Genetic analysis of a novel FBN1 mutation in a pediatric Marfan syndrome patient.

The aim of this study was to investigate a novel FBN1 gene mutation in a pediatric patient with Marfan syndrome (MFS) to provide a theoretical basis for genetic counseling. The subject was a 5-month-old male infant. With informed consent from the proband and his family, 2 mL of peripheral venous blood was collected from the patient, his father, mother, and sister. DNA was extracted using a DNA extraction kit with EDTA-K as an anticoagulant. The extracted DNA was subjected to minigene transcription and bioinformatics analysis. For minigene construction, wild-type and mutant minigenes were inserted into pcMINI and pcMINI-C vectors, respectively. Four recombinant vectors were transfected into the HeLa and 293T cell lines. After transfection for 48 hours, RNA was extracted from eight samples. DNA was also extracted from the family members' samples to construct a library. Target regions were captured using the SureSelect Human All Exon V6 (Agilent) kit and were sequenced with Illumina NovaSeq (sequencing read length 2×150 bp). Bioinformatic analysis identified the c.8226+5del mutation as a variant of uncertain clinical significance (VOUS). Literature and database reviews confirmed that this mutation had not been previously reported, identifying it as a novel mutation. The study identified a novel FBN1 mutation, c.8226+5del, that may be associated with clinical features such as low-set ears and distinctive facial characteristics in the proband. This mutation likely affects normal mRNA splicing, altering the structure and function of Exon 64 and potentially contributing to the development of autosomal dominant MFS.

Generation of Marfan syndrome-specific induced pluripotent stem cells harboring FBN1 mutations.

Marfan syndrome (MFS) is a hereditary condition caused by mutations in the FBN1 gene. Genetic mutations in the FBN1 locus impact the function of the encoded protein, Fibrillin 1, a structural molecule forming microfibrils found in the connective tissue. MFS patients develop severe cardiovascular complications including thoracic aortic aneurysm and aortic dissection, which predispose them to an enhanced risk of premature death. Here, we generated two induced pluripotent stem cell (iPSC) lines harboring mutations in the FBN1 gene (p.C1942C>A and c.1954 T>C), directly derived from MFS patients. We have shown that both iPSC lines displayed expression of pluripotency markers, normal karyotype and ability of trilineage differentiation, representing a valuable tool for the identification of new therapeutic strategies for intervening in this disease.

Targeted next-generation sequencing reveals the genetic mechanism of Chinese Marfan syndrome cohort with ocular manifestation.

BACKGROUND: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders. PURPOSE: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations. METHODS: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases. RESULTS: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families. CONCLUSION: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.

Occurrence of cancer in Marfan syndrome: Report of two patients with neuroblastoma and review of the literature.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in FBN1, with a hitherto unknown association with cancer. Here, we present two females with MFS who developed pediatric neuroblastoma. Patient 1 presented with neonatal MFS and developed an adrenal neuroblastoma with unfavorable tumor genetics at 10 months of age. Whole genome sequencing revealed a germline de novo missense FBN1 variant (NP_000129.3:p.(Asp1322Asn)), resulting in intron 32 inclusion and exon 32 retention. Patient 2 was diagnosed with classic MFS, caused by a germline de novo frameshift variant in FBN1 (NP_000129.3:p.(Cys805Ter)). At 18 years, she developed high-risk neuroblastoma with a somatic ALK pathogenic variant (NP_004295.2:p.(Arg1275Gln)). We identified 32 reported cases of MFS with cancer in PubMed, yet none with neuroblastoma. Among patients, we observed an early cancer onset and high frequency of MFS complications. We also queried cancer databases for somatic FBN1 variants, finding 49 alterations reported in PeCan, and variants in 2% of patients in cBioPortal. In conclusion, we report the first two patients with MFS and neuroblastoma and highlight an early age at cancer diagnosis in reported patients with MFS. Further epidemiological and functional studies are needed to clarify the growing evidence linking MFS and cancer.

High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Outcomes of aortic root replacement in patients with Marfan syndrome: the role of valve-sparing and valve-replacing approaches.

