Síndrome de Marfán / Marfan syndrome

El síndrome de Marfán constituye una enfermedad infrecuente de herencia autosómica dominante, con una incidencia de 2-3 casos por cada 10,000 personas. Es caracterizada por manifestaciones musculo-esqueléticas, cardiovasculares oftalmológicas y pulmonares. Se presentan dos pacientes con lazos familiares, diagnosticados en consulta especializada, con alteraciones somatoesqueléticas características, paladar ojival, signos odontológicos y complicaciones valvulares cardiacas. Se revisa la literatura actualizada y se indican pautas terapéuticas preventivas y de rehabilitación. Es una entidad clínica rara, de pronóstico incierto. Su diagnóstico oportuno prevé la detección de complicaciones que pueden ser invalidantes, a la vez que debe instaurarse un tratamiento precoz que incluya medidas de rehabilitación y posibilite una mejor calidad de vida del paciente para alcanzar una expectativa de vida satisfactoria(AU)

Marfan syndrome is a rare disease of autosomal dominant inheritance, with an incidence of 2-3 cases per 10,000 people. It is characterized by musculoskeletal, cardiovascular, ophthalmological and pulmonary manifestations. We report two patients with family ties, diagnosed in a specialized consultation, with characteristic somatoeskeletal alterations, high palate, dental signs and cardiac valve complications. The updated literature was reviewed and preventive and rehabilitative therapeutic guidelines were indicated. It is a rare clinical entity with uncertain prognosis. Its timely diagnosis foresees the detection of complications that can be invalidating, at the same time that an early treatment must be established that includes rehabilitation measures and allows better quality of life for the patient to achieve satisfactory life expectancy(AU)

Analysis of FBN1 gene mutations in two pedigrees affected with Marfan syndrome / 中华医学遗传学杂志

OBJECTIVE@#To detect mutations of fibrillin-1 (FBN1) gene in two pedigrees affected with Marfan syndrome (MFS).@*WETHODS@#Peripheral blood samples were collected from MFS patients and their healthy family members for extracting genomic DNA. All of the 65 exons of the FBN1 gene were analyzed by next-generation sequencing. PolyPhen-2 and SIFT was used to predict structural and functional changes in FBN1 protein.@*RESULTS@#Patients from both pedigrees presented ocular and skeletal manifestations suggestive of MFS. Two novel heterozygous mutations of the FBN1 gene, including c.1879C>T (p.R627C) in exon 16 and c.2584T>C (p.C862R) in exon 22, were identified. The same mutations were not found among unaffected members. By bioinformatic analysis, the mutations may affect the structure and function of the FBN1 protein.@*CONCLUSION@#The c.1879C>T and c.2584T>C mutations of the FBN1 gene probably account for the disease in the two pedigrees, respectively. Identification of the c.2584T>C has enriched the spectrum of FBN1 gene mutations.

Identification of a novel FBN1 variant in a pedigree affected with Marfan syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Marfan syndrome (MFS).@*METHODS@#Clinical data of the patients was collected. With genomic DNA extracted from peripheral blood samples, potential mutation was detected by targeted exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Targeted exome sequencing and Sanger sequencing revealed a missense c.649T to C(p.Trp217Arg) variant in the exon 7 of FBN1 gene, which was unreported previously. Bioinformatics analysis suggested that the variant can cause amino acid replacement and affect the structure and function of fibrillin-1.@*CONCLUSION@#A novel missense variant of the FBN1 gene was identified, which probably underlies the autosomal dominant MFS in this pedigree.

