Figure 1 Isaiah Austin, former standout basketball player for Baylor University, was diagnosed with Marfan syndrome in the weeks before the National Basketball Association draft. Photograph courtesy of Baylor University, with permission.

Isaiah Austin, a star basketball player from Baylor University, was diagnosed with Marfan syndrome in the weeks prior to the 2014 NBA draft (Figure 1). How did this happen? Isaiah was at the National Basketball Association (NBA) Combine in Chicago, Illinois, in preparation for the upcoming draft. He underwent a screening echocardiogram as part of the process. The echocardiogram was flagged as demonstrating a mildy dilated aortic root. Isaiah Austin was evaluated by a cardiologist, and it was determined that he exhibited some of the features that can be seen in Marfan syndrome. However, the diagnosis was uncertain as he was not considered to have many of the outward features. Noteworthy, Isaiah Austin had suffered a retinal detachment at age 11, which was ascribed to trauma related to a baseball injury. Genetic testing detected a pathogenic mutation in FBN1, confirming the diagnosis of Marfan syndrome. Isaiah Austin was advised to discontinue participation in competitive basketball, and his dreams of playing in the NBA ended.

Diagnosing Marfan Syndrome

Marfan syndrome, affecting 1 in ~5000 individuals, is an autosomal dominant connective-tissue disorder due to mutations in FBN1 (on chromosome 15) encoding for fibrillin-1. Marfan syndrome involves multiple organ systems leading to characteristic features involving the cardiovascular, ocular, and skeletal systems, lung and dura.¹ The phenotype of Marfan syndrome can be quite variable. Some individuals exhibit classic features in the eyes (lens dislocation, high myopia) and skeleton (tall stature, pectus deformities, scoliosis, arachnodactyly, wrist and thumb signs, dural ectasia), while other patients with Marfan syndrome have few skeletal features and the absence of lens dislocation, but have a dilated aortic root and an FBN1 mutation. The diagnosis of Marfan syndrome is based on the Revised Ghent Criteria, which encompasses family history, physical features, imaging (echocardiogram), ocular evaluation (slit lamp eye exam), and genetic testing (Table 1).¹ Examples of the physical characteristics of Marfan syndrome, differential diagnosis, calculation of the systemic score (Table 2), z-score determination and aortic size nomograms are available at the Marfan Foundation website and in the Marfan Foundation's mobile app, Marfan Dx (which can be downloaded from the website for use on a smart phone or tablet). Diagnosing Marfan syndrome requires an appropriately high level of suspicion. Certain athletes, including basketball and volleyball players, may be suspected based on their tall stature. The vast majority of tall athletes do not have Marfan syndrome. However, most people with Marfan syndrome are tall for their respective families. Outward features raising concern about the possibility of Marfan syndrome include long fingers and toes, long arms and legs, pectus deformities (carinatum or excavatum), and scoliosis. Most people with Marfan syndrome have myopia. Patients with Marfan syndrome are at risk for retinal detachment, and ectopia lentis (lens dislocation) is a hallmark feature. Spontaneous pneumothorax due to apical pleural blebs occurs in 5% of people with Marfan syndrome. It is important to obtain a careful family history. As an autosomal dominant condition, an affected parent with Marfan syndrome has a 50% chance of passing the condition to each child. In Marfan syndrome approximately 25% of cases are due to a spontaneous mutation, and neither parent has the condition. Inquiring about a family history of aortic aneurysm, aortic dissection, and features of Marfan syndrome is important when evaluating the suspected patient.

Table 1: Revised Ghent Criteria for the Diagnosis of Marfan Syndrome.

In the absence of a family history of Marfan syndrome, any of the following: Dilated aorta (z-score >2) AND ectopia lentis = Marfan syndrome* Dilated aorta (z-score >2) AND FBN1 mutation = Marfan syndrome Dilated aorta (z-score >2) AND systemic score >7 (see Table 2 below) = Marfan syndrome* Ectopia lentis AND FBN1 associated with known aortic dilatation = Marfan syndrome In the presence of a family history of Marfan syndrome, any of the following: Ectopia lentis AND family history of Marfan syndrome = Marfan syndrome Systemic score >7 AND family history of Marfan syndrome = Marfan syndrome* Dilated aorta (z-score >2 above 20 years old; z-score >3 below 20 years old) AND family history of Marfan syndrome = Marfan syndrome*

*Caveat: without discriminating features of another connective tissue disorder such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome AND after mutation analysis for TGFBR1, TGFBR2, COL3A1 or other genes as appropriate. Other genes/conditions will emerge with time.
Modified from Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85.

Table 2: System Score in the Marfan Syndrome*

Feature	Points
Wrist AND thumb sign	3
Wrist OR thumb sign	1
Pectus carinatum deformity	2
Pectus excavatum or chest asymmetry	1
Hindfoot deformity	2
Plain pes planus	1
Pneumothorax	2
Lumbosacral dural ectasia	2
Protrusio acetabuli	2
Reduced upper segment to lower segment ratio (<0.85 in white adults; <0.78 in black adults) AND increased arm span to height ratio >1.05) AND no severe scoliosis	1
Scoliosis or thoracolumbar kyphosis	1
Reduced elbow extension	1
Facial features (3 out of 5); dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia	1
Skin striae	1
Myopia (>3 diopters)	1
Mitral valve prolapse	1

Maximum total: 20 points; score >7 indicates systemic involvement.
*A detailed explanation of the systemic score and nosology may be found at www.marfandx.org.

