Revised Ghent Nosology Research Articles

MRI-Derived Dural Sac and Lumbar Vertebrae 3D Volumetry Has Potential for Detection of Marfan Syndrome

Purpose: To assess the feasibility and diagnostic accuracy of MRI-derived 3D volumetry of lower lumbar vertebrae and dural sac segments using shape-based machine learning for the detection of Marfan syndrome (MFS) compared with dural sac diameter ratios (the current clinical standard). Materials and methods: The final study sample was 144 patients being evaluated for MFS from 01/2012 to 12/2016, of whom 81 were non-MFS patients (46 [67%] female, 36 ± 16 years) and 63 were MFS patients (36 [57%] female, 35 ± 11 years) according to the 2010 Revised Ghent Nosology. All patients underwent 1.5T MRI with isotropic 1 × 1 × 1 mm3 3D T2-weighted acquisition of the lumbosacral spine. Segmentation and quantification of vertebral bodies L3-L5 and dural sac segments L3-S1 were performed using a shape-based machine learning algorithm. For comparison with the current clinical standard, anteroposterior diameters of vertebral bodies and dural sac were measured. Ratios between dural sac volume/diameter at the respective level and vertebral body volume/diameter were calculated. Results: Three-dimensional volumetry revealed larger dural sac volumes (p < 0.001) and volume ratios (p < 0.001) at L3-S1 levels in MFS patients compared with non-MFS patients. For the detection of MFS, 3D volumetry achieved higher AUCs at L3-S1 levels (0.743, 0.752, 0.808, and 0.824) compared with dural sac diameter ratios (0.673, 0.707, 0.791, and 0.848); a significant difference was observed only for L3 (p < 0.001). Conclusion: MRI-derived 3D volumetry of the lumbosacral dural sac and vertebral bodies is a feasible method for quantifying dural ectasia using shape-based machine learning. Non-inferior diagnostic accuracy was observed compared with dural sac diameter ratio (the current clinical standard for MFS detection).

Genotype and clinical phenotype of children with Marfan syndrome in Southeastern Anatolia

The cardinal phenotypic hallmarks of Marfan syndrome (MFS) include cardiac, ocular, and skeletal abnormalities. Since the clinical phenotype of MFS is highly heterogeneous, with certain symptoms appearing as children age, the diagnostic process and establishing a genotype-phenotype association in childhood MFS can be challenging. The lack of sufficient childhood studies also makes it difficult to interpret the subject. This study aims to evaluate the relationship between clinical symptoms used as diagnostic criteria and FBN1 variations in children with MFS. This study investigated the relationships between genotypes and phenotypes in 131 children suspected of having Marfan syndrome (MFS). Diagnosis of MFS was made according to the revised Ghent nosology. FBN1 variants were categorized based on exon regions, type of variant, and pathogenicity classes. These FBN1 variants were then correlated with the clinical manifestations including cardiovascular, ocular, facial, and skeletal abnormalities. Out of the children, 43 were diagnosed with MFS. FBN1 variant was identified in 32 (74.4%) of the MFS children. MFS diagnosis could not be made in five (15.6%) FBN1 variant-positive children. The most common cardinal finding is cardiac anomalies n = 38 (88.3%). The most common FBN1 pathogenic variant was c.1786 T > C/p.Cys596Arg n = 4 (12.5%). The distribution of pathogenic variants was as follows: 29 (90.6%) missense, 2 (6.3%) frameshift, and 1 (3.1%) nonsense. The numbers of AD and EL of the variant-positive children were 16 (50%) and 14 (43.7%), respectively. Ocular abnormalities were more common in children with FBN1-positive MFS (p = 0.009). There was no difference in the number of cardiac abnormalities between FBN1-positive and FBN1-negative MFS patients (p = 0.139). Conclusion: This study examines the relationship between FBN1 variants and clinical features used as diagnostic criteria in MFS children. The findings emphasize the importance of long-term monitoring of heterogeneous clinical phenotypes and bioinformatic reanalysis in determining the genotype-phenotype relationship in children, as MFS symptoms can vary with age.What is Known:• Marfan syndrome has highly variable phenotypic heterogeneity.• The genotype-phenotype relationship in childhood Marfan syndrome is not clear enough due to the variation in the time of onset of the findings.What is New:• This article provides regional data for the field of research on genotype-phenotype relationships in childhood Marfan syndrome.• Long-term follow-up of clinical findings and bioinformatics reanalysis is an important requirement for a well-established genotype-phenotype relationship in childhood Marfan syndrome.

Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathogenic variants. However, the disease-causing variant in approximately 10% of patients cannot be identified, partly due to some cryptic mutations that may be missed using routine exonic sequencing, such as non-coding intronic variants that affects the RNA splicing process. We present a 32-year female with typical MFS systemic presentation that reached to a clinical diagnosis according to the revised Ghent nosology. We performed whole-exome sequencing (WES) but the report failed to identify known causal variants when analyzing the exonic sequence. However, further investigation on the exon/intron boundaries of the WES report revealed a candidate intronic variant of the fibrillin 1 (FBN1) gene (c.248-3 C>G) that predicted to affect the RNA splicing process. We conducted minigene splicing analyses and demonstrated that the c.248-3 C>G variant abolished the canonical splicing site of intron 3, leading to activation of two cryptic splicing sites and causing insertion (c.248-1_248-2insAG and c.248-1_248-282ins). Our study not only characterizes an intronic variant to the mutational spectrum of the FBN1 gene in MFS and its aberrant effect on splicing, but highlights the importance to not neglect the exon/intron boundaries when reporting and assessing WES results. We point out the need of conducting functional analysis to verify the pathogenicity of intronic mutation, and the opportunity to re-consider the standard diagnostic approaches in cases of clinically diagnosed MFS with normal or variant of unknown significance genetic results.

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

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. 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. 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. 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.

Predictive Physical Manifestations for Progression of Scoliosis in Marfan Syndrome.

A retrospective study of the prospective cohort. To demonstrate the accurate distribution of the severity of scoliosis in patients with Marfan syndrome, and to identify the predictive physical features for progression of scoliosis in Marfan syndrome. To date, no study has unveiled the risk factors for the progression of scoliosis in Marfan syndrome. We retrospectively obtained data from a prospective cohort of the Marfan syndrome clinic at our institute. We enrolled patients whose whole spine radiographs in the standing position were evaluated at the age of 15 or above, from January 2014 to March 2020. The collected variables were physical manifestations defined as in the systemic score of the revised Ghent nosology. We classified the degree of scoliosis into four categories: "not apparent," "mild" (10° ≤ Cobb < 25°), "moderate" (25° ≤ Cobb < 40°), and "severe" (40° ≤ Cobb or surgery conducted). To identify the risk factors for progression of scoliosis in Marfan syndrome, we conducted univariate and multivariate association analyses between severe scoliosis and each physical manifestation. We identified 131 eligible patients (61 men and 70 women) with a mean age of 31.2 years. Scoliosis with a Cobb angle of ≥10° was identified in 116 patients (88.5%). Moderate scoliosis was identified in 33 patients (25.2%) and severe scoliosis in 53 patients (40.5%). The prevalence of each physical manifestation was equivalent to that reported in previous studies. Multivariate logistic regression analysis revealed that female sex (odds ratio, 3.27) and positive wrist sign (4.45) were predictive factors for progression of scoliosis into severe state in patients with Marfan syndrome. The present study demonstrated the accurate distribution of the severity of scoliosis and identified the predictive factors for progression of scoliosis in patients with Marfan syndrome.Level of Evidence: 3.

