Marfan syndrome

Its a rare inherited disorder of connective tissues, with multisystem involvement

1. MARFAN SYNDROME Dr Mujeeb R. Jokhio Fellow Paeds Cardiology NICVD Karachi

2. Introduction

3. Marfan syndrome – is an inherited disorder of connective tissue.

4. Caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin-1 .

5. Historical Background

6. In 1896, Marfan, a French pediatrician described a hereditary disorder of connective tissue in a 5 year old girl with disproportionately long limbs that later became to be known as Marfan syndrome.

7. Ectopia Lentis (Borger; 1914). Autosomal Dominant inheritance ( Weve ; 1931) Aortic Dilatation ( Etter and Grover; 1943) Aortic Dissection (Baer; 1943) Mitral Valve Prolapse (Brown; 1975) Dural Ectasia ( Pyeritz ; 1988)

8. Marfan syndrome Skeleton Heart Blood vessels Eyes Lungs MFS is a multisystem disorder, with cardinal manifestations in the skeletal, cardiovascular, and ocular systems.

9. Epidemiology

10. The incidence is reported to be 1 in 10,000 live births. Approximately one-fourth of cases are sporadic. The disorder shows autosomal dominant inheritance. There is no racial or gender preference.

11. Pathogenesis

12. MFS is associated with abnormal production, matrix deposition and/ or stability of fibrillin-1 (FBN1) , a 350-kDa ECM protein. FBN1 mutations have been identified in over 90 percent patients. More than 1,000 disease-causing mutations identified to date.

13. The fibrillin-1 (FBN1) locus resides on the long arm of chromosome 15 (15q21), and the gene is composed of 65 exons.

14. MFS was traditionally considered to result from a structural deficiency of connective tissues. Mutations in the fibrillin-1 gene result in the production of an abnormal fibrillin protein, leading to abnormalities in the mechanical stability and elastic properties of connective tissue.

15. Reduced fibrillin-1 was thought to lead to a primary derangement of elastic fiber deposition, because both skin and aorta from affected patients show decreased elastin, along with elastic fiber fragmentation.

16. Continued……. More recently, research suggests that transforming growth factor-beta is implicated in the failure of normal elastic tissue formation. TGFBR 1 and 2 mutations – may have similar manifestations. In response to stress (such as hemodynamic forces in the proximal aorta), affected organs were thought to manifest this structural insufficiency with accelerated degeneration.

17. Continued……. Cystic medial necrosis : The term cystic medial necrosis was coined by Erdheim to describe the lacunar appearance of medial degeneration in MFS; however no actual cysts or overt necrosis is present. Cystic medial necrosis and the other histologic findings are not specific for MFS, although greater elastin fragmentation has been described in patients with aortic root aneurysms with MFS. The histologic changes are thought to reflect injury and repair

18. Diagnosis

19. Clinical Manifestation Diagnostic Criteria Step by step approach

20. Clinical Manifestation

21. Skeletal System Overgrowth of the long bones (dolichostenomelia) is often the most obvious manifestation of MFS. Individuals taller than predicted by their genetic background Joint laxity Results in reduced upper segment: lower segment ratio (US : LS) US : LS < 1 for ages 0-5 yr US : LS < 0.95 for ages 6-7 yr US : LS < 0.9 for ages 8-9 yr US : LS < 0.85 above age 10 yr Arm span to height ratio > 1.05 times.

22. continued Paradoxically, some individuals with MFS have reduced joint mobility, particularly of the elbow and digits - reduced elbow extension (≤180 degrees with full extension).

23. continued Arachnodactyly — abnomally long and slender fingers.

24. continued Thumb sign - entire distal phalanx protrudes beyond the ulnar border of a clenched fist with or without the assistance of the patient or examiner to achieve maximum adduction.

25. continued Wrist sign - the top of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist.

26. continued Pectus deformity — Pectus carinatum - more specific for MFS than pectus excavatum or chest asymmetry. Hindfoot valgus — occurs with forefoot abduction and lowering of the midfoot and should be evaluated from anterior and posterior views. Pes planus (flat foot) without hindfoot valgus is less specific Generalized joint hypermobility also may occur, producing findings that overlap with the much more common benign joint hypermobility syndrome.

