Aspekty diagnostyczne i terapeutyczne zespołu Marfana w wieku rozwojowym

Marfan’s syndrome (MFS) is a systemic, autosomal dominant connective tissue disease. It is caused mainly by the mutations in the FBN1 gene and is connected with extracellular matrix protein fibrillin-1. The incidence is about 2-3 per 10 000. About 70-75% of cases are inherited in an autosomal dominant fashion and the remaining are de-novo mutations. The most common findings involve cardiovascular, ocular and skeletal systems. The cardinal manifestations typically involving MFS are aortic root aneurysm/dissection and ectopia lentis. The other common manifestations are mitral valve prolapse, proximal aortic aneurysm, dolichocephaly, pectus carinatum deformity, enophthalmos, scoliosis, long-bone overgrowth. The manifestation in neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is a rapidly progressing multi-valvular cardiac disease. The death connected with congestive heart failure happens mainly within the first year of life. Prognostic factors for life expectancy of patients with Marfan syndrome depend on the type of the MFS and in classical MFS – depend on the rate of aortic root dilatation, which leads to dissection or rupture. Pharmacological management includes beta blockers, angiotensin receptor blockers and angiotensin converting enzyme inhibitor as a preventive treatment to slow aortic root dilation.

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One in a billion: a patient with Marfan syndrome and familial hypocalciuric hypercalcaemia

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-21-0024 ◽

2021 ◽

Vol 2021 ◽

Author(s):

Su Ann Tee ◽

Paul Brennan ◽

Anna L Mitchell

Keyword(s):

Genetic Testing ◽

Marfan Syndrome ◽

Clinical Features ◽

Matrix Protein ◽

Autosomal Dominant ◽

Genomic Medicine ◽

Extracellular Matrix Protein ◽

List Type ◽

Clearance Ratio ◽

Multisystem Disorder

Summary Marfan syndrome is an autosomal dominant multisystem disorder that has an estimated incidence of 1 in 5000. It is caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein type 1 fibrillin. Familial hypocalciuric hypercalcaemia (FHH), also inherited in an autosomal dominant pattern, is a rare benign disorder characterised by hypercalcaemia, hypocalciuria and relative hyperparathyroidism with normal or high plasma PTH levels, with an estimated incidence of between 1 in 10 000 to 1 in 100 000. We report a unique case of a 26-year-old man referred for investigation of hypercalcaemia, who also had clinical features of Marfan syndrome but no previous genetic investigations. Calculated fractional urinary excretion of calcium was low (0.0005) following correction of vitamin D deficiency, raising the possibility of FHH. Genetic testing for Marfan syndrome and FHH, via a hyperparathyroidism multiplex gene panel test, revealed a novel truncating variant in the FBN1 gene (c.8481T>G; p.(Tyr2827Ter)), consistent with Marfan syndrome; and a pathogenic truncating variant in the CaSR gene (c.741dupT; p.[Asp248Ter]), which confirmed the diagnosis of FHH. The patient’s mother was subsequently found to have mild hypercalcaemia (adjusted calcium 2.76 mmol/L) and is also heterozygous for the same CaSR mutation. Genetic testing of his father confirmed the presence of the same FBN1 gene mutation. This case illustrates the importance of making robust diagnoses in the era of modern genomic medicine, confirming FHH as the cause of hypercalcaemia means that no treatment is warranted and the patient can be reassured. Learning points Familial hypocalciuric hypercalcaemia (FHH) should always be excluded during the investigation of hypercalcaemia by measuring urinary calcium: creatinine clearance ratio. Diagnosing FHH is important as the condition is benign and misdiagnosing patients with primary hyperparathyroidism could potentially lead to unnecessary morbidity from parathyroid surgery. Genetic testing is increasingly available for a variety of inherited conditions including Marfan syndrome and FHH. Patients who present with clinical features suggestive of a particular genetic condition should undergo prompt, appropriate confirmatory testing wherever possible. Taking a thorough family history is vital when assessing patients presenting with endocrine conditions, as this could prompt cascade testing and appropriate genetic counselling where necessary.

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Role of angiotensin receptor blockers for management of aortic root dilation associated with Marfan syndrome

Expert Review of Cardiovascular Therapy ◽

10.1586/erc.11.130 ◽

2011 ◽

Vol 9 (10) ◽

pp. 1257-1259 ◽

Cited By ~ 1

Author(s):

Rohit Seth Loomba ◽

Rohit R Arora

Keyword(s):

Marfan Syndrome ◽

Aortic Root ◽

Angiotensin Receptor Blockers ◽

Angiotensin Receptor ◽

Receptor Blockers

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Abstract 15539: Single-cell Analysis of Aortic Tissues From Patients With Marfan Syndrome Reveals Changes in Smooth Muscle Cell Differentiation

Circulation ◽

10.1161/circ.142.suppl_3.15539 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ashley Dawson ◽

Yanming Li ◽

Pingping Ren ◽

Hernan Vasquez ◽

Chen Zhang ◽

...