Detection of pathogenic mutations in Marfan syndrome by targeted next-generation semiconductor sequencing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect pathogenic mutations in Marfan syndrome (MFS) using an Ion Torrent Personal Genome Machine (PGM) and to validate the result of targeted next-generation semiconductor sequencing for the diagnosis of genetic disorders.</p><p><b>METHODS</b>Peripheral blood samples were collected from three MFS patients and a normal control with informed consent. Genomic DNA was isolated by standard method and then subjected to targeted sequencing using an Ion Ampliseq(TM) Inherited Disease Panel. Three multiplex PCR reactions were carried out to amplify the coding exons of 328 genes including FBN1, TGFBR1 and TGFBR2. DNA fragments from different samples were ligated with barcoded sequencing adaptors. Template preparation and emulsion PCR, and Ion Sphere Particles enrichment were carried out using an Ion One Touch system. The ion sphere particles were sequenced on a 318 chip using the PGM platform. Data from the PGM runs were processed using an Ion Torrent Suite 3.2 software to generate sequence reads. After sequence alignment and extraction of SNPs and indels, all the variants were filtered against dbSNP137. DNA sequences were visualized with an Integrated Genomics Viewer. The most likely disease-causing variants were analyzed by Sanger sequencing.</p><p><b>RESULTS</b>The PGM sequencing has yielded an output of 855.80 Mb, with a > 100 × median sequencing depth and a coverage of > 98% for the targeted regions in all the four samples. After data analysis and database filtering, one known missense mutation (p.E1811K) and two novel premature termination mutations (p.E2264X and p.L871FfsX23) in the FBN1 gene were identified in the three MFS patients. All mutations were verified by conventional Sanger sequencing.</p><p><b>CONCLUSION</b>Pathogenic FBN1 mutations have been identified in all patients with MFS, indicating that the targeted next-generation sequencing on the PGM sequencers can be applied for accurate and high-throughput testing of genetic disorders.</p>

Mutation analysis and prenatal diagnosis of FBN1 gene mutations for four patients with Marfan syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To screen for mutations of fibrillin-1 (FBN1) gene in 4 patients with Marfan syndrome in order to provide prenatal diagnosis and genetic counseling.</p><p><b>METHODS</b>Potential mutations of the FBN1 gene in the probands were detected with PCR and DNA sequencing. Subsequently, genomic DNA was extracted from amniotic fluid sampled between 18 to 20 weeks gestation. The mutations were confirmed with denaturing high-performance liquid chromatography - robust microsatellite instability (DHPLC-MSI) analysis with maternal DNA as reference. The products were further analyzed by direct sequencing and BLAST search of NCBI database.</p><p><b>RESULTS</b>An IVS46+1G>A substitution was identified in patient A at +1 position of intron 46 of the FBN1 gene. Two novel missense mutations were respectively discovered at positions +4453 of intron 35 in patient B (Cys1485Gly) and position +2585 of intron 21 in patient C (Cys862Tyr). In patient D, a novel deletion (c.3536 delA) was found at position +3536 of intron 28. In all of the 4 cases, the same mutations have been identified in the fetuses.</p><p><b>CONCLUSION</b>FBN1 gene analysis can provide accurate diagnosis of Marfan syndrome, which can facilitate both prenatal diagnosis and genetic counseling.</p>

Molecular analysis for diagnosis of Marfan syndrome and Marfan-associated disorders / 中华医学杂志(英文版)

Marfan syndrome is a systemic disorder of connective tissue, caused by mutations in the FBN1, TGFBR1 or TGFBR2 genes. This syndrome is characterized by involvement of three major systems, skeletal, ocular, and cardiovascular. The continuing improvements in molecular biology and increasing availability of molecular diagnosis in clinical practice allow recognition of Marfan syndrome in patients with incomplete phenotypes. Additionally, molecular analyses could also be used for preimplantation genetic diagnosis. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening.

Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3' fibrillin-1 gene mutations with phenotype / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection.</p><p><b>METHODS</b>Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed.</p><p><b>RESULTS</b>We found a novel mutation (c.8547T > G, p.Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3' end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death.</p><p><b>CONCLUSIONS</b>These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.</p>

Genetic basis of systemic sclerosis / 中国医学科学院学报

Systemic sclerosis (SSc) is a connective tissue disease characterized by extensive fibrosis, vasculopathy, and activation of the immune system. Its pathogenesis and mechanisms have not been identified. Studies have shown that environmental and genetic factors are involved in the pathogenesis and development of SSc. Although the concordance for the disease among identical twins is low, concordance for antoantibodies associated with SSc and for fibroblast gene expression profiles is higher. However, the candidate-gene approach has not established clear associations between polymorphisms and SSc. Based on the involvement of SSc, the candidate gene can be screened from three groups: fibrosis, immune response, and vascular disease. This article summarizes the recent advances in these three aspects.

