Analysis of a child with Marfan syndrome due to a novel variant of FBN1 gene / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic testing for a child with Marfan syndrome (MFS) and explore its genotype-phenotype correlation.@*METHODS@#Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Functional impact of the variant was predicted by using bioinformatic software.@*RESULTS@#The child, a 13-year-old male, has featured Marfanoid habitus, with arm span exceeding his height, tapering fingers and toes, pectus excavatum and scoliosis, but absence of typical cardiovascular system diseases such as aortic dilation, thoracic-abdominal aortic aneurysm, mitral valve prolapse, and lens dislocation. The child has harbored a novel splice site variant c.7383_7413del (p. N2461Kfs*211) of the FBN1 gene, which was not found in his parents and younger brother. The variant was unreported previously.@*CONCLUSION@#The novel variant of p. N2461Kfs*211 of the FBN1 gene probably underlay the MFS in this child. Above finding has enriched the genotypic and phenotypic spectrum of MFS.

Clinical manifestations and genetic analysis of 4 patients with variants of FBN1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for four patients suspected for Marfan syndrome (MFS).@*METHODS@#Four male patients with suspected MFS and their family members who were treated at West China Second Hospital of Sichuan University from September 12, 2019 to March 27, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from the patients and their parents or other pedigree members for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were validated by Sanger sequencing. The pathogenicity of the variants was determined based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#Genetic testing revealed that all four patients have harbored variants of the FBN1 gene, including c.430_433del (p.His144fs) deletional variant in exon 5, c.493C>T (p.Arg165*) nonsense variant in exon 6, c.5304_5306del (p.Asp1768del) deletional variant in exon 44 and c.5165C>G (p.Ser1722Cys) missense variant in exon 42. According to the ACMG guidelines, the c.430_433del and c.493C>T were classified as pathogenic variants (PVS1+PM2_Supporting+PP4; PVS1+PS1+PS2+PM2_Supporting+PP4). c.5304_5306del and c.5165C>G were classified as likely pathogenic variants (PS2+PM2_Supporting+PM4+PP4; PS2_Moderate+PS1+PM1+PM2_Supporting).@*CONCLUSION@#The c.430_433del and c.5304_5306del variants of the FBN1 gene identified in this study were unreported previously. Above results have enriched the variation spectrum of the FBN1 gene and provided a basis for genetic counseling and prenatal diagnosis of patients with MFS and acromicric dysplasia.

A de novo mutation leading to Marfan syndrome in a case / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring unexplained rapid growth and heart malformation.@*METHODS@#Whole exome sequencing (WES)was carried out for the patient. Suspected variant was verified by Sanger sequencing and subjected to bioinformatic analysis.@*RESULTS@#The child was found to harbor a novel de novo c.5846_5848delATA (p. N1949del) variant in exon 48 of the FBN1 gene, which was predicted to be pathogenic by Mutation Taster. The patient was ultimately diagnosed with Marfan syndrome.@*CONCLUSION@#Above finding has enriched the spectrum of genetic variants associated with Marfan syndrome. WES has provided a powerful tool for the diagnosis of rare diseases.

Rotura de aneurisma de artéria poplítea em paciente clinicamente diagnosticado com síndrome de Marfan / Ruptured popliteal artery aneurysm in a patient with a clinical diagnosis of Marfan syndrome

Resumo A artéria poplítea é o principal local para a ocorrência de aneurismas periféricos. Suas formas de apresentação agudas são potencialmente ameaçadoras à viabilidade do membro e à vida, dentre as quais destacamos a sua rotura. Apesar de ser um evento raro, sua rotura demanda rápida proposta de intervenção para satisfatório desfecho terapêutico. O tratamento padrão-ouro é o cirúrgico convencional e se dá pela interposição de veia safena magna. Trabalhos feitos nas últimas décadas vêm encontrando associações entre a síndrome de Marfan e aneurismas periféricos. Este relato apresenta um caso de um aneurisma de artéria poplítea esquerda roto tratado com sucesso em um paciente de 82 anos diagnosticado clinicamente como portador de síndrome de Marfan previamente desconhecida.

Abstract The popliteal artery is the main site of occurrence of peripheral aneurysms. Acute presentations constitute a potential threat to limb viability and to life, especially in the event of rupture. Rupture is a rare event, but one that demands an immediate intervention decision to achieve a satisfactory treatment outcome. The gold standard treatment is conventional surgery, effecting repair by interposition of a great saphenous vein graft. Studies conducted in recent decades have found associations between Marfan Syndrome and peripheral aneurysms. This report presents a case of a ruptured left popliteal artery aneurysm successfully treated in an 82-year-old patient clinically diagnosed with previously unknown Marfan syndrome.

