Bicuspid Aortic Valve. Marfan Syndrome SUNDAY

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1 Genetic Mutations Predisposing to Thoracic Aortic Aneurysm SUNDAY Daniel Vargas, MD Outline GENETIC MUTATIONS PREDISPOSING TO THORACIC ANEURYSM FORMATION Molecular Background Bicuspid Aortopathy Turner Syndrome L Loeys-Dietz Di SSyndrome d Ehlers-Danlos Syndrome Management and Imaging follow-up DANIEL VARGAS, MD Molecular Background g 1) Fibrillin 1 (FBN1 gene) 2) Ehlers-Danlos syndrome Type III collagen ll (COL3A gene) 3) Non-syndromic Familial Thoracic Aortic Aneurysm (TAAD4) smooth muscle actin (ACTA2 gene) 4) Thoracic aortic aneurysm and patent ductus arteriosus myosin (MYH11 gene) Genetic mutations leading g to TAA may also target interand intra-cellular signaling pathways, most commonly involving TGF-ȕ Activation of TGF-ȕ results in the production of matrix metalloproteinase (MMP) 1 ExxƚƌĂĐĞůůƵůĂƌ Matrixx Molecular Background g Matrix WrŽtĞŽůLJƐiƐ &iďriůůiŷ 1 2 MMP R 2 Ğůů MĞŵďraŶĞ Most common congenital cardiac anomaly (1-2% population) Æ most common genetic cause of ascending thoracic aortic aneurysm Inheritance: Autosomal Dominant Chromosome: 9q Gene/Protein: deficiency in FBN, associated with NOTCH1 Cardiovascular (BAV, Aortic Stenosis, Coarctation, Dissection, Ao Ca2+, associated left heart pathology) CNS ((syncope)) R 2 R 1 ^M P Cytoplasm y p P ϰ MMP degrades and weakens the media, media resulting in aneurysmal dilatation ϯ W SMAD W SMAD EƵĐlĞƵs,PDJH DGDSWHG DQG VLPSOLILHG IURP (O +DPDPV\ HW DO 1DWXUH 5HYLHZV &DUGLRORJ\,PDJH DGDSWHG DQG VLPSOLILHG IURP (O +DPDPV\ HW DO 1DWXUH 5HYLHZV &DUGLRORJ\ Bicuspid p Aortic Valve Inac ǀĞ d'&ͳ ɴ Ac ǀĞ d'&ͳ ɴ Bicuspid p Aortic Valve

2 SUNDAY Bicuspid Aortic Valve Bicuspid Aortic Valve Echo at diagnosis: root and ascending aortic diameters Ascending aortic diameters measuring >4.0 cm cross sectional imagingi Annual monitoring: echo, MR or CT Elective repair with aortic diameter >5.0 cm, OR, >4.5 cm with any of the following: Expansion rate >0.5 cm per year Aortic coarctation 1 st degree relative with dissection i or rupture Small body size Aortic diameter > 4.0cm with indication for aortic valve repair Prevalence: 1:5-10k 10k Inheritance: Autosomal Dominant Chromosome: 15q21.1 Gene/Protein: FBN1/Fibrillin 1 Cardiovascular (Annuloaortic ectasia, TAA, Dissection, AoV Regurgitation, g CHF) MSK (arachnodactyly, pectus deformity) Ophthalmologic (ectopia lentis) CNS (dural ectasia) Echo at diagnosis and 6 months Annual imaging if stable More frequent screening if max diameter is 4.5 cm or greater, significant or accelerated growth from baseline, or if significant aortic regurgitation g is present Prophylactic surgery when aortic diameter reaches 5.0 cm, unless: Family history of dissection at < 5cm, rapidly growing/expanding aneurysm, or significant AVR

3 Turner Syndrome (45 Xo) SUNDAY Prevalence: 1:2500 live female births Karyotype: 45, X or mosaic 46, XX Chromosome: X Gene/Protein: reduced complement of genes typically expressed from both X chromosomes : Cardiovascular (coarctation, BAV, arch elongation, root dilatation, hypoplastic left heart, PAPVR) Gonadal (ovarian failure) MSK (short stature) Renal (horseshoe kidney) Circulatory (cystic hygroma, lymphedema webbed neck) Turner Syndrome (45 Xo) Turner Syndrome (45 Xo) Infants/Children: echo or MRI to detect BAV, coarctation, ascending aortic dilation If normal and no risk factors for dissection, imaging every 5-10yrs or as clinically indicated If cardiac or thoracic abnormalities annual imaging In patients with short stature, normal root diameters do not apply If severe coarctation presents at infancy Surgery Critical aortic stenosis (minority of cases) Surgery BAV (present in 13-34% 34% of patients) surveillance and endocarditis prophylaxis Ehlers-Danlos Type IV Ehlers-Danlos Type IV Prevalence: 1:10-25k ( 4% of all EDS) Inheritance: AD Chromosome: 2q24.3-q31 Gene/Protein: COL3A1/Type III collagen : Vascular (arterial aneurysms, dissection and spontaneous rupture) Connective tissues (translucent skin, easy bruising) MSK (absence of joint hypermobility) Visceral (rupture, perforation)

