (3%) combined aortic root and mitral valve surgery, and 1 (1%) combined aortic root and tricuspid valve surgery. Among patients undergoing aortic root surgery, 30 (30/31, 97%) had MFS and only 1 patient LDS. Fifty-eight percent (18/31) of the aortic root aneurysms were repaired using the valve-sparing Tirone David technique (in one patient combined with tricuspid valve repair), whereas 35% (11/31) received a composite graft (in two patients combined with mitral valve replacement and one another patient combined with mitral valve repair). One patient received an isolated replacement of the ascending aorta, one patient underwent isolated mitral valve replacement and another one mitral valve repair. In two patients, details about the exact surgical technique for aortic root treatment were not available.

Four out of five patients (80%) who underwent mitral valve surgery had genetically proven MFS. In 60% (3/5) of these patients, replacement of the valve was needed; 40% (2/5) were repaired.

One patient of the cohort needed an implantable cardioverter defibrillator (ICD) because of ventricular tachycardia and a positive family history for sudden cardiac death. Two more patients needed implantation of pacemaker owing to postoperative complete atrioventricular block.

All cardiac interventions are summarised in table 5.

Cardiovascular complications and death

Fourteen percent (14/103) of the cohort experienced an aortic dissection; in 10/14 (71%) patients it was a type A dissection, the others had type B aortic dissection. Overall, 93% of these patients (13/14) had MFS, only one patient had LDS.

Three patients died, all of whom had MFS. A 15-year-old girl died from a hypoxic brain injury after out-of-hospital resuscitation because of ventricular fibrillation and an epileptic storm. A 16-year-old boy died from high-grade osteosarcoma in the lateral left femoral condyle. A 45-year-old woman died from infectious complications (mediastinitis) after repeated complex surgeries for type A aortic dissection.

Medication

A total of 64% (66/103) of patients were under therapy with a beta-blocker, an angiotensin II receptor blocker (ARB) and/or an angiotensin converting-enzyme (ACE) inhibitor (more than one medication possible). Forty patients (39%) were on beta-blockers, 44 (43%) were on an ARB and 21 (20%) were on a combination of beta-blocker and ARB. Other medication included ACE inhibitors in 13 (13%) of patients. Nine percent of patients (9/103) were under treatment with a statin. Among the 37 patients not on any medication, we identified 5 adults with a Z-score >3.0.

Family history

Eleven patients (11%) had a family member who suffered or even died from aortic dissection, 26 (25%) patients had a relative with an aortic aneurysm, and 14 (14%) had a positive family history for sudden cardiac death.

Role of genetic testing for confirmation of diagnosis

A systemic score ≥7 (required to document systemic involvement according to the Ghent criteria) was found in only 40 patients (39%). Thus in 41 patients (41/103, 40%) a definitive diagnosis was achieved only with additional information from genetic testing.

Discussion

In our group of 103 patients with clinical suspicion of MFS, 69 were confirmed as having MFS by genetic testing and the 2010 Ghent criteria. In seven patients MFS-related LDS due to mutation in the genes TGFBR1 (LDS1), TGFBR2 (LDS2), SMAD3 (LDS3) or TGFB2 (LDS4) was identified by genetic testing. In 27 patients (26%), MFS was diagnosed on the basis of the Ghent criteria without genetic testing. In our cohort, genetic testing was quite frequent. In three patients fulfilling the revised Ghent criteria no mutation in any of the tested genes has yet been found. In a large number of affected patients, the diagnosis of MFS or a related disorder could be confirmed only by genetic testing in addition to clinical and echocardiographic examination. These results demonstrate the steadily growing impact of genetic testing in patients with suspected CTDs. Genetic testing often not only confirms the specific diagnosis, but may in many cases also has an impact on medical treatment and timing of life-saving aortic surgery.

The frequency and type of cardiovascular surgery in our cohort was comparable to other centres, with valve-sparing surgery used as often as possible [13, 14].

Medical therapy was used according to guidelines in 63% of patients [15, 16].