A c.3037G>A mutation in FBN1 gene causing Marfan syndrome with an atypically severe phenotype / Mutación c.3037G>A en el gen FBN1 causa sindrome de Marfan con fenotipo atípico severo

Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, mostly caused by mutations in the FBN1 gene, which is located on chromosome 15q21.1 and encoding fibrillin 1. We report a case of Marfan syndrome presen ting with severe ocular and systemic manifestations, such as cardiac congenital anomalies. The patient underwent a multidisciplinary approach and his clinical diagnosis was associated with a c.3037G>A mutation in the FBN1 gene. Identification of this genetic alteration should instigate a prompt multidisciplinary assessment and monitoring, in order to prevent devasta ting consequences such as cardiac and ocular phenotype. Molecular modeling of the mutation highlighted the importance of the preservation of the calcium-dependent structure of an epidermal-growth-factor-like domain of fibrillin-1 and consequently the microfibrillar formation process. This report aims to highlight the importance of an early clinical and molecular diagnosis and once more, the importance of the multidisciplinary approach of this genetic entity.

El síndrome de Marfan es una enfermedad pleitrópica del tejido conjuntivo que exhibe un patrón de herencia autosómico dominante, en su mayoría causado por mutacio nes en el gen FBN1 , que se encuentra en el cromosoma 15q21.1 y codifica a la fibrilina 1. Se presenta un caso de síndrome de Marfan que cursa con manifestación sistémica severa cardíaca y principlamente ocular. El paciente presentó una valoración multidisciplinaria y su diagnóstico clínico fue asociado con la mutación c.3037G>A en el gen FBN1 . La identificación de esta alteración genética debe promover una pronta evaluación y supervisión con el fin de evitar las desvastadoras consecuencias, tales como el fenotipo cardíaco y ocular. El modelado comparativo de proteínas resalta la importancia de la conservación de la estructura del dominio de la fibrilina-1 dependiente de calcio similar al factor de crecimiento epidérmico y por lo tanto el proceso de formación microfibrilar. Este informe tiene como objetivo resaltar la importancia de un diagnóstico clínico y molecular temprano y el enfoque multidisciplinariode esta entidad genética.

Disease-specific Growth Charts of Marfan Syndrome Patients in Korea

Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to lambda, mu, and sigma, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.

Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6 percent (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

Aneurismas de aorta torácica e dissecção aórtica / Thoracic aortic aneurysms and aortic dissection

Doença da aorta é uma patologia significante e representa a 12ª maior causa de morte. Apesar de os aneurismas da aorta abdominal e aorta ascendente serem mais comum, aneurismas de aorta ascedentes (AATs) são uma significante contribuição para a patologia. AATs aumentam o risco de dissecção da aorta ou ruptura e representam uma importante fonte de morbidade e mortalidade. Podem ser classificadas como sindrômicas, familiares ou esporádicas. As formas sindrômicas incluem a Síndrome de Marfan, Síndrome de Loeyes-Dietz, Homocistinúria, Sindrome de Ehlers-Danlos, Síndrome B A V e Síndrome de Turner. Em vários casos, já existem testes genéticos específicos que permitem um diagnóstico precoce da patologia em familiares de indivíduos afetados que permitem o acompanhamento precoce com melhora da qualidade de vida e sobrevida desses indivíduos.

Aortic disease is a significant pathology and represents the 12th leading cause of death. Although aneurysms of the ascending aorta and abdominal aorta are more common, descendents aortic aneurysms (TAAs) are a significant contribution to the pathology. TAAs increase the risk of aortic dissection or rupture and represent an important source of morbidity and mortality. They can be classified as syndromic, familial or sporadic. The syndromic forms include Marfan syndrome, Dietz-Loeyes Syndrome, homocystinuria, Ehlers-Danlos syndrome, Turner syndrome and BAV syndrome. In several cases, specific genetic tests are already available and allow an early diagnosis of pathology in relatives of affected individuals that can lead to an early monitoring and improve the quality of life and survival of these individuals.

Síndrome de Marfan: como fazer o diagnóstico e a investigação familiar? / Marfan Syndrome: how to make the diagnosis and the family investigation?

