Features Of Marfan Syndrome Research Articles

Increased Homocysteine in a Patient Diagnosed with Marfan Syndrome

A 53-year-old Caucasian woman was diagnosed in late childhood with Marfan syndrome according to characteristic skeletal features and bilateral lens dislocation. In addition, she has a history of nonischemic cardiomyopathy with severe left ventricular failure and atrial fibrillation, diabetes mellitus type 2, hyperlipidemia, progressive dementia, numbness in the lower extremities, and hypothyroidism following thyroidectomy for thyroid cancer. Additional findings revealed in a physical examination included an upper-to-lower segment ratio of 0.88, an arm span–to–height ratio of 1.02 (an upper-to-lower–segment ratio 1.05 are 2 of the diagnostic criteria for Marfan syndrome), an elongated face, a high arched palate, and crowded dentition. She recently underwent further laboratory testing after a cardiologist did not find 2 characteristic features of Marfan syndrome, namely an enlarged aortic root and mitral valve prolapse. Her total plasma homocysteine and methionine concentrations were increased at 198 μmol/L (reference interval, 5–15 μmol/L) and 370 μmol/L (reference interval, 10–50 μmol/L), respectively. The patient's plasma homocystine concentration was 48 μmol/L (reference interval, <2 μmol/L), and her urine homocystine concentration was also markedly increased. These biochemical abnormalities are not characteristic of Marfan syndrome. Her diagnosis was reconsidered in light of these new data. In this case, a long-standing clinical diagnosis was inconsistent with recently obtained clinical and biochemical data. The biochemical data were virtually diagnostic of homocystinuria [OMIM3 (Online Mendelian Inheritance in Man) 236200], a term historically used to describe inborn errors of metabolism characterized by excessive excretion of homocystine in urine and high concentrations of total plasma homocysteine. Homocystinuria is most commonly caused by autosomal recessive inheritance of a deficiency in cystathionine β-synthase (CBS) activity (1). The worldwide incidence has been estimated to be between 1 in 200 000 and 1 in 335 000 population (2), with the highest incidence (1 in 1800) reported in Qatar …

The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation. © 2010 Wiley-Liss, Inc.

De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome

Interstitial deletions involving the 15q21.1 band are very rare. Only 4 of these cases have been studied using molecular cytogenetic techniques in order to confirm the deletion of the whole FBN1 gene. The presence of clinical features of the Marfan syndrome (MFS) spectrum associated with mental retardation has been described in only 2/4 patients. Here we report on a 16-year-old female referred for suspicion of MFS (positive thumb and wrist sign, scoliosis, joint hyperlaxity, high-arched palate with dental crowding, dysmorphism, mitral insufficiency with dystrophic valve, striae). She had therefore 3 minor criteria according to the Ghent nosology. She also had speech disabilities but could follow normal school training. Direct sequencing of the FBN1, TGFBR1 and TGFBR2 genes was negative. MLPA revealed a genomic deletion of the whole FBN1 gene, confirmed by loss of heterozygosity of maternal alleles for several microsatellite markers surrounding the FBN1 gene. The deletion was confirmed by FISH using a FBN1 probe and was not found in the parents. Array-CGH permitted to define a 2.97 Mb deletion, which was the smallest 15q microdeletion including FBN1. Contrary to the other published observations, our proband does not exhibit mental retardation, but neuropsychological evaluations revealed an attention deficit as well as a deficit in information-processing speed. Haploinsufficiency of FBN1 is likely to contribute to the presence of MFS features. However, attenuated features could be explained because disturbances of TGF-β signalling associated with FBN1 mutations do not exert full phenotypic effect through simple haploinsufficiency. Phenotypic variability in other patients with interstitial deletions including 15q21.1 band may reflect differences in deletion size and/or cys/trans modifying factors.

Dilated Cardiomyopathy in a Patient with Marfan Syndrome Accompanied by Chronic Type A Aortic Dissection and Right Atrial Thrombus

Marfan's syndrome (MFS) is an autosomal dominant disorder of connective tissue involving musculoskeletal, cardiovascular and ocular systems. Aortic disease is the leading cause of mortality in MFS. Among all, dilated cardiomyopathy in the absence of severe valvular dysfunction is a very rare cardiovascular feature of MFS. We report a case of biventricular heart failure in a patient with MFS, complicated by chronic type A aortic dissection and right atrial thrombus. This report clearly highlights the importance of close cardiovascular follow-up in patients with MFS.

