11/19- Disorders of Connective Tissue - Cardiac Flashcards
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?
- 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
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
Marfan syndrome
- vs Loeys Dietz syndrome
- vs Familial thoracic aneurysm and dissection
- vs Ehlers Danlos syndrome, vascular type
What is aortopathy?
Aortopathy is characterized by aortic dilation, which can lead to life threatening aneurysms and/or dissections
Why is early diagnosis of aortopathy critical?
- Timely initiation of pharmacological treatment can slow dilation
- Prophylactic surgery can prevent aortic dissection or rupture
What are the most common causes of
- Abdominal aortic aneurysm (AAA)
- Thoracic aortic aneurysm (TAA)
- 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
Describe the genetics of thoracic aortic aneurysms:
- Genes involved
- Syndromes associated
- Associated symptoms
- Sporadic form
- 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
Recap: What are the genetic syndromes that cause aortic aneurysms?
- Marfan’s
- Loeys Dietz
- FTAAD
- Ehlers Danlos (esp vascular type)
What aortic aneurysm is more likely to be genetic?
Thoracic AA
Which gene causes familial bicuspid aortic valve?
NOTCH1
Describe the genetics of Marfan sydnrome
- Incidence
- Inheritance pattern
- How many are de novo
- Incidence: 1-2/10,000
- Autosomal dominant
- 25% are de novo mutations
What is the diagnostic criteria for Marfan syndrome?
- 2 cardinal features
- Revised Ghent criteria are used for clinical diagnosis of Marfan syndrome
- 2 cardinal features:
- Aortic root aneurysm
- Ectopia lentis
In the absence of family history, what are the criteria for Marfan syndrome?
- 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
In the PRESENCE of family history, what are the criteria for Marfan syndrome?
- Ectopia lentis
- A systemic score ≥ 7 points
- Aortic Root Dilatation Z score ≥ 2 above 20 yrs. old, ≥ 3 below 20 yrs. old
What are some physical/clinical findings in Marfan syndrome?
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)
Describe the genetics and pathophysiology of Marfan syndrome
- What gene
- Mutations
- What chromosome
- What protein
- Process
- 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
Mutations where cause neonatal Marfan syndrome?
Prognosis?
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
Describe the main concepts:
- Point mutations
- Deletions
- 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
What is the management for Marfan syndrome?
- 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)
Recap: list 3 typical findings in pts with Marfan syndrome
- Ectopia lentis
- Aortic root dilation
- Many others: wrist sign, thumb sign, pectus excavatum/carinatum…
Recap: Which gene causes Marfan syndrome?
FBN1
Recap; How often do you find a family history in a pt with Marfan syndrome?
75% (25% are de novo)
Recap: What is the name of the clinical criteria used to diagnose Marfan syndrome?
Ghent criteria
Recap: what conditions cause lens dislocation without cardiovascular features?
- Homcystinuria (may also have cardiac phenotype)
- Familial etopia lentis
Recap: what is neonatal Marfan? Will baby have family history?
- Caused by mutation int he middle of the gene
- De novo, no family history (and don’t live long enough to have kids)
What is seen here?
Phenotypic features of Loeys Dietz syndrome (LDS)
Describe the phenotype of Loeyz Dietz syndrome
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
Describe the genetics behind Loeys Dietz syndrome
- Inheritance pattern
- Expressivity
- Gene involved
- Autosomal dominant
- Variable expressivity
- Mutations in TGFBR1/2
- Mutations in SMAD3 cause osteoarthritis-aneurysm syndrome
- TGFB2/3 overlap with Marfan and LDS
What is management for LDS?
- 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
What is TAAD?
Thoracic Aortic Aneurysm and Dissection
What is seen in TAAD
- Family history
- Genetics
- 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
What is genetic heterogeneity?
Single phenotype caused by multiple number of alleles (allelic heterogeneity) or non-allele (locus heterogeneity) mutations
What is pleiotropy?