Marfan syndrome revisited: From genetics to clinical practice

Abstract Marfan syndrome is an autosomal dominant connective tissue disease with an estimated incidence of 1 in 5000 individuals. In 90% of cases it is caused by mutations in the gene for fibrillin-1, the main constituent of extracellular microfibrils. Studies on animal models of Marfan syndrome have revealed that fibrillin-1 mutations interfere with local TGF-β signaling, in addition to impairing tissue integrity. The cardinal features involve the cardiovascular, ocular and skeletal systems. The diagnosis of Marfan syndrome is made according to the revised Ghent nosology. Early identification and appropriate management are critical for patients with Marfan syndrome, who are prone to the life-threatening cardiovascular complications of aortic aneurysms and aortic dissection. The standard treatment includes prophylactic beta-blockers in order to slow down dilation of the ascending aorta, and prophylactic aortic surgery. The success of current medical and surgical treatment of aortic disease in Marfan syndrome has substantially improved mean life expectancy, extending it above 72 years. This review aims to provide an overview of this hereditary disorder.

Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience

BackgroundMarfan Syndrome (MFS) is a chronic, life-threatening, autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, coding for fibrillin-1. All organ systems may be affected, but particularly the cardiovascular system, eyes, and skeleton. Mortality generally results from cardiovascular complications, mainly aortic dissection. Currently, the diagnosis of MFS is based on the revised Ghent nosology. Molecular analysis of the FBN1 gene reduces diagnostic uncertainty in patients with suspected MFS or MFS-related disorders (MFS-RD). To date, more than 2700 FBN1 mutations are known. MethodsUsing Next Generation Sequencing (NGS) followed by Multiplex Ligation-dependent Probe Amplification on NGS-negative samples, we screened FBN1 gene on 124 unrelated patients (101 MFS fulfilling revised Ghent criteria, 20 suspected MFS, 3 MFS-RD) enrolled from 2008 to 2018 at the Multidisciplinary Marfan Clinic, Tor Vergata Hospital, Rome. ResultsAn FBN1 variant was identified in 107/124 (86.3%) patients, including 48 novel variants (46 pathogenic/likely pathogenic, 2 VUS). A pathogenic/likely pathogenic variant was detected in 90/101 (89.1%) MFS patients. Our approach allowed early diagnosis for 10 young patients (age 3–19 years) with suspected MFS. ConclusionsThis study broadens the mutation spectrum of FBN1, providing a full update of the molecular basis of MFS in Italy.

Genetic testing for Marfan syndrome

Abstract Marfan syndrome (MFS) is an inherited connective tissue disorder caused by heterozygous mutations in the FBN 1 gene. Clinical manifestations of MFS include aortic dilatation and dissection, as well as cardiac valvular, ocular, skeletal and neurological manifestations. Prevalence varies from 6 to 20 per 100,000 individuals. Revised Ghent Nosology (2010) is used to establish a clinically based suspected diagnosis to be confirmed by molecular testing. 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.

Ocular manifestation in Marfan syndrome: corneal biomechanical properties relate to increased systemic score points.

To evaluate corneal deformation to an air puff as a new noninvasive tool to document disease status in Marfan syndrome (MFS) METHODS: Prospective observational cohort study. We included patients diagnosed with MFS who had their routine cardiovascular follow-up and applied the revised Ghent nosology to define two subgroups according to a high (≥ 7) and a low (< 7 points) systemic score. Dynamic Scheimpflug-based biomechanical analyses (CorvisST® [CST; Oculus GmbH]) were performed. The main outcome measure was the displacement of the corneal apex as given by the parameters highest concavity (HC; in ms), peak distance (PD; in mm), and highest concavity deformation amplitude (DA; mm). Forty-three eyes of 43 individuals (19 female, 24 male; mean age 42.0 ± 12.0years, range 18-67years) diagnosed with MFS were included. Applying the Ghent criteria, 21 patients had an advanced systemic score of ≥ 7, and 22 had score points < 7. There were no differences in age or sex between both groups. In contrast, HC was faster (P = 0.004), and PD (P < 0.001) was longer in those individuals with systemic score ≥ 7; maximum DA did not result in a statistically significant difference between the groups (P = 0.250). In vivo noninvasive biomechanical analyses with CST offer a new, non-invasive method to identify pathologic corneal deformation responses in adults with MFS. In the future, corneal deformation to an air puff could thus assist early identification of patients with high Ghent score as an adjunct to existing diagnostic tests.

Peripartum type B aortic dissection in patients with Marfan syndrome who underwent aortic root replacement: a case series study.

