amenophis iv, lincoln, paganini, and rachmaninov

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

CaseCase 21 YO AAM presented to the ED with headache, 21 YO AAM presented to the ED with headache,

neck pain, and N/V for 2 days getting worse with neck pain, and N/V for 2 days getting worse with time. The family noticed him to be starting to time. The family noticed him to be starting to develop mental status changes with lethargy and develop mental status changes with lethargy and difficulty following commands. difficulty following commands.

In ER, LP was done, was found later to have viral In ER, LP was done, was found later to have viral meningitis and was admitted to MICU, and started meningitis and was admitted to MICU, and started on IV Acyclovir.on IV Acyclovir.

He had significant improvement, and transferred He had significant improvement, and transferred to the floor. to the floor.

on the 3on the 3rdrd hospital day he developed mild hospital day he developed mild pleuretic CP on ambulation, so repeat ECG pleuretic CP on ambulation, so repeat ECG showed significant changes in comparison to showed significant changes in comparison to admit ECG, so Cardiology consult requested, admit ECG, so Cardiology consult requested, transferred to telemetry, and CEs checked. transferred to telemetry, and CEs checked.

CaseCase PMH: nonePMH: none PSH: Skin graft to LLQ (burn) PSH: Skin graft to LLQ (burn) SH: previous smoker, previous Marijuana, none SH: previous smoker, previous Marijuana, none recentlyrecently No ETOH No ETOH FH: Aunt with DMFH: Aunt with DM Meds: Acetaminophen, IV AcyclovirMeds: Acetaminophen, IV Acyclovir Allergies: noneAllergies: none ROS: positive for N/V, HA, neck pain, and chillsROS: positive for N/V, HA, neck pain, and chills negative for SOB, visual complaintsnegative for SOB, visual complaints excellent exercise tolerance prior to this admitexcellent exercise tolerance prior to this admit

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

Labs and Diagnostic ImagingLabs and Diagnostic Imaging UDS: negativeUDS: negative Head CT: negativeHead CT: negative MRI of head and whole spine was negative MRI of head and whole spine was negative CEs obtained when the ECG changes were noted:CEs obtained when the ECG changes were noted: 11stst 2 2ndnd 3 3rdrd CKMB 6.6 4.0 2.2CKMB 6.6 4.0 2.2 CKMB index 0.8 0.8 1.3 CKMB index 0.8 0.8 1.3 Trop-I 0.07 0.07 0.02Trop-I 0.07 0.07 0.02 With the positive CEs, 2D echo was requested to With the positive CEs, 2D echo was requested to

assist in the diagnosis assist in the diagnosis

2D Echocardiogram2D Echocardiogram

Chambers: Normal LV size and systolic Chambers: Normal LV size and systolic function, EF is 65-70%function, EF is 65-70%

Mild mitral valve prolapse with mild mitral Mild mitral valve prolapse with mild mitral regurgitationregurgitation

Annuloaortic ectasia with aortic valve Annuloaortic ectasia with aortic valve prolapse and moderate aortic insufficiency prolapse and moderate aortic insufficiency

No evidence of aortic dissection No evidence of aortic dissection Findings consistent with connective tissue Findings consistent with connective tissue

disorder such as Marfan’s syndrome disorder such as Marfan’s syndrome

Marfan Syndrome (MFS)Marfan Syndrome (MFS)OutlineOutline

IncidenceIncidence Historic BackgroundHistoric Background Genetic BackgroundGenetic Background PathogenesisPathogenesis Clinical ManifestationsClinical Manifestations DiagnosisDiagnosis Marfan Related Marfan Related

DisordersDisorders

Overlap Heritable Overlap Heritable Connective Tissue Connective Tissue DisorderDisorder

PrognosisPrognosis ManagementManagement Pregnancy Pregnancy ConclusionConclusion

IncidenceIncidence In the US it affects 1 in 10,000 In the US it affects 1 in 10,000 At least 200,000 people in the US have MFS or a At least 200,000 people in the US have MFS or a

related connective tissue disorderrelated connective tissue disorder This makes MFS one of the most common single-This makes MFS one of the most common single-

gene malformation syndromesgene malformation syndromes May be diagnosed prenatally, at birth, or well into May be diagnosed prenatally, at birth, or well into

adulthood adulthood Internationally, no geographic predilection is Internationally, no geographic predilection is

known known It is pan-ethnicIt is pan-ethnic No gender predilection is knownNo gender predilection is known

Historic BackgroundHistoric Background In 1896 Marfan In 1896 Marfan

described the case of described the case of 5-year old patient: 5-year old patient: Gabriel P.Gabriel P.

