Mutations In FBN1 Gene Research Articles

Mutation in Genes FBN1, AKT1, and LMNA: Marfan Syndrome, Proteus Syndrome, and Progeria Share Common Systemic Involvement

Genetic mutations are becoming more deleterious day by day. Mutations of Genes named FBN1, AKT1, LMNA result specific protein malfunction that in turn commonly cause Marfan syndrome, Proteus syndrome, and Progeria, respectively. Articles about these conditions have been reviewed in PubMed and Google scholar with a view to finding relevant clinical features. Precise keywords have been used in search for systemic involvement of FBN1, AKT1, and LMNA gene mutations. It has been found that Marfan syndrome, Proteus syndrome, and Progeria commonly affected musculo-skeletal system, cardiovascular system, eye, and nervous system. Not only all of them shared identical systemic involvement, but also caused several very specific anomalies in various parts of the body. In spite of having some individual signs and symptoms, the mutual manifestations were worth mentioning. Moreover, all the features of the mutations of all three responsible genes had been co-related and systemically mentioned in this review. There can be some mutual properties of the genes FBN1, AKT1, and LMNA or in their corresponding proteins that result in the same presentations. This study may progress vision of knowledge regarding risk factors, patho-physiology, and management of these conditions, and relation to other mutations.

Molecular mechanisms of inherited thoracic aortic disease - from gene variant to surgical aneurysm.

Aortic dissection is a catastrophic event that has a high mortality rate. Thoracic aortic aneurysms are the clinically silent precursor that confers an increased risk of acute aortic dissection. There are several gene mutations that have been identified in key structural and regulatory proteins within the aortic wall that predispose to thoracic aneurysm formation. The most common and well characterised of these is the FBN1 gene mutation that is known to cause Marfan syndrome. Others less well-known mutations include TGF-β1 and TGF-β2 receptor mutations that cause Loeys-Dietz syndrome, Col3A1 mutations causing Ehlers-Danlos Type 4 syndrome and Smad3 and-4, ACTA2 and MYHII mutations that cause familial thoracic aortic aneurysm and dissection. Despite the variation in the proteins affected by these genetic mutations, there is a unifying pathological end point of medial degeneration within the wall of the aorta characterised by vascular smooth muscle cell loss, fragmentation and loss of elastic fibers, and accumulation of proteoglycans and glycosaminoglycans within vascular smooth muscle cell-depleted areas of the aortic media. Our understanding of these mutations and their post-translational effects has led to a greater understanding of the pathophysiology that underlies thoracic aortic aneurysm formation. Despite this, there are still many unanswered questions regarding the molecular mechanisms. Further elucidation of the signalling pathways will help us identify targets that may be suitable modifiers to enhance treatment of this often fatal condition.

Fibrillin-1 gene mutations in left ventricular non-compaction cardiomyopathy

Left ventricular non-compaction cardiomyopathy (LVNC) is a unique cardiomyopathy with a current yield of about 30–40 % in identifying a causative gene mutation. A retrospective review of all patients with LVNC at our institution was performed and genetic testing was reviewed. Echocardiographic and cardiac magnetic resonance imaging was reviewed to corroborate the reported phenotype. We present a series of patients with LVNC dilated phenotype associated with fibrillin-1 gene mutations. Fifty-one patients were identified as having LVNC with reduced left ventricular function and/or left ventricular dilation. We retrospectively reviewed gene testing in this cohort when available and identified 5 patients (10 %) with an FBN1 gene mutation. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Derangements in fibrillin-1 may impact the compaction process resulting in LVNC. Although causation has not been proven by our report, it certainly raises interest in a possible mechanistic relationship between fibrillin-1 and LVNC given the increased prevalence of Marfan syndrome and fibrillin-1 gene mutations in this cohort.

Cardiac pathologies in Marfan syndrome do not correlate with specific type of mutation in FBN1 gene in childhood

Background: Marfan syndrome (MFS) is an inherited connective-tissue disorder classically caused by different mutations in FBN1 gene. In childhood specific type of mutation and its correlation with cardiac pathologies is deficient known. This study evaluates detailed mutation and association with cardiac pathology. After all we want to evaluate whether there is a need to differentiate between specific mutations concerning prognosis, follow-up and medical treatment.

