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a_Genetics > 11/19- Disorders of Connective Tissue - Cardiac > Flashcards

11/19- Disorders of Connective Tissue - Cardiac Flashcards

1
Q

Case 1)

  • A 30y/o Caucasian male is admitted to the hospital with severe, substernal chest pain.
  • CT thorax shows a dilation of the aortic root with dissection in the arch and descending aorta.
  • He has a family history of blindness in one eye in his father and paternal aunt. His paternal grandfather died at an early age from an aortic rupture at age 48y.
  • What are key parts of this history/presentation?
A
  • Younger individuals with abnormal findings (no clear cut etiology): think genetics
  • Aneurysm of the aortic root: always concerning for Marfan syndrome
  • History of blindness in this setting is indicative of possible lens dislocation (ectopia lentis) which is seen in Marfan syndrome
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2
Q

Case 1)

What is your DDx for the following:

  • A 30y/o Caucasian male is admitted to the hospital with severe, substernal chest pain.
  • CT thorax shows a dilation of the aortic root with dissection in the arch and descending aorta.
  • He has a family history of blindness in one eye in his father and paternal aunt. His paternal grandfather died at an early age from an aortic rupture at age 48y
A

Marfan syndrome

  • vs Loeys Dietz syndrome
  • vs Familial thoracic aneurysm and dissection
  • vs Ehlers Danlos syndrome, vascular type
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3
Q

What is aortopathy?

A

Aortopathy is characterized by aortic dilation, which can lead to life threatening aneurysms and/or dissections

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4
Q

Why is early diagnosis of aortopathy critical?

A
  • Timely initiation of pharmacological treatment can slow dilation
  • Prophylactic surgery can prevent aortic dissection or rupture
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5
Q

What are the most common causes of

  • Abdominal aortic aneurysm (AAA)
  • Thoracic aortic aneurysm (TAA)
A
  • Abdominal aortic aneurysm (AAA): atheroma (combo of genetics and environment)
  • Thoracic aortic aneurysm (TAA): think genetic; usually not related to atheroma and occur at younger age
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6
Q

Describe the genetics of thoracic aortic aneurysms:

  • Genes involved
  • Syndromes associated
  • Associated symptoms
  • Sporadic form
A
  • Monogenic: related to
  • Marfan syndrome
  • Loeys Dietz syndrome
  • FTAAD
  • Associated with Bicuspid aortic valve (BAV): 50% of BAV is associated with an aneurysm.
  • Familial BAV (9% prevalence in first degree relatives) is due to mutations in NOTCH1.
  • Sporadic form: older patients; in 20% another family member presents with TAA
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7
Q

Recap: What are the genetic syndromes that cause aortic aneurysms?

A
  • Marfan’s
  • Loeys Dietz
  • FTAAD
  • Ehlers Danlos (esp vascular type)
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8
Q

What aortic aneurysm is more likely to be genetic?

A

Thoracic AA

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9
Q

Which gene causes familial bicuspid aortic valve?

A

NOTCH1

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10
Q

Describe the genetics of Marfan sydnrome

  • Incidence
  • Inheritance pattern
  • How many are de novo
A
  • Incidence: 1-2/10,000
  • Autosomal dominant
  • 25% are de novo mutations
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11
Q

What is the diagnostic criteria for Marfan syndrome?

  • 2 cardinal features
A
  • Revised Ghent criteria are used for clinical diagnosis of Marfan syndrome
  • 2 cardinal features:
  • Aortic root aneurysm
  • Ectopia lentis
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12
Q

In the absence of family history, what are the criteria for Marfan syndrome?

A
  • Ectopia lentis AND FBN1 with known Aortic Root Dilatation

OR

  • Aortic Root Dilatation Z score ≥ 2 AND one of:
  • Ectopia Lentis
  • FBN1
  • Systemic Score ≥ 7pts
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13
Q

In the PRESENCE of family history, what are the criteria for Marfan syndrome?

A
  • Ectopia lentis
  • A systemic score ≥ 7 points
  • Aortic Root Dilatation Z score ≥ 2 above 20 yrs. old, ≥ 3 below 20 yrs. old
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14
Q

What are some physical/clinical findings in Marfan syndrome?