Background: Marfan syndrome (MFS) is a heritable thoracic aortic disease with pervasive cardiovascular effects, including commonly, a dilated aortic root. Traditionally, the root is replaced using a mechanical composite valve graft (CVG); however, this valve-replacing (VR) approach necessitates a lifelong regimen of anticoagulation with a potential for late bleeding complications. In time, valve-sparing (VS) approaches were developed. Today, several options for aortic root replacement (ARR) exist; each has advantages and disadvantages that helps inform choice. The Aortic Valve Operative Outcomes in Marfan Patients (AVOMP) is a multi-center international registry to analyze clinical outcomes of ARR in MFS patients using either VR or VS techniques to better elucidate choice. We summarize outcomes of AVOMP and present our own experience. Methods: We performed 223 consecutive elective ARR [1991-2023] in patients with MFS; 15 such repairs were included in AVOMP. Repairs included 113 (51%) using a mechanical CVG, 62 (28%) using a VS approach, and 48 (22%) using a bioprosthetic root. Many patients underwent aortic arch repair (30% to 54% by type). Results: The median patient age was 38 [29-52] years. In comparing VS and VR groups, patients were similar in age and rates of major comorbidities and symptoms. Patients with VR repair had a more complex aortic history. The rate of redo sternotomy was 24% (n=54). Operative death was uncommon [4% overall (10/223); ranging from 2% to 8% by type], and stroke was rare [1/223 (<1%)]. Late survival and reoperation differed by operative approach; survival was improved in patients who underwent VS repair. Conclusions: We found that repair in patients with MFS undergoing ARR resulted in low operative risk. Our late results were similar to those of AVOMP in that patients undergoing VS repair tended to experience greater rates of valvular-structural deterioration, although this did not appear to impact survival.

Genetically Triggered Thoracic Aortic Disease: Who Should be Tested?

Up to 25% of patients with thoracic aortic disease have an underlying Mendelian pathogenic variant. This is a heterogeneous group of disorders known as heritable thoracic aortic diseases (HTAD). Diagnosing associated pathogenic gene variants and syndromes is critical, as the underlying genetics have an implication in medical management, surveillance, thresholds for surgical intervention, surgical risk, pregnancy risk, and risk of inheritance by the offspring. Recently released 2022 American College of Cardiology/American Heart Association guidelines for the diagnosis and management of aortic diseases provide specific recommendations to identify patients at risk for heritable conditions and who should undergo genetic testing.

Successful management of Stanford type A aortic dissection with severe scoliosis in the setting of Marfan syndrome: a case report.

Background: Marfan syndrome (MFS) is a connective tissue disorder involving multiple organs. The most severe complications include aortic root dilatation and dissection. In the present report, we provide an uncommon case of acute aortic Stanford type A dissection (AADA) repair with severe scoliosis in an MFS patient and it is even more rare for such surgical treatment to be successfully completed along with holistic management that enables the patient to recover successfully. We offer a reference for future surgical therapy since the specific surgical treatment methods in this case have not been reported in the literature. Case Description: A 40-year-old Chinese female with MFS was rushed to our surgical clinic due to the sudden onset of intense chest pain. Physical examination revealed a diastolic murmur at the aortic valve area, increased arm and pectus carinatum deformity, severe scoliosis, acromicria, arachnodactyly, and planovalgus foot. Subsequently, AADA was discovered through computed tomography scan. In addition, echocardiogram revealed moderate aortic regurgitation and hydropericardium in small amount. Based on revised Ghent criteria, the patient was diagnosed with MFS complicated with aortic dissection. Emergency surgery was successfully performed for repair of the patient's aortic dissection and the diseased aortic valve. Postoperatively, the patient presented with a degree of respiratory insufficiency. However, the respiratory function was not greatly impaired, with good early intervention, such as taking deep breaths and coughing fully, active sputum suction, effective analgesia, ambulation and treadmill exercise. The patient finally recovered completely and was discharged 3 weeks later. Conclusions: We reported on a patient with severe scoliosis who successfully underwent surgical repair of AADA. Our report shows that the application of standard median sternotomy for repairing AADA offers the feasibility of implementation, on the basis of effectively solving various practical problems in the surgery brought about by scoliosis. It has been thoroughly assessed and addressed how the postoperative condition of such patients affects subsequent respiratory function and postoperative recovery. This report further provides a successful clinical reference for the implementation of this type of surgery and the postoperative management of respiratory function.