Ventricular arrhythmia in patients with FBN1 gene mutations

Objectives: The frequency of and risk factors for ventricular arrhythmia are unknown in patients with FBN1 gene mutations.

Het syndroom van Marfan

Marfan syndrome is a genetic disorder of the connective tissue caused by mutations in FBN1 gene. There are approximately 2-3,000 Marfan patients in The Netherlands. It has a broad clinical spectrum with features in most organ systems. Aortic root aneurysm is the most important clinical problem in these patients as it is progressive and leads to dissection and rupture if untreated. Endocarditis prophylaxis is indicated in all Marfan patients with aortic root aneurysm and operated patients. Timely diagnosis and specialized patient care are essential for the prognosis of this disease.

Signes cliniques évocateurs d’un syndrome de Marfan chez l’enfant de moins de 10 ans

Diagnosing Marfan syndrome in young children is difficult because of the great variability of expression of the disease and because the phenotype evolves over the life course. The goal of this retrospective study was to describe the first clinical symptoms in children under 10 years of age with Marfan syndrome and to evaluate the pertinence of the new 2010 Ghent criteria in comparison with the 1996 criteria. Seventeen patients under 10 by the time of the first medical examination were included. All children had an FBN1 gene mutation that was secondarily demonstrated. Clinical data including ophthalmological, cardiac, and orthopaedic examinations obtained during the first medical examination were analyzed. The most frequent abnormalities encountered were high arched palate (82%), arachnodactyly (71%), and flatfoot (59%). Aortic aneurysm (47%) and ectopic lens (35%) were also seen at the time of diagnosis. According to the 2010 Ghent criteria, the diagnosis of Marfan syndrome could be obtained in 71% of patients after identification of the mutation of the FBN1 gene, whereas only 59% of patients were diagnosed using the older criteria. All organs can be affected during childhood. An early diagnosis is essential in order to set up specific management.

Impact of 2010 Ghent criteria and subgroups definition to optimize diagnosis, avoid aortic dissection and choose the right surgical timing in the experience of the Tor Vergata Marfan Centre registry

Purpose: Aim of this study was to verify how Marfan Syndrome (MFS) patients followed by our Centre were distributed in the different subgroups highlighted by new 2010 Ghent nosology: 3 in the presence of family history (FH), FH and aortic dilatation (Ao), FH e score system ≥7 (SS), FH and ectopia lentis (EL), 4 in the absence of family history (Ao e EL, Ao e SS, Ao e FBN1, EL e FBN1 mutation) and to define the impact of aortic root dilatation in the diagnosis of the syndrome to support a cardiac surgery department's management of a Marfan Diagnostic Centre. Methods: We reviewed clinical features of 500 subjects visited in our Centre from January 2008 to December 2012; 146 patients (74 men and 72 women) had MFS clinical diagnosis. The population included 29 children (age 40 y). All patients was submitted to echocardiographic exam and measurement of aortic root along the American Society of Echocardiography guidelines, genetic advice, orthopedic visit, eye and dental examination and pediatric counseling, the last for patients younger than 14 y. In all cases spine and hips X-ray were performed. Results: In presence of family history 78 patients (53%) were in FH and Ao subgroup, 8 patients (5,4%) in FH and SS and 3 (2%) in FH and EL. In 45 patients the was no FH and the diagnosis was possible for the concomitance of Ao and EL in 33 patients (22%), of Ao and SS in 20 (13%), in 2 cases (1,3%) for Ao and FBN1 mutation, and in 2 cases (1,3%) for EL and FBN1 gene mutation. Among the 78 patients with FH, 32 belong to one big kin family with high incidence of sudden cardiac death for dissection. Main characteristics in our population were aortic dilation with Z-score ≥2 in adults and ≥3 in children present in 133 (91%) patients, FH in 89 (61%), SS≥7 in 55 (37%), ectopia lentis in 36 (24%), the FBN1 mutation response was present in 31 (21%). Fifty-four patient (37%) underwent to cardiac surgery, 50 patient for aortic root replacement and 4 patients for mitral valve procedure. We had no deaths for aortic dissection in 4 years of observation. Conclusions: New 2010 Ghent Criteria allow an excellent clinical definition of MFS and a rapid diagnosis thanks the possibility to include patients in a specific subgroup. Aortic dilation was the main feature of our population. A clear diagnosis and a cardiac surgery vision of follow-up are crucial for an optimal management and surgical decision.

