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

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.

Aspekty diagnostyczne i terapeutyczne zespołu Marfana w wieku rozwojowym

2018 ◽  
Vol 22 (2) ◽  
Author(s):  
Małgorzata Ludzia ◽  
Ewa Smereczyńska-Wierzbicka ◽  
Bożena Werner
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Matrix Protein ◽  
Autosomal Dominant ◽  
De Novo ◽  
Enzyme Inhibitor ◽  
Angiotensin Receptor Blockers ◽  
Extracellular Matrix Protein ◽  
Long Bone ◽  
De Novo Mutations

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.

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

Circulation ◽  
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.

Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽  
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.

scholarly journals Marfan Syndrome with Varieties of Clinical Features

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

Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽  
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.

scholarly journals Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

2020 ◽  
Vol 21 (19) ◽  
pp. 7024
Author(s):  
Felke Steijns ◽  
Marjolijn Renard ◽  
Marine Vanhomwegen ◽  
Petra Vermassen ◽  
Jana Desloovere ◽  
...  
Keyword(s):  
Mouse Model ◽  
Right Ventricular ◽  
Marfan Syndrome ◽  
Matrix Protein ◽  
Ex Vivo ◽  
Wide Spectrum ◽  
Extracellular Matrix Protein ◽  
Aortic Dilatation ◽  
Cardiac Phenotype ◽  
Fibrillin 1

Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1mgR/mgR mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1mgR/mgR mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/mgR MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.

scholarly journals Periodontal condition in growing subjects with Marfan Syndrome: a case-control study

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6606
Author(s):  
Nicolò Venza ◽  
Carlotta Danesi ◽  
Diego Contò ◽  
Francesco Fabi ◽  
Gianluca Mampieri ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Matrix Protein ◽  
Mean Value ◽  
Extracellular Matrix Protein ◽  
Control Group ◽  
Depth Information ◽  
Gingival Thickness ◽  
Periodontal Condition ◽  
Significant Difference ◽  
The Mean

Background Marfan’s syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin-1. Orofacial characteristics may be useful in identification of the syndrome. Severe periodontitis is sometimes observed in MFS patients, but no in-depth information has been reported in Italian groups of growing subjects with MFS. The aim of this study was to analyze the periodontal condition on a group of growing subjects affected by MFS, in comparison with a typically developed control group. Methods A group of 16 subjects with diagnosed MFS were recruited from the Centre for Rare Diseases for Marfan Syndrome and Related Disorders of Tor Vergata University Hospital. The Marfan Group (MG) was compared with a Control Group (CG) composed by 20 nonsyndromic subjects. The periodontal clinical parameters like Marginal Gingival Thickness (GT), Plaque Index (PI), Bleeding On Probing (BOP) and Modified Periodontal Screening and Recording (PSR) were assessed. Results The mean value of PI in MG was 59%, instead in CG it reached 21%. Analysis showed a significant difference between MG and CG also for the BOP. In MG the mean value of BOP attained 36% and in CG it reached 16%. A statistical significant difference of distribution of PSR index between the two groups was found for all sextant examined. Discussion Patients with Marfan syndrome reveal a higher presence of plaque and consequently a generalized inflammation in the oral cavity when compared with a control group.

scholarly journals Takayasu’s Arteritis Concurrent with Marfan syndrome Associated with Severe Renovascular Hypertension

2018 ◽  
Vol 13 (1) ◽  
pp. 29-32
Author(s):  
Naveen Sheikh ◽  
Mohammad Safiuddin ◽  
Afia Zainab Tanni ◽  
Nahid Sultana ◽  
Md Ashraf Uddin Sultan ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Matrix Protein ◽  
Takayasu’S Arteritis ◽  
Delayed Diagnosis ◽  
Connective Tissue Disorder ◽  
Extracellular Matrix Protein ◽  
Tall Stature ◽  
Takayasu's Arteritis ◽  
Bilateral Renal Artery Stenosis ◽  
Definitive Therapy

Marfan syndrome (MS) is a dominantly inherited connective tissue disorder characterized by arachnodactyly, tall stature, the presence of aortic aneurysm, and lens dislocation. Takayasu’s arteritis(TA) is an inflammatory disease often affecting the ascending aorta and aortic arch, causing obstruction of the aorta and its major arteries. The disease commonly presents in the 2nd or 3rd decade of life, often with a delayed diagnosis. The disease is progressive and there is no definitive therapy. We report an unusual case of concomitant Takayasu’s arteritis and Marfan syndrome manifesting bilateral renal artery stenosis and aortic root dilatation. The patient had severe hypertension. The simultaneous presence of TA and MS could be a coincidence, however; the pathogenesis of TA might be linked with autoimmunity induced by abnormal extracellular matrix protein derived from the genetic mutations in MS.University Heart Journal Vol. 13, No. 1, January 2017; 29-32

scholarly journals Genetic testing for Marfan-like disorders

2018 ◽  
Vol 2 (s1) ◽  
pp. 38-41
Author(s):  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Stefano Paolacci ◽  
Carla Marinelli ◽  
Marco Castori ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Differential Diagnosis ◽  
Genetic Testing ◽  
Marfan Syndrome ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Disease Gene ◽  
Pathogenic Variant ◽  
Molecular Testing ◽  
Gene Test

Abstract Marfan-like disorders are inherited conditions with features resembling Marfan syndrome but without a pathogenic variant in FBN1, and/or without a clinical diagnosis of Marfan syndrome according to the Revised Ghent criteria, and/or with a pathogenic variant in a different disease gene. Marfan-like disorders are clinically and genetically heterogeneous and have variable prognosis. They may have autosomal dominant or autosomal recessive patterns of inheritance. The prevalence of most Mar-fan-like disorders is unknown. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials.

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