27. Hind foot valgus PES PLANNUS Hypermobile joint

28. continued Scoliosis and kyphosis A Cobb’s angle of at least 20 degrees (on an anteriorposterior radiographic view of the spine, the angle between a line drawn along the superior end plate of the superior end vertebra and a second line drawn along the inferior end plate of the inferior end vertebra of the scoliosis) Exaggerated kyphotic thoracolumbar spinal curvature.

29. continued Protrusio acetabuli Can be diagnosed by plain radiograph, computed tomography (CT), or magnetic resonance imaging (MRI). On an anterior-posterior pelvic film, medial protrusion of the acetabulum ≥3mm beyond the ilio-ischial (Kohler) line is diagnostic.

30. continued Facial features — dolichocephaly (reduced cephalic index or head width/length ratio), enophthalmos, downslanting palpebral fissures, malar hypoplasia, and retrognathia.

31. Dural ectasia Enlargement of the spinal canal owing to progressive ectasia of dura and neural foramina and to erosion of vertebral bone. Usually involves the lumbosacral spine 60-90% pts on MRI/CT. It is sensitive but not specific sign of MFS, and is commonly seen in Loeys -Dietz syndrome and Shprintzen -Goldberg syndrome, has been reported in the vascular form of Ehlers-Danlos syndrome.

32. MRI most sensitive technique. No correlation appears to exist between the severity of dural ectasia and the degree of aortic dilatation.

33. Ocular Abnormalities Ectopia lentis : 50 to 80 percent. Detected on slit-lamp examination after maximal dilatation of the pupil and the lens is usually displaced upward and temporally. It is caused by failure of the supporting ciliary zonules.

34. Myopia >3 diopters - secondary myopia due to increased axis globe length.

35. continued Flat cornea. Hypoplastic iris. Hypoplastic ciliary muscle causing miosis. Retinal detachment. Glaucoma and early cataract formation. Retinal tears and detachment are commonly bilateral.

36. Pulmonary disease — Some patients develop emphysematous changes with lung bullae predominantly in the upper lobes, can predispose to spontaneous pneumothorax.

37. Skin striae — The presence of striae atrophicae contributes one point to the systemic score if not associated with pronounced weight changes or pregnancy and if in uncommon location such as the mid back, lumbar region, upper arm, axillary region, or thigh.

38. CVS INVOLVEMENT

39. Within the heart, thickening of the atrioventricular valves is common and often associated with valvular prolapse. Variable degrees of regurgitation may be present. In children with early onset and severe MFS, insufficiency of the mitral valve can lead to congestive heart failure, pulmonary hypertension and death in infancy; this manifestation is the leading cause of morbidity and mortality in young children with the disorder.

40. Supraventricular arrhythmias and ventricular dysrhythmias may be seen in association with mitral valve dysfunction, and there is an increased prevalence of prolonged QT interval. Dilated cardiomyopathy occurs with increased prevalence in patients with MFS, most often attributed to volume overload imposed by valve regurgitation. Aortic valve dysfunction is generally a late occurrence and attributed to stretching of the aortic annulus by an expanding aortic root aneurysm.

41. Aortic Disease Aortic root disease, leading to aneurysmal dilatation, aortic regurgitation, and dissection - main cause of morbidity and mortality Aortic enlargement is typically located at the level of sinuses of Valsalva and may eventually extend to the sinotubular junction and proximal ascending aorta Although dilated, the aorta in MFS tends to be stiffer and less distensible

42. Dilatation of the aorta, often (about 25%) accompanied by aortic regurgitation, progresses with time. 50 percent of young children with MFS 60 to 80 percent of adult patients with MFS

43. continued The incidence of serious cardiovascular complications, including aortic dissection or rupture, has been estimated to be around 4.3% in childhood with a rise to approximately 20% in adolescence . Aortic regurgitation may develop in 15% to 44% of MFS patients during childhood and adolescence, and has been strongly associated with acute cardiovascular events

44. continued Dilatation may also involve other segments of the thoracic aorta, the abdominal aorta, the root of the pulmonary artery or even the carotid and intracranial arteries. The normal range for aortic diameter varies with body size and age - nomograms and Z-scores used to identify aortic dilatation. Undiagnosed and untreated MFS - frequently associated with aortic dissection. May have a family history of dissection.