Systemic sclerosis sera affect fibrillin-1 deposition and focal adhesion molecule expression by dermal blood microvascular endothelial cells: Therapeutic implications of cyclophosphamide

Systemic sclerosis (SSc, scleroderma) is characterized by fibrosis of the skin and internal organs, autoantibodies and diffuse microangiopathy. In SSc, fibrillin-1 microfibrils are disorganized and unstable. Mutations in FBN1 gene and anti-fibrillin- 1 autoantibodies have also been reported in SSc patients. Fibrillin-1 microfibrils sequester in the extracellular matrix the latent form of the potent pro-fibrotic cytokine transforming growth factor-β (TGF-β). We herein report the effects of SSc sera on the deposition of fibrillin-1 and microfibril-associated glycoprotein-1 (MAGP-1) and the expression of focal adhesion molecules by dermal blood (B-MVECs) and lymphatic (Ly-MVECs) microvascular endothelial cells. Cells were challenged with sera from SSc patients, naive or under cyclophosphamide (CYC) treatment, and healthy controls. Fibrillin-1/MAGP-1 synthesis and deposition and the expression of αvβ3 integrin/ phosphorylated-FAK and vinculin/actin were evaluated by immunofluorescence and quantified by morphometric analysis. Fibrillin-1 and MAGP-1 co-localized in all experimental conditions, forming a honeycomb pattern in B-MVECs and a dense mesh of short segments in Ly-MVECs. In B-MVECs, fibrillin-1/MAGP-1 production and αvβ3 integrin expression significantly decreased upon challenge with sera from naive SSc patients compared with healthy controls. Vinculin was overexpressed in the cells exposed to the serum of naive patients with the diffuse form of SSc. B-MVECs challenged with sera from CYC-treated SSc patients showed fibrillin-1, αvβ3 integrin and vinculin levels comparable to those of controls. Ly-MVECs challenged with SSc sera did not differ from controls in the expression of any of the molecules assayed. Due to the critical role of fibrillin-1 in sequestering TGF-β in the extracellular matrix, its decreased deposition by B-MVECs challenged with SSc sera might contribute to dermal fibrosis. CYC treatment might limit fibrosis through the maintenance of physiologic fibrillin-1 synthesis and deposition by B-MVECs. CYC-induced normalization of αvβ3 integrin expression may restore effective interaction of endothelial cells with fibrillin. Since vinculin is necessary for angiogenesis, its normalization upon CYC treatment may contribute to restore the impaired angiogenesis found in SSc.

FBN1 gene mutation characteristics and clinical features for the prediction of mitral valve disease progression