To date, over 200 heritable CTDs have been described, affecting various organ systems, including heart, blood vessels, bone, eyes, skin, joints and lungs [17]. Over the past few decades, many of the underlying molecular defects have been identified, including genes encoding for structural proteins (e.g., FBN1, COL1A1, COL3A1, COL5A1, BGN), modifying enzymes (e.g., ADAMTS2, PLOD1), or components of the transforming growth factor-beta (TGFβ)-signalling pathways (e.g., SKI, SMAD2/3, TGFBR1/2 and TGFB2/3). However, as of now these genes do not exclusively explain all causes of CTDs and thus many genes still await discovery [17]. In the majority of patients with clinical suspicion of MFS, mutations (disease-causing sequence variants) in FBN1 have been identified; however, mutations in the genes causing LDS (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3), one of the most important differential diagnosis of MFS, or in other aortopathy-related genes such as ACTA2, MYH11, MYLK, MAT2A, MFAP5 and PRKG1 have also been detected. In particular, patients with mutations in genes causing LDS can present with distinct and characteristic clinical phenotypes including hypertelorism and bifid uvula, both features not found in MFS. Patients with ACTA2 mutations often have livedo reticularis and iris flocculi. Such signs can help in the clinical differentiation. However, bifid uvula is not specific for LDS and has been found in other diseases such as cleft palate (e.g., SKI-related Shprintzen-Goldberg Syndrome) or phosphoglucomutase 1 (PGM1) deficiency, a disease not related to a CTD.

Some CTDs present with distinct clinical phenotypes, but many of them lead to overlapping clinical features despite the fact that they are have different genetic aetiologies. This is one explanation of why the clinical Ghent score is insufficient for a final diagnosis and illustrates the importance of molecular testing in the diagnosis of MFS and other CTDs. The frequency of genetic testing in this study was relatively high and comparable to the data published by Schoenhoff et al. from Berne [18], the largest MFS centre in Switzerland (76% in 2014), but considerably higher than those from the Mayo Clinic involving 59 patients with suspected MFS undergoing aortic root surgery from a similar time period, where genetic testing was performed in only 25% [13].

The criteria of the revised Ghent Marfan systemic score were published in 2010 [6]. A total score of at least 7 is considered essential in the diagnosis of MFS. However, as shown in our cohort, the majority of patients (61%) did not score 7 points. This might be because two of the clinical features, protrusio acetabuli and dural ectasia, can be found only radiologically and are thus not routinely assessed, although it is known that dural ectasia, for example, is present in 95% of children with MFS [19]. In addition, the specificity of dural ectasia has never been examined to the best of our knowledge. Therefore, in current practice the use of the 2010 Ghent criteria is only somewhat helpful as they include two criteria that cannot be commonly assessed.

Ectopia lentis, which is not present in LDS, is found in 62% of cases of MFS [20], but can also be an isolated finding not associated with MFS. In our cohort, ectopia lentis was present in only 28%, which is considerably less than reports in the current literature. To exclude glaucoma and cataracts in the MFS eye, patients should have an annual ophthalmological examination. In order to offer tailored treatment and clinical follow up, molecular genetic testing should be performed in all patients with suspected MFS or CTD.

Cardiac interventions

Cardiac surgery was needed in 33%, including aortic root surgery (30%) and mitral valve surgery (5%). Additionally, one patient needed an ICD. As expected, most of the cardiac procedures were on the aortic root. The most frequent surgical technique was the valve-sparing Tirone David procedure, which was comparable to other centres [13, 21, 22]. The thresholds used for intervention in the aortic root were 4.5–5.0 cm in adults with MFS (depending on family history); the thresholds may be lower if fast growth of the aortic root is observed or before planned pregnancy. In LDS, the threshold is 4.2 cm in adults and in children if the 99th percentile of the aortic root is exceeded and the aortic annulus surpasses 1.8–2.0cm [15, 16]. Lower thresholds are used depending on growth of the aorta, planned pregnancy or small size of the patient.

Benefits of the valve-sparing operation are that the patients keep their own aortic valve and that there is no need of lifelong anticoagulation, which is desirable especially in young women who wish to have a child. For 1-year survival there is no difference between the two techniques, but severe mitral regurgitation was observed more often after the valve-sparing surgery [21]. Currently, other surgical techniques such as PEARS (personalised external aortic root support) and the Florida sleeve operation play a negligible role in MFS patients [23, 24]. Another option would be to use an aortic bioprothesis with subsequent percutaneous aortic valve replacement if needed. There are limited data on percutaneous mitral valve reconstruction with MitraClip in MFS [25]. However, there are no data on the performance of percutaneous cardiac interventions on subsequent risk of aortic dissection in MFS. Long-term outcome data in MFS show that aortic surgery in other segments is quite frequent; even after elective aortic root replacement the risk of reintervention is more than 10% with about 15% of patients suffering from type B dissection over time. After type A dissection the risk of reintervention is 50% or higher [26–28].

