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Amenophis IV, Lincoln, Paganini, and Rachmaninov

Amenophis IV, Lincoln, Paganini, and Rachmaninov Shadwan Alsafwah, MD Cardiology Fellow Staff Support: Dr. Richard Davis

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Amenophis IV, Lincoln, Paganini, and Rachmaninov

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  1. Amenophis IV, Lincoln, Paganini, and Rachmaninov Shadwan Alsafwah, MD Cardiology Fellow Staff Support: Dr. Richard Davis The University of Tennessee at Memphis

  2. Case • 21 YO AAM presented to the ED with headache, neck pain, and N/V for 2 days getting worse with time. The family noticed him to be starting to develop mental status changes with lethargy and difficulty following commands. • In ER, LP was done, was found later to have viral meningitis and was admitted to MICU, and started on IV Acyclovir. • He had significant improvement, and transferred to the floor. • on the 3rd hospital day he developed mild pleuretic CP on ambulation, so repeat ECG showed significant changes in comparison to admit ECG, so Cardiology consult requested, transferred to telemetry, and CEs checked.

  3. Case • PMH: none • PSH: Skin graft to LLQ (burn) • SH: previous smoker, previous Marijuana, none recently No ETOH • FH: Aunt with DM • Meds: Acetaminophen, IV Acyclovir • Allergies: none • ROS: positive for N/V, HA, neck pain, and chills negative for SOB, visual complaints excellent exercise tolerance prior to this admit

  4. Case • PE: on the 3rd hospital stay General: mildly lethargic, H: 6 00, W: 132 LBS Vitals: 110/60, 45, 16, 100, 97% on RA Neck: no JVD, mild nuchal rigidity Chest: CTAB CVS: Bradycardic, RRR, no S3 or S4, mid systolic click heard widely all over the precordium that moved toward S2 with squatting, and toward S1 with standing. There was also II/VI early decrescendo diastolic murmur at LSB Abdomen: Soft, NT, ND, NABS, + graft scar Ext: no edema, clubbing, cyanosis Muskeloskeletal system: without gross abnormalities Neuro: mildly lethargic, but oriented x3, no focal deficits

  5. Labs and Diagnostic Imaging • UDS: negative • Head CT: negative • MRI of head and whole spine was negative • CEs obtained when the ECG changes were noted: 1st 2nd 3rd CKMB 6.6 4.0 2.2 CKMB index 0.8 0.8 1.3 Trop-I 0.07 0.07 0.02 • With the positive CEs, 2D echo was requested to assist in the diagnosis

  6. 2D Echocardiogram • Chambers: Normal LV size and systolic function, EF is 65-70% • Mild mitral valve prolapse with mild mitral regurgitation • Annuloaortic ectasia with aortic valve prolapse and moderate aortic insufficiency • No evidence of aortic dissection • Findings consistent with connective tissue disorder such as Marfan’s syndrome

  7. Incidence Historic Background Genetic Background Pathogenesis Clinical Manifestations Diagnosis Marfan Related Disorders Overlap Heritable Connective Tissue Disorder Prognosis Management Pregnancy Conclusion Marfan Syndrome (MFS)Outline

  8. Incidence • In the US it affects 1 in 10,000 • At least 200,000 people in the US have MFS or a related connective tissue disorder • This makes MFS one of the most common single-gene malformation syndromes • May be diagnosed prenatally, at birth, or well into adulthood • Internationally, no geographic predilection is known • It is pan-ethnic • No gender predilection is known

  9. Historic Background • In 1896 Marfan described the case of 5-year old patient: Gabriel P. • Weve in 1931 described its autosomal dominant inheritance • Dietz in 1991 described FBN1 gene mutation as the cause of Marfan syndrome Antoine Marfan, MD 1858-1942

  10. Amenophis IV Lincoln Paganini Rachmaninov

  11. Genetic Background • Inherited connective tissue disorder transmitted as an autosomal dominant trait • 75% of patients have an affected parent • The other 25% is due to new mutations • Most of the time results from molecular defects in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1

  12. FBN1 Gene FBN1 is a large gene composed of 9000 nucleotides dispersed in 65 exones located at chromosome 15q-21.1

  13. Genetic Background • Different mutations involving FBN1 gene, but associated with similar phenotypes have been demonstrated • However, FBN1 mutations occur across a wide range of milder phenotypes that overlap the classic Marfan phenotype • In a minority of cases of typical MFS, a mutation in FBN1 is not identified. In some of these cases an inactivating mutation in a gene encoding a receptor for transforming growth factor-beta (TGFR2) may be responsible for up to 10% of Marfan syndrome