Until today, FBN1 gene mutation characteristics were not compared with clinical features for the prediction of mitral valve disease progression. Therefore, we conducted a study of 116 patients (53 men, 63 women aged 33 ± 15 years) with a causative FBN1 gene mutation and ≤ moderate mitral valve regurgitation at baseline. During 7.4 ± 6.8 years 30 patients developed progression of mitral valve regurgitation ≥ 1 grade (primary endpoint), and 26 patients required mitral valve surgery (secondary endpoint). Cox regression analysis identified an association of atrial fibrillation (hazard ratio (HR)=2.703; 95% confidence interval (CI) 1.013-7.211; P=.047), left ventricular ejection fraction (HR=.970; 95%CI .944-.997; P=.032), indexed end-diastolic left ventricular diameter (HR=15.165; 95%CI 4.498-51.128; P<.001), indexed left atrial diameter (HR=1.107; 95%CI 1.045-1.173; P=.001), tricuspid valve prolapse (HR=2.599; 95%CI 1.243-5.437; P=.011), posterior leaflet prolapse (HR=1.075; 95%CI 1.023-1.130; P=.009), and posterior leaflet thickening (HR=3.368; 95%CI 1.265-8.968; P=.015) with progression of mitral valve disease, whereas none of the FBN1 gene mutation characteristics were associated with progression of mitral valve disease. However, Cox regression analysis identified a marginal relationship of FBN1 gene mutations located both in a transforming-growth-factor beta-binding protein-like (TGFb-BP) domain (HR=3.453; 95%CI .982-12.143; P=.053), and in the calcium-binding epidermal growth factor-like (cbEGF) domain (HR=2.909; 95%CI .957-8.848; P=.060) with mitral valve surgery, a finding that was corroborated by Kaplan-Meier analysis (P=.014; and P=.041, respectively). Clinical features were better predictors of mitral valve disease progression than FBN1 gene mutation characteristics.

Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1)

Purpose: The purpose of this paper is to describe ophthalmic findings in a family with isolated ectopia lentis (EL) caused by a specific FBN1 mutation.Methods: Detailed family histories and clinical data were recorded for six isolated EL patients of 11 family members. The ophthalmological and systematic examinations were performed on patients and unaffected members of the investigated family. The detailed ocular examinations included visual acuity, anterior chamber depth, pupil size, lens location, optometry, central corneal thickness, keratometry, slitlamp examination, fundus examination, axial length, ocular B-ultrasound, gonioscope checking, ultrasound biomicroscopy (UBM) and intraocular pressure (IOP; Goldmann applanation tonometer). Systematic examinations included the measurement of echocardiogram, height, arm span, skull, face, jaw, tooth, breast bone, spinal column, and skin. Genomic DNA was extracted using the phenol-chloroform extraction method for all subjects, and sequencing was carried out on an ABI Prism 3730 Genetic Analyzer.Results: A heterozygous mutation, c.184C>T (p.Arg62Cys) in exon 2 of FBN1 was identified in all affected members but was not found in any unaffected member of the family. Our study presented detailed clinical manifestations, including some novel ophthalmic findings, such as pupillary abnormality, different types of glaucoma, and progressive hyperopia.Conclusions: Ophthalmic findings and the p.Arg62Cys mutation of FBN1 gene were reported in a family with early-onset isolated ectopia lentis.

Recurrent N1173K mutation in FBN1 gene in a Chinese family with ectopia lentis

To study the disease-causing gene mutation in a Chinese family with ectopia lentis. The phenotype of each family member in a Chinese family with ectopia lentis was identified by detailed clinical examination. The inheritance mode in this family was ascertained by the pedigree analysis. Linkage analysis was performed by microsatellite markers on chromosome 15 and LOD Score was calculated by Mlink program. Gene mutations were detected by sequence analysis to the whole coding region and exon-intron boundaries of the candidate gene. A significant LOD score of 3.01 was obtained at D15S978 on chromosome 15q21.1, where FBN1 gene was located. A C3519G change in exon 29 of FBN1 gene, resulting in asparagine change to lysine at codon 1173, was detected by direct sequence analysis. This mutation was absent in the normal family members and 100 normal controls. Our results indicate that c.C3519G (p.N1173K) mutation in FBN1 gene is the underlying molecular pathogenesis of this family with ectopia lentis.