Keyword(s):

Smooth Muscle ◽

Single Cell ◽

Marfan Syndrome ◽

Immune Cells ◽

Matrix Protein ◽

Immune Cell ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Cardiac Transplant ◽

Control Tissue

Background: Thoracic aortic aneurysms associated with Marfan syndrome (MFS) carry a high risk of mortality; however, the molecular and cellular processes leading to aortopathy in this population remain poorly understood. We aimed to use single-cell RNA (scRNA) sequencing to define the non-immune cell populations present within the aortic wall in MFS, hypothesizing that these would differ from those of non-aneurysmal control tissue. Methods: We performed scRNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and of age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). The Seurat package in R was used for analysis. Differentially expressed genes were identified using edgeR. Results: Eighteen non-immune cell clusters were identified, with conserved gene expression of the largest of the clusters consistent with smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (n=3). The SMCs and fibroblasts exhibited graded changes in their expression of contractile and extracellular matrix protein genes, supportive of a phenotypic continuum. Additionally, we identified differences in the proportions of non-immune cells in MFS tissues compared to controls. In control tissues, the most common non-immune cells expressed markers of contractile SMC maturity including CNN1 , MYH11 , and SMTN . In contrast, the largest clusters in MFS tissue were most closely related to SMCs on correlation analysis, but displayed increased expression of cyclin genes as well as immune, endothelial, and fibroblast genes indicative of de-differentiated, proliferative SMCs. Additionally, expression of genes associated with SMC phenotypic maturity, including MYH11 and MYOCD , were significantly downregulated in several of the MFS SMC clusters. Conclusion: Our data demonstrate a phenotypic continuum between fibroblasts and SMCs, with aortas from patients with MFS exhibiting an increased proportion of de-differentiated, proliferative SMCs compared to controls. Additionally, markers of SMC maturity were downregulated in SMCs in MFS compared to controls. This may be due to disruption of signaling pathways that promote differentiation.

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160 ◽

2018 ◽

pp. 713-715

Author(s):

Dorien Schepers ◽

Bart Loeys

Keyword(s):

Extracellular Matrix ◽

Marfan Syndrome ◽

Transforming Growth Factor Beta ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Aortic Disease ◽

Extracellular Matrix Protein ◽

Genetic Defects ◽

Fibrillin 1 ◽

Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

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Transcription Factor Erg Variants and Functional Diversification of Chondrocytes during Limb Long Bone Development

The Journal of Cell Biology ◽

10.1083/jcb.150.1.27 ◽

2000 ◽

Vol 150 (1) ◽

pp. 27-40 ◽

Cited By ~ 50

Author(s):

Masahiro Iwamoto ◽

Yoshinobu Higuchi ◽

Eiki Koyama ◽

Motomi Enomoto-Iwamoto ◽

Kojiro Kurisu ◽

...

Keyword(s):

Transcription Factor ◽

Limb Development ◽

Matrix Protein ◽

Molecular Mechanisms ◽

Articular Chondrocytes ◽

Bone Cells ◽

Expression Patterns ◽

Extracellular Matrix Protein ◽

Long Bone ◽

Chondrocyte Maturation

During limb development, chondrocytes located at the epiphyseal tip of long bone models give rise to articular tissue, whereas the more numerous chondrocytes in the shaft undergo maturation, hypertrophy, and mineralization and are replaced by bone cells. It is not understood how chondrocytes follow these alternative pathways to distinct fates and functions. In this study we describe the cloning of C-1-1, a novel variant of the ets transcription factor ch-ERG. C-1-1 lacks a short 27–amino acid segment located ∼80 amino acids upstream of the ets DNA binding domain. We found that in chick embryo long bone anlagen, C-1-1 expression characterizes developing articular chondrocytes, whereas ch-ERG expression is particularly prominent in prehypertrophic chondrocytes in the growth plate. To analyze the function of C-1-1 and ch-ERG, viral vectors were used to constitutively express each factor in developing chick leg buds and cultured chondrocytes. We found that virally driven expression of C-1-1 maintained chondrocytes in a stable and immature phenotype, blocked their maturation into hypertrophic cells, and prevented the replacement of cartilage with bone. It also induced synthesis of tenascin-C, an extracellular matrix protein that is a unique product of developing articular chondrocytes. In contrast, virally driven expression of ch-ERG significantly stimulated chondrocyte maturation in culture, as indicated by increases in alkaline phosphatase activity and deposition of a mineralized matrix; however, it had modest effects in vivo. The data show that C-1-1 and ch-ERG have diverse biological properties and distinct expression patterns during skeletogenesis, and are part of molecular mechanisms by which limb chondrocytes follow alternative developmental pathways. C-1-1 is the first transcription factor identified to date that appears to be instrumental in the genesis and function of epiphyseal articular chondrocytes.