Weve in 1931 Weve in 1931 described its described its autosomal dominant autosomal dominant inheritanceinheritance

Dietz in 1991 Dietz in 1991 described FBN1 gene described FBN1 gene mutation as the cause mutation as the cause of Marfan syndrome of Marfan syndrome Antoine Marfan, MD

1858-1942

Amenophis IV Lincoln Paganini Rachmaninov

Genetic BackgroundGenetic Background

Inherited connective tissue disorder Inherited connective tissue disorder transmitted as an autosomal dominant transmitted as an autosomal dominant traittrait

75% of patients have an affected parent 75% of patients have an affected parent The other 25% is due to new mutationsThe other 25% is due to new mutations Most of the time results from molecular Most of the time results from molecular

defects in the fibrillin-1 (FBN1) gene defects in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1located on chromosome 15q21.1

FBN1 GeneFBN1 Gene

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

Genetic BackgroundGenetic Background Different mutations involving FBN1 gene, but Different mutations involving FBN1 gene, but

associated with similar phenotypes have been associated with similar phenotypes have been demonstrateddemonstrated

However, FBN1 mutations occur across a wide However, FBN1 mutations occur across a wide range of milder phenotypes that overlap the range of milder phenotypes that overlap the classic Marfan phenotypeclassic Marfan phenotype

In a minority of cases of typical MFS, a mutation In a minority of cases of typical MFS, a mutation in FBN1 is not identified. In some of these cases in FBN1 is not identified. In some of these cases an inactivating mutation in a gene encoding a an inactivating mutation in a gene encoding a receptor for transforming growth factor-beta receptor for transforming growth factor-beta (TGFR2) may be responsible for up to 10% of (TGFR2) may be responsible for up to 10% of Marfan syndrome Marfan syndrome

Genetic BackgroundGenetic Background

The first report of an FBN1 mutation was in 1991The first report of an FBN1 mutation was in 1991 By 1998 a total of 137 FBN1 mutations has been By 1998 a total of 137 FBN1 mutations has been

characterized in patients MFS characterized in patients MFS The majority of these occur as isolated mutations The majority of these occur as isolated mutations

throughout the genethroughout the gene To date, no correlation between the specific type of To date, no correlation between the specific type of

FBN1 mutation and the clinical phenotype has FBN1 mutation and the clinical phenotype has been recognizedbeen recognized

Mutation analysis can identify the exact mutation Mutation analysis can identify the exact mutation in the fibrilin gene, and linkage analysis can track in the fibrilin gene, and linkage analysis can track an abnormal fibrilin gene in a family. However, no an abnormal fibrilin gene in a family. However, no molecular diagnosis is currently available molecular diagnosis is currently available commercially. No single gene probe or group of commercially. No single gene probe or group of probes is available to detect most FBN1 mutations probes is available to detect most FBN1 mutations

PathogenesisPathogenesis The fibrillin-1 (FBN1) The fibrillin-1 (FBN1)

gene encodes the gene encodes the glycoprotein fibrillin, a glycoprotein fibrillin, a major building block of major building block of microfibrilsmicrofibrils

The microfibrils The microfibrils constitute the constitute the structural components structural components of the suspensory of the suspensory ligaments of the lens, ligaments of the lens, and serve as a and serve as a substrates for elastin in substrates for elastin in the aorta and the other the aorta and the other connective tissuesconnective tissues

The Functions of MicrofibrilsThe Functions of Microfibrils They act as a scaffolding for the elastic fiber formationThey act as a scaffolding for the elastic fiber formation They are extensible, and may contribute to the They are extensible, and may contribute to the

mechanical properties of the mature elastic tissues by mechanical properties of the mature elastic tissues by means of load redistribution between individual elastic means of load redistribution between individual elastic fibersfibers

They provide structural anchorage in non-elastic They provide structural anchorage in non-elastic tissues, such as ciliary zonulestissues, such as ciliary zonules

They may serve to anchor endothelial cells and They may serve to anchor endothelial cells and epithelial cells to elastic fibers of the ECM via cell epithelial cells to elastic fibers of the ECM via cell binding domainsbinding domains

A role for the microfibrils in the provision of a flexible A role for the microfibrils in the provision of a flexible mechanical anchor at epithelial-mesenchymal mechanical anchor at epithelial-mesenchymal basement membrane interfaces, has been proposed basement membrane interfaces, has been proposed

PathogenesisPathogenesis Production of abnormal fibrillin-1 monomers from Production of abnormal fibrillin-1 monomers from

the mutated gene disrupts the multimerization of the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formationfibrillin-1 and prevents microfibril formation

This pathogenetic mechanism has been termed This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 dominant-negative because the mutant fibrillin-1 disrupts microfibril formation even though normal disrupts microfibril formation even though normal fibrillin is being encoded on the other fibrillin fibrillin is being encoded on the other fibrillin genegene