The relation of aortic dimensions and obesity in adults with Marfan or Loeys-Dietz syndrome.

Background: Aortic aneurysm and aortic dissection can have a major impact on the life expectancy of Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS) patients. Although obesity can influence the development of aortic complications, evidence on whether obesity influences the development of aortic aneurysm or dissection in MFS and LDS is limited. The aim of the present study was to elucidate the relationship between aortic size and body composition, assessed by modern bioelectrical impedance analysis (BIA) in MFS/LDS-patients. Methods: In this exploratory cross-sectional study in MFS or LDS patients, enrolled between June 2020 and May 2022, 34 patients received modern BIA and magnetic resonance imaging (MRI) (n=32) or computed tomography (CT) imaging (n=2) of the entire aorta. A P value of <0.05 was considered significant. Results: Fifty-one patients (66% female; mean age: 37.7±11.7; range, 17-68 years) with MFS or LDS were enrolled; 34 patients, 27 with MFS and 7 with LDS, underwent aortic MRI or CT scanning. The mean aortic length was 503.7±58.7 mm, and the mean thoracic aortic length and abdominal aortic length were 351.5±52.4 and 152.2±27.4 mm, respectively. The aortic bulb and the ascending aorta were measured only in the non-surgically repaired patients. Fifteen MFS (88.2%) and two LDS (40.0%) patients had an aortic aneurysm. In these, the aortic bulb tended to be larger in MFS than in LDS patients [42.6×41.9×41.2 vs. 37.8×37.4×36.8 mm; P=0.07 (-1.1; 9.1); P=0.07 (-1.2; 8.4); P=0.07 (-1.5; 7.9)]. BIA revealed mean body fat levels of 31.6%±8.7% (range, 9.5-53.5%), indicating that 18 patients (52.9%) were obese. There was a significant correlation between body fat content and thoracic aortic length (R=-0.377; P=0.02), muscle mass and total aortic length (R=0.359; P=0.03), thoracic aortic length (R=0.399; P=0.02), extracellular mass (ECM), and total aortic length (R=0.354; P=0.04), and connective tissue and aortic diameters at the aortic arch (R=0.511; P=0.002), aortic isthmus (R=0.565; P<0.001), and abdominal aorta (R=0.486; P=0.004). Older age was correlated with wider aortic arch, isthmus, and abdominal aorta. Male patients had a longer aorta. Conclusions: While a slender habitus is commonly known for MFS and LDS patients, our data show that many MFS and LDS patients (especially female) do not fit this phenotypic characteristic and are obese, which is associated with a more severe aortic phenotype. This topic should be included in the clinical assessment of affected MFS and LDS patients, in addition to measurement of the aortic diameters. Physicians should systematically screen MFS and LDS patients for obesity, educate them about the potential risk of resulting aortic complications, and encourage them to adopt a healthy lifestyle, that includes (mild) exercise and a balanced diet.

Updated genetic studies of Marfan syndrome in China.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disease that affects multiple systems such as the ocular, skeletal, and cardiovascular systems. This disease is relatively rare and has no effective treatment except for symptomatic treatment. As a result, early detection, early intervention, and preventing the occurrence of adverse cardiovascular outcomes are crucial to the diagnosis and treatment of MFS. The rapid development of gene sequencing technology has facilitated the detection of MFS at the genetic level, allowing a more accurate and efficient diagnosis of the disease. Therefore, research on MFS-related genes has become a topic of interest. This article reviews the recent progress of genetic research on MFS in China.

Effects of Simulated Microgravity on Wild Type and Marfan hiPSCs-Derived Embryoid Bodies.

