Diagnosis Of Marfan Syndrome Research Articles

Indirect genotype analysis as a diagnostic procedure in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue characterized by skeletal, ocular and cardiovascular manifestations. The disease is caused by mutations in the FBN1 gene, encoding fibrillin, an important component of elastic fibers. Diagnosis of Marfan syndrome is currently based on detailed clinical examination and/or mutation analysis in the fibrillin gene. Clinical expression varies widely both among and within families, rendering clinical diagnosis extremely difficult. In this study, we performed segregation analysis of allelic DNA polymorphisms to support diagnosis of Marfan syndrome. This type of genotype analysis is a useful, additional diagnostic tool for families with Marfan syndrome and provides incremental information of diagnosis or exclusion of Marfan syndrome based on clinical findings.

A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome

PurposeTo compare the Berlin and Ghent diagnostic criteria for Marfan syndrome and evaluate the utility of screening for dural ectasia in the diagnosis of Marfan syndrome. MethodsReview of clinical and radiographic data on 73 patients evaluated for Marfan syndrome at the National Institutes of Health. ResultsNineteen percent of patients diagnosed under the Berlin criteria failed to meet the Ghent standard. Dural ectasia was the second most common major diagnostic manifestation, and screening for dural ectasia established the diagnosis of Marfan syndrome in 23% of patients under the Ghent criteria. ConclusionsSome patients are appropriately excluded from the diagnosis of Marfan syndrome by the Ghent criteria. Determination of dural ectasia is valuable in the diagnosis of Marfan syndrome.

Results of brace treatment of scoliosis in Marfan syndrome.

Retrospective review of a defined Marfan population with traditional indications for bracing. To determine the success rate of brace treatment in keeping curves from progressing by more than 5 degrees or exceeding 45 degrees. Few studies exist regarding brace treatment of Marfan syndrome, and they include many patients with curves of more than 45 degrees, as well as some who are near maturity. All of the prior studies risk the possibility of some selection bias. Patients were selected from support groups and several institutions. Inclusion criteria were: Definite diagnosis of Marfan syndrome, curve of 45 degrees or less, Risser sign 2, 1, or 0 at inception of bracing, recommended wear of 18 hours or more per day, and follow-up until maturity or surgery (minimum, 2 years). Success was defined as curve progression of 5 degrees or less and final curve remaining 45 degrees or less. Failure was a final curve of more than 45 degrees. Twenty-four patients met the criteria. There were 15 girls and 9 boys. Twenty-two patients wore a brace as recommended. Two additional patients were unable to tolerate it. Mean age at inception of bracing was 8.7 years (range, 4-12 years). There were 14 double major, 6 thoracic, and 4 thoracolumbar curves with a mean size of 29 degrees at the beginning of bracing. The stated wearing time averaged 21 hours per day. Five patients had significant pain over bony prominences. Although correction of the curve in brace was good (45%), only 4 of the patients had success, and in 20 of the 24 treatment was considered a failure. Mean progression was 6 degrees +/- 8 degrees per year, for a final mean curve of 49 degrees. Sixteen of the patients had, or were advised to have, surgical correction. The difference in age and degree of curvature were not statistically significant between the success and nonsuccess groups. The success rate for brace treatment of Marfan scoliosis is 17%, which is lower than that reported for idiopathic scoliosis. Possible reasons include increased progressive forces, altered transmission of corrective pressure to the spine, and younger age at inception of bracing. Because there was no control group, it is unknown whether bracing slowed curve progression. Physicians should understand that most patients with Marfan syndrome who have a curve of more than 25 degrees and a Risser sign of 2 or less will reach the surgical range, even with brace treatment.

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.

Diagnosis of Marfan syndrome: dural ectasia

Diagnosis of Marfan syndrome: dural ectasia

Familial patterns of thoracic aortic aneurysms.

