[Show abstract][Hide abstract] ABSTRACT: Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high performance liquid chromatography (DHPLC), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90 bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole genome sequencing. This article is protected by copyright. All rights reserved
[Show abstract][Hide abstract] ABSTRACT: To determine the effect of losartan on aortic dilatation rate in adults with Marfan syndrome.
Randomised, controlled multicentre clinical trial.
Adult Marfan patients from the 4 Marfan centres in the Netherlands with a maximum of 1 aortic prosthesis were randomised to 100 mg losartan once daily or no additional losartan treatment. All patients continued their standard treatment, which consisted mainly of β-blockers. The primary outcome measure was a reduction in aortic dilatation rate. The secondary outcome measures were an increase in aortic volume and the incidence of the combined outcome measure: cardiovascular mortality, aortic dissection and aorta surgery. This trial was registered with the Dutch Trial Register (NTR1423).
233 patients were included. Absolute aortic diameters were measured at the beginning and at the end of the study. The aortic root dilatation rate after 3 years was significantly lower in patients in the losartan group than in those in the control group (0.77 mm/3 years (SD: 1.36) vs. 1.35 mm/3 years (SD: 1.55); p = 0.014). The dilatation rate in the trajectory beyond the aortic root was comparable in the two groups. There were no differences in the secondary outcome measures between the two groups. A subanalysis of patients with aortic root replacement surgery prior to inclusion in the study demonstrated that in this group losartan treatment led to a significant decrease in aortic arch dilatation rate versus standard treatment (0.50 mm/3 years (SD: 1.26) vs. 1.01 mm/3 years (1.31); p = 0.033).
In adult Marfan patients, losartan treatment reduces the aortic root dilatation rate. After aortic root surgery, losartan treatment reduces dilatation rate of the aortic arch.
Nederlands tijdschrift voor geneeskunde 01/2014; 158(2):A6845.
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular manifestations in patients with Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, dilatation of the left ventricle (LV) can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients with MFS with LV dilatation. 182 patients fulfilling the MFS criteria, without valvular abnormalities or previous aortic surgery, with a complete FBN1 analysis, were studied. FBN1 mutations were identified in over 81% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (LV end diastolic diameter corrected for age and body surface area >112%). FBN1-positive patients carrying a non-missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p<0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p<0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology.
[Show abstract][Hide abstract] ABSTRACT: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients.
In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated.
In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.
European Heart Journal 09/2013; · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Prevention of aortic dissection and sudden death in patients with Marfan syndrome (MFS) requires accurate diagnosis. MFS is diagnosed by the Ghent criteria, which are primarily based on clinical features of Caucasian MFS populations. We determined whether the Ghent criteria apply to Asian MFS populations. Methods and Results: In this multicenter study, we included 255 adult MFS patients according to the Ghent criteria of 2010. Patients were excluded if they were neither Caucasian nor Asian. The Asian MFS population (n=49) had a smaller body surface area (BSA: 1.8m² vs. 2.0m², P<0.001), a more severely affected aortic root (absolute aortic diameter: 42.9mm vs. 43.3mm, P=0.802; corrected for BSA: 24.9mm vs. 21.7mm, P<0.001; Z-score: 4.5 vs. 3.6, P=0.013), and more often a positive systemic score (75.5% vs. 60.0%, P=0.045), but less frequently ectopia lentis (24.5% vs. 48.1%, P=0.004) compared with the Caucasian population (n=206). Conclusions: The Ghent criteria do not necessarily apply to Asian MFS populations, resulting in a more severely affected cardiovascular system. This may be related to under diagnosis of MFS by multiple factors, including the use of Z-score, and genetic and racial differences. The Ghent criteria should be adapted for Asian populations in order to accurately diagnose MFS.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Patients with Marfan syndrome (MFS) are at risk for cardiovascular disease. Marfan associated mutations in the FBN1 gene lead to increased transforming growth factor-β (TGF-β) activation. The aim of this study was to investigate the role of plasma TGF-β as a biomarker for progressive aortic root dilatation and dissection. METHODS: Plasma TGF-β level and aortic root diameter by means of echocardiography were assessed in 99 MFS patients. After 38months of follow-up measurement of the aortic root was repeated and individual aortic root growth curves were constructed. Clinical events were evaluated. The primary composite endpoint was defined as aortic dissection and prophylactic aortic root replacement. RESULTS: TGF-β levels were higher in MFS patients as compared to healthy controls (109pg/ml versus 54pg/ml, p<0.001). Higher plasma TGF-β levels correlated with larger aortic root dimensions (r=0.26, p=0.027), previous aortic root surgery (161pg/ml versus 88pg/ml, p=0.007) and faster aortic root growth rate (r=0.42, p<0.001). During 38months of follow-up, 17 events were observed (four type B dissections and 13 aortic root replacements). Patients with TGF-β levels above 140pg/ml had a 6.5 times higher risk of experiencing the composite endpoint compared to patients with TGF-β levels below 140pg/ml (95% CI: 2.1 to 20.1, p=0.001) with 65% sensitivity and 78% specificity. CONCLUSION: Elevated TGF-β level in patients with Marfan syndrome is correlated with larger aortic root diameters and faster aortic root growth. Level of plasma TGF-β predicts cardiovascular events and might serve as a prognostic biomarker in MFS.