BACKGROUND: Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including the inhibition of regenerative stem cell differentiation. In this work, we investigate the effects of microgravity simulation on early lineage commitment of hiPSCs from healthy and Marfan Syndrome (MFS; OMIM #154700) donors, using the embryoid bodies model of tissue differentiation and evaluating their ultra-structural conformation. MFS model involves an anomalous organization of the extracellular matrix for a deficit of fibrillin-1, an essential protein of connective tissue. METHODS: In vitro models require the use of embryoid bodies derived from hiPSCs. A DRPM was used to simulate microgravity conditions. RESULTS: Our data suggest an increase of the stemness of those EBs maintained in SMG condition. EBs are still capable of external migration, but are less likely to distinguish, providing a measure of the remaining progenitor or stem cell populations in the earlier stage. The microgravity response appears to vary between WT and Marfan EBs, presumably as a result of a cell structural component deficiency due to fibrillin-1 protein lack. In fact, MFS EBs show a reduced adaptive capacity to the environment of microgravity that prevented them from reacting and making rapid adjustments, while healthy EBs show stem retention, without any structural changes due to microgravity conditions. CONCLUSION: EBs formation specifically mimics stem cell differentiation into embryonic tissues, this process has also significant similarities with adult stem cell-based tissue regeneration. The use of SMG devices for the maintenance of stem cells on regenerative medicine applications is becoming increasingly more feasible. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-021-00680-1.

Respiratory manifestations of Marfan syndrome: a narrative review.

OBJECTIVE: The prevalence of Marfan syndrome (MFS) is estimated to be 1 in 10,000 to 15,000 individuals, but the phenotype of MFS may not be apparent and hence its diagnosis may not be considered by clinicians. Furthermore, the effects of MFS on the lungs and breathing are underrecognized despite the high morbidity that can occur. The objective of this Narrative Review is to delineate the molecular consequences of a defective fibrillin-1 protein and the skeletal and lung abnormalities in MFS that may contribute to respiratory compromise. It is important for clinicians to be cognizant of these MFS-associated respiratory conditions, and a contemporaneous review is needed. BACKGROUND: MFS is an autosomal dominant, connective tissue disorder caused by mutations in the FIBRILLIN-1 (FBN1) gene, resulting in abnormal elastic fibers as well as increased tissue availability of transforming growth factor-beta (TGFß), both of which lead to the protean clinical abnormalities. While these clinical characteristics are most often recognized in the cardiovascular, skeletal, and ocular systems, MFS may also cause significant impairment on the lungs and breathing. METHODS: We searched PubMed for the key words of "Marfan syndrome," "pectus excavatum," and "scoliosis" with that of "lung disease," "breathing", or "respiratory disease." The bibliographies of identified articles were further searched for relevant articles not previously identified. Each relevant article was reviewed by one or more of the authors and a narrative review was composed. CONCLUSIONS: Though the classic manifestations of MFS are cardiovascular, skeletal, and ocular, FBN1 gene mutation can induce a variety of effects on the respiratory system, inducing substantial morbidity and potentially increased mortality. These respiratory effects may include chest wall and spinal deformities, emphysema, pneumothorax, sleep apnea, and potentially increased incidence of asthma, bronchiectasis, and interstitial lung disease. Further research into approaches to prevent respiratory complications is needed, but improved recognition of the respiratory complications of MFS is necessary before this research is likely to occur.

Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-ß Signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-ß signaling, and will discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

Pathophysiology and Pathogenesis of Marfan Syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease manifests in many different ways, the most life-threatening manifestations are related to cardiovascular complications including mitral valve prolapse, aortic insufficiency, dilatation of the aortic root, and aortic dissection. In the past 30 years, research efforts have not only identified the genetic locus responsible but have begun to elucidate the molecular pathogenesis underlying this disorder, allowing for the development of seemingly rational therapeutic strategies for treating affected individuals. In spite of these advancements, the cardiovascular complications still remain as the most life-threatening clinical manifestations. The present chapter will focus on the pathophysiology and clinical treatment of Marfan syndrome, providing an updated overview of the recent advancements in molecular genetics research and clinical trials, with an emphasis on how this information can focus future efforts toward finding betters ways to detect, diagnose, and treat this devastating condition.