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MARFAN SYNDROME AND PREGNANCY: CLINICAL IMPLICATIONS AND MANAGEMENT

Fetal and Maternal Medicine Review ◽

10.1017/s0965539510000082 ◽

2010 ◽

Vol 21 (3) ◽

pp. 225-241

Author(s):

ARIADNA C GRIGORIU ◽

JACK COLMAN ◽

CANDICE K SILVERSIDES ◽

RACHEL WALD ◽

SAMUEL C SIU ◽

...

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Autosomal Dominant ◽

De Novo ◽

Connective Tissue Disorder ◽

Multiple Organ ◽

Clinical Implications ◽

Organ Systems

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects multiple organ systems, primarily the cardiovascular, ocular and skeletal. It is the most common inherited condition affecting the heart and the aorta, occurring in 1:5000–1:9800 people. There is no ethnic or gender predisposition; 20 to 35% of cases arise fromde novomutations.

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Marfan Syndrome with Varieties of Clinical Features

Journal of Medicine ◽

10.3329/jom.v19i1.34845 ◽

2017 ◽

Vol 19 (1) ◽

pp. 58-62

Author(s):

Goutam Kumar Acherjya ◽

Keya Tarafder ◽

Md Din Ul Islam ◽

Mahabubur Rahman ◽

Mostofa Kamal Chowdhury

Keyword(s):

Marfan Syndrome ◽

Matrix Protein ◽

Positive Family History ◽

Body Height ◽

Severe Form ◽

Extracellular Matrix Protein ◽

Thin Body ◽

Chromosome 15 ◽

Autosomal Dominant Disorder ◽

Arm Span

Marfan Syndrome is an autosomal dominant disorder caused by mutation in the extracellular matrix protein fibrilin-1 gene located on chromosome 15. It has variable range of expression.We describe a case of a 12 year aged girl with positive family history including lean and thin body stature, skin striae, joint hyper mobility, high arched palate, mal occlusion of teeth, pectus excavatum, winging of scapula, scoliosis of back bone, total arm span more than total body height (1.11:1), lower segment greater than upper segment (1.40:1), severe form of mitral valve prolapse and aortic root dilatation. There are a lot of features of Marfan Syndrome in our single patient which is rare in earlier available case reports.J MEDICINE Jan 2018; 19 (1) : 58-62

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Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype–phenotype correlations in the Chinese population

Bioscience Reports ◽

10.1042/bsr20203356 ◽

2020 ◽

Vol 40 (12) ◽

Author(s):

Yuduo Wu ◽

Hairui Sun ◽

Jianbin Wang ◽

Xin Wang ◽

Ming Gong ◽

...

Keyword(s):

Exome Sequencing ◽

Marfan Syndrome ◽

Whole Exome Sequencing ◽

Chinese Population ◽

De Novo ◽

Low Frequency ◽

Monogenic Disease ◽

De Novo Mutations ◽

Fbn1 Gene ◽

Whole Exome

Abstract Marfan syndrome (MFS) is a dominant monogenic disease caused by mutations in fibrillin 1 (FBN1). Cardiovascular complications are the leading causes of mortality among MFS. In the present study, a whole-exome sequencing of MFS in the Chinese population was conducted to investigate the correlation between FBNI gene mutation and MFS. Forty-four low-frequency harmful loci were identified for the FBN1 gene in HGMD database. In addition, 38 loci were identified in the same database that have not been related to MFS before. A strict filtering and screening protocol revealed two patients of the studied group have double mutations in the FBN1 gene. The two patients harboring the double mutations expressed a prominent, highly pathological phenotype in the affected family. In addition to the FBN1 gene, we also found that 27 patients had mutations in the PKD1 gene, however these patients did not have kidney disease, and 16 of the 27 patients expressed aortic related complications. Genotype-phenotype analysis showed that patients with aortic complications are older in the family, aged between 20 and 40 years.

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