International journal of cardiology 04/2013; · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:Aortic sinus diameter dilatation expressed as a Z-score >2.0 is diagnostic in Marfan syndrome. In addition to the classic equation (Z1) for calculating Z-scores, two new equations were recently introduced (Z2 and Z3).Methods:We studied the effects of obesity, age, and the absolute cut point of 40 mm on these three equations in 2,674 echocardiographic measurements of 260 patients with Marfan syndrome.Results:Diameters ≥40 mm were associated with Z1 scores <2.0 in 109 measurements (11.0%; 35 patients), Z2 scores <2.0 in 37 measurements (3.8%; 13 patients), and Z3 scores <2.0 in 24 measurements (2.4%; 11 patients). Mean diameters increased after the 40th birthday: 42.0 (37.3-44.8 mm interquartile range) to 42.5 (39.0-45.0 mm interquartile range; P = not significant) and mean Z1 scores decreased from 3.60 to 2.17 (P < 0.01), whereas Z2 and Z3 scores tended to increase (Z2: 3.04-3.27; Z3: 3.39-3.55; P = not significant for both). Comparing Z-scores between patients with body mass index <25 kg/m² (group A) and those with body mass index ≥25 kg/m² (group B), median Z1 scores differed between groups (Z1 = 3.00 in group A, Z1 = 1.78 in group B; P = 0.012), whereas Z2 (Z2 = 2.82 in group A, Z2 = 2.47 in group B; P = 0.52) and Z3 scores (Z3 = 2.72 in group A, Z2 = 3.12 in group B; P = 0.32) did not.Conclusion:Z1 scores are inferior to Z2 and Z3 scores in Marfan syndrome. In particular, the Z3 score, correcting aortic sinus diameter for body height, seems excellent.Genet Med advance online publication 10 January 2013Genetics in Medicine (2013); doi:10.1038/gim.2012.172.
Genetics in medicine: official journal of the American College of Medical Genetics 01/2013; · 3.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant condition characterized by aneurysms throughout the arterial tree in combination with osteoarthritis. The objective of the present study was to evaluate progression rate of aortic dilation and surgical outcome in AOS patients. METHODS: All AOS patients are regularly monitored according to our clinical AOS protocol. Patients with at least two follow-up visits or who underwent aortic root surgery during follow-up were included in this cohort study. Clinical and surgical data were obtained from chart abstraction. RESULTS: We included 22 patients (aged 38 ± 15 years; 41% male) with the molecular diagnosis of AOS. Follow-up duration was 3.3 years (interquartile range, 1.6 to 5.1). In the 17 patients who were managed conservatively, aortic root diameter increased from 37.5 ± 5.1 mm at baseline to 40.3 ± 6.2 mm at follow-up (p = 0.008). Progression rate of aortic dilation was highest at the level of the sinus of Valsalva (2.5 ± 5.8 mm per year) and significantly correlated with the initial diameter (r = 0.603, p = 0.017). Ten patients successfully underwent valve-sparing aortic root replacement, 5 after previous watchful waiting. Mean preoperative aortic diameter was 46.6 ± 4.0 mm. The operations were not complicated by fragility of tissue. After a postoperative period of 2.8 years (interquartile range, 0.7 to 5.4), no mortality or reoperations had occurred, and all patients remained asymptomatic. CONCLUSIONS: Aneurysm growth in AOS patients can be fast and unpredictable, warranting extensive and frequent cardiovascular monitoring. Valve-sparing aortic root replacement is a safe and effective procedure for the management of aortic root aneurysms in AOS patients.