This leads to fragmentation and disorganization This leads to fragmentation and disorganization of the elastic fibers in the aortic media and other of the elastic fibers in the aortic media and other connective tissues (inappropriately called cystic connective tissues (inappropriately called cystic medial necrosis)medial necrosis)

PathogenesisPathogenesis

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

ManifestationsManifestations Wide range of clinical Wide range of clinical

severity associated with severity associated with MFS MFS

Classically it has Classically it has muskeloskeletal, occular, muskeloskeletal, occular, and cardiovascular and cardiovascular abnormalities abnormalities

MFS patients also MFS patients also demonstrate significant demonstrate significant involvement of lung, skin, involvement of lung, skin, CNSCNS

A severe and rapidly A severe and rapidly progressive form of MFS progressive form of MFS may present at birth may present at birth

Muskeloskeletal ManifestationsMuskeloskeletal Manifestations

Pectus excavatum

Pectus carinatum

Reduced upper to lower body segment ratioArm span/height ratio>1.05Arms and legs unusually long in proportion to torso (dolichostenomelia)Reduced extension of elbows<170


Steinberg (thumb) sign

Walker (wrist) sign

Arachnodactyly

Joint hypermobility

Highly arched palate


Pes planus

Scoliosis Kyphosis

Ocular ManifestationsOcular Manifestations

Ectopia Lentis: the lens dislocation is usually bilateral, symmetrical and upward

Other Ocular ManifestationsOther Ocular Manifestations

Nuclear sclerotic cataractMyopia due to increased axial length of the globe

Hypoplastic iris Retinal detachment

DuraDura

Dural Ectasia

Pulmonary ManifestationsPulmonary Manifestations

Spontaneous pneumothorax Apical pulmonary blebs

Skin ManifestationsSkin Manifestations

Striae atrophicae

Incisional Hernia

Cardiac Manifestations in Marfan Cardiac Manifestations in Marfan SyndromeSyndrome

OutlineOutline

IncidenceIncidence Mitral valve involvementMitral valve involvement Aortic root involvementAortic root involvement Aortic dissectionAortic dissection Other cardiac manifestationsOther cardiac manifestations

Cardiac ManifestationCardiac ManifestationIncidenceIncidence

The most common cardiovascular features The most common cardiovascular features are MVP and dilation of sinuses of Valsalvaare MVP and dilation of sinuses of Valsalva

Associated clinical problems of mitral Associated clinical problems of mitral regurgitation, aortic regurgitation, and regurgitation, aortic regurgitation, and aortic dissection account if untreated for aortic dissection account if untreated for most of early mortality that results in an most of early mortality that results in an average age of death in the fourth decade average age of death in the fourth decade of life of life

Children tend to be more severely affected Children tend to be more severely affected by mitral valve disease; whereas aortic by mitral valve disease; whereas aortic disease is progressive and more likely in disease is progressive and more likely in adolescence and beyond adolescence and beyond

Mitral Valve Involvement in MFSMitral Valve Involvement in MFS

MVP is age dependentMVP is age dependent More common in More common in

females females Incidence reaches 60-Incidence reaches 60-

80% when patients 80% when patients are studied by 2D are studied by 2D echoecho

The valve leaflets The valve leaflets have an elongated have an elongated and redundant and redundant appearance appearance

Mitral Valve Involvement in MFSMitral Valve Involvement in MFS

Progression in severity as judged by the Progression in severity as judged by the appearance of or worsening of MR by appearance of or worsening of MR by clinical and echo criteria occurs in at least clinical and echo criteria occurs in at least 25% of patients (a much higher rate in 25% of patients (a much higher rate in compared to MVP in the general compared to MVP in the general population) population)

The mitral annulus dilates and contributes The mitral annulus dilates and contributes to the regurgitation, as do stretching and to the regurgitation, as do stretching and occasional rupture of chordae occasional rupture of chordae

10% of patients with marked prolapse 10% of patients with marked prolapse have calcification of mitral annulushave calcification of mitral annulus

Aortic Root Involvement in Marfan Aortic Root Involvement in Marfan Syndrome Syndrome

The sinuses of Valsalva are The sinuses of Valsalva are often dilated at birthoften dilated at birth

Dilation of the aorta is Dilation of the aorta is found in 50% of children found in 50% of children with Marfan and will with Marfan and will progress with time progress with time

60-80% of adults with 60-80% of adults with Marfan have dilation of the Marfan have dilation of the aortic root, often with aortic root, often with aortic regurgitationaortic regurgitation

The rate of progression The rate of progression varies widely among varies widely among patients in general, thus patients in general, thus predicting long term risks predicting long term risks of developing aortic of developing aortic regurgitation is fraught regurgitation is fraught with uncertainty.with uncertainty.