4 SUNDAY Ehlers-Danlos Type IV No imaging follow-up consensus Non-invasive modalities: ultrasound, MR or CTA may help to identify aneurysms, dissections and vascular ruptures Invasive angiography risk of procedure related vascular complication at catheter entry site. Prevalence: Rare Inheritance: AD Chromosome: 3p24-25, 25 9q Gene/Protein: TGF1, TGF2 Surgical repair limited to emergent cases (elective repair discouraged due to poor outcomes relating to tissue friability) Vascular (vessel tortuosity, root dilatation, Dissection occur at smaller diameters that Marfan) Craniofacial (hypertelorism, bifid uvula, cleft palate) MSK (pectus) Complete aortic imaging at initial diagnosis and 6 months Echo at frequent intervals to monitor ascending Ao diameter Frequency of MRA/CTA of the entire arterial tree (head to pelvis) depends d on symptoms half of individuals with LDS studied had an aneurysm distant from the aortic root Surgical repair in adolescents and adults when maximal aortic dimension i approaches 4.0cm Surgical repair in children when max dimension exceeds the 99 th percentile and annulus > cm Complete aortic imaging at initial diagnosis and 6 months Echo at frequent intervals to monitor ascending Ao diameter Frequency of MRA/CTA of the entire arterial tree (head to pelvis) depends d on symptoms half of individuals with LDS studied had an aneurysm distant from the aortic root Surgical repair in adolescents and adults when maximal aortic dimension i approaches 4.0cm Surgical repair in children when max dimension exceeds the 99 th percentile and annulus > cm

5 Congenital Contractural Arachnodactyly (Beals Syndrome) SUNDAY Prevalence: rare Inheritance: AD Chromosome: 5q23.3 Gene/Protein: FBN2/Fibrillin 2 Vascular (mild dilatation of Sinus of Valsalva) MSK (Marfanoid habitus, hand/ankle/knee contractures, kyphosis/scoliosis, pectus) Other: Severe forms have been associated with ASD, interrupted Aortic arch Congenital Contractural Arachnodactyly (Beals Syndrome) Name Clinical Features Chromosome Gene/Protein Protein Location Imaging Echo every 2 years until establish the aorta is not involved Treat clinical findings as they arise Noonan syndrome (ie. Male Turner Syndrome) Polycystic Kidney Disease Marfan-like syndrome Short Stature, facial dysmorphism, congenital heart defects (including ASD/VSD, cardiomyopathy, aortic coarctation) Renal cysts, liver cysts, intracranial aneurysm formation, cardiac valve disease (eg. Aortic regurgitation), g collagen and/or extracellular matrix abnormalities predisposing to aortic root and annulus dilatation Similar features of Marfan syndrome, but not fulfilling all clinical criteria 12q24.1 2p p12.1 PTPN11/PTPN!! Unidentified Unidentified 16p13.3 PKD1/Polycystin 1 4q PKD2/Polycystin 2 Intracellular Cell membrane Cell membrane Cell membrane 3p24-25 TGFBR2/TGF-R2 Cell surface Aneurysmosteoarthritis syndrome Ascending aortic aneurysm, arterial tortuosity, and earlyonset osteoarthritis 15q22.2-q24.2 SMAD3 Intracellular Name Chromosome Gene/Protein Protein Location FAA1 (Familial Aortic Aneurysm) 11q23-24 Unidentified Unidentified TAAD1 (Thoracic Aortic Aneurysm and Aortic Dissection) 5q13-14 Unidentified Unidentified TAAD2 3p24-25 TGFBR2/TGF-R2 Cell surface TAAD3 15q24-26 Unidentified Unidentified TAAD4 10q23-24 ACTA2/Smooth muscle actin Intracellular TAAD PDA (Thoracic Aortic Aneurysm and Aortic Dissection and Patent Ductus Arteriosus) 16p12-13 MYH11/-MHC Intracellular Additional Recommendations 2010 AACF/AHA/AATS/ACR/ASA/SCAI/SIR/STS/SVM guidelines recommend aortic imaging for 1 st degree relatives of patients with TAA and/or dissection to identify those with asymptomatic disease If one or more 1 st degree relative of a patient with known TAA and/or aortic dissection are found to have thoracic aortic dilatation, aneurysms or dissection, then imaging of 2 nd degree relatives is reasonable TAAD5 9q33-34 TGFBR1/TGF-R1 Cell surface

6 SUNDAY Additional Recommendations References If there is a known family history, or confirmed genetic mutation known to predispose to aortic aneurysms and dissections (TGFBR1, TGFBR2, FBN1, ACTA2, or MYH11), imaging of the entire aorta and cerebrovascular systems should be considered 1. Pomianowski P, Elefteriades JA. The genetics and genomics of thoracic aortic disease. Annals of Cardiothoracic Surgery. 2013; 2(3): Linde DL, van de Laar I, Bertoli-Avella AM, et al. Aggressive Cardiovascular Phenotype of Aneurysms- Osteoarthritis Syndrome Caused by Pathogenic SMAD3 Variants. Journal of the American College of Cardiology. 2012; 60(5): Tadros TM, Klein MD, Shapira OM. Ascending Aortic Dilatation Associated with Biscuspid Aortic Valve: Pathophysiology, h Molecular l Biology, and Clinicall Implications. Circulation. 2009; 119: El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nature Reviews Cardiology. 2009; 6: Germain DP. Review: Ehlers-Danlos Syndrome Type IV. Orphanet Journal of Rare Diseases. 2007; 2:32 6. Albornoz G, Coady MA, Roberts M, et al. Familial Thoracic Aortic Aneurysms and Dissections Incidence, Modes of Inheritance, and Phenotypic Patters. Annals of Thoracic Surgery. 2006; 82: Donaldson MDC, Gault EJ, Tan KW, et al. Optimising management in Turner Syndrome: From Infancy to Adult Transfer. Achives of Disease in Childhood. 2006; 91: Tunçbilek E, Alanay Y. Review: Congenital Contractural Arachnodactyly (Beals Syndrome). Orphanet Journal of Rare Diseases. 2006; 1:20 9. Drera B, et al. type I and II: clinical findings and novel mutations in two Italian patients. t Orphanet Journal of Rare Diseases. 2009; 4:24