45. continued The frequency with which MFS is responsible for aortic dissection varies with age. 50% of those under age 40 2 % of those with age 40 - 70 No patient over age 70

46. continued Additional predictors of aortic complications include younger age at presentation and a family history of severe aortic disease . Patients diagnosed with MFS during childhood have significantly fewer adverse cardiac events compared to those diagnosed during adulthood, highlighting the importance of early identification of the disease

47. continued Following diagnosis of MFS, an echocardiogram is recommended at 6 months to assess the progression of aortic disease If measurements remain stable, echocardiographic follow-up can be performed every 6 months in children and on an annual basis in Adults.

48. continued Children who do not meet the full diagnostic criteria of the disease should be screened at least every 5 years, until they reach adulthood Baseline echocardiographic imaging requires diameter measurement at the level of the sinuses of Valsalva and should be indexed to age and body surface area In the instance of poor echocardiographic windows, magnetic resonance imaging (MRI) or computed tomography (CT) angiograms should be performed.

49. continued Routine CT or MRI imaging of the entire thoracic aorta is recommended in patients who present with descending aortic dilation, type B aortic dissection, or following ascending aortic aneurysm repair

50. continued Mitral valve prolapse (MVP) Common but nonspecific – only 1 point in systemic scoring 40-54% MFS adults; upto 90% in some series frequency of MVP increases with age; greater in women. Tricuspid valve prolapse may also occur. On echo mitral leaflets elongated and redundant either or both leaflets may prolapse most have mild or less regurgitation

51. continued Approximately 25 percent of patients with MVP have progressive disease - defined by the appearance or worsening of clinical symptoms of mitral regurgitation or worsening on echocardiography. Heart failure attributable to mitral valve prolapse and regurgitation represents a major source of morbidity and mortality in young children with the most extreme and rapidly progressive presentation of MFS. Some report suggest - some patients may have a cardiomyopathy with biventricular enlargement and generally asymptomatic mild systolic dysfunction unrelated to valvular disease

52. Step by step Approach History and physical examination (including slit-lamp ophthalmic examination with pupil dilation) in conjunction with imaging of the aortic root and the ascending, descending, and abdominal aorta (echo, CT, MRI) are usually sufficient for diagnosis. Family history of Marfan's syndrome, or of aortic dissection or aneurysm. There is also a weak association with high parental age

53. Other historical considerations Family history of myopia, astigmatism, strabismus, amblyopia, premature cataract or other lens abnormalities, glaucoma, retinal detachment, dental extraction or braces for dental crowding, hernias, or spontaneous pneumothorax.

54. Physical examination Tall stature, wide arm span, high level of pubic bone, high arched palate, arachnodactyly, positive wrist and thumb sign, pectus excavatum, pectus carinatum, scoliosis, striae, flat feet, thick spectacles for myopia, hernias, aortic or mitral valve murmur may be present. Spontaneous pneumothorax or emphysematous bullae may present as dyspnoea .

55. There may be signs of heart failure due to valve disease or cardiomyopathy. Complete ophthalmic examination, including fundus examination with pupil dilation - signs of lens subluxation or dislocation, cataract, glaucoma, or retinal detachment. May present with acute aortic dissection or rupture

56. Initial investigations Echocardiography, thorax CT, and thorax MRI are used initially for aortic root imaging. Abdominal ultrasound, CT, and MRI are used for visualization of the descending aorta. CXR is performed to exclude the presence of a pneumothorax, and may reveal emphysematous bullae.