Combining clinical examination with exome sequencing for the diagnosis and treatment of Marfan syndrome: a case series of 6 families from China.

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder. Diagnosing MFS can be challenging as the disease's severity and clinical manifestations differ between pathogenic variants, and because a lack of published information currently exists on phenotype-genotype correlations. This report aims to underline the clinical manifestations associated with fibrillin-1 (FBN1) gene mutations by assessing MFS in 6 families from China. METHODS: We diagnosed 6 patients and their relatives with MFS by combining a clinical examination (based on the 2010 revised Ghent nosology criteria) with a targeted next-generation sequencing analysis. The functional analysis of the causal mutations and clinical details of the affected patients were then assessed. RESULTS: We identified 6 pathogenic mutations in FBN1, including 1 novel frameshift, 1 nonsense, and 4 missense mutations. Most uniquely, mitral valve prolapses (MVP) and ectopia lentis (EL) were found in the cysteine-related mutations. Typically, facial symptoms of MFS are observed in frameshift or nonsense mutants, not in cysteine-related ones. Furthermore, the patients with premature terminal codons had a more serious skin condition than patients with missense mutations, partly indicating the important effect FBN1 has on skin. CONCLUSIONS: This study expands the mutation spectrum of MFS and highlights possible genotype-phenotype correlations, thereby improving the early diagnosis and symptomatic treatment of the disease.

Systematic review and meta-analysis of aortic valve-sparing surgery versus replacement surgery in ascending aortic aneurysms and dissection in patients with Marfan syndrome and other genetic connective tissue disorders.

BACKGROUND: Aortic aneurysm and dissection are important causes of morbimortality in patients with Marfan syndrome (MFS) and other connective tissue diseases that affect the cardiovascular tissues. Timely intervention through different surgical techniques improves the prognosis. Both sparing and replacement-type interventions of the aortic valve are used, but selection depends on the condition of the patient at the time of diagnosis, the patient's emergency condition, surgeon preference and hospital resources. Previous meta-analyses have suggested an advantage with the use of sparing-type interventions, but this finding must be updated and extended to patients with other connective tissue disorders. The objetive of this study is to evaluate the outcomes of valve-sparing root replacement versus aortic root replacement procedures in patients with MFS and similar connective tissue diseases that present with aortic aneurysm or dissection. METHODS: A systematic review of cohort studies that evaluated sparing-type (preserving, remodeling, reimplantation, Yacoub, David or Florida Sleeve) or replacement-type (repair, Bentall, Button-Bentall, composite valve graft or Cabrol) procedures in patients with Marfan, Loeys-Dietz, Beals-Hecht or Ehlers-Danlos syndromes was done. Studies were retrieved from the SCOPUS, MEDLINE, CINAHL, EMBASE and LILACS electronic databases up to January 2020 without language restrictions. Only studies that directly compared sparing- versus replacement-type procedures were included in the meta-analysis. RESULTS: A total of 33 studies (n=1,807 subjects) reported sparing-type surgical interventions and 26 studies (n=2,218 subjects) reported replacement-type surgical interventions. Pooled rates of endocarditis, thromboembolism and aneurysm were higher in replacement-type surgical intervention studies. Sixteen studies were included in the meta-analysis. Sparing-type interventions were associated with a reduced risk of endocarditis (RR =0.13, 95% CI: 0.03-0.61); however, replacement-type interventions favored freedom from valve reoperation (RR =2.39, 95% CI: 1.24-4.60). All studies were at low risk of bias. CONCLUSIONS: The choice of the best surgical technique is dependent on the type of disease (MFS or other connective tissue diseases) as well as the accompanying aortic and cardiovascular damage, since these key factors are heterogeneous. Although the results of this meta-analysis tend to show some advantages for one type of surgical intervention over the other and viceversa, the surgeon can only make the best decision during the surgical act.