Rutherfurd syndrome associated with Marfan syndrome

Rutherfurd syndrome is a rare genetic disorder that is primarily characterised by the classical triad of gingival fibromatosis, delayed tooth eruption and corneal dystrophy. Associated features of the condition include abnormally shaped teeth, mental retardation and aggressive behaviour. His Consultant Clinical Geneticist referred a 2-year-old boy to the Dept. of Paediatric Dentistry at Manchester Dental Hospital. The child and his father had a diagnosis of Rutherfurd Syndrome; a rare autosomal-dominant condition featuring corneal dystrophy, gingival hypertrophy, abnormally shaped teeth and delayed eruption. The only erupted teeth were 52, 71 and 81. The patient also suffers from features of Marfan syndrome, a condition he has inherited from his mother. Preventive advice was provided and the patient was placed on regular review. By the age of 4 years, 52, 61, 72, 71 and 81 were the only teeth present clinically. Maxillary and mandibular dentures were provided, which he refused to wear. At age 8 years, 31 and 41 were erupted lingual to the primary incisors. No other permanent teeth had erupted. Radiographs revealed failure of eruption of multiple primary and permanent teeth. The second premolars had formed above the unerupted mandibular primary second molars. The patient continued to refuse any intervention. Treatment options discussed included overdentures and /or removal of primary teeth and exposure of permanent teeth. This case has presented a rare syndrome with two important dental features, namely gingival hyperplasia and failure of eruption. The case has a long term follow up of 6 years and has a first time association to Marfan syndrome. It also highlights the importance of family history and how it can affect the attitude of the child towards dental treatment.

The Roles of Two NovelFBN1Gene Mutations in the Genotype–Phenotype Correlations of Marfan Syndrome and Ectopia Lentis Patients with Marfanoid Habitus

Mutations in the fibrillin-1 (FBN1) gene have been identified in patients with Marfan syndrome (MFS) and Marfan-like connective tissue disorders. In this study, two Chinese families were recruited. The patients in family 1 were well characterized with MFS, while those in family 2 displayed Marfan-like disorders such as ectopia lentis (EL) and marfanoid habitus, but did not develop cardiovascular diseases. We aimed to analyze the pathogenic mutations and their relationships with phenotypes in these two Chinese families. All participants underwent complete physical, ophthalmic, and cardiovascular examinations. The 65 exons and flanking intronic sequences of FBN1 were amplified by polymerase chain reaction, and screened for mutations by denaturing high-performance liquid chromatography and sequencing. One hundred and fifteen unrelated controls were analyzed using the same methods to confirm the mutations. In family 1, we identified the mutation p.C499S in the calcium-binding epidermal growth factor (cbEGF)-like domain 3 of FBN1. In family 2, the mutation p.C908Y was identified in an interdomain region of the hybrid motif 2 linked to the cbEGF-like domain 10. It can be concluded that FBN1 mutations involving cysteine substitutions are usually associated with MFS and EL with some MFS features. Moreover, pathology seemed more serious when the mutations disrupted the three disulfide bridges in the cbEGF-like domains, which was more likely to cause typical MFS than if the mutations occurred in the hybrid motifs. Our data preliminarily establish a genotype-phenotype correlation in the diagnostic process of MFS and predominant EL with Marfan-like features.

Comparison of computed radiography and multi-detector computed tomography in the detection of post mortem metacarpal index

Background The sudden, unexpected death of young persons from ruptured thoracic aortic dissection is suggestive of Marfan syndrome (MFS), a genetic disorder of fibrillin. Establishing such a diagnosis is important so that the same fate might be avoided in living relatives. MFS diagnosis is difficult in the deceased but the presence of arachnodactyly, a common morphological feature of MFS, can be established by assessing the metacarpal index (MCI). MCI is routinely determined using radiographic techniques including computed radiography (CR). The wider availability of computed tomography (CT) in the forensic environment provides an alternative method. CT is predicted to produce measurements at least as accurate as CR. The aims of this study therefore were to (1) validate MCI measurements by comparing CT and CR with direct measurement using calipers on human skeletonised hands, and (2) compare cadaveric CT and CR MCI measurements. Methods The metacarpals of 12 human skeleton hands were measured using CT and CR, and compared with direct measurement using calipers (the “gold standard”). Fifty randomly selected cadavers between 20 and 40 years had the MCI of both hands measured using CT and CR. Results CT was found to be more accurate in the measurement of MCI than CR. There were significant differences in the MCIs obtained for CT and CR (females: p = 0.01; males: p < 0.0001) and between CR and calipers ( p = 0.004). There were no significant differences between MCIs obtained for CT and calipers ( p = 0.71). CR was found to consistently overestimate the MCI by an average of 7.97%. Conclusion CT is more accurate in determination of the MCI than CR and should provide the basis for future skeletal measurements.