The expression of fibrillin 1 in pathologic scars and its significance / 中华整形外科杂志

<p><b>OBJECTIVE</b>To probe into the mechanism of fibrillin 1 in pathologic scar, by examining the expressions of fibrillin 1 and TGF-beta1 as well as their correlations in the tissues of keloid, hypertrophic scar and normal skin.</p><p><b>METHODS</b>The tissues of keloid, hypertrophic scar and normal skin were tested. RT-PCR was used to assess the mRNA expression levels of the aimed genes. The distribution of fibrillin 1 in scars and normal skin was examined by immunohistochemistry staining.</p><p><b>RESULTS</b>The mRNA level of fibrillin 1 in keloid (0.802 +/- 0.116) was increased by 218.25% (P < 0.01) than that in normal skin (0.252 +/- 0.067). The expression of the gene in hypertrophic scar (0.628 +/- 0.144) was higher by 149.21% (while, P > 0.05) than that in normal skin. The expression of TGF-beta1 in keloid and hypertrophic scar were more than that in normal skin. The expression of fibrillin 1 was related to that of TGF-beta1 positively (r = 0.820, P < 0.01). Fibrillin 1 protein was stained positively in basic membranes, endothelial cells, fibroblasts and extracellular matrix of skin tissues. In dermal, the protein levels of fibrillin 1 in keloid (0.117 +/- 0.042) was decreased than those in normal skin (0.185 +/- 0.043) and hypertrophic scar (0.181 +/- 0.048), the inhibition rates were 36.76%, 35.36% respectively (both P < 0.01).</p><p><b>CONCLUSIONS</b>The expression of fibrillin 1 in keloid was changed and related to the expression of TGF-beta1 positively, which appears that fibrillin 1 was a cicatrix specific gene. Fibrillin 1 might play an important role in the formation of keloid.</p>

Expressions of fibrillin-1, elastin and matrix metalloproteinase-1 and -9 in chronic actinic dermatitis in elderly patients / 南方医科大学学报

<p><b>UNLABELLED</b>To investigate the expressions of fibrillin-1, elastin and matrix metalloproteinase-1 and -9 (MMP-1, 9) in chronic actinic dermatitis in elderly patients and explore the pathogenesis of the disease.</p><p><b>METHODS</b>Twenty-three patients with chronic actinic dermatitis were examined for the expressions of fibrillin-1, elastin, MMP-1, and MMP-9 with immunohistochemistry in the skin lesions. Image analysis was carried out to measure MMP-1 and MMP-9 expressions semi-quantitatively.</p><p><b>RESULTS</b>In the skin lesions of patients with chronic actinic dermatitis, elastin expression was obviously reduced or absent in the papillary dermis. The elastic fibers were disorderly arranged in the reticular dermis with local aggregation in some regions. Obvious fibrillin-1 deposition was found in the reticular dermis. Increased expressions of MMP-1, but not that of MMP-9, was found in the skin lesions of the patients.</p><p><b>CONCLUSION</b>Elastin and fibrillin-1 deposition can be found in the skin lesions in patients with chronic actinic dermatitis, suggesting the association of increased MMP-1 expression with the elastic tissue degeneration in the lesions. MMP-9 does not exhibit an obvious association with the pathogenesis of chronic actinic dermatitis in elderly patients.</p>

Two gene mutations in fibrillin 1 of Marfan syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect novel mutations in the fibrillin 1 (FBN1) and transforming growth factor beta receptor type II (TGFBR2) genes by screening the genes from 14 patients with Marfan syndrome.</p><p><b>METHODS</b>Denaturing high performance liquid chromatography (DHPLC) was introduced to screen for FBN1 and TGFBR2 mutations exon-by-exon. The DNA amplification fragments which DHPLC elution profiles showed different from the corresponding normal elution profile were sequenced to identify the positions and types of mutations. Restriction fragment length polymorphism (RFLP) was employed to further prove the mutations when needed.</p><p><b>RESULTS</b>Two gene mutations of the FBN1 were found in the patients with Marfan syndrome. They were a novel substitutional mutation (Intron29 +4A > T) of FBN1 and a recurrent nonsense mutation (8080C >T) of FBN1.</p><p><b>CONCLUSION</b>Intron29 +4A > T and 8080C > T of FBN1 are possibly the pathogenesis of the MFS patients.</p>