Villous Papillary Thyroid Carcinoma: a Variant Associated with Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant hereditary disorder of connective tissue associated with perturbations in transforming growth factor β (TGF-β) biology, most often due to mutations in FBN1 gene that encodes fibrillin-1. To our knowledge, there is no known association of MFS with thyroid carcinoma. We report a 46-year-old man with known history of MFS who developed an unusual histological variant of papillary thyroid carcinoma. The tumor exhibited a widely invasive florid papillary growth pattern with prominent long villous fronds. Immunohistochemical and molecular analysis revealed a BRAF(V600E) mutation, evidence of aggressive biomarker expression (positivity for HBME-1, cytokeratin 19, galectin-3 and cyclin D1, and loss of p27), and changes associated with TGF-β-related epithelial-to-mesenchymal transition with active phospho-SMAD signaling. We introduce a unique histological pattern of papillary thyroid carcinoma that is associated with MFS. The combination of BRAF(V600E) mutation in the setting of altered TGF-β signaling and weak connective tissue integrity associated with MFS may cooperate and possibly be responsible to form this unique villous morphology with epithelial-to-mesenchymal transition and invasive growth.

Novel de novo nonsense mutation of FBN1 gene in a patient with Marfan syndrome

Marfan syndrome is an autosomal-dominant disorder of the connective tissue that primarily involves the cardiovascular, ocular and skeletal systems (Judge and Dietz 2005). Mutations in FBN1 gene (which encodes a connective protein, fibrillin-1) are reported to be causal for this disease. Diagnosis is made on the basis of a set of clinical and genetic criteria that are termed the Ghent nosology (De Paepe et al. 1996). In the Ghent nosology, clinical features are assessed within seven body ‘systems’, to determine whether that system provides a major criterion, or only system involvement. Diagnosis of Marfan syndrome requires a major criterion in two systems and involvement of a third. To date, most of the reported mutations are missense mutations affecting the conserved cysteine residues or residues of the consensus sequence of calcium-binding epidermal growth factor (cbEGF)-like motifs (Faivre et al. 2008). Here we describe a case of Marfan syndrome in a patient who is a carrier of a novel de novo nonsense mutation in the FBN1 gene. Interestingly, the patient presented with only few clinical features of Marfan syndrome.

Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome

Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

Genotypic characterization of a Portuguese population of Marfan syndrome patients

IntroductionThe diagnosis of Marfan syndrome (MFS) depends on a multidisciplinary clinical evaluation. Molecular study to identify mutations in the FBN1 gene can establish a definitive diagnosis even with atypical or “incomplete” phenotypes and enable earlier diagnosis in asymptomatic patients. ObjectivesThe aim of the present work was to evaluate the frequency and type of FBN1 gene mutations in a population of Marfan syndrome patients referred to a tertiary care center with cardiothoracic surgery. MethodsOur sample included 30 individuals with MFS (from 14 families), evaluated in cardiology, rheumatology and ophthalmology consultations. In all patients, DNA was extracted from a peripheral blood sample and mutation screening of the entire coding sequence of the FBN1 gene was then performed, using the polymerase chain reaction. ResultsWe identified 12 different mutations in the 14 families studied. Of these, only two had been previously described in the literature, while the other 10 were found to be new mutations; 36% of patients carried a Missense mutation and 50% carried a mutation leading to a premature termination codon. ConclusionsTo the best of our knowledge this is the first genotypic description of Portuguese patients with MFS. In this study, we highlight the need for comprehensive clinical evaluation of these patients and the value of FBN1 mutation analysis in selected cases. By describing 10 new mutations, we have also helped broaden the spectrum of known FBN1 mutations associated with MFS.

Caracterização genotípica de uma população de doentes portugueses com síndrome de Marfan

Introduction The diagnosis of Marfan syndrome (MFS) depends on a multidisciplinary clinical evaluation. Molecular study to identify mutations in the FBN1 gene can establish a definitive diagnosis even with atypical or «incomplete» phenotypes and enable earlier diagnosis in asymptomatic patients. Objectives The aim of the present work was to evaluate the frequency and type of FBN1 gene mutations in a population of Marfan syndrome patients referred to a tertiary care center with cardiothoracic surgery. Methods Our sample included 30 individuals with MFS (from 14 families), evaluated in cardiology, rheumatology and ophthalmology consultations. In all patients, DNA was extracted from a peripheral blood sample and mutation screening of the entire coding sequence of the FBN1 gene was then performed, using the polymerase chain reaction. Results We identified 12 different mutations in the 14 families studied. Of these, only two had been previously described in the literature, while the other 10 were found to be new mutations; 36% of patients carried a missense mutation and 50% carried a mutation leading to a premature termination codon. Conclusions To the best of our knowledge this is the first genotypic description of Portuguese patients with MFS. In this study, we highlight the need for comprehensive clinical evaluation of these patients and the value of FBN1 mutation analysis in selected cases. By describing 10 new mutations, we have also helped broaden the spectrum of known FBN1 mutations associated with MFS.