To investigate pregnancy outcomes, especially the risk of pregnancy-related aortic dissection (AD), in patients with Marfan syndrome (MFS) after prophylactic aortic root replacement (ARR). Retrospective case series study. Tertiary perinatal care centre at a university hospital. Pregnant women fulfilling the revised Ghent nosology (2010) criteria for MFS who were managed at our institute. The pregnancy outcomes of all patients with MFS managed at our institute between 1982 and September 2016 were reviewed retrospectively based on medical records. Obstetrical management and complication including the incidence of AD throughout the peripartum period. Among 22 patients (28 pregnancies) who had been managed as potential MFS or related disorders, 14 (17 pregnancies) fulfilled the revised Ghent nosology (2010) criteria for MFS and were enrolled in this study. Five patients (five pregnancies) had received ARR before conception: three (60%) developed type B aortic dissection [AD(B)] during the peripartum period, compared with only one of 10 patients (12 pregnancies) without ARR (P<0.05, Chi-square test). Our study results suggest that MFS patients after prophylactic ARR are still at high risk of AD(B) during the peripartum period. Careful pre-pregnancy counselling and multidisciplinary care throughout the peripartum period are essential for the management of MFS, even after surgical repair of an ascending aortic aneurysm. MFS patients after prophylactic ARR are still at high risk of type B aortic dissection during the peripartum period.

Differential Diagnosis of Marfan Syndrome in a Teenage Volleyball Athlete

Introduction Marfan syndrome (MFS) is an autosomal dominant hereditary disease mainly caused by mutations in the fibrillin-1 (FBN1) gene. It is characterized by the occurrence of thoracic aortic aneurysm and/or dissection, ectopia lentis, and systemic abnormalities. The highest risk of death associated with the syndrome is attributed to cardiovascular abnormalities, in particular, progressive aortic root aneurysm, leading to aortic dissection and rupture if not corrected surgically. The clinical diagnosis of MFS may be established by the revised Ghent nosology, although [...]

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse

BackgroundMitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. MethodsThis retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38±17years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42±15years with mean follow-up of 66±49months. ResultsAt baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P<.001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P<.001). In contrast, the incidence of endocarditis (P=.292), heart failure (P=.644), and mitral valve surgery (P=.140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P=.013), moderate MVR (P=.019) and flail MV leaflet (P=.017) as independent predictors of mitral valve surgery. ConclusionsThe study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

Clinical Characteristics of Marfan Syndrome in Korea.

Background and ObjectivesMarfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance and a highly variable clinical spectrum. However, there are limited data available on the clinical features of Korean patients with MFS. The aim of the present study was to describe the clinical characteristics and outcomes of Korean patients with MFS.Subjects and MethodsWe included all patients who were diagnosed with MFS between January 1995 and May 2015 at a single tertiary medical center. Patients with an MFS-related disorder including MASS phenotype (myopia, mitral valve prolapse, borderline and non-progressive aortic root dilatation, skeletal findings, and striae), mitral valve prolapse syndrome, and ectopia lentis syndrome were excluded. A total of 343 Korean patients aged ≥15 years who satisfied the revised Ghent nosology were included.ResultsThe mean patient age at diagnosis was 35.9±12.6 years and 172 (50.1%) patients were male. Median follow-up duration was 52.8 months. A total of 303 patients (88.6%) had aortic root dilatation with Z score ≥2 or aortic root dissection. Ectopia lentis was relatively less common (163 patients, 55.1%) and systemic score ≥7 was found in 217 patients (73.8%). Among 219 probands, a family history of MFS was present in 97 patients (44.5%) and sporadic cases in 121 patients (55.5%). Among the 157 probands who underwent genetic analysis, 141 (89.8%) had an FBN1 mutation associated with aortic root aneurysm/dissection. Aortic dissection (AD) or intramural hematoma (IMH) was identified in 110 patients (32.1%). Among the 221 patients without AD or IMH, descending aortic aneurysms were identified in 19 patients (8.6%). Two hundred thirteen patients (62%) underwent cardiovascular surgery of any type. Eight patients died during follow-up.ConclusionWe described the clinical characteristics and outcomes of Korean MFS patients. Cardiovascular manifestations were commonly detected and FBN1 mutation was present in approximately 90% of patients. In contrast, ectopia lentis was identified in approximately half of patients. Our findings will be informative for the evaluation of patients with MFS.