Transclival cerebrospinal fluid fistula in a patient with Marfan’s syndrome

Marfan's syndrome is a disease associated with reduced structural integrity of connective tissues. We report a 36-year-old patient with Marfan's syndrome who presented with rhinorrhoea, occipital headache and vomiting. Physical examination revealed typical Marfan's syndrome features including dolicocephalous, mandibular micrognathia, tall stature, disproportionately long limbs and digits, and hypermobility of the joints. A high-resolution CT scan demonstrated pneumoencephalous, cerebrospinal fluid (CSF) filling the sphenoidal sinus, and a small bone defect of the clivus. Surgery performed through a transsphenoidal approach revealed the sphenoid sinus to be filled with CSF and a small fenestration in the clivus. The arachnoid diverticulum and the fenestration were repaired and covered with a graft of abdominal fat. In this patient, a deficiency in bone development associated with Marfan's syndrome gave rise to a clival fenestration and a transclival CSF fistula. Although abnormalities of the spinal meningeal membranes have been reported in Marfan's syndrome, to our knowledge, this is the first report of a fistula located in the cranial base in this condition.

Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan‐related phenotypes

In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study. A total of 27 FBN1 mutations (22 novel) in 27 patients (55%, 27/49), 1 novel TGFBR1 mutation in 1 (2%, 1/49), and 2 recurrent TGFBR2 mutations in 2 (4%, 2/49) were identified. No FBN2 mutation was found. Three patients with either TGFBR1 or TGFBR2 abnormality did not fulfill the Ghent criteria, but expressed some overlapping features of MFS and Loeys-Dietz syndrome (LDS). In the remaining 19 patients, either of the genes did not show any abnormalities. This study indicated that FBN1 mutations were predominant in MFS but TGFBRs defects may account for approximately 5-10% of patients with the syndrome.

TGFBR1andTGFBR2mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by manifestations in the cardiovascular, skeletal, ocular, and other organ systems. MFS type1 (MFS1) is caused by mutations in the gene encoding fibrillin (FBN1). Recently, the transforming growth factor-beta receptor-2 gene, TGFBR2, has been shown to be associated with a second type of this disorder with typically mild or absent ocular involvement (MFS type 2; MFS2). Several point mutations were found in the highly conserved serine/threonine kinase domain of TGFBR2. Mutations in both TGFBR1 and TGFBR2 are associated with Loeys-Dietz aortic aneurysm syndrome (LDS). We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, two mutations and two polymorphisms were detected. In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS.

Spectrum of Aortic Operations in 300 Patients With Confirmed or Suspected Marfan Syndrome

Cardiovascular disease is the main cause of morbidity and mortality in patients with Marfan syndrome. Many patients with presumed Marfan syndrome do not meet current diagnostic criteria. This study reviews the surgical aspects of aortic disease in 300 patients referred with the diagnosis of Marfan syndrome. During a 16-year period, 300 patients with presumed Marfan syndrome underwent 398 operations on the aorta and branch arteries, including 125 aortic root operations, 59 aortic arch repairs, 31 descending thoracic aortic repairs, and 178 thoracoabdominal aortic repairs. Based on medical record review, patients were classified as confirmed Marfan syndrome if documented features satisfied current diagnostic criteria; patients not meeting these criteria were classified as suspected Marfan syndrome. There were 17 operative deaths (4.3%) after the 398 operations. Survival after the initial referral operation was 96.2% +/- 1.5% at 1 year, 82.7% +/- 2.4% at 5 years, and 74.6% +/- 3.1% at 10 years. Presentations, operative details, and outcomes were remarkably similar in the 137 patients (45.7%) with confirmed Marfan syndrome and the 163 patients (54.3%) with suspected Marfan syndrome. Freedom from repair failure, however, was significantly better in patients with confirmed Marfan syndrome (90.3% +/- 2.3% at 10 years) than in those with suspected Marfan syndrome (82.0% +/- 3.1% at 10 years; p = 0.001). Operative treatment of the full spectrum of aortic disease in Marfan patients enables excellent long-term survival. Similarities in surgical aspects of aortic disease suggest that patients with features of Marfan syndrome who do not meet diagnostic criteria should be managed in the same manner as patients with confirmed Marfan syndrome.

Shprintzen-Goldberg Syndrome With Tetralogy of Fallot and Subvalvar Aortic Stenosis

Shprintzen-Goldberg syndrome is a rare and lethal association of craniosynostosis with features of Marfan syndrome. 1 It has been traced to a defect of chromosome 15. 2 Cardiac features include progressive aortic root dilatation. To our knowledge, there is no known association of this syndrome with congenital heart defects.