Modified from Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485.

When suspicion of Marfan syndrome is raised, an echocardiogram and a slit lamp eye exam are necessary. Lens dislocation occurs in approximately 60% of people with Marfan syndrome.² The majority of Marfan patients have mitral valve prolapse. Dilatation of the aortic root at the sinuses of Valsalva is the cardinal cardiovascular feature in Marfan syndrome, placing the individual at risk for aortic dissection. It is important to make an accurate measurement of the aortic root and reference the aortic diameter to age, gender, and body size to determine if dilatation is present. Nomograms and formulae are available for reporting an aortic z-score or determining dilatation.³ An aortic z-score greater than 2 (or an aortic size more than 2 standard deviations above the mean) is considered dilated.³ In general, aortic diameters >4.0 cm for tall adult men or >3.6 cm for tall adult women are usually considered to be dilated.⁴ Genetic testing can be very helpful in establishing or confirming the diagnosis of Marfan syndrome (or related disorders). Mutation analysis can currently detect an FBN1 mutation in more than 90% of patients satisfying the Revised Ghent criteria for the diagnosis of Marfan syndrome.

When evaluating the athlete with aortic dilatation and suspected Marfan syndrome or related disorder making the correct diagnosis is imperative. There are other familial thoracic aortic aneurysm syndromes (Loeys-Dietz syndrome [due to TGFBR1 and TGFBR2 mutations] and those related to mutations in SMAD3, TGFB2, and TGFB3), which may share some of the features of Marfan syndrome.⁵ However, these conditions are notable for the absence of lens dislocation. They also have features that are not present in Marfan syndrome, including craniosynostosis, hypertelorism, cleft palate, bifid or broad uvula, soft velvety and translucent skin with easily visible veins, blue sclera, Chiari malformations, and club feet. If these features are present, or if FBN1 mutation analysis (including duplication/deletion testing) is negative in suspected Marfan syndrome, genetic testing for these conditions is recommended. Evaluation in a specialized center with cardiology and medical genetics expertise in Marfan syndrome and related disorders is recommended when the diagnosis is uncertain or for confirmation of diagnosis and treatment when appropriate.

Participation in Sports for the Athlete With Marfan Syndrome

Participation in competitive athletics for the individual with Marfan syndrome is prohibited except for low intensity sports such as golf, bowling, and others not associated with intense physical exertion and bodily collision as outlined in the 36th Bethesda Conference⁵ This recommendation is based on the concern that more intense sports with higher levels of isometric and dynamic exercise leads to greater aortic wall stress and increases the risk for aortic dilatation and dissection. New guidelines for disqualification from competition for athletes with aortic disease including Marfan syndrome have been sanctioned by the American Heart Association and will be published soon. These new guidelines will emphasize making a correct diagnosis, role of genetic testing, and the importance of long-term follow-up athletes with mildly dilated aortas even when they do not satisfy current criteria for a specific thoracic aortic aneurysm syndrome.

People with Marfan syndrome correctly diagnosed and treated (before aortic dissection) have an average lifespan which approaches that of the general population.⁷ Routine, safe levels of aerobic activity are important for health and well-being, including for those with Marfan syndrome. It is important to recognize the features of Marfan syndrome and establish a correct diagnosis. Life can depend upon it.

References

1. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85.
2. Drolsum L, Rand-Hendriksen S, Paus B, Geiran OR, Semb SO. Ocular findings in 87 adults with Ghent-1 verified Marfan syndrome. Acta Ophthalmol 2015;93:46-53.
3. Devereux RB, de Simone G, Arnett DK, et al. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons > 15 years of age. Am J Cardiol 2012;110:1189-94.
4. Pelliccia A, Di Paolo FM, De Blasiis E, et al. Prevalence and clinical significance of aortic dilatation in highly trained competitive athletes. Circulation 2010;122:698-706.
5. Gillis E, Van Laer L, Loeys BL. Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-β signaling and vascular smooth muscle cell contractility. Circ Res 2013;113:327-40.
6. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005;45:1340-45.
7. Silverman DI, Burton KJ, Gray J, et al. Life expectancy in the Marfan syndrome. Am J Cardiol 1995;75:157-60.

Keywords: Aorta, Aortic Aneurysm, Aortic Aneurysm, Thoracic, Arachnodactyly, Athletes, Basketball, Body Size, Chromosomes, Human, Pair 15, Craniosynostoses, Diagnosis, Differential, Dilatation, Dilatation, Pathologic, Ectopia Lentis, Ehlers-Danlos Syndrome, Enophthalmos, Funnel Chest, Genetic Testing, Genetics, Medical, Hypertelorism, Kyphosis, Loeys-Dietz Syndrome, Marfan Syndrome, Microfilament Proteins, Mitral Valve Prolapse, Mutation, Myopia, Nomograms, Phenotype, Physical Exertion, Pneumothorax, Retinal Detachment, Retrognathia, Sclera, Scoliosis, Sports, Syndrome, Uvula, Viverridae, Transforming Growth Factor beta3, Universities

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