Marfan s Syndrome Meraj Ud Din Shah MD, DM, FICC

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1 91 Marfan s Syndrome Meraj Ud Din Shah MD, DM, FICC Case Report: A 2 year male child was having routine check up for respiratory infection and was detected to have grade 3/6 murmur in precordium. Patient was referred for echocardiography for precordial murmur. Echo revealed normal situs with AV and VA concordance. Chambers were normal. All valves were redundant with prolapse of MV, TV. Aortic root was dilated. Doppler and color flow mapping revealed moderate mitral and tricuspid regurgitation. These features go with connective tissue disease leading to dilatation of aortic root and multi-valvular prolapse. Marfan s Syndrome is the connective tissue disease involving cardiac valves and aorta. Parasternal long axis and Apical 4 chamber echocardiograms are given below. They show bileaflet prolapse of Mitral valve and similarly prolapse of Tricuspid valve. Parasternal long Axis View Marfan s syndrome is inherited connective disorder with complete penetrance. Inheritance is autosomal dominant. Prevalence is worldwide. Although connective tissue throughout body is involved, cardinal manifestations are in eyes, skeletal system cardiovascular and neurological. Apical 4-Chamber View.

2 92 HISTORY Marfan s syndrome was first time reported in Antoine-Bernard-Jean Marfan reported a five year girl with kyphoscoliosis, digital and joint contractures and long limbs. This could well have been a case of contractural arachnodactyly but Marfan s name is now associated with disease due to defective fibrillin gene FBN1 (1). Mckusik in 1955 gave the name connective tissue disease to a group of disorders and Marfan s syndrome is classic example of these disorders (2). Although aortic involvement was reported way back in 1943 (3), but shortening of life due to rupture aortic aneurysm in Marfan s syndrome was documented in 1972 (4). It was in early 1990 s that Hollister defined role of fibrillin abnormality in genesis of disease. This was followed by discovery of association of Chromosome 15q21 with Marfan s syndrome (5), and subsequently Dietz and associates found mutations in fibrillin gene FBN1 is the cause of the disease (6). PATHOGENESIS Mutation of fibrillin gene FBN1 leads to faulty formation of fibrillin. This is important component of microfibrils of elastic tissue and extracellular non-elastic tissue as in aortic adventitia and suspensory ligaments of eye. This leads to abnormal elasticity of connective tissue with loss of tensile strength of elastic tissue thus abnormalities in skeletal, cardiovascular systems. It may occur on one hand as severe neonatal / infantile disease which has a progressive fatal course (7) and on other hand there may be milder forme fruste with tall stature or arachnodactyly or ectopia lentis with normal life span. This variability is evident as more than 600 mutations involving FBN1 gene have been reported. Fibrilin regulation of transforming growth factor-β may be responsible for some manifestations of syndrome (8). DIAGNOSIS Marfan s Syndrome is pan-ethnic, equally prevalent in males and females, found in 1 in 5-10 thousand general population. It may be diagnosed prenatally, at birth and in adulthood. Diagnostic criteria were developed in 1986 in Berlin. It was based mainly on clinical criteria as molecular basis of disease was discovered later on. Due to weakness in clinical only criteria it was changed in World s leading clinicians and investigators of Marfan s Syndrome revised the diagnostic criteria and provided what is known as Ghent Criteria (9). Table 1. Diagnostic criteria for the Marfan syndrome (Ghent nosology) Skeletal System Presence of at least four of the following manifestations: Pectus carinatum Pectus excavatum requiring surgery Reduced upper to lower segment ratio or arm span to height ratio > 1.05 Positive wrist and thumb signs Scoliosis of > 20 or spondylolisthesis Reduced extension of the elbows (< 170 ) Medial displacement of the medial malleolus causing pes planus Protrusio acetabulae of any degree (ascertained on X-ray) Pectus excavatum of moderate severity Joint hypermobility Highly arched palate with dental crowding Facial appearance (dolicocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures) For the skeletal system to be involved, at least two of the components comprising the major criterion, or one component comprising the major criterion plus two of the minor criteria must be present. Ocular System Major criterion: Ectopia lentis

3 93 Abnormally flat cornea (as measured by keratometry) Increased axial length of globe (as measured by ultrasound) Hypoplastic iris or hypoplastic ciliary muscle causing a decreased miosis For the ocular system to be involved, at least two of the minor criteria must be present. Cardiovascular System Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva, or Dissection of the ascending aorta Mitral valve prolapse with or without mitral valve regurgitation Dilatation of main pulmonary artery, in absence of valvular or peripheral pulmonic stenosis or any other obvious cause, under the age of 40 years Calcification of the mitral annulus below the age of 40 years, or Dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years For the cardiovascular system to be involved, a major criterion or only one of the minor criteria must be present. Pulmonary System None Spontaneous pneumothorax, or Apical blebs (ascertained by chest radiography) For the pulmonary system to be involved, one of the minor criteria must be present. Skin and Integument Major criterion: Lumbosacral dural ectasia by computed tomography or magnetic resonance imaging Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy or repetitive stress, or Recurrent or incisional herniae For the skin and integument to be involved, the major criterion or one of the minor criteria must be present. Family History Having a parent, child, or sibling who meets the diagnostic criteria listed below independently Presence of a mutation in FBN1 known to cause the Marfan syndrome, or Presence of a haplotype around FBN1, inherited by descent, known to be associated with unequivocally diagnosed Marfan syndrome in the family None For the family history to be contributory, one of the major criteria must be present. Requirements for the diagnosis of Marfan syndrome For the index case: Major criteria in at least two different organ systems and involvement of a third organ system. For a family member: Presence of a major criterion in the family history and one major criterion in an organ. Various physical signs are helpful in diagnosis of Marfan s Syndrome. These are Wrist sign, Thumb sign, Hyperextensibility of joints (Figures 1,2,3,4). 1. Adult with Marfan syndrome. Note tall and thin built. 2. Hypermobility of finger joints disproportionately long arms and legs, and kyphoscoliosis.

