SM 235: Inherited Disorders of Connective Tissue

Question 1

What are the general causes of inherited CT disorders?

Answer 1

Alterations of: ECM Matrix/Bone Protein structure and PTM’s (collagen) GAG structure (Mucopolysaccharidoses) Signaling Regulation

Question 2

Which molecules can cause inherited CT disorders through alterations in protein structure and post-translational modifications?

Answer 2

Colllagen

Question 3

Which diseases arise through alterations in GAG structure?

Answer 3

Mucopolysaccharidoses

Question 4

How are radiographs in children different from adults?

Answer 4

Cartilage precursors of bone are not mineralized and therefore will not be visible on radiographs

Question 5

What features on a child’s radiograph appear different from adults?

Answer 5

Growth plate/metaphysis appears radiolucent until growth ceases Epiphyses are also lucent and mineralize at predictable times during childhood

Question 6

How can the lack of mineralization in children’s bone be used to diagnose illness?

Answer 6

Compare the “radiographic” age of bone to the chronologic age of the child

Question 7

What imaging approach should be used when evaluating bone dysplasias?

Answer 7

Complete bone survey - XRay ever bone in the body

Question 8

What should be considered in a complete bone survey?

Answer 8

Shape of the bone and the portions of the bone that are altered

Question 9

What are the radiographic terms for the 3 segments of long bone?

Answer 9

Rhizomelic = proximal Mesomelic = middle Acromelic = distal

Question 10

What is Acromelic long bone?

Answer 10

Distal long bone on radiography

Question 11

What is Mesomelic long bone?

Answer 11

Middle long bone on radiography

Question 12

What is Rhizomelic long bone?

Answer 12

Proximal long bone on radiography

Question 13

How should Xrays in a child be evaluated?

Answer 13

Watch them over time to see the different radiographic changes that correspond with an illness

Question 14

What is Achondroplasia?

Answer 14

An autosomal dominant disease that causes disproportionate shortening of rhizomelic limb segments (humerus and femur) as well as a short base of the skull and macrocephaly

Question 15

What are the changes in the skull in Achondroplasia and why are they significant?

Answer 15

Achondroplasia causes shortening of the bone at the base of the skull, leading to stenosis of the Foramen magnum and spinal canal stenosis

Question 16

Why is the femur, humerus, and base of the skull affected by Achondroplasia?

Answer 16

These bones are formed from Cartilage

Question 17

How does Achondroplasia alter the intelligence of affected patients?

Answer 17

It doesn’t - normal intelligence

Question 18

How should growth in Achondroplasia be assessed?

Answer 18

Use an Achondroplasia growth chart to track stunted developmental milestones

Question 19

What is a trident hand and what disease is it associated with?

Answer 19

A hand where Digits 2/3 and 4/5 are stuck together like Spock’s hand, common in Achondroplasia

Question 20

What is the inheritance pattern of Achondroplasia and what causes it?

Answer 20

Autosomal dominant primarily due to de novo paternal mutations in the FGFR3 gene

Question 21

Which gene is mutated in Achondroplasia?

Answer 21

FGFR3 - constitutively active, resulting in constant growth inhibition

Question 22

What joint is altered in Achondroplasia and how?

Answer 22

The pelvis is altered - horizontal Acetabelum and sharp sacro-sciatic notch

Question 23

What is this showing, and which inherited CT disorder does it correspond to?

Answer 23

Stenosis of the Foramen Magnum, a hallmark of Achondroplasia

Question 24

Which zone of cartilage does Achondroplasia affect?

Answer 24

Zoen of hypertrophy

Question 25

How does Achondroplasia manifest changes in the Zone of Hypertrophy?

Answer 25

Smaller and fewer cells

Question 26

How is FGFR3 signalling altered in Achondroplasia?

Answer 26

FGFR3 binds FGF to inhibit growth, and in Achondroplasia, FGFR3 is constitutively active, leading to stunted growth

Question 27

What molecule can rescue Acondroplasia and how?

Answer 27

CNP can bind to the NPR receptor to inhibit FGFR3 signaling and disinhibit growth

Question 28

What type of mutation drives Achondroplasia?

Answer 28

Gain of Function FGFR3 = constitutive activitu

Question 29

What is Thanatophoric Dysplasia?

Answer 29

Really bad Achondroplasia, autosomal dominant FGFR3 mutation that leads to stillborn death

Question 30

What is Osteogenesis Imperfecta?

Answer 30

An Autosomal Dominant Type I collagen disease that leads to brittle bones

Question 31

What are the genetics underlying Osteogenesis Imperfecta?

Answer 31

Abnormal Type I collagen driven by haploinsufficiency

Question 32

What drugs may treat Osteogenesis Imperfecta?

Answer 32

Bisphosphonates

Question 33

How does osteoegenesis imperfecta present?

Answer 33

Blueish sclera, short limbs

Question 34

What is Perinatal Lethal Osteogenesis Imperfecta?

Answer 34

Serious Osteogenesis Imperfecta that leads to congenital fractures of the rib cage which lead to death, due to an autosomal dominant type I collagen defect

Question 35

If you see this Xray in a newborn, what disease and prognosis are you thinking?

Answer 35

Mulltiple rib fractures in a newborn = Osteogenesis Imperfecta with perinatal lethality

Question 36

What is Ehlers-Danlos sydnrome?

Answer 36

A syndrome of hyperelastic, fragile skin due to a defect in Type V Collagen that causes joint hypermobility and cardiac valve issues

Question 37

What mutations drive Ehler-Danlos syndrome and how?

Answer 37

Mutations in Type V collgen lead to a null allele and haploinsuffiency and an Autosomal Dominant inheritance

Question 38

What are the genetics Marfan Syndrome?

Answer 38

An autosomal dominant disease that is fully penetrant with varaible expressivity (always show symptoms, but symptoms may vary)

Question 39

What is Marfan Syndrome?

Answer 39

A syndrome of CVD, ectopia lentis, and long bones (arms/legs/fingers)

Question 40

What bone abnormalities accomponay Marfan Syndrome?

Answer 40

Arachnodactyly = long fingers Long arms and legs Thumb sign = long thumb Scoliosis

Question 41

What is Ecotpia Lentis and what disease does it accompany?

Answer 41

Ectopia Lentis is a disclocation of the lens of the eye and it accompanies Marfan syndrome

Question 42

What are the CVD manifestations of Marfan syndrome?

Answer 42

Dilation of the Aorta leads to Aortic Regurg Aortic Dissection leads to Abdominal Aortic Aneurysm Both are driven by Fibrillin mutations

Question 43

What is the cause of spontaneous death in Marfan syndrome?

Answer 43

Fibrillin defect = Aortic dissection/aneursym = sudden death Main cause of mortality

Question 44

What is the genetic basis of Marfan syndrome?

Answer 44

Mutations in the Fibrillin gene, leading to widespread effects on CT, heart, lung, eyes, and kindey

Question 45

How does the Fibrillin mutation in Marfan cause disease?

Answer 45

Fibrillin monomors normally form CT microfibrils and act as a scaffold to inhib TGFbeta signalling In Marfan, these monomers are mutated and disinhibit TGFbeta signalling, leading to excess TGFbeta and systemic manifestations like Aortic aneurysm