To provide evidence that genetic factors contribute to the development of thoracic aortic aneurysms (TAA) by demonstrating familial patterns of the disease. Retrospective review. University hospital. We sought to identify familial patterns of TAA from a database of 598 patients evaluated or treated for TAA at the Yale Center for Thoracic Aortic Disease, New Haven, Conn, from January 1985 to August 1998. Of the 598 patients, 45 patients had a diagnosis of Marfan syndrome and 553 patients had no known history of any collagen vascular disorder. Of the 553 patients in the latter category, 398 patients had confirmed TAA, 66 had TAA with concomitant aortic dissections, and 89 had aortic dissections. From the group of 464 patients with TAA with or without concomitant aortic dissections, 2 interviewers attempted to contact 150 randomly selected patients for telephone screening to determine the presence of familial patterns of aortic disease. Fifteen of these patients were lost to follow-up. Complete medical and family histories of the remaining 135 patients (85 men, 50 women) were reviewed. Of the 135 individuals screened, 26 (18 men, 8 women) (19.3%) were found to belong to multiplex pedigrees. These 26 patients with familial nonsyndromic TAA were compared with the remaining 109 patients with sporadic TAA and the 45 patients with Marfan syndrome-associated TAA. Groups were examined for statistical differences in age and aortic size at the time of diagnosis, growth rates of TAA, and rates of concomitant diseases. Nonsyndromic family pedigrees were analyzed and potential modes of inheritance were determined. The mean age at presentation for patients with familial nonsyndromic TAA (56.8 years) was significantly younger than the mean age of presentation in sporadic cases (64.3 years, P< or =.03), and significantly older than that of patients with Marfan syndrome (24.8 years, P< or =.001). Patients with a family history of aortic aneurysms had faster growth rates (0.22 cm/y) compared with patients with sporadic TAA (0.03 cm/y) (P< or =.001) and patients with Marfan syndrome (0.10 cm/y) (P< or =.04). Familial nonsyndromic TAA in patients with a concomitant aortic dissection had a growth rate of 0.33 cm/y, which was greater than that of patients with sporadic TAA (0.10 cm/y) and patients with Marfan syndrome (0.08 cm/y) with associated aortic dissection. This growth of 0.33 cm/y was significantly faster than the overall growth rate estimate of aneurysms in patients with aortic dissection (0.14 cm/y) (P< or =.05). Ten pedigrees (38.5%) showed direct father to son transmission, consistent with an autosomal dominant mode of inheritance. Six family pedigrees (23.1%) suggested an autosomal dominant or X-linked mode of inheritance. Seven pedigrees (26.9%) suggested a recessive mode of inheritance; 2 an autosomal recessive mode, and 5 an X-linked recessive or autosomal recessive mode. The remaining 3 pedigrees displayed more complex modes of inheritance. This study supports the role of genetic factors influencing familial aggregation of TAA. Thoracic aortic aneurysms in association with multiplex pedigrees represent a new risk factor for aneurysm growth. Pedigree analysis suggests genetic heterogeneity. The primary mode of inheritance seems to be autosomal dominant, but X-linked dominant and recessive modes are also evident.

Preimplantation genetic diagnosis of Marfan syndrome with the use of fluorescent polymerase chain reaction and the Automated Laser Fluorescence DNA Sequencer

Objective: To develop and apply clinical preimplantation genetic diagnosis (PGD) for Marfan syndrome. Design: Case report. Setting: Centers for medical genetics and reproductive medicine in university hospitals. Patient(s): One couple in which the husband was affected with Marfan syndrome. Intervention(s): The couple underwent three intracytoplasmic sperm injection cycles. Main Outcome Measure(s): The correct diagnosis was obtained for embryos in three PGD cycles. Result(s): Although all the PGD cycles were followed by ET, no pregnancy ensued. Conclusion(s): This assay can provide a reliable and accurate preimplantation diagnosis of Marfan syndrome.

Marfan syndrome: is early diagnosis useful?

Marfan syndrome is an uncommon disorder of connective tissue characterized by abnormalities in the skeleton, eyes and cardiovascular system. It may present in infancy or childhood, although frequently the diagnosis is not made until adulthood. In recent years there have been major advances in our understanding of the aetiology, pathogenesis and diagnosis of Marfan syndrome. This has led to a rational strategy for diagnosis and management in the child. The purpose of this chapter is to discuss the diagnosis of Marfan syndrome in childhood and to address the question: 'Is early diagnosis useful?'

