218 slide Skeletal Bone Genetics MARFAN SYNDROME PowerPoint Presentation on CD For Sale

218 slide Skeletal Bone Genetics MARFAN SYNDROME PowerPoint Presentation on CD


Buy Now

218 slide Skeletal Bone Genetics MARFAN SYNDROME PowerPoint Presentation on CD :
$12.99

All derivative (i.e. change in media; by compilation) work from this underlying U.S. Government public domain/public release data is COPYRIGHT © GOVPUBS

$3.00 first class shipping in U.S. and rest of world.

Includes the Adobe Acrobat Reader for reading and printing publications.

Numerous illustrations and matrices.

Contains the following key public domain (not copyrighted) U.S. Government publication(s) on one CD-ROM in both Microsoft PowerPoint and Adobe Acrobat PDF file formats:

TITLE:

Marfan Syndrome, 218 pages (slides)

SLIDE TOPICS, SUBTOPICS and CONTENTS:

Marfan Syndrome

Hang T. Nguyen, CPT, MC

Rheumatology Service

WRAMC

History

The Marfan syndrome (MFS) was first described in 1896 by aFrench pediatrician, Antoine Marfan

He documented the clinical signs of a 5 ½ year old girl withlong thin limbs

Epidemiology

One of the most common inherited disorders of connectivetissue

Autosomal dominant inheritance, variable penetrance

Incidence 1 in 10,000 to 20,000 individuals

Equal gender and ethnic distribution

Question

Mutations on which gene are associated with Marfan Syndrome?

Genetics

FBN1

Elastic and nonelastic tissue

Chromosome 15q21.1

More than 97 mutations identified

No correlation between specific mutation and clinicalphenotype

25% MFS cases result from spontaneous mutations

Bonus Question

What heritable disorder of connective tissue is associatedwith mutations in the Fibrillin-2 gene?

Skeletal Manifestations

Arachnodactyly

Cardiac Manifestations

Aortic disease is main cause of morofferity and mortality inMFS

Dilatation found in 50% of children

60 to 80% of adults have aortic root dilatation

Cardiac Manifestations

Aortic Disease

Cystic medial necrosis

Other cardiac disease

Mitral valve prolapse leading to mitral regurgitation

Seen in 60-80% of MFS by echocardiogram

More common in women

Age-dependent

Pregnancy

Pregnant women are at particular risk for aortic dissection

Complications are most often seen in the second and thirdtrimester

C-section

ß-blockers

Ocular Manifestations

Ectopia lentis

50 to 80 percent of MFS patients

Usually bilateral

Lens upwardly displaced

Other Findings

Dural Ectasia (Major Manifestation)

Lumbosacral region

Occurs in >90% of MFS patients

MRI most sensitive for diagnosis

Clinical significance?

Other Manifestations

Pulmonary System

Spontaneous pneumothorax

Apical blebs

Integumentary System

Striae atrophicae

Recurrent or incisional hernia

Marfan Syndrome

Diagnosis of MFS and other related conditions are based onclinical features

Detection of a fibrillin mutation contributes to thediagnostic criteria, but the diagnosis is primarily clinical

Diagnostic Requirements for MFS

Index case

If family or genetic history is not contributory

Major criteria in at least two different organ systems

Involvement of a third organ system

If the mutation known to cause Marfan syndrome in others isdetected

One major criterion in an organ system

Involvement of a second organ system

Diagnostic Requirements for MFS

Relative of Index case

Major criterion in an organ system

Involvement of a second organ system

Skeletal SystemMajor if at least 4; Involved if either 2 major or 1 major and 2 minor

Major

Pectus carinatum or pectus excavatum (requiring surgery)

(+) wrist & thumb signs

Scoliosis >20 ° or kyphosis

Reduced upper/lower segment (<0.85)

Arm span/height ratio >1.05

Reduced elbow extension

Protrusio acetabulae

Pes planus

Minor

Pectus excavatum (moderate)

Joint hypermobility

High arched palate with dental crowding

Typical facies, including

Dolichocephaly

Malar hypoplasia

Retrognathia

Enophthalmos

Downslanting palpebral fissures

Ocular system

Major if

Ectopia lentis

Involved if (two or more)

Flat cornea

Increased axial length of globe leading to myopia

Hypoplastic iris or ciliary muscle causing decreased miosis

Cardiovascular system

Major if (1 or more)

Dilatation of the ascending aorta

Dissection of the ascending aorta

Involved if (1 or more)

Mitral valve prolapse

Dilatation of pulmonary artery <age 40

Mitral annular calcification <age 40

Dilatation or dissection of descending aorta <age 50

Mitral regurgitation

Left ventricular dilatation

Tricuspid valve prolapse

Neurologic

Major

Lumbosacral dural ectasia (by CT or MRI)

Involved (if 1 or more)

Spontaneous pneumothorax

Apical blebs on CXR

Striae atrophicae

Recurrent or incisional hernia

Question

A 23 year-old man is referred to you for evaluation afterhaving suffered a pathologic vertebral fracture. He is tall (6 ft 7 in), hasdolichostenomelia, arachnodactyly and pectus excavatum and scoliosis as well asdownward displacement of both lenses. Nomurmurs are audible on exam. He showsmoderate mental retardation. His parentsand siblings are of normal stature with no musculoskeletal abnormalities.