The Annals of thoracic surgery 08/2012; · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations.
AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis.
AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies.
We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005).
AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.
Journal of the American College of Cardiology 05/2012; 60(5):397-403. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene.
A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed.
Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome.
The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.
Journal of Medical Genetics 01/2012; 49(1):47-57. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.
Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.
In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.
PLoS ONE 01/2012; 7(3):e32963. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marfan syndrome (MFS) is an autosomal, dominantly inherited, connective tissue disorder usually caused by a mutation in the fibrillin-1 gene (FBN1). As fibrillin-1 is a component of the extracellular matrix of the myocardium, mutations in FBN1 may cause impairment of ventricular function. Furthermore, aortic elasticity is decreased in patients with MFS, which might also impair ventricular function. We assessed biventricular function and the influence of aortic elasticity in patients with MFS by means of cardiac MRI.
Cardiac magnetic resonance was performed in 144 patients with MFS without significant valvular dysfunction, previous cardiac surgery or previous aortic surgery. Biventricular diastolic and systolic volumes were measured, and ejection fractions were calculated. Flow wave velocity, a measurable derivative of aortic elasticity, was measured between the ascending aorta and the bifurcation. When compared to healthy controls (n = 19), left ventricular ejection fraction (LVEF) was impaired in patients with MFS (53% ± 7% vs 57% ± 4%, p < 0.005), as was right ventricular ejection fraction (RVEF) (51% ± 7% vs 56% ± 4%, p < 0.005). LVEF and RVEF were strongly correlated. (r = 0.7, p < 0.001). No significant differences were found between patients with β-blocker treatment and those without. There was no correlation between aortic elasticity as measured by flow wave velocity and LVEF.
Biventricular ejection fraction was impaired in patients with MFS, and the impairment was independent of aortic elasticity and β-blocker usage. There was also a strong correlation between LVEF and RVEF. Our findings suggest intrinsic myocardial dysfunction in patients with MFS. Clinical trial registration http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1423. Unique Identifier: NTR1423.
[Show abstract][Hide abstract] ABSTRACT: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for sudden cardiac death (SCD), and cardiac events during follow-up in predictively tested-not known to have a clinical diagnosis of HCM before the DNA test-carriers of a sarcomeric gene mutation and associations with age and gender to determine the best cardiological screening strategy.
One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed manifest HCM was <10% per person-year under the age of 40 years and >10% in older carriers, although numbers were small in carriers <15 years. Twenty-three percent of carriers, with and without manifest disease, had established risk factor(s) for SCD (no significant difference). During an average follow-up of 3.5 ± 1.7 years two carriers, both with manifest disease, died suddenly (0.13% per person-year). A high-risk status for SCD (≥2 risk factors and manifest HCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associated with a high-risk status for SCD.
Thirty percent of carriers had or developed manifest HCM after predictive DNA testing and risk factors for SCD were frequently present. Our data suggest that the SCD risk is low and risk stratification for SCD can be omitted in carriers without manifest disease and that frequency of cardiological evaluations can possibly be decreased in carriers between 15 and 40 years as long as hypertrophy is absent.
European Heart Journal 04/2011; 32(9):1161-70. · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.
[Show abstract][Hide abstract] ABSTRACT: Radonic T, de Witte P, Groenink M, de Bruin-Bon RACM, Timmermans J, Scholte AJH, van den Berg MP, Baars MJH, van Tintelen JP, Kempers M, Zwinderman AH, Mulder BJM. Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome. Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.
[Show abstract][Hide abstract] ABSTRACT: The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.
European journal of human genetics: EJHG 11/2010; 19(3):247-52. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Down syndrome is the most common chromosomal abnormality. A simultaneous occurrence with Marfan syndrome is extremely rare. We present a case of a 28-year-old female with Down syndrome and a mutation in the fibrillin-1 gene. The patient showed strikingly few manifestations of Marfan syndrome. Although variable expression is known to be present in Marfan syndrome, phenotypic expression of Marfan syndrome in our patient might be masked by the co-occurrence of Down syndrome. (Neth Heart J 2009;17:345-8.).
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 09/2009; 17(9):345-8. · 1.41 Impact Factor