Medical treatment

Overall, 64% of the patients in our cohort were on some form of cardiac medical treatment: 39% were treated with a beta-blocker, 43% with an ARB and 13% with an ACE inhibitor. These results are similar to recently published studies [13]. Of the 37 patients not on medication, 23 (62%) were <17 years old and the mean diameters were 3.1 ± 0.9 cm for the aortic root and 2.4 ± 0.7 cm for the ascending aorta. Of those >17 years of age, after excluding the patients who undergone Tirone David or composite graft procedures or having Z-score <2.0, we identified 5 patients with Z-score >3.0 not on medication,

Since 1994, when Shores and colleagues showed that treatment with beta-blockers in MFS patients slows aortic growth rate, beta-blockers belong to the standard of care in MFS patients with either aortic root dilatation and/or positive family history for aortic root dilatation and/or a mutation know to be associated with an aortic phenotype [29–32]. Therefore we anticipated a much higher percentage of patients under beta-blocker therapy. Our data show that patient education is important and should be a main focus in treatment of these patients.

Since ARB therapy has been shown in a MFS mouse model to have a protective effect on the aorta for aneurysms and dissection, its use has been widespread [33]. In 2014, Mueller et al. showed in a cohort of paediatric MFS patients that ARB and beta-blocker therapy both slow aortic root dilatation [34]. Losartan and beta-blockers such as atenolol seem to be equivalent [35]. The Taiwan Marfan trial and the compare trial both demonstrated that combined therapy with a beta-blocker and ARB was more effective than beta-blockers alone [36, 37]. Larger trials such as the Pediatric Heart Network randomised trial of atenolol versus losartan in children and young adults showed similar efficacy [38]. Therefore it is up to the treating clinician to choose a beta-blocker and/or ARB in patients with MFS; however, at least one of these medications should be used.

There are no data showing that ACE inhibitors are non-inferior to ARB or beta-blocker therapy; some studies have suggested less efficacy [39]. Calcium channel blockers are not routinely recommended in the treatment of MFS patients [40].

Other organ involvement

Regular orthopaedic assessment is strongly recommended as noncardiovascular procedures are often needed in MFS patients, including scoliosis surgery, foot surgery, herniotomy, lensectomy and pleurodesis after spontaneous pneumothorax. In our cohort, 12% of patients had back surgery with an incidence of scoliosis of 51%.

Study limitations

Assessment of dural ectasia with magnetic resonance imaging and hip radiography to assess protrusio acetabuli were not routinely performed without clinical indication. Therefore, the Ghent score was most likely underestimated. However, in clinical practice, dural ectasia and hip are not routinely assessed radiographically in most centres.

Clinical genetic testing has become more important to make or confirm the diagnosis, allowing the identification and counselling of at-risk relatives as well. However, the current ability to sequence is greater than the ability to interpret the detected sequence variants with diagnostic and lifetime value [41].

We retrospectively analysed a limited group of patients from cardiovascular centres without taking into account patients from orthopaedic and ophthalmology clinics. We do not know the impact of this limitation on our data. Besides, we cannot exclude an ascertainment bias and some patients supposed to have MFS were retrospectively found to have LDS. However, genetic testing was offered to all patients in this study group, so there was no bias in that regard. The selection criteria were such that we included only patients from the echocardiography database with an aortic root aneurysm or type A aortic dissection where analysis of the clinical reported showed at least one feature suggestive of a CTD. Therefore, the prevalence is falsely low.

It is a retrospective study from a relatively small cohort, thus the results have to be confirmed in larger studies. We are not aware of any patients in the five centres fulfilling the inclusion criteria who were not included and therefore this study fulfils the criteria in the STROBE statement [42].

Conclusion

This study shows that in our centres in Switzerland a high percentage of patients fulfilling the revised Ghent criteria for MFS undergo genetic testing, often leading to or confirming the diagnosis of MFS. Clinical evaluation in combination with genetic testing is by far superior to clinical evaluation alone.

Cardiac surgery was performed according to guidelines and most often for the dilated aortic root [15, 16]. This study did not analyse long-term outcome and cannot report the frequency of reintervention, which is considerable in this cohort.

Only 63% of the patients were under therapy with beta-blockers, ARBs and/or ACE inhibitors. Thus conservative management in MFS has to be improved, necessitating more time for physician/patient interaction.

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