Aortic Root Involvement in Marfan Aortic Root Involvement in Marfan SyndromeSyndrome

AI often appear in adults at a AI often appear in adults at a diameter of 50 mm, but may diameter of 50 mm, but may be absent at diameter of more be absent at diameter of more than 60 mm than 60 mm

The aortic dilation is limited to The aortic dilation is limited to the ascending aorta. Hence, the ascending aorta. Hence, TTE is sufficient for detecting TTE is sufficient for detecting and monitoring changes in and monitoring changes in aortic root diameteraortic root diameter

The rate of aortic diameter The rate of aortic diameter change is slow, measured in change is slow, measured in millimeters per yearmillimeters per year

Patients with dilation less than Patients with dilation less than 1.5 times the mean diameter 1.5 times the mean diameter predicted for their body size predicted for their body size can be observed annually, but can be observed annually, but as the diameter increases, the as the diameter increases, the wall tension increases, and wall tension increases, and more frequent evaluation is more frequent evaluation is necessarynecessary

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.

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.

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.

http://hyperphysics.phy-astr.gsu.edu/hbase/pasc.html#pp

http://hyperphysics.phy-astr.gsu.edu/hbase/press.html#pre

Aortic Dissection in Marfan Aortic Dissection in Marfan SyndromeSyndrome

Marfan is the cause of 50% of aortic dissections Marfan is the cause of 50% of aortic dissections occurring before the age of 40, compared to only 2% occurring before the age of 40, compared to only 2% of older patients of older patients

The risk of dissection increase with the size of the The risk of dissection increase with the size of the aorta.aorta.

Many patients with Marfan and aortic dissection have Many patients with Marfan and aortic dissection have a family history of dissectiona family history of dissection

Fortunately occurs infrequently below a diameter of 55 Fortunately occurs infrequently below a diameter of 55 mm in adults mm in adults

Hence, many physicians have adopted the criteria of Hence, many physicians have adopted the criteria of 50 to 55 mm maximal aortic root dimension for 50 to 55 mm maximal aortic root dimension for performing elective surgery in Marfan regardless of the performing elective surgery in Marfan regardless of the severity of AI. severity of AI.

Marfan patient’s with family history of aortic dissection Marfan patient’s with family history of aortic dissection should have the surgery with the Aortic root max should have the surgery with the Aortic root max diameter of 50 mm diameter of 50 mm

Aortic Dissection in Marfan Aortic Dissection in Marfan Syndrome Syndrome

Usually begins just above Usually begins just above the coronary ostia, and the coronary ostia, and extends the entire length of extends the entire length of the aortathe aorta

About 10% of dissections About 10% of dissections begin distal to the left begin distal to the left subclavian arterysubclavian artery

Rarely, the dissection is Rarely, the dissection is limited to the abdominal limited to the abdominal aortaaorta

Not all acute dissections in Not all acute dissections in patients with Marfan involve patients with Marfan involve severe tearing chest pain severe tearing chest pain radiating to the back, as radiating to the back, as some extensive dissections some extensive dissections have been occult, have been occult, reinforcing the need for a reinforcing the need for a high level of suspicion by high level of suspicion by physicians physicians

Other Cardiac ManifestationsOther Cardiac Manifestations Arrhythmias: Arrhythmias: Ventricular Ventricular Supraventricular: often associated with chronic MRSupraventricular: often associated with chronic MR LV dysfunction: LV dysfunction: occasional patients with Marfan syndrome who have no occasional patients with Marfan syndrome who have no

clinically important valvular abnormalities develop clinically important valvular abnormalities develop moderate-severe LV dysfunctionmoderate-severe LV dysfunction

-Could represent the unlikely coincidence of Marfan -Could represent the unlikely coincidence of Marfan syndrome and IDCMsyndrome and IDCM -there has been evidence that certain fibrillin mutations -there has been evidence that certain fibrillin mutations could have detrimental effect on the myocardial could have detrimental effect on the myocardial functionfunction Further studies are neededFurther studies are needed

DiagnosisDiagnosisThe Berlin CriteriaThe Berlin Criteria

Was implemented in 1988Was implemented in 1988 MFS diagnosis was based on involvement of skeletal MFS diagnosis was based on involvement of skeletal

system system andand two other systems two other systems andand at least 1 major manifestation: at least 1 major manifestation: Ectopia lentisEctopia lentis Aortic dilation or dissection Aortic dilation or dissection Dural ectasiaDural ectasia Because some of the symptoms and signs of Marfan Because some of the symptoms and signs of Marfan

