Revised Criteria May Increase Accuracy of Marfan Diagnosis

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.