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder that affects the skeletal, ocular, and cardiovascular system. The disease's severity and clinical manifestations vary greatly due to pathogenic variants which, combined with a lack of research on the correlation between MFS's genotype and phenotype, make MFS a challenging disease to diagnose. This study aims to further the understanding of MFS by shedding light on the clinical manifestation of a novel variant in fibrillin-1 (FBN1)-the protein responsible for the genetic defects that lead to MFS. METHODS: A patient was diagnosed with MFS by combining a clinical examination (based on the 2010 revision to Ghent nosology criteria) with a targeted next-generation sequence analysis. The functional analysis of the causal mutation and the clinical details of the affected patient were then analyzed. RESULTS: The FBN1 heterozygous variant c.5081_5082insT, which is known to delete large fragments from amino acids 1702 to 2871, was found in the proband patient and her son. The two also displayed the skeletal and cardiovascular manifestations of MFS. In addition, the 14-year-old son was identified as having a dilated aortic bulb at the same rupture site of the proband's dissection, and the proband's mother also died at age 32 due to aortic dissection. CONCLUSIONS: The FBN1 variant c.5081_5082insT (p.Leu1694fs*9) is a pathogenic mutation that can cause MFS patients to experience early-onset familial thoracic aortic aneurysms (TAA). We hope that this discovery can provide further insight into the treatment of MFS patients with truncating variants in exons 42-65.

Quality of life in patients with Marfan syndrome: a cross-sectional study of 102 adult patients.

BACKGROUND: Marfan syndrome (MFS) is a genetically determined multiorgan disease that leads to severe physiological and psychological impairments in adult life. Little consensus exists regarding quality of life (QOL) in individuals with MFS. The present study sought to investigate QOL in a representative cohort of adults with MFS. METHODS: Patient-reported outcome measures from a representative sample of 102 adults with MFS (39.3±13.1 years of age; 40.2% female) were retrospectively analyzed and compared with those from adults with different congenital heart defects (CHD), at the German Heart Center Munich. QOL was assessed using the updated five-level version of the EQ-5D. RESULTS: Differences between both populations were analyzed. Subjects affected by MFS reported an overall reduced QOL. Compared to CHD patients, individuals with MFS scored significantly lower in the dimensions of pain/discomfort, anxiety/depression, mobility and usual activities (P<0.05). CONCLUSIONS: Patients with MFS are at high risk for impaired QOL, especially in mental and physical domains. Psychosocial consequences of MFS cost resources for both, patients and professionals. Current findings highlight the great importance of additional psychological support to cope with disease-related challenges. Increased attention should be directed towards enhancing their subjective wellbeing to potentially improve their QOL and long-term health outcomes.

Optimal treatment of pneumothorax in adolescents with Marfan syndrome.

PURPOSE: Pneumothorax often develops in patients with Marfan syndrome (MFS). Here, we examined the effects of conservative and surgical pneumothorax treatments in children with MFS. METHODS: In this study, 23 patients, less than 20 years old, diagnosed with both MFS and pneumothorax between 1999 and 2019 were included. All data were collected retrospectively from patients' medical records. RESULTS: In total, 18 of 23 patients (78%) had relapsed pneumothorax either on the ipsilateral or contralateral side. Among these 18 patients, 6 (26%) patients had multiple relapses. Conservative and surgical treatments of pneumothorax were attempted in 33 and 29 lungs, respectively. The conservative treatment was attempted as a definitive therapy in 21 lungs. Twelve conservative treatments (57%) failed, which required surgical intervention. In 9 lungs (43%) with successful conservative treatment, 6 (67%) had ipsilateral relapses. In contrast to the above findings, only 4 (13%) ipsilateral relapses were observed in 29 surgical treatments. CONCLUSIONS: Our study revealed a low response and high relapse rate when MFS adolescents who diagnosed pneumothorax were subjected to the conservative treatment modality. Thus, we recommend surgical intervention as the first line of therapy to treat pneumothorax in adolescents diagnosed with MFS. LEVEL OF EVIDENCE: Ⅲ (Treatment Study).