(such as joint hypermobility) are much more often seen in (such as joint hypermobility) are much more often seen in patients without the disease, this has led to a recognized patients without the disease, this has led to a recognized tendency to overdiagnose Marfan syndrome in index tendency to overdiagnose Marfan syndrome in index cases or family members cases or family members

Furthermore, no Family history or molecular data were Furthermore, no Family history or molecular data were incorporated in the diagnosis incorporated in the diagnosis

DiagnosisDiagnosisGhent criteriaGhent criteria

Was implemented in 1996, and have Was implemented in 1996, and have incorporated molecular data and family incorporated molecular data and family history, to the clinical data history, to the clinical data

More stringent: about 19% of patients More stringent: about 19% of patients diagnosed under Berlin criteria did not diagnosed under Berlin criteria did not meet the Ghent criteria meet the Ghent criteria

Note that some of the criteria used to diagnosis Marfan Note that some of the criteria used to diagnosis Marfan syndrome arise with age. Therefore, a child may fail to syndrome arise with age. Therefore, a child may fail to meet the criteria at first, but may have manifestations meet the criteria at first, but may have manifestations that definitely meet the criteria at a later date. This that definitely meet the criteria at a later date. This phenomena of partial expression of Marfan syndrome in a phenomena of partial expression of Marfan syndrome in a child that one suspects will meet the full criteria at an child that one suspects will meet the full criteria at an older age has been termed "emerging Marfan syndrome".older age has been termed "emerging Marfan syndrome".

DiagnosisDiagnosisGhent criteriaGhent criteria

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

System Major Criteria Minor Criteria

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

greater than 1.05

* Wrist and thumb signs

* Scoliosis > 20d or spondylolisthesis

* Reduced extensions at the elbows (<170d)

* Medial displacement of the medial malleolus causing pes planus

* Protrusio acetabulae of any degree (ascertained on radiographs)

* Pectus excavatum of moderate severity

* Joint hypermobility

* Highly arched palate with crowding of teeth

* Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos,

retrognathia, down-slating palpebral fissures)

Ocular System

* Ectopia lentis (dislocated lens) * Abnormally flat cornea (as measured by keratometry)

* Increased axial length of globe (as measured by ultrasound)


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 the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age

of 40

* Calcification of the mitral annulus below the age of 40

* Dilatation of dissection of the descending thoracic or abdominal

aorta below the age of 50

Pulmonary System

None* Spontaneous pneumothorax

* Apical blebs (ascertained by chest radiography)

Skin and Integument

None * Stretch marks not associated with marked weight changes, pregnancy

or repetitive stress

* Recurrent incisional hernias


Dura * Lumbosacral dural ectasia by

CT or MRI

None

Family/Genetic History

* Having a parent, child or sibling who meets these diagnostic

criteria independently

* Presence of a mutation in FBN1 known to cause the Marfan

syndrome

* Presence of a haplotype around FBN1, inherited by descent, known to be associated with

unequivocally diagnosed Marfan syndrome in the family

None

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

Marfan Related Disorders

ConditionSymptom Overlap with Marfan Syndrome

Mutation in Fibrillin-1 Gene?

Familial Aortic AneurysmAortic enlargement and dissection, Variable skeletal

findingsGenerally not

Bicuspid Aortic Valve with Aortic Dilation

Aortic enlargement and/or dissection unknown

Familial Ectopia Lentis (Dislocated Lens)

Eye lens dislocation Common skeletal findings

Yes

MASS phenotype, Mitral Valve Prolapse, Myopia

Borderline aortic enlargement Skin and skeletal findings

At least sometimes

Skeletal Features (Marfan Body Type)

Skeletal findings At least

sometimes

Mitral Valve Prolapse Syndrome

Mitral valve prolapse Variable skeletal findings

At least sometimes

Congenital Contractural Arachnodactyly (CCA or

Beals syndrome)

Mitral valve prolapseVariable skeletal findings

No (FBN-2 mutation)

Stickler SyndromeMyopia Retinal detachment

Joint hypermobility or contractureScoliosis

Mitral Valve Prolapse

No (Collagen genes

mutation)

Shprintzen-Goldberg Syndrome

Aortic enlargement Skin and skeletal findings

Rare

Ehlers-Danlos Syndrome Skin and skeletal findings

Aortic enlargement/dissection in selected types onlyNo (Collagen

gene mutation)

HomocystinuriaMitral Valve Prolapse Eye lens dislocation

Skin and skeletal findings

No (metabolic disorder)

Overlap Heritable Connective Overlap Heritable Connective Tissue DisorderTissue Disorder

According to a study at Johns Hopkins, more than According to a study at Johns Hopkins, more than half of all patients evaluated in their clinic for the half of all patients evaluated in their clinic for the possible diagnosis of a heritable disorder of possible diagnosis of a heritable disorder of connective tissue could not be determined to connective tissue could not be determined to have any specifically defined disorder. have any specifically defined disorder.