Marfan syndrome: diagnosis of cardiovascular manifestations

With the availability of modern imaging modalities such as magnetic resonance imaging (MRI), contrast-enhanced computed tomography (CT), and transesophageal echocardiography (TEE), diagnostic options in the evaluation of Marfan patients have been improved profoundly. The most recent diagnostic advances comprise noninvasive tissue characterization of the aortic wall, immunofluorescence studies or pulse chase analyses of skin and cultured dermal fibroblasts, and molecular analysis at the cDNA/DNA level of the fibrillin-1 gene. New diagnostic insights have eventually led to revised nosologic criteria for the diagnosis of Marfan syndrome. The diagnostic reliability as well as the advantage and limitation of these recent diagnostic strategies are discussed; moreover diagnostic concepts for patients with neonatal as well as classic Marfan syndrome are presented and discussed in the context of the clinical management during adolescence, gravidity as well as in the pre- and postoperative patient.

Prenatal and presymptomatic diagnosis of Marfan syndrome using fluorescence PCR and an automated sequencer.

The Marfan syndrome (MFS) is an autosomal dominant heritable connective tissue disorder characterized by variable and pleiotropic manifestations primarily in the skeletal, ocular, and cardiovascular systems (). Molecular defects in fibrillin-1, a 350 kDa glycoprotein, encoded by the FBN1 gene located on chromosome 15 are now well documented in individuals and families with MFS (see ref. for a review). The variability in phenotypic expression of MFS is significant not only between families, but also within a family, while the effective treatment of patients with MFS relies heavily on early and accurate diagnosis. It, therefore, seems likely that prenatal and presymptomatic molecular genetic analysis would prove a valuable adjunct to clinical diagnosis for purposes of risk assessment (, , ). Mutations have been found along the entire 10 kb coding region of fibrillin and in most of its 65 exons. In addition, most families appear to have unique mutations. Therefore, the routine use of mutation screening for prenatal and presymptomatic diagnosis is impractical in this disorder. We have used intragenic polymorphic markers in FBN-1 () to perform linkage analyses in MFS families. We have adapted a “one-step” or “two-step” fluorescence PCR and automated sequencer to accurately, reproducibly, and rapidly perform prenatal or presymptomatic diagnosis of MFS in informative families.

Metacarpophalangeal pattern profile in Marfan syndrome and Marfan-like patients

Marfan syndrome (MFS) is an autosomal dominant trait due to mutations in the fibrillin gene (FBN1). The MFS expressivity is variable, and its diagnosis relies completely on clinical criteria. Atypical cases and Marfan-like (marfanoid) clinical presentations are commonly found. The metacarpophalangeal pattern profile (MCPP), a radiological method in which the 19 tubular hand bones are assessed, has been used in the diagnosis of various syndromes. To investigate whether the MCPP was adequate to discriminate between MFS and Marfan-like subjects, we studied 38 patients who were referred to our service because they had an MFS diagnosis, diagnostic hypothesis, or differential diagnosis or had arachnodactyly with dolichostenomelia. Two groups were formed: 1) MFS: 21 patients with a mean age of 18.3 (10.8 S.D.) years and 2) Marfan-like syndromes: 16 patients who did not meet the current criteria, with a mean age of 14.6 (4.6 S.D.) years. The MCPP was performed in each case following the classical technique, and a characteristic mean profile was obtained for group I (MFS), with Z scores ranging from 0.69 to 2.73 (1.80+/-0.50; mean+/-S.D.). In group I, three cases had no correlation with the typical MFS pattern. In group II, three cases had an MFS pattern. The correlation with the mean MCPP of MFS permitted the differential diagnosis of MFS and marfanoid syndromes with 86% sensitivity, 81% specificity, and 86% positive and 81% negative predictive values. The results suggest that MCPP can be used effectively as an auxiliary tool in the nosology of these conditions and, because there is no change in MCPP with age, can be helpful in early diagnosis.