4 94 3.Positive thumb (Steinberg) sign. 4.Positive wrist (Walker) sign. 5. Arachnodactyly. Differential Diagnosis: 1. Congenital contractural arachnodactyly (Beals syndrome) with features of Marfan s syndrome caused by mutation of FBN2 gene. This also has autosomal dominant inheritance. 2. Familial arachnodactyly. 3. Familial ectopia lentis. 4. Marfanoid habitus with no systemic involvement. 5. Familial Aortic aneurysm Syndrome (Loeys-Dietz syndrome) 6. Homocystinuria. INVESTIGATIONS: Radiography: X-Ray chest to look for blebs in lungs usually seen at apices. We also can see widening of mediastinum due to dilatation of aorta/aortic aneurysm. Pelvic radiography may help in detecting protrusio acetabula. Radiography of hands to assess metacarpal index is also helpful. Echocardiography: Helps in assessment for mitral valve/tricuspid valve prolapse, dilatation of aortic root. Aortic root size >1.9cm/sq.mtr body surface area is diagnostic of aortic root dilatation. Doppler studies helps in assessment of regurgitant valves. CT/ MRI: These can be used for assessment of aortic root, aorta, dissection of aorta. Lumbosacral CT to assess for dural ectasia is also diagnostic. Aortography: Less commonly aortography may be required for diagnosis of aortic aneurysm and dissection. Slit Lamp Examination: Slit lamp examination of eye helps in detection of ectopia lentis. In addition histological evaluation and chromosomal studies are taken for assisting diagnosis and family evaluation. TREATMENT General measures like moderate restriction of physical activity, avoiding contact sports, endocarditis prophylaxis and regular follow up and echocardiography to watch for progress of disease. Younger patients should have echocardiography assessment every 6-12 months. Drug Treatment. Most of patients especially those with dilatation of aorta are treated with B-blockers. The role of B-blockers is controversial yet it is the standard care therapy of Marfan s syndrome. They are supposed to delay the progression of aortic dilatation due to negative chronotropic and negative ionotropic effects. Aortic dilatation is slowed down but not stopped. A recent study of 63 patients of Marfans syndrome suggests that that beta-blocker therapy does not significantly alter the rate of aortic root dilation in children with Marfan syndrome. Based on these data,

5 95 the recommendation of lifetime beta-blocker therapy instituted during childhood needs to be reassessed (10). Other drugs reported to be helpful are Angiogenesis Converting Enzyme (ACE) inhibitors (11), and Angiotensin Receptor Blocking drugs (12). In fact in a comparative study enalapril was found to be better than b-blockers in slowing the progression of aortic root dilatation (11). Surgery. Surgery is advised for aortic aneurysm. Prophylactic surgery for aortic aneurysm is advocated for aortic root diameter >5 cm. In cases with family history of dissection elective surgery with diameters <5cm and diameter exceeding >1cm per year prophylactic elective surgery is advised. (13). Traditional aortic graft surgery requires lifetime anticoagulation. Ectopia lentis needs surgery less commonly. Pregnancy. There is risk of progression of aortic dilatation and rupture during pregnancy. This needs to be explained to patients. There is also 50% risk of involvement in siblings. Patients who have composite aortic root surgery and need anticoagulants should be shifted on heparin during pregnancy. References 1. Marfan MA-B. Un cas de deformation congenitale des quatre membres, plus prononcee aux extremites, caracterisee par l'allongement des os avec un certain degre d'amincissement. Bull Mem Soc Med Hop Paris 1896;13: (quoted IMAJ 2008;10:175) 2. McKusick VA. The cardiovascular aspects of Marfan's syndrome. Circulation 1955;11: Etter LE, Glover LP. Arachnodactyly complicated by dislocated lens and death from rupture of dissecting aneurysm of aorta. JAMA 1943;123: Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 1972;286: 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: Dietz HC, Cutting GR, Pyeritz RE, et al. Defects in the fibrillin gene cause the Marfan syndrome; linkage evidence and identification of a missense mutation. Nature 1991;352: Tiecke F, Katzke S, Booms P, et al. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons Eur J Hum Genet 2001; 9: Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003;33: DePaepe A, Deitz HC, Devereux RB, Hennekem R, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62: Elif Seda Selamet Tierney, Brian Feingold, Beth F. Printz etal. Beta-Blocker Therapy Does Not Alter the Rate of Aortic Root Dilation in Pediatric Patients with Marfan Syndrome. J Pediatr 2007;150: Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 2005;95: Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, and Dietz HC. Angiotensin II Blockade and Aortic-Root Dilation in Marfan s Syndrome. N Engl J Med 2008;358: Davies RR, Goldstein LJ, Coady MA, et al. Yearly rupture or dissection rates for thoracic aortic aneurysms: simple prediction based on size. Ann Thorac Surg 2002;73: Conflict of Interest: None. Author Information: Dr. Meraj Ud Din Shah, MD, DM (Cardiology), FICC; is Senior Consultant Cardiologist at Al Kareem Cardiac Center, Srinagar, Kashmir, India. drmerajuddin@gmail.com