In spite of that, those patients had considerable In spite of that, those patients had considerable clinical evidence of a systemic defect of the clinical evidence of a systemic defect of the extracelular matrix (MVP, Aortic root dilatation, extracelular matrix (MVP, Aortic root dilatation, muskeloskeletal abnormalities…) muskeloskeletal abnormalities…)

The authors described these patients as having The authors described these patients as having an an "overlap disorder""overlap disorder". .

They suggest that there is a continuum of They suggest that there is a continuum of connective disorder symptoms with mitral valve connective disorder symptoms with mitral valve prolapse at the mild end and Marfan syndrome at prolapse at the mild end and Marfan syndrome at the more severe end.the more severe end.

PrognosisPrognosis The life span of untreated patients with the classic MFS was The life span of untreated patients with the classic MFS was

about 32 years in 1972about 32 years in 1972 Improved therapy has resulted in marked increase in life Improved therapy has resulted in marked increase in life

expectancy up to 61 years in 1996 expectancy up to 61 years in 1996 Cardiovascular disease, especially aortic dilation and Cardiovascular disease, especially aortic dilation and

dissection is the major cause of morbidity and mortalitydissection is the major cause of morbidity and mortality Progression from MVP to MR is the most common cause of Progression from MVP to MR is the most common cause of

infant morbidityinfant morbidity Aortic dissection is uncommon in childhood and Aortic dissection is uncommon in childhood and

adolescence adolescence Death after infancy usually involves ascending aortic Death after infancy usually involves ascending aortic

dissection and chronic AIdissection and chronic AI For reasons that are not well understood, life expectancy is For reasons that are not well understood, life expectancy is

significantly lower in men than womensignificantly lower in men than women A family history of premature death or aortic surgery may A family history of premature death or aortic surgery may

identify patients at increased riskidentify patients at increased risk

ManagementManagement

Beta BlockersBeta Blockers Restriction of strenuous physical activitiesRestriction of strenuous physical activities Monitoring of the aortic root sizeMonitoring of the aortic root size Elective surgical repair of the aorta Elective surgical repair of the aorta SBE prophylaxisSBE prophylaxis Correctional ophthalmologic and Correctional ophthalmologic and

orthopedic surgeries orthopedic surgeries Management during pregnancyManagement during pregnancy

Prokop EK, et al. Circ Res 1970;27:121-127

It has been suggested that the It has been suggested that the shape of the pulse wave (rate shape of the pulse wave (rate of change in the central of change in the central arterial pressure with respect arterial pressure with respect to time designated as dp/dt) is to time designated as dp/dt) is the most important initiator of the most important initiator of the force which acts on the the force which acts on the aortic wall to cause extension aortic wall to cause extension and rupture of acute and rupture of acute dissecting aneurysmsdissecting aneurysms

To test this, a standard model To test this, a standard model of the aorta was constructed, of the aorta was constructed, using tygon tubing with rubber using tygon tubing with rubber cement lining cement lining

An “intimal tear” was An “intimal tear” was produced and aortic model produced and aortic model was subjected to nonpulsatile was subjected to nonpulsatile and pulsatile flowand pulsatile flow

dp/dtdp/dtmaxmax

The aortic models were The aortic models were first subjected to a steady first subjected to a steady flow of water at rates flow of water at rates starting at 500 ml/min, and starting at 500 ml/min, and increasing in increments to increasing in increments to a max 6000 ml/mina max 6000 ml/min

Then the flow was held Then the flow was held constant at 2500 ml/min, constant at 2500 ml/min, the initial pressure was 50 the initial pressure was 50 mm Hg. The pressure was mm Hg. The pressure was then increased in then increased in increments by changing increments by changing the resistance in the distal the resistance in the distal tube, until a final pressure tube, until a final pressure of 250 mm Hg was reachedof 250 mm Hg was reached

Pressure waveforms were Pressure waveforms were measured through cathetermeasured through catheter


The aortic models was The aortic models was then subjected to pulsatile then subjected to pulsatile flow. With pumping rate flow. With pumping rate 70 strokes/min, with 70 strokes/min, with systole being 60% and systole being 60% and diastole 40% of the entire diastole 40% of the entire cycle cycle

The rate of dissection was The rate of dissection was calculated by recording calculated by recording the time necessary to the time necessary to dissect the intimal lining dissect the intimal lining from the Tygon tubing from the Tygon tubing (cm/min)(cm/min)