Two novel mutations in fibrillin-1 gene of Marfan syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect novel mutations in the fibrillin-1(FBN1) gene by screening the gene from 9 patients with Marfan syndrome (MFS).</p><p><b>METHODS</b>Denaturing high-performance liquid chromatography (DHPLC) was used to screen for FBN1 mutation exon by exon. The DNA amplification fragments of which the DHPLC elution profiles showed difference in comparison with the corresponding normal elution profile were sequenced to identify the position and nature of mutation. The detected mutations were further proved by allele specific PCR or restriction fragment length polymorphism.</p><p><b>RESULTS</b>Two novel FBN1 gene mutations were found and identified in two Marfan patients respectively, one of which was a small insertion in exon 34 at nucleotide 4307-4308 (4307insTCGT) and the other a missense mutation in exon 43 at nucleotide 5309 (5309G>A).</p><p><b>CONCLUSION</b>The findings suggested that the frameshift mutation (4307insTCGT) and point mutation (5309G>A) caused the corresponding patients to have MFS.</p>

FBN1 mutation in Chinese patients with Marfan syndrome and its gene diagnosis using haplotype linkage analysis / 中华医学杂志(英文版)

<p><b>OBJECTIVES</b>To analyze the FBN1 mutations in Chinese patients with Marfan syndrome (MFS) and to make a genetic diagnosis based on haplotype linkage analysis for MFS.</p><p><b>METHODS</b>Nine MFS families (17 patients) were analyzed with single strand conformation polymorphism (SSCP) and sequencing. Four primers were designed for the flanking sequences of FBN1 gene and used for haplotype-segregation analysis of MFS(B).</p><p><b>RESULTS</b>SSCP band alteration was detected in the PCR products for exon 25 in MFS(A) II:1. Direct sequencing revealed a small 13 bp deletion; the deleted sequence is gccTc Tgcaccca at bases 3243-3456 of the cDNA in exon 25. This mutation was novel. MFS(B) families were analyzed using the haplotype linkage technique. The data suggested that MFS(B) families were linked to the FBN1 gene. The proband's daughter was an asymptomatic patient.</p><p><b>CONCLUSION</b>The combination of mutation detection and chromosome haplotype analysis can provide better evidence for a genetic diagnosis of MFS.</p>

Fibrillin-1 gene mutation in Chinese patients with Marfan syndrome and its gene diagnosis by haplotype analysis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze fibrillin-1 (FBN(1)) gene mutation in Chinese patients with Marfan syndrome(MFS) and to make a gene diagnosis by haplotype analysis for MFS.</p><p><b>METHODS</b>Nine MFS families were analysed with single strand conformation polymorphism(SSCP) and DNA sequencing. With the use of four primers designed in the flanking sequences of each short-sequence tandem-repeat region in FBN(1) gene, the haplotype-segregation analysis for MFS(B) was performed.</p><p><b>RESULTS</b>In MFS(A)II(1), PCR-SSCP detected SSCP band alterations in exon 25 of FBN(1) gene; direct sequencing showed a small 13bp deletion, the deleted sequence being gcctctgcaccca at base 3243-3456 of cDNA. This mutation caused a frame-shift which was never seen in any unaffected members of the family, and it was a heterozygous mutation; neither of them was identified in 100 chromosomes from 50 normal control individuals. Haplotype-segregation analysis suggested that the disease was passed from Subject I(2) to Subject II(2), Subject II(3), Subject II(5) with the same allele in MFS B family, the proband's daughter also inherited the allele. These data indicated that MFS(B) family was linked to FBN(1) gene, the proband's daughter was an asymptomatic patient.</p><p><b>CONCLUSION</b>The combination of mutation analysis and haplotype analysis can provide more evidence for gene diagnosis.</p>