A Síndrome de Marfan é uma doença do tecido conjuntivo, de origem genética, autossômica dominante e que afeta principalemente três sistemas: esquelético, ocular e cardiovascular. Embora os dois primeiros acarretem graus significativos de morbidade como, por exemplo, a perda de visão, a mortalidade precoce desta síndrome se deve principalmente às complicações no sistema cardiovascular. A base molecular do efeito está numa mutação do gene da fibrilina, principal constituinte das microfibrilas. A prevalência da Síndrome de Marfan é estimada em torno de 1/10.000 indivíduos. As principais alterações cardiovasculares nas Síndromes de Marfan são: a dilatação progressiva e o aneurisma da aorta ascendente, com ruptura ou dissecção desta e o prolapso da válvula mitral com diversos graus de refluxo valvar. A descoberta de achados moleculares e sua correlação com o fenótipo deram origem aos critérios de GHENT. Recentemente, os critérios diagnósticos de GHENT foram reavaliados e consideraram que os mesmos mostram excelente especificidade. Decorrente das complicações cardiovasculares, a expectativa de vida nestes pacientes atingia poucos anos atrás até a terceira ou quarta década de vida. Nos últimos anos, porém, o prognóstico tem melhorado significativamente...

Marfan Syndrome is a connective tissue disease, genetic, autosomal dominant, which primarily affects three systems: skeletal, ocular and cardiovascular systems. Although the first two systems cause significant levels of morbidity, e.g., vision loss, the early mortality of this syndrome is mainly due to complications in the cardiovascular system. Molecular basis of the defect is a mutation of the fibrillin gene, major constituent of microfibrils. The prevalence of Marfan Syndrome is estimated at around 1/10.000 people.The main cardiovascular changes in Marfan Syndrome are progressive dilatation and ascending aortic aneurysm with rupture or dissection and mitral valve prolapse with varying degrees of valve regurgitation. The discovery of molecular findings and their correlation with the phenotype developed GHENT criteria. Recently, GHENT diagnostic criteria were reassessed and considered they demonstrated great specificity...

Marfan's syndrome: an overview / A síndrome de Marfan: uma revisão geral

Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder affects many parts of the body. The diagnosis of Marfan's syndrome is established in accordance with a review of the diagnostic criteria, known as the Ghent nosology, through a comprehensive assessment largely based on a combination of major and minor clinical manifestations in various organ systems and the family history. Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of Marfan's syndrome. The pathogenesis of Marfan's syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations. The treatment may include prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta, and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in Marfan's syndrome. The present article aims to provide an overview of this rare hereditary disorder.

Síndrome de Marfan é uma condição autossômica dominante com prevalência estimada de 1 em 10.000 a 20.000 indivíduos. É uma rara desordem hereditária do tecido conjuntivo que afeta muitas partes do corpo. O diagnóstico da síndrome de Marfan é feito de acordo com uma revisão dos critérios diagnósticos conhecida como a nosologia Ghent, por meio de uma avaliação abrangente, em grande parte baseada em uma combinação de pequenas e grandes manifestações clínicas em vários sistemas de órgãos e na história familiar. Dilatação da raiz aórtica e prolapso da valva mitral são as principais apresentações entre as malformações cardiovasculares da síndrome de Marfan. A patogênese da síndrome de Marfan não foi totalmente esclarecida, mas acredita-se que mutações genéticas de fibrillina-1 exercem um efeito negativo dominante. Portanto, a síndrome de Marfan é denominada como fibrilinopatia, juntamente com outras desordens do tecido conectivo, com sutis diferenças nas manifestações clínicas. O tratamento pode incluir β-bloqueadores profiláticos e bloqueadores dos receptores da angiotensina II, a fim de retardar a dilatação da aorta ascendente e cirurgia profilática da aorta. De importância, a terapia com β-bloqueadores pode reduzir a ativação de TGF-β, que foi reconhecido como um fator contribuinte da síndrome de Marfan. O presente artigo visa proporcionar uma visão global desta rara desordem de hereditariedade.

Novel CHD7 and FBN1 mutations in an infant with multiple congenital anamolies.

The first case of an infant with a dual genetic diagnosis of CHARGE and Marfan syndrome is reported here. The patient had multiple congenital anamolies, many of them consistent with CHARGE syndrome and genetic testing identified a heterozygous mutation c.3806_11del6insA in the CHD7 gene. In addition, his father had physical features consistent with Marfan syndrome. Fibrillin-1 (FBN1) mutation screening identified a heterozygous c.3990insC mutation in both father and the patient.