  14. Genetic Background • The first report of an FBN1 mutation was in 1991 • By 1998 a total of 137 FBN1 mutations has been characterized in patients MFS • The majority of these occur as isolated mutations throughout the gene • To date, no correlation between the specific type of FBN1 mutation and the clinical phenotype has been recognized • Mutation analysis can identify the exact mutation in the fibrilin gene, and linkage analysis can track an abnormal fibrilin gene in a family. However, no molecular diagnosis is currently available commercially. No single gene probe or group of probes is available to detect most FBN1 mutations

  15. The fibrillin-1 (FBN1) gene encodes the glycoprotein fibrillin, a major building block of microfibrils The microfibrils constitute the structural components of the suspensory ligaments of the lens, and serve as a substrates for elastin in the aorta and the other connective tissues Pathogenesis

  16. The Functions of Microfibrils • They act as a scaffolding for the elastic fiber formation • They are extensible, and may contribute to the mechanical properties of the mature elastic tissues by means of load redistribution between individual elastic fibers • They provide structural anchorage in non-elastic tissues, such as ciliary zonules • They may serve to anchor endothelial cells and epithelial cells to elastic fibers of the ECM via cell binding domains • A role for the microfibrils in the provision of a flexible mechanical anchor at epithelial-mesenchymal basement membrane interfaces, has been proposed

  17. Pathogenesis • Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation • This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 disrupts microfibril formation even though normal fibrillin is being encoded on the other fibrillin gene • This leads to fragmentation and disorganization of the elastic fibers in the aortic media and other connective tissues (inappropriately called cystic medial necrosis)

  18. Pathogenesis • Mucin stain of the wall of the aorta demonstrates cystic medial necrosis, typical for Marfan's syndrome and causes the connective tissue weakness that explains the aortic dissection. Pink elastic fibers, instead of running in parallel arrays, are disrupted by pools of blue mucinous (mucopolysaccharide) ground substance, these accumulations are the so-called “cysts” of cystic medial necrosis.

  19. Wide range of clinical severity associated with MFS Classically it has muskeloskeletal, occular, and cardiovascular abnormalities MFS patients also demonstrate significant involvement of lung, skin, CNS A severe and rapidly progressive form of MFS may present at birth Manifestations

  20. Muskeloskeletal Manifestations Pectus excavatum Reduced upper to lower body segment ratio Arm span/height ratio>1.05 Arms and legs unusually long in proportion to torso (dolichostenomelia) Reduced extension of elbows<170 Pectus carinatum

  21. Muskeloskeletal Manifestations Joint hypermobility Steinberg (thumb) sign Arachnodactyly Highly arched palate Walker (wrist) sign

  22. Muskeloskeletal Manifestations Pes planus Kyphosis Scoliosis

  23. Ocular Manifestations Ectopia Lentis: the lens dislocation is usually bilateral, symmetrical and upward

  24. Other Ocular Manifestations Myopia due to increased axial length of the globe Nuclear sclerotic cataract Retinal detachment Hypoplastic iris

  25. Dura Dural Ectasia

  26. Pulmonary Manifestations Apical pulmonary blebs Spontaneous pneumothorax

  27. Skin Manifestations Striae atrophicae Incisional Hernia

  28. Cardiac Manifestations in Marfan SyndromeOutline • Incidence • Mitral valve involvement • Aortic root involvement • Aortic dissection • Other cardiac manifestations

  29. Cardiac ManifestationIncidence • The most common cardiovascular features are MVP and dilation of sinuses of Valsalva • Associated clinical problems of mitral regurgitation, aortic regurgitation, and aortic dissection account if untreated for most of early mortality that results in an average age of death in the fourth decade of life • Children tend to be more severely affected by mitral valve disease; whereas aortic disease is progressive and more likely in adolescence and beyond

  30. MVP is age dependent More common in females Incidence reaches 60-80% when patients are studied by 2D echo The valve leaflets have an elongated and redundant appearance Mitral Valve Involvement in MFS

  31. Mitral Valve Involvement in MFS • Progression in severity as judged by the appearance of or worsening of MR by clinical and echo criteria occurs in at least 25% of patients (a much higher rate in compared to MVP in the general population) • The mitral annulus dilates and contributes to the regurgitation, as do stretching and occasional rupture of chordae • 10% of patients with marked prolapse have calcification of mitral annulus