57. Subsequent investigations Blood screening for mutations in the fibrillin-1 (FBN1) gene confirms the diagnosis if in doubt. Once detected, the mutation can be used to screen other relatives, and used for antenatal diagnosis and pre-implantation genetic diagnosis.

58. Lower spine CT scan or MRI can be performed to exclude dural ectasia. Plasma homocysteine levels help in unclear cases to differentiate homocystinuria. Skin biopsy is indicated only if Ehlers-Danlos syndrome is suspected.

59. Diagnostic Criteria

60. The Ghent Criteria A definite diagnosis can be made applying the Ghent criteria, which are based on demonstration of symptoms from different organ systems and family history of MFS. However, Ghent nosology cannot exclude MFS in children, due to the variability in onset and severity of symptoms in this age group. Recently, an international expert board has published a revised Ghent nosology, in which aortic root aneurysm and ectopia lentis are the cardinal features of MFS with a new scoring system for other systemic features of the disease

61. Management

62. The prognosis of patients with MFS has improved with the use of medical therapy (beta blockers and angiotensin receptor blockers). R outine and noninvasive monitoring of aortic size. E lective surgical repair of the aorta. Restriction of vigorous physical exercise

63. Medical

64. Beta-blockers Exercise Limitation If beta -blockers not well tolerated then calcium channel blockers In small number of patients use ARBs significantly slowed the rate of progression of aortic root dilatation.

65. AORTIC MONITORING Monitoring of the thoracic aortic diameter is recommended to identify patients at high risk for aortic dissection.

66. Surgical

67. Due to the absence of general consensus in the pediatric population, most centers advise prophylactic surgery using the diameter criterion for adults (∼50 mm) but also take into consideration the presence of accelerated aortic growth (>10 mm/ yr ), development of aortic regurgitation, or need for mitral valve surgery If the aortic valve is affected-a composite replacement of the valve and ascending aorta is performed

68. In cases with no substantial aortic valve disease, valve-sparing techniques can be applied, including remodeling of the aortic root or reimplantation of the aortic valve. Following aortic root surgery, close follow-up and continuation of medical therapy is necessary, since distal segments of the aorta may also be affected

69. Recent Advances Personalized external aortic support (PEARS) is an experimental surgical alternative being investigated in Europe, which has so far been applied in young adults only, mostly in the setting of MFS . The patient's own aortic dimensions are used to manufacture a replica of the aorta in plastic on which a bespoke external support is made of a fabric mesh. This can be positioned around the aortic root and ascending aorta without cardiopulmonary bypass and involves a shorter operation, than that for the conventional approach

70. Summery & Recommendations

71. The diagnosis of Marfan syndrome (MFS) in familial and sporadic cases are based upon the presence of characteristic manifestations, particularly aortic root dilatation/dissection and ectopia lentis , as well as other systemic features. MFS is caused by a variety of mutations in the FBN1 gene. FBN1 mutations have been identified in over 90 percent of patients with MFS. Revised Ghent criteria is used for diagnosing Marfan syndrome.

72. continued The differential diagnosis for MFS includes a variety of conditions with phenotypic features that partially overlap the Marfan phenotype, including disorders associated with FBN1/2 or TGFBR1/2 mutations, as well as a variety of other genetic disorders. First degree relatives of patients with a gene mutation associated with aortic aneurysms and/or dissection ( eg , FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) should undergo counseling and genetic testing. Those found to have the genetic mutation should then undergo aortic imaging.

73. For patients with aortic aneurysm and/or dissection without a known mutation, aortic imaging is recommended for first degree relatives to identify those with asymptomatic disease. If one or more first degree relatives are found to have thoracic aortic dilatation, aneurysm, or dissection, then imaging of second degree relatives is reasonable.

74. continued Echocardiography is recommended at initial diagnosis and at six months to assess the aortic root and ascending aorta in patients with MFS. Monitoring should be performed at least annually in patients with Ao root diameter more than 4.0 cm, and biannually in patients at higher risk ( Ao root diameter more than 4.5 cm; Ao root enlargement more than 0.5 cm per year ; family history of Ao dissection).