Radiofrequency ablation of a left-sided atrioventricular pathway in a patient with Marfan syndrome

Supraventricular tachycardia is a documented feature of Marfan syndrome. The safety and efficacy of radiofrequency ablation in this population of patients, however, has not been reported. We report on the successful use of radiofrequency ablation utilizing a trans-septal approach for the treatment of supraventricular tachycardia produced by an accessory muscular atrioventricular connection in a patient with Marfan syndrome.

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and “overlap” connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed.

Aortic root dilatation among young competitive athletes: Echocardiographic screening of 1929 athletes between 15 and 34 years of age

Background Aortic dilatation can be lethal for young competitive athletes. The prevalence among athletes is not known, however, and thus a reasonable approach to early recognition remains uncertain. Methods and results Echocardiograms of 1929 normotensive athletes 15 to 34 years of age were analyzed. Five (0.26%) athletes had aortic dilatation; 4 of the 5 played basketball. This made the prevalence of aortic dilatation 0.96% (4 of 415) among basketball and volleyball players, who represented a population of especially tall athletes. Tallness aside, only 2 of the 5 athletes had features of Marfan syndrome. Among the athletes without aortic dilatation, the relation between body surface area and aortic root dimension was nonlinear and best described with a quadratic regression model. Athletes with aortic dilatation fell well outside the 95% confidence interval. Conclusion Because a higher incidence of aortic dilatation is to be anticipated among very tall athletes, inclusion of echocardiography in screening before participation in certain sports should be considered.

The Marfan syndrome.

The Marfan syndrome (MFS), initially described just over 100 years ago, was among the first conditions classified as a heritable disorder of connective tissue. MFS lies at one end of a phenotypic continuum, with people in the general population who have one or another of the features of MFS at the other end, and those with a variety of other conditions in between. Diagnosis of MFS and these other conditions remains based on clinical features. Mutations in FBN1, the gene that encodes fibrillin-1, are responsible for MFS and (in a few patients) other disorders in the continuum. In addition to skeletal, ocular, and cardiovascular features, patients with MFS have involvement of the skin, integument, lungs, and muscle tissue. Over the past 30 years, evolution of aggressive medical and surgical management of the cardiovascular problems, especially mitral valve prolapse, aortic dilatation, and aortic dissection, has resulted in considerable improvement in life expectancy.

A comparison of the Berlin and Gent Nosologies in the diagnosis of Marfan syndrome: the NIH experience

We reviewed clinical and radiographic data on 73 patients evaluated for possible Marfan syndrome (MFS) at the National Institutes of Health for the purpose of comparing the 1987 Berlin and 1996 Gent diagnostic criteria. All patients had a physical examination, all had echocardiograms or known aortic root dilatation, 64 (88%) had ophthalmologic exams or known ectopia lentis, and 35 (48%) have had MRI scans to screen for dural ectasia. Thirty-one had a first degree relative who had been diagnosed with MFS, and we directly confirmed this diagnosis in 22 cases. Forty-eight patients met diagnostic criteria under the Berlin criteria and 39 under the Gent criteria (kappa correlation coefficient K=0.75). No patient who met diagnostic criteria under the Gent criteria failed to meet the Berlin criteria. Of patients diagnosed under the Berlin criteria, all had skeletal features of MFS, 40 (83%) had aortic root dilatation, 19 of 27 examined (70%) had dural ectasia, 27 (56%) had an affected first degree relative, and 12 of 44 examined (27%) had ectopia lentis. Determination of dural ectasia established the diagnosis for 9 patients under the Gent criteria but had no effect on diagnoses made under the Berlin criteria (K=0.53 comparing Berlin to Gent without dural ectasia data). In summary, approximately 20 percent of patients diagnosed with Marfan syndrome using the Berlin criteria do not meet the Gent diagnostic standard. Long term follow-up or molecular diagnostic data are necessary to establish the relative sensitivity and specificity of these diagnostic tools.

Toward an Understanding of the Cause of Mitral Valve Prolapse

Toward an Understanding of the Cause of Mitral Valve Prolapse

The association of absent suspensory ligaments of the liver and Marfan syndrome

Gastrointestinal manifestations of collagen diseases are very rare. The authors report on a patient who has features of Marfan syndrome with mobile liver caused by the absence of its suspensory ligaments. This patient presented with an acute intestinal obstruction secondary to a congenital band across the distal transverse colon. Recurrent intestinal obstruction after resection of the band necessitated the performance of partial colectomy with ileotransverse anastomosis. The patient's phenotypic features are suggestive but not diagnostic of Marfan syndrome. Nevertheless, isolated skeletal manifestations of Marfan syndrome with documented FBN1 gene mutation have been reported, suggesting the existence of milder forms of the syndrome not exhibiting the classic diagnostic criteria. The authors postulate that the absence of suspensory ligaments of the liver in this patient could be attributed to the defective connective tissue of Marfan syndrome.

Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes

Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.