Single gene may cause multiple phenotypic expressions/disorders; FBN1 can cause Marfan syndrome and Familial ectopia lentis
What is management of TAAD?
- 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
What genes should you test in a pt suspected of Marfan syndrome but is negative for FBN1 mutations?
TGFBR1/2
What is a typical craniofacial feature of LDS?
Bifid uvula
A 30 yo pt with aortic aneurysm is found to ha e early onset of osteoarthritis. What gene is the likely suspect?
SMAD3
Why is it important to make a diagnosis of hereditary aortopathy?
- Risk assessment
- Children
- Aggressive monitoring/management of aortic size
What is Ehlers-Danlos syndrome?
Group of related conditions that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues
What is Vascular EDS?
- What % of EDS cases
- What are the diagnostic criteria (4)
- Special considerations
(Vascular = type 4)
- 5-10% of cases
4 criteria:
- Characteristic facies (acrogeria- pinched nose)
- Thin and translucent skin with highly visible subcutaneous vessles
- Ecchymoses, hematomas
- Arterial, digestive and obstetrical complications
Important:
- NO hyperelasticity of skin
- Very easy to rupture hollow organs (especially dangerous in pregnancy)
How many different types of Ehlers-Danlos syndrome are there?
- Collective prevalence?
- 6 types
- Collective prevalence is 1/5000
What is the most common type of EDS? Second?
Type III (hypermobility)
- Occurs in 1/10,000
Classic type is next common (1/20,000)
- Hypermobility + classic account for 90% of all cases
Describe classic type EDS
- Inheritance pattern
- “type”
- Major criteria
- Minor criteria
- 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)
What is the most widely accepted grading system for joint hypermobility?
Beighton scale
Describe hypermobility type EDS
- Inheritance pattern
- “type”
- Major criteria
- Minor criteria
- 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
Describe vascular type EDS
- Inheritance pattern
- “type”
- Major criteria
- Minor criteria
- Autosomal dominant
- Type IV
Major criteria:
- Thin skin
- Rupture
- Extensive bruising
- Facial featurees
Minor criteria
- Acrogeria
- Small joints
- Clubfoot
- Varicose veins
- Pneumothorax
Describe kyphoscoliosis type EDS
- Inheritance pattern
- “type”
- Major criteria
- Minor criteria
- 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
Describe arthrochalasia type EDS
- Inheritance pattern
- “type”
- Major criteria
- Minor criteria
- Autosomal dominant
- Types VIIA/B
Major criteria
- Congenital bilateral dislocated hips
- Hypermobility
- Subluxations
Minor criteria
- Skin
- Atrophic scars
- Hypotonia
- Easy bruising
- Kyphoscoliosis
Describe dermatosparaxis type EDS
- Inheritance pattern
- “type
” - Major criteria
- Minor criteria
- Autosomal recessive
- Type VIIC
Major criteria
- Severe skin fragility
- Saggy, redundant skin
Minor criteria
- Soft skin
- Easy bruising
- PROM
- Hernias
What are the genes responsible for the different types of EDS?
- Is testing available
- Rate of detection
Describe genetics of EDS
- How many run in family
- Inherited vs. de novo in different forms
- Main genes
- 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
What is management for EDS?
- Echocardiogram
- DEXA (bone density scan)
- Vitamin D levels
- Eye exam
- Physical therapy
- Pain control
What can be done for pain management in EDS?
- Heated pools
- Gentle stretching
- Walking
- Head and cold packs
- Splints
- Yoga
- Relaxation therapy
- Ergonomic environment
Which type of EDS is the most common? How will you diagnose it?
Hypermobility type
- Beighton score
What is cardinal feature of:
- Classic EDS
- Vascular EDS
- Hypermobility EDS
- Classic EDS: stretchy skin
- Vascular EDS: organ/vascular rupture
- Hypermobility EDS: recurrent dislocations
What is the most common pattern of inheritance in EDS?
Autosomal dominant