Health Supervision for Children With Marfan Syndrome

This Clinical Report was revised. See https://doi.org/10.1542/peds.2023-061450. This set of guidelines is designed to assist the pediatrician in caring for children with Marfan syndrome confirmed by clinical criteria. Although pediatricians usually first see children with Marfan syndrome during infancy, occasionally they will be called on to advise the pregnant woman who has been informed of the prenatal diagnosis of Marfan syndrome. Therefore, these guidelines offer advice for this situation as well.

Is the metacarpal index useful in the diagnosis of marfan syndrome?

Aim: This study was undertaken to analyse the importance of the Metacarpal Index (MCI) in making the diagnosis of Marfan syndrome. Patients and methods: The characteristics of 42 patients with Marfan syndrome as defined by strict criteria were analysed. Fifty-one consecutive accident and emergency patients comprised the control group for the MCI measurements. Results: Using MCI alone four (7.8%) of controls had an abnormal MCI, and seven (16.6%) of Marfan patients were normal. Thirty-two (76%) of Marfan patients had an abnormal MCI and three (13.4%) were equivocal. Using other skeletal parameters (upper segment to lower segment ratio, arm span 3 cm or more greater than height, or palate, pectus or scoliosis deformity) 40 (95%) of the Marfan group had an abnormality. Other parameters: 18 (43%) in the Marfan group gave a history of retinal detachment or ectopia lentis. Echocardiographic measurements showed aortic root dilatation in 29 (69%) and in 21 (50%) mitral valve prolapse was found; 37 (88%) had one or other cardiac abnormality. Using all parameters excluding MCI: All the patients would still have fulfilled the diagnostic criteria for the diagnosis of Marfan syndrome. Conclusion: The role of the MCI, a radiation dependent and time consuming measurement, is probably insignificant in diagnosis of the majority of Marfan patients. Combined with clinical measurements, an echocardiogram is probably the single most useful investigation, aiding both diagnosis and management.

Molecular etiology, pathogenesis and diagnosis of the Marfan syndrome

It is now known that most, if not all cases of classic Marfan syndrome are caused by primary mutations in the gene (FBN1) encoding the extracellular matrix protein fibrillin-1. The challenge ahead is to use this information in a responsible manner to improve the lives of affected patients and families. While the prospect for gene therapy, the most dramatic potential application, is now exciting and real, many theoretical and technological obstacles must be overcome. Among these is an incomplete but expanding comprehension of the pathogenesis of Marfan syndrome. Nevertheless, molecular analysis has led to an increased understanding of the origins of pleiotropy and clinical variability in the Marfan syndrome, a pre-requisite for the development of rationale therapeutic strategies. Of more immediate practical importance, it is now possible to apply molecular methods to the pre-symptomatic and prenatal diagnosis of Marfan syndrome, providing the first opportunity for disease prevention and for presumptive rather than symptomatic intervention. Two genetic methods are routinely applied to determine whether an individual or fetus is at risk for the development of a phenotype concordant with that seen in other affected family members. Linkage analysis is both efficient and accurate, but requires the existence and involvement of many affected and unaffected family members. Direct mutational analysis obviates many of these requirements, but is both time and cost intensive. In selected circumstances, protein analyses, such as immunohistochemistry and metabolic labeling studies, may be useful in the evaluation of individuals at risk for the development of Marfan syndrome or related disorders. It must be stressed that molecular data must always be considered in conjunction with a thorough phenotypic assessment. No test, in isolation, is sufficient for the unequivocal assignment of affected or unaffected status. The Marfan syndrome is now, and shall always remain, a clinical diagnosis. When applied in conjunction with a consideration of each family's beliefs, expectations, resources, and priorities, molecular analysis can be a useful adjunct in patient management and counseling.