Does he have Marfan syndrome?

What would be the prime consideration in your differentialgiven the clinical history?

Homocystinuria

Triad of mental retardation, connective tissue disorder andthrombosis

Differential Diagnoses of Marfan Syndrome

Homocystinuria

MASS phenotype

Congenital contractural arachnodactyly

Isolated ectopia lentis

Ehlers-Danlos syndromes types I, II and III

Stickler syndrome (hereditary arthroophthalmopathy)

Klinefelter syndrome

Question

A23-year-old woman is self-referred for a routine examination. She has nospecific complaints and has no symptoms on review of systems. Physicalexamination shows a tall, thin, young woman with a mild pectus excavatum, anincreased arm span–to–height ratio, and arachnodactyly. Her pulse rate is80/min and regular, respiratory rate is 16/min, and blood pressure is 120/60 mmHg. Cardiac examination shows a loud S1 and a physiologically split S2 with nomurmurs or gallops. An echocardiogram shows loss of the aortic sinotubularjunction with mild aortic root dilatation (40 mm versus an expected dimensionof 34 mm for her age and body size).

Which of the following is most appropriate?

Question

Provide reassurance; no further evaluation or therapy is needed.

Recommend echocardiography for all her first-degreerelatives.

Initiate therapy with an angiotensin-converting enzyme inhibitor.

Discuss the need for permanent contraception.

Encourage increased physical activity.

Question

Provide reassurance; no further evaluation or therapy isneeded.

Recommend echocardiography for all her first-degreerelatives.

Initiate therapy with an angiotensin-converting enzymeinhibitor.

Discuss the need for permanent contraception.

Encourage increased physical activity.

Cardiac Causes of Sudden Death in Competitive Athletes

Life Expectancy in MFS

Management

Restriction of vigorous physical activity

Monitoring of aortic size

ß-blockers

Elective aortic root repair

Aortic root diameter > 55mm

50mm if considering pregnancy

Management

Annual ophthalmology exam

Semi-annual orthopedic evaluation

Bracing

Surgical intervention when scoliosis>40 degrees

Hormonal advancement of pubarche

Famous People with MFS

Take Home Points

Aortic dissection is the primary cause of death in MFS

Periodic echocardiographic evaluation is key in managementof aortic dilatation

Echocardiographic screening for first-degree relatives

QUESTIONS?

Marfan Syndrome

LCDR Michael Keith

Rheumatology Fellow

March 23, 2005

Overview

History

Epidemiology

Genetics

Clinical features

Diagnosis

Mortality

Management

History

First described 1896

Dr. Antoine Marfan

Medical Society of Paris Hospitals

5 year-old female

Other Historical Figures

History

1914: Adoption of Marfan syndrome

Arachnodactyly

Dislocated lenses

1931: Autosomal dominant inheritance

1943: Association with aortic dissection

Epidemiology

Common inherited connective tissue disorder

Autosomal dominant, variable penetrance

Incidence about 1 in 10,000

Epidemiology

Equal gender and ethnic distribution

25% cases are sporadic

Arise from new mutation

Spectrum of Hereditary Disorders

Genetics

Late 1980s: Abnormalities of fibrillin

Important component of elastic tissues

Skin, aorta, arteries, ligaments, lung parenchyma

1991: Dietz et al.

Mutation of Fibrillin-1 gene

Mostly on chromosome 15

Over 50 mutations described

One family with mutation unknown gene chromosome 3

Genetics

Variable penetrance of fibrillin-1 mutation

Incomplete forms of disease

Milder or non-existant cardiovascular features

MASS

Myopia, MVP, Aorta, Skin, Skeletal

Isolated ectopia lentis

Clinical Features

Skeletal

Habitus

Hypermobility

Cardiovascular

Murmur

Echocardiographic abnormalities

Ocular

Lens displacement

Diagnosis

De Paepe et al. 1996

Clinical and Genetic Features

Ghent Nosology

Major criteria in 2 organ systems

Involvement of third organ system

Less stringent when + family hx

Diagnosis

Skeletal: Pectus

Excavatum

Carinatum

Skeletal: Dolichostenomelia

Skeletal: Steinberg’s sign

Positive when:

Thumb enclosed in the clenched fist

Nail extends beyond hypothenar border

Skeletal: Walker-Murdoch sign

Overlap of thumb and 5th digit as they encircle wrist

Skeletal: Arachnodactyly

Skeletal: Metacarpal index

Mean of the length divided by midpoint width of the 2nd –4th metacarpals

Normal

5.4 to 7.9

MFS

>8.4

Skeletal: Spine involvement

Scoliosis > 20°

Kyphosis

Skeletal: Protrusio acetabulae

Positon of medial wall acetabulum c/w ilioischial line

Women

Normal: 1 mm medial

MFS: 6 mm medial

Men

Normal: 2 mm lateral

MFS: 3 mm medial

Skeletal: Miscellaneous

Major

Elbow extension <170°

Pes planus

Involvement

Minor pectus excavatum

Joint hypermobility

High arched palate

Typical facies

Dolichocephaly

Malar hypoplasia

Retrognathia

Enophthalmos

Downslanting palpebral fissures

Ocular: Ectopia Lentis

About 60% of cases

Typically bilateral

Upward displacement

Ocular: Involvement

Flat cornea

Increased axial length of globe

Myopia

Hypoplastic iris or ciliary muscle

Decreased miosis

Cardiovascular: Major

Dilatation of Aortic Root

Includes sinus of Valsalva

Dissection of Ascending Aorta

Stanford A

DeBakey I,II

Cardiovascular: Involved

Mitral valve prolapse

PA dilatation, age < 40

Mitral Annular Calcification, age < 40

Other Aortic dilatation or dissection

Pulmonary

Major

None defined

Involvement

Spontaneous pneumothorax

Apical blebs

Cutaneous

Major (none)