Screening of FBN1 gene mutations in a family with Marfan syndrome

To identify FBN1 gene mutations in a Chinese family with Marfan syndrome. Four affected and two unaffected individuals in the family were recruited after informed consent. Five ml blood samples were drawn from each family member and genomic DNA was extracted. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of FBN1 gene. Polyphen program was used to predict the functional and structural changes of the mutant protein. We found all four affected individuals carried FBN1gene mutations, c.2261A > G (p.Y754C), in exon18 by sequence analysis, while two unaffected family members and 100 normal controls did not have this mutation. A PSIC score of 2.6 was acquired by Polyphen program analysis. Our study supports that FBN1 gene mutation, c.2261A > G (p.Y754C), is the underlying molecular pathogenesis of this family with Marfan syndrome. This mutation is identified for the first time in Chinese population.

Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome

Mutations in the human FBN1 gene cause Marfan syndrome, a complex disease affecting connective tissues but with a highly variable phenotype. To identify genes that might participate in epistatic interactions with FBN1, and could therefore explain the observed phenotypic variability, we have looked for genes that are co-expressed with Fbn1 in the mouse. Microarray expression data derived from a range of primary mouse cells and cell lines were analysed using the network analysis tool BioLayout Express(3D). A cluster of 205 genes, including Fbn1, were selectively expressed by mouse cell lines of different mesenchymal lineages and by mouse primary mesenchymal cells (preadipocytes, myoblasts, fibroblasts, osteoblasts). Promoter analysis of this gene set identified several candidate transcriptional regulators. Genes within this co-expressed cluster are candidate genetic modifiers for Marfan syndrome and for other connective tissue diseases.

314 Outcomes and prognosis in patient with TGFBR2 or FBN1 gene mutation

TGFBR2 mutations were recently recognized among patients with a Marfan-like phenotype and have been associated with poor cardiovascular prognosis (early deaths, aortic dissections or early surgery for thoracic ascending aorta aneurysm). Clinical features and outcomes were analysed in a group of 71 patients (including 22 children) with a TGFBR2 mutation. Patients were compared with age- and gender-matched patients harbouring the FBN1 mutation (FBN1 group n=243). The proportion of patients with aortic dilatation was similar in the TGFBR2 group and in the FBN1 group in both adults [74% vs. 76%] and children [86%vs. 86%] and aortic dilatation was very variable in both TGFBR2 and FBN1 groups. The incidence and average age of thoracic aortic surgery for aortic dissection or aortic dilatation were similar in the 2 groups (31% vs. 27% and 35±16 vs. 39±13 years, NS). Both the frequency and the age of occurrence of aortic dissection were similar in the TGFBR2 and the FBN1 groups for the ascending aorta [14% vs. 10%, p=0.26; 38±12 vs. 39±9 years, p=0.82] and for the descending aorta (3/71 vs. 8/243, p=0.72; 34±6 vs. 44±10 years, p=0.16). In contrast, aortic dilatation, dissection or sudden death was the index event leading to genetic diagnosis within the family in 65% of families with TGFBR2 mutations and only 32% in families with FBN1 mutations (p = 0.002). When these family members were included in the survival analysis, mortality was worse in TGFBR2 families than in FBN1 families (p= 0.017) whereas it was similar if only patients benefiting for preventive care (i.e. in whom the mutation had been identified) were included (p = 0.39). The wide clinical spectrum of patients with TGFBR2 gene mutations underscores the importance of molecular biology for early diagnosis. The prognosis of a patient depends on the clinical expression of the disease and not solely on the presence of a mutation in the TGFBR2 gene.