A

Score of > 7 is what indicates

Marfans:

  • Wrist and thumb sign (3) (thumb sticks out of fist
  • Pectus carinatum(2)/excavatum(1)
  • Hindfoot deformity(2)
  • Flat feet(1)
  • Spontaneous pneumothorax(2)
  • Dural ectasia(2)
  • Reduced elbow extension(1)
  • 3/5 facial features(1)
  • Striae(1)
  • Protrusio acetabulae(2)
  • Myopia(1)
  • Mitral valve prolapse(1)
  • Scoliosis(1)
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15
Q

Describe the genetics and pathophysiology of Marfan syndrome

  • What gene
  • Mutations
  • What chromosome
  • What protein
  • Process
A
  • FBN1 gene
  • Missense (70%)
  • Deletions (2%)
  • Chromosome 15q
  • Fibrillin protein

Process:

  • Fibrillin is a component of microfibrils
  • Microfibrillar meshwork in the ecm is important in the integrity of the connective tissue: collagens, elastin and fibrillin contribute to elasticity, tensile strength and durability of various connective tissues
  • Fibrillin is particularly rich in the wall of the proximal aorta and ocular lens
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16
Q

Mutations where cause neonatal Marfan syndrome?

Prognosis?

A

Mutations in the middle of the gene (exons 24-32) cause neonatal Marfan syndrome

  • Death within first years of life

These mutations are usually de novo

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17
Q

Describe the main concepts:

  • Point mutations
  • Deletions
A
  • Point mutations: most frequent type of mutation with monogenic disorders
  • Alterations that affect one single base pair (could be substitution, insertion, deletion)
  • Deletions: large genomic rearrangements that affect the function of individual genes
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18
Q

What is the management for Marfan syndrome?

A

- Periodic echocardiogram (once yearly) to look at aortic dilation; as main marker for risk of dissection is the maximal aortic diameter

- Surgery is recommended when aortic diameter reaches 50mm

  • Avoid intense physical activity and contact sports
  • Use beta blockers/Angiotensin receptor blockers (prevents progression of aortic dilation)
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19
Q

Recap: list 3 typical findings in pts with Marfan syndrome

A
  • Ectopia lentis
  • Aortic root dilation
  • Many others: wrist sign, thumb sign, pectus excavatum/carinatum…
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20
Q

Recap: Which gene causes Marfan syndrome?

A

FBN1

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21
Q

Recap; How often do you find a family history in a pt with Marfan syndrome?

A

75% (25% are de novo)

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22
Q

Recap: What is the name of the clinical criteria used to diagnose Marfan syndrome?

A

Ghent criteria

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23
Q

Recap: what conditions cause lens dislocation without cardiovascular features?

A
  • Homcystinuria (may also have cardiac phenotype)
  • Familial etopia lentis
24
Q

Recap: what is neonatal Marfan? Will baby have family history?

A
  • Caused by mutation int he middle of the gene
  • De novo, no family history (and don’t live long enough to have kids)
25
Q

What is seen here?

A

Phenotypic features of Loeys Dietz syndrome (LDS)

26
Q

Describe the phenotype of Loeyz Dietz syndrome

A

Vascular findings:

  • Cerebral, thoracic, abdominal arterial aneurysms and/or dissection
  • Recall: Marfan was really more isolated to aorta

Skeletal manifestations:

  • Pectus
  • Scoliosis
  • Joint laxity
  • Arachnodactyly (long fingers)
  • Talipes equinovarus

Craniofacial

  • Hypertelorism
  • Bifid uvula
  • Cleft palate

Skin:

  • Easy bruising
  • Translucent skin
27
Q

Describe the genetics behind Loeys Dietz syndrome

  • Inheritance pattern
  • Expressivity
  • Gene involved
A
  • Autosomal dominant
  • Variable expressivity
  • Mutations in TGFBR1/2
  • Mutations in SMAD3 cause osteoarthritis-aneurysm syndrome
  • TGFB2/3 overlap with Marfan and LDS
28
Q

What is management for LDS?