Minor

Striae atrophicae

Recurrent hernia

Incisional hernia

Differential Diagnosis

Homocystinuria

Ectopia lentis (downward displacement)

Mental retardation

Risk of thrombosis

MASS phenotype

mitral valve prolapse

aortic dilatation

skin involvement

skeletal involvement

lower risk of aortic aneurysm rupture

Differential Diagnosis

Congenital contractural arachnodactyly

Mutation of fibrillin-2 gene, chromosome 5

80% homology to fibrillin-1

Marfanoid habitus, no cardiac or eye findings

Isolated ectopia lentis

Associated with fibrillin-1 gene

No other findings

Differential Diagnosis

Ehlers-Danlos syndromes (I,II,III)

Stickler syndrome

Hereditary arthro-ophthalmopathy

Type II collagen

Klinefelter syndrome

XXY genotype

Tall stature, small testes, gynecomastia

No cardiac or ocular manifestations

Mortality

Aortic dissection

Main cause of premature death

Improved life expectancy

1972 mean 32 years

1995 mean 45 years

Mortality

Decrease in death from aortic dissection

1972: 70%

1995: 48%

Improved medical and surgical management

Sudden Cardiac Death

Often excel in sports

Height: volleyball, basketball

Flexibility: ballet, gymnastics

Aortic Dissection in Marfan Syndrome

Study by Maron et al. JAMA 1996;276:199-204.

Third most common cause of SCD in athletes

Frequency = 5%

Management

Focus on cardiovascular complications

Serial echocardiogram

Baseline

Every 6-12 months

Management

Risk factors for aortic dissection

Aortic diameter > 5 cm

Dilatation beyond sinus of Valsalva

Family history

Rapid rate of increased dilatation

> 5 % / year

> 2 mm / year in adults

Management

Pregnancy

Increased risk of aortic dissection

Gestational hypertension

Pre-eclampsia

Especially when aorta > 4 cm

Frequent monitoring during pregnancy and puerperium

Medical Therapies

β-blockers (usually lifelong)

Atenolol, metoprolol, propranolol

Decrease aortic stiffness and pulse velocity

Most effective in aorta < 4cm

? Calcium channel blockers

? Angiotensin inhibition (Ace-I / Arb)

Surgical Therapy

Better outcome with early surgery

Worse outcome with late or emergent surgery

Referral for elective surgery

Adults with aorta > 5.5 cm

Children with aorta > 5.0 cm

Other System Management

Annual ophthalmology exam

Attempts of refractive correction

Surgery may be required for ectopia lentis

Semi-annual orthopedic evaluation

Bracing

Surgical intervention when scoliosis>40 degrees

Conclusion: Key Points

Diagnosis is largely clinical

Aortic dissection = primary cause of death

Remember SCD in athletes

Periodic echocardiographic evaluation

Screening for 1st-degree relatives

Consider lifelong beta-blockade

Genetic counselling

Questions?

Marfan Syndrome

LCDR Michael Keith

WRAMC Rheumatology

January 10, 2006

Overview

History

Epidemiology

Genetics

Diagnosis and Clinical features

Mortality

Management

Recognition of Features

1914: Adoption of Marfan syndrome

Arachnodactyly

Dislocated lenses

1931: Autosomal dominant inheritance

1943: Association with aortic dissection

Epidemiology

Common inherited connective tissue disorder

Autosomal dominant, variable penetrance

Incidence about 1 in 10,000

Epidemiology

Equal gender and ethnic distribution

25% cases are sporadic

Arise from new genetic mutation

Genetics

Late 1980s: Abnormalities of fibrillin

Important component of elastic tissues

Skin, aorta, arteries, ligaments, lung parenchyma

1991: Dietz et al.

Mutation of Fibrillin-1 gene

Mostly on chromosome 15

More than 100 mutations described

One family described

Mutation of unknown gene chromosome 3

Fibrillin

Important protein

Elastic connective tissues

Also non-elastic tissues

At least 2 forms

Fibrillin-1

Fibrillin-2

Genetics

Variable penetrance of fibrillin-1 mutation

Incomplete forms of disease

Milder or non-existant cardiovascular features

MASS

Myopia, MVP, Aorta, Skin, Skeletal

Isolated ectopia lentis

Key Clinical Features

Skeletal

Habitus

Hypermobility

Cardiovascular

Murmur

Echocardiographic abnormalities

Ocular

Lens displacement

Diagnosis

De Paepe et al. 1996

Clinical and Genetic Features

Ghent Nosology

Major criteria in 2 organ systems

Involvement of third organ system

Less stringent when + family hx

Ghent Nosology

Skeletal SystemMajor if at least 4; Involved if either 2 major or 1 major and 2 minor

Major

pectus carinatum

pectus excavatum (requiring surgery)

(+) wrist & thumb signs

scoliosis >20 ° or spondylolithesis

reduced upper/lower segment (>0.85) or arm span/heightratio >1.05

reduced elbow extension

pes planus

Minor

pectus excavatum (moderate)

joint hypermobility

high arched palate with dental crowding

typical facies, including

Dolichocephaly

malar hypoplasia

retrognathia

enophthalmos

downslanting palpebral fissures

Steinberg’s sign

Thumb enclosed in the clenched fist

Nail extends beyond hypothenar border

Walker-Murdoch Sign

Overlap of thumb and 5th digit as they encircle wrist

Skeletal: Arachnodactyly

Metatarsal Index

Recently proposed in Marfan syndrome

Not validated in other papers

Measurements similar to MCI

Average metatarsal index

12.7 in Marfan patients

9.8 in controls (P<0.0005)

Spine Involvement

Scoliosis > 20°

Kyphosis

Protrusio Acetabulae

Positon of medial wall acetabulum c/w ilioischial line

Women

Normal: 1 mm medial

MFS: 6 mm medial

Men

Normal: 2 mm lateral

MFS: 3 mm medial

Ocular System

Major

Ectopia lentis

Involved if (two or more)

Flat cornea

Increase axial length of globe

Hypoplastic iris or ciliary muscle causing decreased miosis

Ectopia Lentis

About 60% of cases

Typically bilateral

Upward displacement

Cardiovascular System

Major if (1 or more)

dilation of the ascending aorta

dissection of the ascending aorta

Involved if (1 or more)

MVP

dilation of pulmonary artery <40 years

MACC <40 years

dilation or dissection of descending aorta <50 years

Mitral regurgitation

Left ventricular dilatation

Tricuspid valve prolapse

Aortic Disease

Cystic medial necrosis

Aortic Root Aneurysm

Aortic Root Dilatation

Pulmonary

Major

None defined

Involvement

Spontaneous pneumothorax

Apical blebs

Differential Diagnosis

Homocystinuria

Ectopia lentis (downward displacement)

Mental retardation

Risk of thrombosis

MASS phenotype

mitral valve prolapse

aortic dilatation

skin involvement

skeletal involvement

lower risk of aortic aneurysm rupture

Differential Diagnosis

Congenital contractural arachnodactyly

Mutation of fibrillin-2 gene, chromosome 5

80% homology to fibrillin-1

Marfanoid habitus, no cardiac or eye findings

Isolated ectopia lentis

Associated with fibrillin-1 gene

No other findings

Differential Diagnosis

Ehlers-Danlos syndromes (I,II,III)

Stickler syndrome

Hereditary arthro-ophthalmopathy

Type II collagen

Klinefelter syndrome

XXY genotype

Tall stature, small testes, gynecomastia

No cardiac or ocular manifestations

Question

A 23-year-old woman is self-referred for a routineexamination. She has no specific complaints and has no symptoms on review ofsystems. Physical examination shows a tall, thin, young woman with a mildpectus excavatum, an increased arm span–to–height ratio, and arachnodactyly.Her pulse rate is 80/min and regular, respiratory rate is 16/min, and bloodpressure is 120/60 mm Hg. Cardiac examination shows a loud S1 and aphysiologically split S2 with no murmurs or gallops. An echocardiogram showsloss of the aortic sinotubular junction with mild aortic root dilatation (40 mmversus an expected dimension of 34 mm for her age and body size).

Which of the following is most appropriate?

Question

(A)Provide reassurance; no further evaluation ortherapy is needed.

(B)Recommend echocardiography for all herfirst-degree relatives.

(C)Initiate therapy with anangiotensin-converting enzyme inhibitor.

(D)Discuss the need for permanent contraception.

(E)Encourage increased physical activity.

Question

(A)Provide reassurance; no further evaluation ortherapy is needed.

(B)Recommend echocardiography for all herfirst-degree relatives.

(C)Initiate therapy with anangiotensin-converting enzyme inhibitor.

(D)Discuss the need for permanent contraception.

(E)Encourage increased physical activity.

Mortality

Aortic dissection

Main cause of premature death

Aortic dilatation in 50% of children with MFS

Improving life expectancy

1972 mean 32 years

1995 mean 45 years

Life Expectancy In MFS

Mortality

Decrease in death from aortic dissection

1972: 70%

1995: 48%

Improved medical and surgical management

Sudden Cardiac Death

Marfan Patients often excel in sports

Height: volleyball, basketball

Flexibility: ballet, gymnastics

Aortic Dissection in Marfan Syndrome

Maron et al. JAMA 1996;276:199-204.

Third most common cause of SCD in athletes

Frequency = 5%

Cardiac Causes of Sudden Death in Competitive Athletes

Management

Awareness of risk factors for aortic complications

Focus on cardiovascular complications

Medical

Surgical

Serial echocardiogram

Baseline

Every 6-12 months

Management

Risk factors for aortic dissection

Aortic diameter > 5 cm

Dilatation beyond sinus of Valsalva

Family history

Rapid rate of increased dilatation

> 5 % / year

> 2 mm / year in adults

Management

Pregnancy

Increased risk of aortic dissection

Gestational hypertension

Pre-eclampsia

Especially when aorta > 4 cm

Frequent monitoring during pregnancy and puerperium

Medical Therapies

β-blockers (usually lifelong)

Atenolol, metoprolol, propranolol

Decrease aortic stiffness and pulse velocity

Most effective in aorta < 4cm

? Calcium channel blockers

? Angiotensin blockade

Recent data suggest benefit for Enalapril

Yetman AT, Bornemeier RA, McCrindle BW. Am J Cardiol. 2005May 1;95(9):1125-7.

Surgical Therapy

Better outcome with early surgery

Worse outcome with late or emergent surgery

Referral for elective surgery

Adults with aorta > 5.5 cm

Children with aorta > 5.0 cm

Other System Management

Annual ophthalmology exam

Attempts of refractive correction

Surgery may be required for ectopia lentis

Semi-annual orthopedic evaluation

Bracing

Surgical intervention when scoliosis>40 degrees

Key Points

Diagnosis is largely clinical

Aortic dissection = primary cause of death

Remember SCD in athletes

Periodic echocardiographic evaluation

Screening for 1st-degree relatives

Consider lifelong beta-blockade

Genetic counseling

Questions?

Marfan Syndrome

Michael A. Malloy, M.D., M.P.H.

Rheumatology Service

WRAMC

History

The Marfan syndrome (MFS) was first described in 1896 by aFrench pediatrician, Antoine Marfan

He documented the clinical signs of a 5 ½ year old girl withlong thin limbs

Epidemiology

MFS is one of the most common inherited disorders ofconnective tissue

Autosomal dominant inheritance

Incidence 1 in 10,000 to 20,000 individuals

Pregnancy

Pregnant women are at particular risk for aortic dissection

Complications are most often seen in the second and thirdtrimester

C-section

ß-blockers

Musculoskeletal manifestations

Arachnodactyly

Other findings

Ectopia lentis

Dural ectasia

Integument

Marfan Syndrome

Diagnosis of MFS and other related conditions are based onclinical features

Mutations in the FBN1, the gene that encodes fibrillin-1,are responsible for MFS

Diagnostic Requirements for MFS

Index case

If family or genetic history is not contributory

Major criteria in at least two different organ systems

Involvement of a third organ system

If the mutation known to cause Marfan syndrome in others isdetected

One major criterion in an organ system

Involvement of a second organ system

Diagnostic Requirements for MFS

Relative of Index case

Presence of a major criterion in the family history

Major criterion in an organ system

Involvment of a second organ system

Skeletal SystemMajor if at least 4; Involved if either 2 major or 1 major and 2 minor

Major

pectus carinatum

pectus excavatum (requiring surgery)

(+) wrist & thumb signs

scoliosis >20 ° or spondylolithesis

reduced upper/lower segment (>0.85) or arm span/heightratio >1.05

reduced elbow extension

pes planus

Minor

pectus excavatum (moderate)

joint hypermobility

high arched palate with dental crowding

typical facies, including

Dolichocephaly

malar hypoplasia

retrognathia

enophthalmos

downslanting palpebral fissures

Ocular system

Major if

Ectopia lentis

Involved if (two or more)

Flat cornea

Increase axial length of globe

Hypoplastic iris or ciliary muscle causing decreased miosis

Cardiovascular system

Major if (1 or more)

dilation of the ascending aorta

dissection of the ascending aorta

Involved if (1 or more)

MVP

dilation of pulmonary artery <40 years

MACC <40 years

dilation or dissection of descending aorta <50 years

Mitral regurgitation

Left ventricular dilatation

Tricuspid valve prolapse

Skin & Integument

Major

lumbosacral dural ectasia (by CT or MRI)

Involved (if either)

striae atrophicae

recurrent or incisional hernia

Pulmonary

Involved (if either)

spontaneous pneumothorax

apical blebs on CXR

Differential Dx of Marfan syndrome

Homocystinuria

MASS phenotype

Congenital contractural arachnodactyly

Isolated ectopia lentis

Ehlers-Danlos syndromes types II and III

Stickler syndrome (hereditary arthroophthalmopathy)

Klinefelter syndrome

Question

A 23-year-old woman is self-referred for a routineexamination. She has no specific complaints and has no symptoms on review ofsystems. Physical examination shows a tall, thin, young woman with a mildpectus excavatum, an increased arm span–to–height ratio, and arachnodactyly.Her pulse rate is 80/min and regular, respiratory rate is 16/min, and bloodpressure is 120/60 mm Hg. Cardiac examination shows a loud S1 and aphysiologically split S2 with no murmurs or gallops. An echocardiogram showsloss of the aortic sinotubular junction with mild aortic root dilatation (40 mmversus an expected dimension of 34 mm for her age and body size).

Which of the following is most appropriate?

Question

(A)Provide reassurance; no further evaluation ortherapy is needed.

(B)Recommend echocardiography for all herfirst-degree relatives.

(C)Initiate therapy with anangiotensin-converting enzyme inhibitor.

(D)Discuss the need for permanent contraception.

(E)Encourage increased physical activity.

Question

(A)Provide reassurance; no further evaluation ortherapy is needed.

(B)Recommend echocardiography for all herfirst-degree relatives.

(C)Initiate therapy with anangiotensin-converting enzyme inhibitor.

(D)Discuss the need for permanent contraception.

(E)Encourage increased physical activity.

Cardiac Causes of Sudden Death in Competitive Athletes

Treatment

Life span

ß-blockers

Elective aortic root repair

Life expectancy in MFS

Treatment

Life span

ß-blockers

Elective aortic root repair

Question

All of the following conditions preclude participating inhigh-intensity competitive sports EXCEPT:

(A)Pulmonary hypertension of whatever cause
(B)Hypertrophic cardiomyopathy
(C)Ventricular septal defect with a pulmonic systemic blood flowratio of less than 2
(D)Marfan’s syndrome with aortic root dilatation
(E)Symptomatic paroxysmal supraventricular tachycardia

Question

All of the following conditions preclude participating in high-intensitycompetitive sports EXCEPT:

(A)Pulmonary hypertension of whatever cause
(B)Hypertrophic cardiomyopathy
(C)Ventricular septal defect with a pulmonic systemic blood flowratio of less than 2
(D)Marfan’s syndrome with aortic root dilatation
(E)Symptomatic paroxysmal supraventricular tachycardia

Famous people with MFS

Case

A 32-year-old woman with Marfan syndrome has mild dilatationof the ascending aorta with a maximum root dimension 1.3 times expected for herage and body size. She begins ß-blocker therapy, and both her children and hersiblings undergo echocardiographic examinations. Annual echocardiographicexaminations of the patient show a gradual increase from 42 to 48 mm in maximumroot dimension. Four years after the initial diagnosis, the patient has asudden onset of severe chest pain that radiates to her back.

Echocardiography shows acute ascending dissection, and thepatient undergoes emergency aortic valve and root replacement.

Take Home Points

Aortic dissection is the primary cause of death amongpatients with Marfan syndrome

Periodic echocardiographic evaluation of aortic rootdilatation is key in the treatment of patients with Marfan syndrome

First-degree relatives should undergo echocardiographicscreening for this autosomal dominant disorder

Name that tune…

Marfan Syndrome (MFS)

Thomas Kremenski

Rheumatology Service

WRAMC

Heritable Collagen Diseases

Over 200 different heritable disorders of connective tissue(examples):

- Marfan Syndrome

- Homocystinuria

- Ehlers-DanlosSyndrome(s)

- CongenitalContractural Arachnodactyly

- SticklerSyndrome

Epidemiology of MFS

Prevalence = 1 case/3000-5000 in the U.S.

Approximately 50,000 cases in the U.S.

Both sexes affected equally

All races affected equally

Marfan Syndrome (MFS)

Major organ systems affected in MFS:

- Skeletal

- Ocular

- Cardiovascular

- Pulmonary

- Integumentary

- Nervous

- Neurological

History of MFS

First described by Dr. Antoine Marfan in 1896

1914: ectopia lentis

1931: autosomal dominant inheritance

1943: aortic dilatation and dissection

1970: ECHO introduced for MFS

1975: MVP

1988: dural ectasia

History of MFS cont.

1931: thought to be caused by defect in mesoderm

1955: MFS included in group of heritable D/Os

1986: clinical criteria for diagnosis in Berlin Nosology

1991: discovery of gene (15q21) on Chromosome 15 wheremutation occurs in MFS

Famous people with MFS!

Cause of MFS

Mutation in gene 15q21 on Chromosome 15 which codes for themicrofibrillar protein Fibrillin-1 (FBN1)

To date, more than 4 dozen mutations in the FBN-1 gene havebeen found in people with MFS

FBN1 is the major protein of connective tissue microfibrilsessential to normal “elastic” fibrillogenesis

Cause of MFS cont.

Variable expression: defective gene expresses itself indifferent ways in different people (even with same gene mutation)

MFS is “autosomal dominant”: 50-50 chance of inheritingdisorder if parent has MFS

Approximately 25% of cases occur as a result of aspontaneous mutation of the FBN-1 gene

Characteristics of MFS
(Skeletal System)

Patients are typically tall, slender, and loose-jointed

Dolichostenomelia: arm span > height by > 5%

Abnormally low US/LS ratio

- Measure totalheight and top of pubis symphysis to floor

- Normal whiteadult = 0.92

- NormalAfrican-American = 0.87

Arachnodactyly: elongated fingers/toes

- also seen in other disorders (e.g., EDS,Homocystinuria)

- Positive“Thumb” and “Wrist” signs

- Abnormal“metacarpal index” done via radiograph

Characteristics of MFS cont.
(Skeletal System)

Pectus excavatum and carinatum

- pes planus (flatfeet)

-hyperextensibility of elbows, fingers, knees, hips

- recurrentdislocations of patella due to ligament laxity

Scoliosis, thoracic kyphosis, spondylolisthesis

Dolichocephaly: long and narrow face

Protusio acetabulae with deep hip socket

Congenital contractures of appendicular joints

Highly arched palate and crowding of teeth

Characteristics of MFS cont.
(Ocular System)

Most have myopia

More than 50% experience ectopia lentis: subluxation of lens(usually displaced upwards)

Retinal detachment

Glaucoma

Cataracts

Characteristics of MFS cont.
(Cardiovascular System)

At least 90% will have cardiovascular involvement

Dilatation of ascending aorta with or without regurgitationand involving at least sinuses of Valsalva

- Aortic dissection/rupture is the main causeof death (90%)

MVP occurs in approximately 80% and leads to significantmitral regurgitation in 10%

Characteristics of MFS cont.
(Integumentary System)

Increased striae (stretch marks) seen: poses no health risk

- over pectoral,deltoid, and lumbar areas

- helpfuldiagnostic sign

Increased risk of abdominal/inguinal hernias

Characteristics of MFS cont.
(Nervous System)

Dural ectasia: results from enlargement of spinal canal andcan produce erosion of lumbar and sacralvertebrae

- requires MRI orCT to diagnose

- may lead to nerve root problems (radiculopathy)

Characteristics of MFS cont.
(Pulmonary System)

Generally not a common or significant problem

Apical bullae can lead to pneumothorax in 5%

Thoracic kyphosis associated with decreased lung capacity

Differential Diagnosis

Homocystinuria: diagnosis made by measurement of plasma aminoacid concentration (e.g., total homocysteine)

Congenital Contractural Arachnodactyly: multiplecontractures, arachnodactyly, and ext. ear malformations

MASS: myopia, MVP, mild aortic dilatation, skin and skeletal

Stickler Syndrome: myopia, vitreal degeneration,sensorineural hearing loss, hyper- or hypo-mobile joints, mandibular hypoplasia

Benign Hypermobility Syndrome: diagnose by Beighton’sciteria and exclude MFS, EDS, etc.

Diagnosis of MFS

Revised Diagnostic Criteria from 1996

- First publishedin American Journal of Medical Genetics

Relies on recognition of both “major”and “minor” clinicalmanifestations involving skeletal, cardiovascular, ocular pulmonary, andintegumentary systems and dura

In general, there are “major” and “minor” criteria for eachsystem (except pulmonary and skin - “minor” only)

“System Involvement”: additional criteria carrying lessweight than “major” criterion

Diagnosis of MFS cont.

Family/Genetic History of MFS considered “major” criterian

“Major” include:

- 4 of 8 typicalskeletal manifestations

- ectopia lentis

- aortic rootdilatation involving sinuses of Valsalva

- LS dural ectasiaby CT or MRI

- Family orgenetic history of MFS

Diagnosis of MFS cont.

If patient has family history of MFS, you need:

- 1 “major”criterion in an organ system and “involvement” in a second organ system

If considered an “index” case, you need:

- “major” criteriafrom at least two systems and “involvement” of a third organ system

Diagnosis of MFS cont.

In general, the work-up will include:

- Cardiologyconsult and ECHO to assess for MVP, MR, aortic root dilatation, and AR

- TransesophagealECHO, chest CT/MRI, aortography for suspected aortic dissection

- CXR

- Ophthalmologicalexam with slit lamp evaluation

- Orthopedicevaluation (e.g., scoliosis)

Management of MFS

Regular cardiac evaluation and annual ECHOs (q6 months

when aortic rootdiameter > 4.5 cm)

Endocarditis prophylaxsis

Use of beta- blokersto reduce progression of aortic root dilatation (all patients includingchildren)

Elective aortic root replacement when aortic root diameterin the 5.0-6.0 cm range

Regular ophthalmological evaluation and treatment

Management of MFS cont.

Regular orthopedic evaluation and treatment (especially ingrowing children)

- back-bracingwhen spine curve in 20 - 40 degree range and surgery when 40-50 degree range

- surgery forsevere pectus excavatum

- orthotics forflat feet

In pregnancy:

- need closeregular follow-up by specialists experienced with MFS and counseling on risk ofaortic dissection

Management of MFS cont.

Consider genetic counseling

Patient education regarding physical limitations

- should notengage in very strenuous activities such as weight lifting, wrestling,football, basketball, soccer, hockey, moving heavy furniture, or otheractivities that increase stress on aorta

- may engage inrelatively non-strenuous, non-contact activities like golf, swimming,non,competitive biking

Address other psychosocial issues like self-esteem

- e.g., counselingand support groups

Prognosis of MFS

The average life span of untreated MFS was about 32 years in1972

Early detection and medical and surgical treatment haveincreased the average life span dramatically by more than 25% from 48 years in1972 to 72 years in 1996

INTRACITY GRAND ROUND

Walter M. Downs

Walter Reed Army Medical Center

15 February 2001

Case: Tall Stature

22 year-old male referred for evaluation of tall stature& left breast enlargement

He has no complaints

Differential Diagnosis

Marfan syndrome

Congenital contractural arachnodactyly

MASS phenotype

Ehlers-Danlos syndrome

Stickler syndrome

Homocystinuria

Endocrine disorder

Klinefelter syndrome

Fragile X syndrome

Acromegaly /Gigantism

History

22 year-old male

nickname of “tree” and “pretezel”

left breast / chest enlargement for 3 months

History

PMH/PSH

Left leg laceration

Social History

Tobacco 1/2 ppd

ETOH moderate

Active duty cook

History

Family History

Father 6’4”

Mother 5’11”

Sister 6’4”

No known inherited connective tissue disorder

Review of Systems

No joint dislocation, hernias or poor wound healing /scarring

No vision problems

No bleeding or easy bruisibility

Physical Exam

Gen: tall thinwhite male, height 6’9”