The aortic model was The aortic model was subjected to a step subjected to a step increase of dp/dtincrease of dp/dtmaxmax. This . This was accomplished by was accomplished by changing the systole-changing the systole-diastole time ratio of the diastole time ratio of the pulsatile pumppulsatile pump


The same experiment were The same experiment were performed on dog aorta modelsperformed on dog aorta models

The descending aortas were The descending aortas were removed from 15 sacrificed dogs removed from 15 sacrificed dogs

the aorta was subjected to the aorta was subjected to nonpulsatile flow, with nonpulsatile flow, with incremental increase in peak incremental increase in peak systolic pressure until a final systolic pressure until a final pressure of 175 mm Hg was pressure of 175 mm Hg was reached reached

The aorta was then subjected to The aorta was then subjected to pulsatile flow at rate 60 pulsatile flow at rate 60 strokes/min. strokes/min.

Then the aortas were subjected to Then the aortas were subjected to step increase in dp/dtstep increase in dp/dtmaxmax

The presence of dissection were The presence of dissection were noted every 3 min or until the noted every 3 min or until the vessel ruptured vessel ruptured


ResultsResults

With nonpulsatile flow alone (97 experiments) no With nonpulsatile flow alone (97 experiments) no dissection occurred at pressures up to 400 mm Hgdissection occurred at pressures up to 400 mm Hg

Pulsatile flow produced rapid and usually complete Pulsatile flow produced rapid and usually complete dissection with a maximum systolic pressure of 120 dissection with a maximum systolic pressure of 120 mm Hgmm Hg

The extent of dissection per pulse was related to The extent of dissection per pulse was related to dp/dtdp/dtmaxmax

No dissection occurred until a critical value of No dissection occurred until a critical value of dp/dtdp/dtmaxmax (790 mm Hg/sec) was reached (790 mm Hg/sec) was reached

Similar results were obtained with dog aortas Similar results were obtained with dog aortas The rationale for decreasing dp/dtThe rationale for decreasing dp/dtmaxmax as a as a

worthwhile method of therapy in acute dissective worthwhile method of therapy in acute dissective aneurysms of the aorta is supported by this study aneurysms of the aorta is supported by this study


Beta BlockersBeta Blockers Recommended in all patients with Marfan Recommended in all patients with Marfan

including children unless contraindicated including children unless contraindicated Propranolol was the BB found to have a Propranolol was the BB found to have a

beneficial effect on slowing aortic dilation, beneficial effect on slowing aortic dilation, but other BB may be used as well but other BB may be used as well

The dose should be adjusted to maintain The dose should be adjusted to maintain the heart rate at 110 beats/minute after the heart rate at 110 beats/minute after submaximal exercisesubmaximal exercise

In pregnancy, labetolol is the preferred BB, In pregnancy, labetolol is the preferred BB, as atenolol may impair fetal growth as atenolol may impair fetal growth

If intolerance to BB, then CCB may be If intolerance to BB, then CCB may be used used

Beta Blockers Beta Blockers An NIH-funded, open-label, randomized trial of propranolol in 70 An NIH-funded, open-label, randomized trial of propranolol in 70

adolescent and adult patients with classic Marfan’s syndrome:adolescent and adult patients with classic Marfan’s syndrome: 32 treated32 treated 38 untreated (control)38 untreated (control) Done at the center for Medical Genetics, Johns Hopkins University,Done at the center for Medical Genetics, Johns Hopkins University, Baltimore Baltimore The Aortic-root dimensions, and clinical end points were monitored:The Aortic-root dimensions, and clinical end points were monitored: Aortic regurgitationAortic regurgitation Aortic dissectionAortic dissection Cardiovascular surgeryCardiovascular surgery CHFCHF DeathDeath Average f/u: Average f/u: 10.7 years in the treatment group10.7 years in the treatment group 9.3 years in the control group9.3 years in the control group The dose of propranolol was individualized; the mean dose was 212+-68 The dose of propranolol was individualized; the mean dose was 212+-68

mg per day mg per day

Shores, J, et al. N Eng J Med 1994;330:1335


Empirical Distribution Functions of the Rate of Change in the Aortic Ratio

Changes in the Aortic Ratio in the Treatment Group and the Control Group.

The height of each curve at any point shows the proportion of patients with values at or below the value given on the x axis

P<0.001

(The aortic ratio is obtained by dividing the measured aortic diameter by the diameter predicted from the patient height, weight, and age)


Kaplan-Meier survival analysis based on the clinical end points in the Study (death, CHF, AI, aortic dissection, cardiovascular surgery)

Numbers of patients who reached clinical end points and their initial aortic ratios.