A
  • Frequent echocardiograms
  • MRA/CTA chest to evaluate arterial findings
  • Avoid competitive sports, contact sports
  • Beta blockers to reduce hemodynamic stress
  • Natural history: aggressive arterial aneurysms (mean age at death = 26.1 yrs) + high incidence of pregnancy related complications
29
Q

What is TAAD?

A

Thoracic Aortic Aneurysm and Dissection

30
Q

What is seen in TAAD

  • Family history
  • Genetics
A
  • Dilation of ascending thoracic aorta
  • Dissections of thoracic aorta involving ascending/descending aorta
  • 20% of individuals have a first degree relative with thoracic aortic disease
  • Genes: TGFBR1/2, MYH11, ACTA2, MYLK, SMAD3
31
Q

What is genetic heterogeneity?

A

Single phenotype caused by multiple number of alleles (allelic heterogeneity) or non-allele (locus heterogeneity) mutations

32
Q

What is pleiotropy?

A

Single gene may cause multiple phenotypic expressions/disorders; FBN1 can cause Marfan syndrome and Familial ectopia lentis

33
Q

What is management of TAAD?

A
  • Elective repair of ascending aorta (4.2-5cm) with confirmed mutations in TGFBR1/2 and/or family history of aortic dissection with minimal aortic enlargement
  • Periodic monitoring with echo/CT/MRI
  • Avoid uncontrolled HTN, smoking body building/weight training exercise and competitive sports
  • Autosomal dominant with variable expression and reduced penetrance
34
Q

What genes should you test in a pt suspected of Marfan syndrome but is negative for FBN1 mutations?

A

TGFBR1/2

35
Q

What is a typical craniofacial feature of LDS?

A

Bifid uvula

36
Q

A 30 yo pt with aortic aneurysm is found to ha e early onset of osteoarthritis. What gene is the likely suspect?

A

SMAD3

37
Q

Why is it important to make a diagnosis of hereditary aortopathy?

A
  • Risk assessment
  • Children
  • Aggressive monitoring/management of aortic size
38
Q

What is Ehlers-Danlos syndrome?

A

Group of related conditions that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues

39
Q

What is Vascular EDS?

  • What % of EDS cases
  • What are the diagnostic criteria (4)
  • Special considerations
A

(Vascular = type 4)

  • 5-10% of cases

4 criteria:

  1. Characteristic facies (acrogeria- pinched nose)
  2. Thin and translucent skin with highly visible subcutaneous vessles
  3. Ecchymoses, hematomas
  4. Arterial, digestive and obstetrical complications

Important:

  • NO hyperelasticity of skin
  • Very easy to rupture hollow organs (especially dangerous in pregnancy)
40
Q

How many different types of Ehlers-Danlos syndrome are there?

  • Collective prevalence?
A
  • 6 types
  • Collective prevalence is 1/5000
41
Q

What is the most common type of EDS? Second?

A

Type III (hypermobility)

  • Occurs in 1/10,000

Classic type is next common (1/20,000)

  • Hypermobility + classic account for 90% of all cases
42
Q

Describe classic type EDS

  • Inheritance pattern
  • “type”
  • Major criteria
  • Minor criteria
A
  • Autosomal dominant
  • Type I and II

Major criteria:

  • Skin hyperextensibility!
  • Widened atrophic scars: manifestation of tissue fragility; wounds tend to gape or split after slight trauma
  • Joint hypermobility: affects both large and small joints, and is usually noted when a child starts to walk

Minor criteria:

  • Smooth velvety skin
  • Easy bruising
  • Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as elbows and knees
  • Subcutaneous spheroids; small, cyst-like, hard shot-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms
  • Joint hypermobility (sprains, dislocations, subluxations, pes planus)
  • Muscle hypotonia, delayed gross motor devo
  • Surgical complications; post op hernia
  • Manifestations of tissue extensibility and fragility (e.g., hiatal hernia, anal prolapse in childhood, cervical insufficiency)
43
Q

What is the most widely accepted grading system for joint hypermobility?