Aspectos clínicos y moleculares relevantes del síndrome de Marfan / Marfan's syndrome: relevant clinical and molecular aspects: knowledge obtained from the follow-up of one family throughout three consecutive generations

El síndrome de Marfan (SM) es un trastorno genético del tejido conectivo, autosómico dominante, que afecta principalmente los sistemas ocular , musculoesquelético y cardiovascular. Las complicaciones cardiovasculares son las principales causas de morbimortalidad. La patogenia del SM se debe a mutaciones en el gen de fibrilina 1 (FBN1) aunque actualmente emergen otros factores patogénicos de importancia. Los intentos de establecer correlaciones genotipo/fenotípicas han sido dificultosos por la gran variabilidad clínica de la enfermedad. El enfoque familiar resulta particularmente útil ya que permite definir el rango de variabilidad y excluir trastornos alélicos, siempre y cuando sea complementado por un seguimiento lo suficientemente prolongado. El estudio de las bases moleculares del SM posibilitó perfeccionar el diagnóstico, precisar el pronóstico, proponer intervenciones terapéuticas más efectivas y brindar mejor asesoramiento genético.

Síndrome de Marfan. Reporte de un caso / The Marfan's Syndrome. A case report

El síndrome de Marfan es un proceso autosómico dominante con penetrancia completa, pero de expresividad variable. Se diagnostica basándose en los datos clínicos, algunos de los cuales depende del crecimiento. En este trabajo se presenta un caso de un niño de 8 años de edad, que se ingresó en el Hospital General Docente de Morón con la variedad clínica clásica del síndrome, que mostraba afectación esquelética, ocular y cardiovascular. Se describen las características clínicas del paciente y se compara con la literatura médica revisada. Se destaca la importancia del consejo genético.

Anomalias oculares e características genéticas na síndrome de Marfan / Ocular abnormalities and genetic findings in Marfan's syndrome

Objetivo: Para se identificar as alterações oculares presentes na síndrome de Marfan, este trabalho apresenta a avaliação oftalmológica de 46 indivíduos portadores desta doença. Métodos: Estudo prospectivo com avaliação clínica de 46 pacientes portadores de síndrome de Marfan com avaliação oftalmológica completa. Dezessete pacientes também foram submetidos a exame genético clínico e estudo molecular. Resultados: Dos quarenta e seis pacientes incluídos neste estudo, as seguintes alterações oculares foram encontradas com maior freqüência: subluxação do cristalino (67,3 por cento), hipoplasia de íris (23,9 por cento), descolamento de retina (7,6 por cento), córnea plana (2,2 por cento), megalocórnea (2,2 por cento) e miopia ou astigmatismo miópico (34,8 por cento). Cinco pacientes (10,9 por cento) apresentaram exame ocular normal em ambos os olhos. Detectou-se uma mutação patogênica distinta das relatadas na literatura em uma paciente, uma mutação de sentido trocado que ocorreu no éxon 28 levando à mudança de aminoácido C 1166Y. Conclusões: As alterações oculares da síndrome de Marfan são freqüentes e o conhecimento do gene responsável FBN-1 e de sua expressão no olho auxiliam para o diagnóstico e tratamento destas anomalias.

Molecular biology of aortic diseases

The elastic property of several tissues is conferred by the elastic fiber, composed of a homogeneous core of elastin surrounded by microfibrils. Defects in these components lead to different genetic diseases with important cardiovascular manifestations in the aorta. Here we will review these genetic disorders associated with pathologies of the aorta, focusing on the molecular defects underlying them, and on how the elucidation of the molecular lesion can lead to a better understanding of disease progression. In particular, we will discuss the recent advances in the molecular basis of supravalvar aortic stenosis, Williams syndrome, Marfan syndrome, and the fibrillinopathies.

The Antley-Bixler syndrome: two new cases.

The Antley-Bixler syndrome is a rare multiple congenital anomaly with a high mortality rate. The characteristic manifestations include craniosynostosis, radiohumeral synostosis, midface hypoplasia, joint contractures and arachnodactyly. We report two new cases of this syndrome and address the diagnostic features, associated malformations, inheritance patterns, prenatal findings, and briefly review the literature.

Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report

We report the case of a 3-1/2-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA). The serum muscle enzimes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous