- Email: [email protected]
Clinical consult: Marfan syndrome
Prim Care Clin Office Pract 31 (2004) 739–742
Clinical consult: Marfan syndrome Sarah J. Grimes, MSa,b,*, Louise S. Acheson, MD, MSc,d, Anne L. Matthews, RN, PhDa,b, Georgia L. Wiesner, MDa,b a
Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Avenue, LKS 1500, Cleveland, OH 44106, USA b Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA c Department of Family Medicine and Oncology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA d Department of Reproductive Biology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA
Case A 14-year-old boy, as part of a routine sports physical examination, was noted by his primary care physician to have a heart murmur. The physician also noted that the boy was tall for his age at 6919 and had lax joints, a thin build, and long fingers and toes. The family history was significant for a mother with scoliosis and myopia and a maternal uncle with a tall, thin build and pectus excavatum. The boy’s maternal grandfather reportedly died suddenly of ‘‘heart problems’’ at age 30. Based on these findings, the physician recommended that the boy be evaluated for Marfan syndrome. Marfan syndrome is a heritable disorder of connective tissue. This relatively common genetic condition affects approximately 2 to 3 per 10,000 individuals [1], without a particular gender, racial, geographic, or ethnic predilection. If unrecognized, patients with Marfan syndrome can have lifethreatening cardiovascular complications. Identification and proper management of the disorder can improve the prognosis greatly, however, and extend the patient’s life span.
This work was supported by Grant No. 00-179 from the Rockefeller Brothers Fund. * Corresponding author. E-mail address: [email protected] (S.J. Grimes). 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.04.005
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S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
Disease characteristics and natural history Marfan syndrome affects primarily the cardiovascular, skeletal, ocular, integumentary, and pulmonary systems [1]. The most serious medical complication of Marfan syndrome is dilation and dissection of the ascending aorta, which can lead to aortic rupture and premature death if untreated. Other cardiovascular complications include mitral valve prolapse, aortic regurgitation, tricuspid valve prolapse, and dilation of the main pulmonary artery. The skeletal manifestations of the condition include tall stature; thin habitus with increased arm span-to-height ratio; long, slender fingers (arachnodactyly); elongated face; high arched palate; pes planus; joint laxity; scoliosis; and pectus deformity. Ectopia lentis (lens dislocation) is a hallmark ocular feature, present in approximately 60% of patients [2]. Other ocular findings include corneal flatness, increased axial globe length leading to near-sightedness, and hypoplastic irides. Spontaneous pneumothorax or apical blebs are the most common pulmonary abnormalities. Other cardinal features involve the skin, integument, and dura and include striae atrophicae (ie, stretch marks), recurrent hernias, and lumbosacral ectasia. Phenotypic manifestations vary among affected individuals, showing wide interfamilial and intrafamilial variability. Many of the features develop or progress with age. Inheritance and genetics Marfan syndrome is caused by mutations in the fibrillin-1 gene (FBN1) [3], located on chromosome 15q21 [4,5]. The FBN1 gene encodes the structural protein fibrillin-1, an extracellular matrix glycoprotein, which is a major component of connective tissue microfibrils. Marfan syndrome is an autosomal dominant disorder, meaning that each offspring of an affected parent has a 50% chance of inheriting the altered FBN1 gene. In approximately 75% of cases, an individual inherits the disorder from an affected parent; the remaining 25% of cases result from de novo mutations [6]. The penetrance of FBN1 mutations is high, but the phenotypic expression is extremely variable, even within families. Multiple causative mutations in the FBN1 gene have been identified, with most mutations being unique to a given family. Conversely, not all FBN1 mutations are associated with the classic Marfan phenotype. Diagnosis Marfan syndrome is a clinical diagnosis determined by standard criteria [7] and should be made by a physician or geneticist experienced with the condition. Because the clinical manifestations of Marfan syndrome become more evident with age, patients should be periodically re-evaluated, especially during childhood and adolescence, to confirm or exclude the diagnosis.
S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
741
The diagnostic evaluation of Marfan syndrome should include a detailed family history and thorough evaluation of the cardiac, skeletal, and ocular systems to look for the presence of characteristic clinical features. The cardiac evaluation should include auscultation and echocardiography. A full skeletal examination should be done, including anthropometric measurements (height, arm span-to-height ratio, upper-to-lower segment ratio, hand and foot measurements) and evaluation for bone deformities (eg, scoliosis, pectus deformities). Ophthalmologic examination with pupilary dilation should be done to evaluate for the presence of lens dislocation. The diagnostic evaluation also should include serum amino acid analysis to exclude homocystinuria. For a more in-depth review of the diagnostic criteria for Marfan syndrome, see De Paepe et al [7]. DNA analysis of the FBN1 gene is clinically available, but is not sensitive and specific enough to be the main criterion for diagnosis. Prenatal testing by direct DNA analysis is possible for families in which an FBN1 mutation has been identified previously. Differential diagnosis Mutations in FBN1 may result in overlapping phenotypes, including the MASS phenotype (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, and nonspecific skin and skeletal features) and familial thoracic aortic aneurysms. Other syndromes that should be considered include homocystinuria and other connective tissue disorders, such as Ehlers-Danlos syndrome, Stickler’s syndrome, and congenital contractural arachnodactyly (Beals’ syndrome). Management Management should be multidisciplinary and include a treatment plan tailored to each individual’s manifestations of Marfan syndrome. Patients should receive regular evaluation by a cardiologist familiar with the condition, including an annual echocardiogram to monitor the size and function of the heart and aorta. Management routinely includes use of b-adrenergic blockers, which have been shown to slow the progressive widening of the aorta in many patients with Marfan syndrome [8]. Surgical intervention is indicated in patients with an aortic root diameter greater than 50 to 55 mm [9]. Prophylactic antibiotics before dental procedures for patients with mitral valve prolapse or regurgitation also are recommended. Lifestyle adaptations, including restrictions of physical activity, are recommended to reduce excessive stress on the aorta and eye injury. Guidelines include the avoidance of competitive contact sports and weight training [10]. Management of the skeletal manifestations of the condition should include monitoring of the skeletal system during childhood and adolescence for scoliosis and other joint abnormalities. Annual ophthalmologic
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S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
examination, including screening and treatment for strabismus, myopia, and lens dislocation, is recommended. Patients should be referred for genetic counseling, including psychosocial support and recurrence risk assessment for patients and relatives. The Marfan Syndrome Foundation (http:// www.marfan.org) is a resource for patients, family members, and health care professionals. Information about clinical experts is available through this organization.
References [1] Dietz HC, Pyeritz RE. Marfan syndrome and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 8th edition. New York: McGraw-Hill; 2001. p. 5287–311. [2] Cross HE, Jensen AD. Ocular manifestations in the Marfan syndrome and homocystinuria. Am J Ophthalmol 1973;75:405–20. [3] Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337–9. [4] Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323: 935–9. [5] Dietz HC, Pyeritz RE, Hall BD, et al. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 1991;9:355–61. [6] Gray JR, Bridges AB, Faed MJ, et al. Ascertainment and severity of Marfan syndrome in a Scottish population. J Med Genet 1994;31:51–4. [7] De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–26. [8] Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994; 330:1335–41. [9] Baumgartner WA, Cameron DE, Redmond JM, Greene PS, Gott VL. Operative management of Marfan syndrome: the Johns Hopkins experience. Ann Thorac Surg 1999;67: 1859–60. [10] National Marfan Foundation Inc. Marfan syndrome: physical education and activity guidelines. Port Washington: National Marfan Foundation Inc; 1995.
Clinical consult: Marfan syndrome Sarah J. Grimes, MSa,b,*, Louise S. Acheson, MD, MSc,d, Anne L. Matthews, RN, PhDa,b, Georgia L. Wiesner, MDa,b a
Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Avenue, LKS 1500, Cleveland, OH 44106, USA b Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA c Department of Family Medicine and Oncology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA d Department of Reproductive Biology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA
Case A 14-year-old boy, as part of a routine sports physical examination, was noted by his primary care physician to have a heart murmur. The physician also noted that the boy was tall for his age at 6919 and had lax joints, a thin build, and long fingers and toes. The family history was significant for a mother with scoliosis and myopia and a maternal uncle with a tall, thin build and pectus excavatum. The boy’s maternal grandfather reportedly died suddenly of ‘‘heart problems’’ at age 30. Based on these findings, the physician recommended that the boy be evaluated for Marfan syndrome. Marfan syndrome is a heritable disorder of connective tissue. This relatively common genetic condition affects approximately 2 to 3 per 10,000 individuals [1], without a particular gender, racial, geographic, or ethnic predilection. If unrecognized, patients with Marfan syndrome can have lifethreatening cardiovascular complications. Identification and proper management of the disorder can improve the prognosis greatly, however, and extend the patient’s life span.
This work was supported by Grant No. 00-179 from the Rockefeller Brothers Fund. * Corresponding author. E-mail address: [email protected] (S.J. Grimes). 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.04.005
740
S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
Disease characteristics and natural history Marfan syndrome affects primarily the cardiovascular, skeletal, ocular, integumentary, and pulmonary systems [1]. The most serious medical complication of Marfan syndrome is dilation and dissection of the ascending aorta, which can lead to aortic rupture and premature death if untreated. Other cardiovascular complications include mitral valve prolapse, aortic regurgitation, tricuspid valve prolapse, and dilation of the main pulmonary artery. The skeletal manifestations of the condition include tall stature; thin habitus with increased arm span-to-height ratio; long, slender fingers (arachnodactyly); elongated face; high arched palate; pes planus; joint laxity; scoliosis; and pectus deformity. Ectopia lentis (lens dislocation) is a hallmark ocular feature, present in approximately 60% of patients [2]. Other ocular findings include corneal flatness, increased axial globe length leading to near-sightedness, and hypoplastic irides. Spontaneous pneumothorax or apical blebs are the most common pulmonary abnormalities. Other cardinal features involve the skin, integument, and dura and include striae atrophicae (ie, stretch marks), recurrent hernias, and lumbosacral ectasia. Phenotypic manifestations vary among affected individuals, showing wide interfamilial and intrafamilial variability. Many of the features develop or progress with age. Inheritance and genetics Marfan syndrome is caused by mutations in the fibrillin-1 gene (FBN1) [3], located on chromosome 15q21 [4,5]. The FBN1 gene encodes the structural protein fibrillin-1, an extracellular matrix glycoprotein, which is a major component of connective tissue microfibrils. Marfan syndrome is an autosomal dominant disorder, meaning that each offspring of an affected parent has a 50% chance of inheriting the altered FBN1 gene. In approximately 75% of cases, an individual inherits the disorder from an affected parent; the remaining 25% of cases result from de novo mutations [6]. The penetrance of FBN1 mutations is high, but the phenotypic expression is extremely variable, even within families. Multiple causative mutations in the FBN1 gene have been identified, with most mutations being unique to a given family. Conversely, not all FBN1 mutations are associated with the classic Marfan phenotype. Diagnosis Marfan syndrome is a clinical diagnosis determined by standard criteria [7] and should be made by a physician or geneticist experienced with the condition. Because the clinical manifestations of Marfan syndrome become more evident with age, patients should be periodically re-evaluated, especially during childhood and adolescence, to confirm or exclude the diagnosis.
S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
741
The diagnostic evaluation of Marfan syndrome should include a detailed family history and thorough evaluation of the cardiac, skeletal, and ocular systems to look for the presence of characteristic clinical features. The cardiac evaluation should include auscultation and echocardiography. A full skeletal examination should be done, including anthropometric measurements (height, arm span-to-height ratio, upper-to-lower segment ratio, hand and foot measurements) and evaluation for bone deformities (eg, scoliosis, pectus deformities). Ophthalmologic examination with pupilary dilation should be done to evaluate for the presence of lens dislocation. The diagnostic evaluation also should include serum amino acid analysis to exclude homocystinuria. For a more in-depth review of the diagnostic criteria for Marfan syndrome, see De Paepe et al [7]. DNA analysis of the FBN1 gene is clinically available, but is not sensitive and specific enough to be the main criterion for diagnosis. Prenatal testing by direct DNA analysis is possible for families in which an FBN1 mutation has been identified previously. Differential diagnosis Mutations in FBN1 may result in overlapping phenotypes, including the MASS phenotype (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, and nonspecific skin and skeletal features) and familial thoracic aortic aneurysms. Other syndromes that should be considered include homocystinuria and other connective tissue disorders, such as Ehlers-Danlos syndrome, Stickler’s syndrome, and congenital contractural arachnodactyly (Beals’ syndrome). Management Management should be multidisciplinary and include a treatment plan tailored to each individual’s manifestations of Marfan syndrome. Patients should receive regular evaluation by a cardiologist familiar with the condition, including an annual echocardiogram to monitor the size and function of the heart and aorta. Management routinely includes use of b-adrenergic blockers, which have been shown to slow the progressive widening of the aorta in many patients with Marfan syndrome [8]. Surgical intervention is indicated in patients with an aortic root diameter greater than 50 to 55 mm [9]. Prophylactic antibiotics before dental procedures for patients with mitral valve prolapse or regurgitation also are recommended. Lifestyle adaptations, including restrictions of physical activity, are recommended to reduce excessive stress on the aorta and eye injury. Guidelines include the avoidance of competitive contact sports and weight training [10]. Management of the skeletal manifestations of the condition should include monitoring of the skeletal system during childhood and adolescence for scoliosis and other joint abnormalities. Annual ophthalmologic
742
S.J. Grimes et al / Prim Care Clin Office Pract 31 (2004) 739–742
examination, including screening and treatment for strabismus, myopia, and lens dislocation, is recommended. Patients should be referred for genetic counseling, including psychosocial support and recurrence risk assessment for patients and relatives. The Marfan Syndrome Foundation (http:// www.marfan.org) is a resource for patients, family members, and health care professionals. Information about clinical experts is available through this organization.
References [1] Dietz HC, Pyeritz RE. Marfan syndrome and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 8th edition. New York: McGraw-Hill; 2001. p. 5287–311. [2] Cross HE, Jensen AD. Ocular manifestations in the Marfan syndrome and homocystinuria. Am J Ophthalmol 1973;75:405–20. [3] Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337–9. [4] Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323: 935–9. [5] Dietz HC, Pyeritz RE, Hall BD, et al. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 1991;9:355–61. [6] Gray JR, Bridges AB, Faed MJ, et al. Ascertainment and severity of Marfan syndrome in a Scottish population. J Med Genet 1994;31:51–4. [7] De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–26. [8] Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994; 330:1335–41. [9] Baumgartner WA, Cameron DE, Redmond JM, Greene PS, Gott VL. Operative management of Marfan syndrome: the Johns Hopkins experience. Ann Thorac Surg 1999;67: 1859–60. [10] National Marfan Foundation Inc. Marfan syndrome: physical education and activity guidelines. Port Washington: National Marfan Foundation Inc; 1995.