A

Beighton scale

44
Q

Describe hypermobility type EDS

  • Inheritance pattern
  • “type”
  • Major criteria
  • Minor criteria
A
  • Autosomal dominant
  • Type III

Major criteria:

  • Joint
  • Skin

Minor criteria

  • Recurrent joint dislocation
  • Chronic pain

Clinical features:

  • Recurrent dislocations/subluxations or joint hypermobility
  • Chronic musculoskeletal pain
  • Autonomic dysfunction: POTS, postural hypotension, dizziness, Raynaud’s disease, temperature intolerance
  • Temporo-mandibular joint dysfunction
  • Dental caries
  • Migraines
  • Irritable bowel syndrome/celiac disease/constipation/bloating
  • Blurry vision
  • Increased allergies/increased infections
  • Heavy menses/endometriosis/pelvic congestion
45
Q

Describe vascular type EDS

  • Inheritance pattern
  • “type”
  • Major criteria
  • Minor criteria
A
  • Autosomal dominant
  • Type IV

Major criteria:

  • Thin skin
  • Rupture
  • Extensive bruising
  • Facial featurees

Minor criteria

  • Acrogeria
  • Small joints
  • Clubfoot
  • Varicose veins
  • Pneumothorax
46
Q

Describe kyphoscoliosis type EDS

  • Inheritance pattern
  • “type”
  • Major criteria
  • Minor criteria
A
  • Autosomal recessive
  • Type VI

Major criteria:

  • Joint laxity
  • Hypotonia at birth
  • Progressive scoliosis
  • Scleral fragility

Minor criteria

  • Tissue fragility
  • Easy bruising
  • Arterial rupture
  • Marfanoid
  • Microcornea
  • Osteopenia
47
Q

Describe arthrochalasia type EDS

  • Inheritance pattern
  • “type”
  • Major criteria
  • Minor criteria
A
  • Autosomal dominant
  • Types VIIA/B

Major criteria

  • Congenital bilateral dislocated hips
  • Hypermobility
  • Subluxations

Minor criteria

  • Skin
  • Atrophic scars
  • Hypotonia
  • Easy bruising
  • Kyphoscoliosis
48
Q

Describe dermatosparaxis type EDS

  • Inheritance pattern
  • “type

” - Major criteria

  • Minor criteria
A
  • Autosomal recessive
  • Type VIIC

Major criteria

  • Severe skin fragility
  • Saggy, redundant skin

Minor criteria

  • Soft skin
  • Easy bruising
  • PROM
  • Hernias
49
Q

What are the genes responsible for the different types of EDS?

  • Is testing available
  • Rate of detection
A
50
Q

Describe genetics of EDS

  • How many run in family
  • Inherited vs. de novo in different forms
  • Main genes
A
  • Only one type of EDS runs in the family
  • Diagnosis is established by clinical exam and confirmed by molecular diagnosis
  • Classic: 50% inherited; 50% de novo
  • 46% of cases from COL5A1; 4% from COL5A2
  • Hypermobility: most have an affected parent; de novo rate is unknown
  • Vascular: 50% inherited; 50% de novo >95% mutations in COL3A1
51
Q

What is management for EDS?

A
  • Echocardiogram
  • DEXA (bone density scan)
  • Vitamin D levels
  • Eye exam
  • Physical therapy
  • Pain control
52
Q

What can be done for pain management in EDS?

A
  • Heated pools
  • Gentle stretching
  • Walking
  • Head and cold packs
  • Splints
  • Yoga
  • Relaxation therapy
  • Ergonomic environment
53
Q

Which type of EDS is the most common? How will you diagnose it?

A

Hypermobility type

  • Beighton score
54
Q

What is cardinal feature of:

  • Classic EDS
  • Vascular EDS
  • Hypermobility EDS
A
  • Classic EDS: stretchy skin
  • Vascular EDS: organ/vascular rupture
  • Hypermobility EDS: recurrent dislocations
55
Q

What is the most common pattern of inheritance in EDS?

A

Autosomal dominant

a_Genetics (18 decks)

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