Heent: no high arched palate

Lung: CTA

CV: RRR w/omurmur or rub

Chest: bilateralgynecomastia, no other

deformity

Abd: (+)striae, no HSM or bruit

Physical Exam: Striae

No marked weight change

Not a weight lifter

No repetitive stress

Physical Exam

GU: small testes < 2 cm in size

Ext: no synovitis,FROM

no hyperextensible skin

scars with wide mouth

upper/lower ratio 0.8 (nl <0.85)

arm span/height ratio 1.0 (nl <1.05)

arachnodactyly w/ hyperextensible joints

pes planus

Physical Exam: Hypermobile Joints

Physical Exam: Arachnodactyly

Thumb (Steinberg) sign

is positive when the thumb,

enclosed in the clenched fist,

extends beyond the

hypothenar border

Physical Exam: Arachnodactyly

Wrist (Walker-Murdock) sign

is positive when there is

overlap of the thumb and

the 5th digit as they

encircle the opposite wrist

Ancillary Evaluation

DEXA Scan

osteoporotic

AP spine -2.89

hip - 1.03

Echocardiogram

normal study

Ophthalmology c/s

normal exam

Skeletal Survey

arachnodactyly

pes planus

no scoliosis

no spondylolithesis

no pectus deformity

Radiology: Arachnodactyly

Metacarpal index =

mean value of the length divided by the

mean mid point widths of

the 2nd, 3rd, & 4th metacarpals

Normal 5.4 - 7.9

Marfan > 8.4

Patient 9.75

Laboratory Evaluation

TSH 0.63 (0.5-4.9)

Homocystine 14 (8-20)

LH 19.7 (1.7-8.6)

FSH 55.4 (1.5-12.4)

Estradiol <20

Testosterone 114 (241-827)

Genetic Analysis 47XXY

Diagnosis

KLINEFELTER SYNDROME

? Collagen defect

Marfan Syndrome

The Marfan syndrome (MFS), initially described just over 100years ago, was among the first conditions classified as a heritable disorder ofconnective tissue.

MFS lies at one end of the phenotypic continuum, with peoplein the general population who have one or another feature of MFS at the otherend.

Marfan Syndrome

Diagnosis of MFS and other related conditions remain basedon clinical features.

Mutations in theFBN1, the gene that encodes fibrillin-1, are responsible for MFS.

In addition to skeletal, ocular and cardiovascular features,patients have involvement of the skin, integument, lungs and muscle tissue.

*Diagnostic Criteria for MFS

Major criteria in two systems,

Plus involvement of a third system

or

Family history positive

Major criteria in one organ system

Plus involvement ofsecond system

From De Paepe et al., Am J Med Genet 62:417-426, 1996

Family History

First degree relative independently meets diagnosticcriteria

Presence of a mutation in FBN1 know to cause Marfan syndrome

Presence of a haplotype around FBN1, inherited by descent,associated with unequivocally diagnosed Marfan syndrome in the family

Skeletal SystemMajor if at least 4; Involved if either 2 major or 1 major and 2 minor

Major

pectus carinatum

pectus excavatum (requiring surgery)

(+) wrist & thumb signs

scoliosis >20 or spondylolithesis

reduced upper/lower segment (>0.85) or arm span/heightratio >1.05

reduced elbow extension

pes planus

Minor

pectus excavatum (moderate)

joint hypermobility

high arched palate with dental crowding

typical facies, including

Dolichephaly

malar hypoplasia

retrognathia

enophthalmos

downslanting palpebral fiocssures

Ocular system

Major if

Ectopia lentis

Involved if (two or more)

Flat cornea

Increase axial length of globe

Hypoplastic iris or ciliary muscle causing decreased miosis

Cardiovascular system

Major if (1 or more)

dilation of the ascending aorta

dissection of the ascending aorta

Involved if (1 or more)

MVP

dilation of pulmonary artery <40 years

MACC <40 years

dilation or dissection of descending aorta <50 years

Skin & Integument

Major

lumbosacral dural ectasia (by CT or MRI)

Involved (if either)

striae atrophicae

recurrent or incisional hernia

Pulmonary

Involved (if either)

spontaneous pneumothorax

apical blebs on CXR

Questions?

Any further evaluation for collagen defect?

Recommended follow up?



Buy Now

Related Items:

MICHAEL JORDAN Chicago Bulls MJ #23 Olympics MVP HOF VINCENT ASKEW SLIDE 218 picture

MICHAEL JORDAN Chicago Bulls MJ #23 Olympics MVP HOF VINCENT ASKEW SLIDE 218

$50.00



DY06 TRAIN ENGINE LOCOMOTIVE 35MM SLIDE RAILROAD AT&SF218 FLAGSTAFF, AZ 1997 picture

DY06 TRAIN ENGINE LOCOMOTIVE 35MM SLIDE RAILROAD AT&SF218 FLAGSTAFF, AZ 1997

$12.43



218 slide Skeletal Bone Genetics MARFAN SYNDROME PowerPoint Presentation on CD  picture

218 slide Skeletal Bone Genetics MARFAN SYNDROME PowerPoint Presentation on CD

$12.99



Powered by WordPress. Designed by WooThemes