Revised diagnostic criteria for the Marfan syndrome

In 1986, the diagnosis of the Marfan syndrome was codified on the basis of clinical criteria in the Berlin nosology [Beighton et al., 1988]. Over time, weaknesses have emerged in these criteria, a problem accentuated by the advent of molecular testing. In this paper, we propose a revision of diagnostic criteria for Marfan syndrome and related conditions. Most notable are: more stringent requirements for diagnosis of the Marfan syndrome in relatives of an unequivocally affected individual; skeletal involvement as a major criterion if at least 4 of 8 typical skeletal manifestations are present; potential contribution of molecular analysis to the diagnosis of Marfan syndrome; and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes.

Is Marfan Syndrome Associated With Symptomatic Intracranial Aneurysms?

Marfan syndrome is a heritable disorder of connective tissue caused by a deficiency of the glycoprotein fibrillin. In several publications and neurological textbooks, a relationship between Marfan syndrome and intracranial aneurysms has been assumed. The records of 135 patients classified as having Marfan syndrome who visited the Amsterdam Marfan clinic or were admitted to the departments of neurology and neurosurgery and the records of all patients with a subarachnoid hemorrhage or intracranial aneurysm who visited or were admitted to the departments of neurology and neurosurgery between January 1, 1982, and January 1, 1994, were retrieved. The literature was reviewed regarding Marfan syndrome and intracranial aneurysms. No patient visiting the Marfan clinic had a symptomatic intracranial aneurysm. No patient with Marfan syndrome had been admitted with a ruptured intracranial aneurysm at the departments of neurology or neurosurgery in this period, while during that period 826 patients with symptomatic intracranial aneurysms had been admitted. During follow-up of 129 of the 135 patients with Marfan syndrome (2850 retrospective patient observation years and 581 prospective patient observation years), none presented a symptomatic intracranial aneurysm. The suggested relationship between Marfan syndrome and intracranial aneurysms is based mainly on 10 case reports. However, the diagnosis of Marfan syndrome is doubtful in several of these reports. Several large studies of patients with Marfan syndrome did not mention a ruptured intracranial aneurysm as a clinical manifestation. We conclude that there is insufficient evidence to presume a relationship between symptomatic intracranial aneurysms and Marfan syndrome on the basis of currently available data.

Fibrillin abnormalities and prognosis in marfan syndrome and related disorders

Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the fibrillin protein. To determine the sensitivity and specificity of fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including homocystinuria and Ehlers-Danlos syndrome. Abnormal fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including arachnodactyly, striae distensae, cardiovascular manifestations, and fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened "event-free" survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with fibrillin abnormalities. Our results indicate that fibrillin defects at the protein level per se are not specific for MFS, but that the drastically reduced fibrillin deposition, caused by a dominant-negative effect of abnormal fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance.

Marfan syndrome as a paradigm for transcript-targeted preimplantation diagnosis of heterozygous mutations.

Among the many clinical applications of the polymerase chain reaction (PCR) is its potential use in preimplantation diagnosis of genetic disorders. Performing PCR on single blastomeres from early cleavage stage (six- to eight-cell) human embryos should, in principle, enable reliable determination of disease status for certain inherited conditions. However, reports of misdiagnoses using this technique have diminished enthusiasm for its widespread clinical use. One principal source of error is the propensity for genome-targeted PCR to exclusively amplify one allele in reactions assaying a single heterozygous diploid cell. Complete reaction failure is also common. Employing the Marfan syndrome (MFS) as a paradigm, we have developed a reliable, reverse transcription-PCR-based method of genotyping single cells that overcomes these obstacles. The technique should facilitate accurate preimplantation diagnosis of MFS and other selected genetic diseases caused by heterozygous or compound-heterozygous mutations.

The Marfan syndrome. An underdiagnosed killer

The Marfan syndrome is an inherited connective-tissue disorder. The sequela of the syndrome is premature death that is most often due to cardiac complications and that can be prevented with early diagnosis and aggressive management. Although research has identified a gene responsible for the myriad of phenotypic presentations, the diagnosis of Marfan syndrome remains clinical. The family physician is well positioned, with consultation from an experienced cardiac surgeon, to orchestrate the diagnosis and management of the Marfan syndrome.