  32. The sinuses of Valsalva are often dilated at birth Dilation of the aorta is found in 50% of children with Marfan and will progress with time 60-80% of adults with Marfan have dilation of the aortic root, often with aortic regurgitation The rate of progression varies widely among patients in general, thus predicting long term risks of developing aortic regurgitation is fraught with uncertainty. Aortic Root Involvement in Marfan Syndrome

  33. AI often appear in adults at a diameter of 50 mm, but may be absent at diameter of more than 60 mm The aortic dilation is limited to the ascending aorta. Hence, TTE is sufficient for detecting and monitoring changes in aortic root diameter The rate of aortic diameter change is slow, measured in millimeters per year Patients with dilation less than 1.5 times the mean diameter predicted for their body size can be observed annually, but as the diameter increases, the wall tension increases, and more frequent evaluation is necessary Aortic Root Involvement in Marfan Syndrome

  34. Why does wall tension increase with radius? If the upward part of the fluid pressure remains the same, then the downward component of the wall tension must remain the same. But if the curvature is less, then the total tension must be greater in order to get that same downward component of tension.

  35. LaPlace's Law The larger the vessel radius, the larger the wall tension required to withstand a given internal fluid pressure. For a given vessel radius and internal pressure, a spherical vessel will have half the wall tension of a cylindrical vessel.

  36. Pascal's principle requires that the pressure is everywhere the same inside the balloon at equilibrium. But examination immediately reveals that there are great differences in wall tension on different parts of the balloon. The variation is described by Laplace's Law.

  37. Aortic Dissection in Marfan Syndrome • Marfan is the cause of 50% of aortic dissections occurring before the age of 40, compared to only 2% of older patients • The risk of dissection increase with the size of the aorta. • Many patients with Marfan and aortic dissection have a family history of dissection • Fortunately occurs infrequently below a diameter of 55 mm in adults • Hence, many physicians have adopted the criteria of 50 to 55 mm maximal aortic root dimension for performing elective surgery in Marfan regardless of the severity of AI. • Marfan patient’s with family history of aortic dissection should have the surgery with the Aortic root max diameter of 50 mm

  38. Usually begins just above the coronary ostia, and extends the entire length of the aorta About 10% of dissections begin distal to the left subclavian artery Rarely, the dissection is limited to the abdominal aorta Not all acute dissections in patients with Marfan involve severe tearing chest pain radiating to the back, as some extensive dissections have been occult, reinforcing the need for a high level of suspicion by physicians Aortic Dissection in Marfan Syndrome

  39. Other Cardiac Manifestations • Arrhythmias: Ventricular Supraventricular: often associated with chronic MR • LV dysfunction: occasional patients with Marfan syndrome who have no clinically important valvular abnormalities develop moderate-severe LV dysfunction -Could represent the unlikely coincidence of Marfan syndrome and IDCM -there has been evidence that certain fibrillin mutations could have detrimental effect on the myocardial function Further studies are needed

  40. DiagnosisThe Berlin Criteria • Was implemented in 1988 • MFS diagnosis was based on involvement of skeletal system and two other systems and at least 1 major manifestation: Ectopia lentis Aortic dilation or dissection Dural ectasia • Because some of the symptoms and signs of Marfan (such as joint hypermobility) are much more often seen in patients without the disease, this has led to a recognized tendency to overdiagnose Marfan syndrome in index cases or family members • Furthermore, no Family history or molecular data were incorporated in the diagnosis

  41. DiagnosisGhent criteria • Was implemented in 1996, and have incorporated molecular data and family history, to the clinical data • More stringent: about 19% of patients diagnosed under Berlin criteria did not meet the Ghent criteria • Note that some of the criteria used to diagnosis Marfan syndrome arise with age. Therefore, a child may fail to meet the criteria at first, but may have manifestations that definitely meet the criteria at a later date. This phenomena of partial expression of Marfan syndrome in a child that one suspects will meet the full criteria at an older age has been termed "emerging Marfan syndrome".

  42. DiagnosisGhent criteria • The diagnosis is made if: - In family members: presence of major involvement in 1 organ system as well as involvement in a second organ system - If the family and genetic histories are not contributory: major criteria in 2 different organ systems and involvement of a third organ system are required

  43. American Journal of Medical Genetics 62:417-426, 1996

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