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome.

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%–53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.

Analysis of Protrusio Acetabuli Using a CT-based Diagnostic Method in Korean Patients with Marfan Syndrome: Prevalence and Association with Other Manifestations.

A new CT-based diagnostic method of protrusio acetabuli (PA) was introduced. However, prevalence of PA by this method and correlation between PA and other manifestations of Marfan syndrome (MFS) is unknown in Korean MFS patients. This study aimed to investigate the prevalence of PA diagnosed by a CT-based method in Korean patients with MFS, the association of PA with other manifestations of MFS, and the contribution of PA to MFS diagnosis. We retrospectively reviewed the records of 146 MFS patients with the presence of a causative FBN1 mutation and 146 age- and sex-matched controls from a single tertiary care center. All MFS patients underwent a complete assessment of criteria based on the revised Ghent nosology. PA was assessed quantitatively using a CT-based circle-wall distance (CWD) method. PA was diagnosed in 77.4% of patients in the MFS group and in 11.0% of the control group. CWD was significantly different between the two groups (1.50 mm vs. -0.64 mm, P<0.001). The presence of PA did not correlate with the presence of ectopia lentis, aortic root diameter, or history of aortic dissection. The presence of PA did not have a significant impact on the final diagnosis of MFS. Even though the presence of PA does not related to the cardinal clinical features of MFS or influence MFS diagnosis, its presence may be helpful for the suspicion of MFS when aortic dissection or aneurysm is found on CT angiography of the aorta because of the high frequency of PA in MFS patients.

Diagnosis and treatment of Marfan syndrome: an update

> But in no regard was he more peculiar than in his personal appearance. He was singularly tall and thin. He stooped much. His limbs were long and emaciated. His...

Síndrome de Marfan, mutaciones nuevas del gen FBN1

Marfan syndrome (SM) is a systemic disorder caused by mutations in the extracellular matrix protein fibrillin 1 (FBN1). With a dominant autosomal pattern, SM patients are characterized by ocular, cardiovascular and skeletal involvement, all within a variable clinical spectrum. It has been suggested that the intrafamilial and interfamilial phenotypic variability, characteristic of the syndrome, occurs by the association of other mutations called driver mutations. Even though there is a clear genetic causation, the recently described driver mutations are not yet fully elucidated. We present a SM case with a mutation not previously described in the fibrilin 1 gene, applying the revised Ghent nosology and analyzing the role of this new mutation and of the driver mutations in the genesis of the disease.

The revised ghent nosology; reclassifying isolated ectopia lentis

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term 'IEL' should be avoided in such cases.

Phenotype Presentation for a Novel Mutation Affecting a Conserved Cysteine Residue in Exon 63 of Fibrillin-1 (Cys2633Arg)

Marfan syndrome is an autosomal dominant disease caused by mutations in the gene encoding for fibrillin-1 (FBN1). More than 1,000 FBN1 mutations have been identified, which may lead to multiple organ involvement, particularly of the ocular, skeletal, and cardiovascular systems. Mutations in exons 59-65 have been reported in the past to cause mild Marfan-like fibrillinopathies. We report a family with a mutation in exon 63 that manifests with significant cardiovascular system involvement such as aortic root dilatations, dissection of the aorta, and sudden death at a young age. Genetic analysis revealed that four related individuals are positive for a novel heterozygous Cys2633Arg mutation in exon 63. Their genotype-phenotype profile (based on the revised Ghent nosology) is described. We postulate that the Cys2633Arg mutation may manifest with significant and progressive enlargement of the aortic root, risk of aortic dissections, and minor skeletal abnormalities, without involving the ocular system (i.e., ectopia lentis).

小児Marfan症候群における改訂Ghent基準の有用性

小児Marfan症候群における改訂Ghent基準の有用性