Monitoring of the Aortic root Monitoring of the Aortic root SizeSize

The recommended threshold for elective surgery for The recommended threshold for elective surgery for aortic root dilation in adults is 50 mmaortic root dilation in adults is 50 mm

In adults yearly sonographic measurement of aortic In adults yearly sonographic measurement of aortic root diameter is recommended if the aortic root size root diameter is recommended if the aortic root size is <45 mm. Twice yearly monitoring should be is <45 mm. Twice yearly monitoring should be performed for those with diameters performed for those with diameters 45 mm45 mm

In children, it has been suggested that the aortic In children, it has been suggested that the aortic root dimensions be plotted serially against BSA, and root dimensions be plotted serially against BSA, and an operation be considered if the diameter begin to an operation be considered if the diameter begin to increase rapidly from a previously stable percentile increase rapidly from a previously stable percentile even if the absolute measurement is less than 50 even if the absolute measurement is less than 50 mm. Also, an increase of >10 mm/year is regarded mm. Also, an increase of >10 mm/year is regarded as rapid enlargement in children as rapid enlargement in children

Elective replacement of aortic rootElective replacement of aortic root

In a series of 675 In a series of 675 patients from Johns patients from Johns Hopkins, the 30 day Hopkins, the 30 day mortality was studied mortality was studied for:for:

-elective repair-elective repair -urgent repair -urgent repair (within 7 days of (within 7 days of

surgical consultation)surgical consultation) -emergency repair -emergency repair

(within 24 hour of (within 24 hour of surgical consultation)surgical consultation)

Gott, VL, et al. N Engl J Med 1999;340:1307

Kaplan–Meier Survival Analysis of 675 Patients with Marfan's Syndrome, According to the Urgency of the Procedure. I bars are 95 percent confidence intervals


PregnancyPregnancy Women with Marfan syndrome who are contemplating surgery Women with Marfan syndrome who are contemplating surgery

should have a screening TTE to assess aortic root dimensionshould have a screening TTE to assess aortic root dimension Elective repair before conception is recommended if the diameter Elective repair before conception is recommended if the diameter

is is 50 mm 50 mm Pregnancy should be discouraged if the diameter is Pregnancy should be discouraged if the diameter is 40 mm 40 mm If the diameter is <40, then:If the diameter is <40, then: -Careful clinical and echocardiographic monitoring -Careful clinical and echocardiographic monitoring -BB should be given (labetolol is preferred) -BB should be given (labetolol is preferred) -Epidural anesthesia to minimize pain during vaginal -Epidural anesthesia to minimize pain during vaginal delivery delivery -Surgical aortic repair during pregnancy should be -Surgical aortic repair during pregnancy should be considered if there is progressive dilation of the aortic considered if there is progressive dilation of the aortic root during gestation. Discussion of possible surgical root during gestation. Discussion of possible surgical intervention is appropriate when the aortic root diameter intervention is appropriate when the aortic root diameter is 55 mm or at an earlier time if the aortic root is is 55 mm or at an earlier time if the aortic root is dilating rapidlydilating rapidly

SummarySummary The diagnosis of MFS is based on the presence of characteristic The diagnosis of MFS is based on the presence of characteristic

skeletal, cardiovascular, and ocular findings in familial and skeletal, cardiovascular, and ocular findings in familial and sporadic cases. Although it is possible to identify mutations sporadic cases. Although it is possible to identify mutations involving the FBN1 and TGFBR2 genes in many MFS patients, involving the FBN1 and TGFBR2 genes in many MFS patients, these genetic tests are not necessary for routine clinical diagnostic these genetic tests are not necessary for routine clinical diagnostic purposespurposes

Monitoring the aortic root diameter using U/S is recommended as Monitoring the aortic root diameter using U/S is recommended as a means of identifying patients at risk for aortic dissection. In a means of identifying patients at risk for aortic dissection. In adults, yearly U/S is recommended as long as the aortic root adults, yearly U/S is recommended as long as the aortic root diameter is <45 mm. Twice yearly if diameter is <45 mm. Twice yearly if 45 mm45 mm

Restriction of physical activity, and BB are essential treatment Restriction of physical activity, and BB are essential treatment modalities modalities

Because elective aortic repair is associated with reduced mortality Because elective aortic repair is associated with reduced mortality in comparison to urgent or emergent repair, it should be in comparison to urgent or emergent repair, it should be considered when the aortic root is considered when the aortic root is 50 mm50 mm

Women with MFS who are contemplating pregnancy should have a Women with MFS who are contemplating pregnancy should have a TTE. If the aortic root diameter is TTE. If the aortic root diameter is 40 mm then the pregnancy is 40 mm then the pregnancy is strongly discouraged. If the diameter is <40 then close monitoring strongly discouraged. If the diameter is <40 then close monitoring is recommended is recommended

Thank you

amenophis iv, lincoln, paganini, and rachmaninov

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