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BMC Pediatrics Oct 2023Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants...
BACKGROUND
Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants clustered in exons 24-32 of fibrillin-1 (FBN1) gene result in more severe clinical phenotypes. Furthermore, genotype-phenotype correlation studies suggested that more severe cardiovascular phenotypes were related to variants held responsible for haploinsufficiency. Our objective was to analyze the differences in clinical manifestations and genotypes of individuals with early-onset Marfan syndrome and to assess their impact on management strategies.
METHODS
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
RESULTS
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24-32 of the FBN1. The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
CONCLUSIONS
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
Topics: Child; Humans; Infant, Newborn; Child, Preschool; Marfan Syndrome; Fibrillins; Cysteine; Mutation; Genotype; Phenotype; Prognosis
PubMed: 37891508
DOI: 10.1186/s12887-023-04357-8 -
Journal of the American College of... Jun 2021
Topics: Cardiovascular System; Humans; Marfan Syndrome; Phenotype
PubMed: 34140104
DOI: 10.1016/j.jacc.2021.04.073 -
BMJ Case Reports Dec 2013Marfan syndrome is a rare autosomal dominant disorder of the connective tissue, with skeletal, ligamentous, orooculofacial, pulmonary, abdominal, neurological and the...
Marfan syndrome is a rare autosomal dominant disorder of the connective tissue, with skeletal, ligamentous, orooculofacial, pulmonary, abdominal, neurological and the most fatal, cardiovascular manifestations. It has no cure but early diagnosis, regular monitoring and preventive lifestyle regimen ensure a good prognosis. However, the diagnosis can be difficult as it is essentially a clinical one, relying on family history, meticulous physical examination and investigation of involved organ systems. Patients of Marfan syndrome portray very typical physical and orofacial characteristics, suggesting obvious recognition, but due to variable phenotypic expression, cases often go unnoticed unless a full range of attributing features is apparent. Dental practitioners are very likely to encounter patients of Marfan syndrome at an early age as they frequently present for dental treatment. The present case report illustrates the preliminary screening of Marfan syndrome in a dental office followed by timely diagnosis and appropriate referrals.
Topics: Adolescent; Diagnosis, Differential; Diagnosis, Oral; Female; Humans; Malocclusion; Marfan Syndrome; Physical Examination; Referral and Consultation; Tooth Extraction; Toothache; Treatment Outcome
PubMed: 24336584
DOI: 10.1136/bcr-2013-201632 -
BMJ (Clinical Research Ed.) Dec 1991
Topics: Famous Persons; Fibrillins; History, 19th Century; Humans; Marfan Syndrome; Microfilament Proteins; United States
PubMed: 1773142
DOI: 10.1136/bmj.303.6815.1414 -
Biomolecules Jan 2022About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic... (Review)
Review
About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.
Topics: Aortic Dissection; Angiotensin II; Animals; Aorta; Aortic Aneurysm, Thoracic; Humans; Marfan Syndrome; Mice
PubMed: 35053276
DOI: 10.3390/biom12010128 -
Archives of Disease in Childhood Apr 2007In recent years, there have been many advances in the treatment of cardiac disease in children with Marfan's syndrome. Early diagnosis, meticulous echocardiographic... (Review)
Review
In recent years, there have been many advances in the treatment of cardiac disease in children with Marfan's syndrome. Early diagnosis, meticulous echocardiographic follow-up and multidisciplinary assessment are essential. Medical treatment with beta-blockers is probably helpful in most children with aortic root dilatation. Research on TGFbeta signalling and the potential treatment role of TGFbeta antagonists may lead to exciting new treatments, but the results of clinical trials are awaited. In managing the cardiovascular complications of Marfan's syndrome, the paediatrician has to walk a difficult path. On the one hand, restrictive lifestyle advice and drugs may need to be prescribed, often in the context of a family history of major surgery or even sudden death. On the other hand, it is essential to encourage the often asymptomatic child to develop and mature as normally as possible.
Topics: Adrenergic beta-Antagonists; Aortic Valve; Dilatation, Pathologic; Female; Heart Defects, Congenital; Heart Valve Prosthesis Implantation; Humans; Infant; Infant, Newborn; Marfan Syndrome
PubMed: 17376944
DOI: 10.1136/adc.2006.097469 -
Journal of the American Heart... Oct 2020
Topics: Androgens; Animals; Aortic Aneurysm, Thoracic; Fibrillin-1; Male; Marfan Syndrome; Mice; Transforming Growth Factor beta
PubMed: 33059494
DOI: 10.1161/JAHA.120.018814 -
Journal of the American College of... Mar 2020
Topics: Aortic Dissection; DNA Mutational Analysis; Fibrillin-1; Genetic Variation; Humans; Marfan Syndrome
PubMed: 32130919
DOI: 10.1016/j.jacc.2019.12.042 -
Lancet (London, England) Sep 2022Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments.
METHODS
In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva.
FINDINGS
We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in β-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042).
INTERPRETATION
In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery.
FUNDING
Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Aorta; Humans; Marfan Syndrome; Randomized Controlled Trials as Topic
PubMed: 36049495
DOI: 10.1016/S0140-6736(22)01534-3 -
The Journal of Thoracic and... Mar 2022
Topics: Fluoroquinolones; Humans; Marfan Syndrome
PubMed: 33189346
DOI: 10.1016/j.jtcvs.2020.10.057