3 MSK Development

Question 1

What is the timeline of limb development?

Answer 1

Occurs from 3-8 weeks

4 - arm and leg buds come from C5-8 and L3-5

5 - paddle hands and feet

6 digital webbed rays

8 - programmed cell death separates fingers

Question 2

2 specialised structures that allow limbs to grow out normally are?

Answer 2

Apical Ectodermal Ridge (AER) - ridge of cells around the dorsoventral axis

Zone of Polarising Activity (ZPA) cells around posterior limb

Question 3

List the stages of foetal development

Answer 3

Critical period is 24-36 days post fertilisation

0-2 weeks: blastocyst

3-8: embryonic (5mm to 3cm)

9 weeks: foetal

Question 4

What is gestational age? What is embryonic age?

Answer 4

G - the time since last menstruation

E - the time since fertilsation (shorter)

Question 5

Genes involved in limb position?

Answer 5

• Hox* determine limb position
• FGF10* expression in the lateral mesoderm stimulates expression of WNT3 in the ectoderm to form the AER
• FGF10* also stimulates expression of FGF8 in the ectoderm to cause proliferation of mesenchyme cells - + FB loop

Question 6

Genes involved in limb identity?

Answer 6

T-box genes

• Tbx5* - only expressed in forelimb
• Tbx4* and Pitx1 - only expressed in hindlimb
• Tbx2* and 3 - expressed in both

Question 7

What is Hult-oran syndrome?

Answer 7

A Tbx5 mutation that affects heart and forelimb growth

In zebrafish KOs they did not have their pectoral fins (arms)

Question 8

Genes involved in proximo-distal axis?

Answer 8

FGF8 as it is produced by the cells in the AER.

It keeps the mesenchymal cells proliferating in the right direction

If it is removed you only have proximal growth

The later you remove it the more distal growth you have

Question 9

Genes involved in antero-posterior axis?

(this is lateral to medial in anatomical position)

Answer 9

Cells in the ZPA express Sonic hedgehog protein (Shh).

This is expressed in a gradient from posterior to anterior across the limb bud

Specifies fingers vs. thumb

Question 10

Genes involved in the dorso-ventral axis?

Answer 10

Wnt7a ensures that the dorsal side of the limb develops and is expressed in the dorsal ectoderm.

in Wnt7a KO the backs fo the hands turn into palms

En-1 ensures that the ventral side of the limb develops and is expressed in the ventral ectoderm

in En-1 KO the palms turn into back of hands

Question 11

What proteins are important in signalling programmed cell death?

Answer 11

Bone morphogenic proteins (BMPs)

Gremlin protein (a BMP inhbitor) induces webbing

Question 12

What gene is important in muscle migration?

Answer 12

Lbx1

Question 13

Syndactyly

Answer 13

fusion of digits - problems withBMP or Shh

Question 14

Polydactyly

Answer 14

extra digits (Shh disrupted)

Question 15

Adactyly

Answer 15

absence of digits - later loss of FGF8

Question 16

Amelia

Answer 16

absence of entire limb - early loss of FGF8

Question 17

Mechanism for thalidomide deformities

Answer 17

loss of immature vasculature

• > mesenchymal cells can’t proliferate
• > longer exposure to FGF8 from AER

results in more distal structre growth than proximal structure growth

(hands appearing from shoulders)

Question 18

What is breech position at birth?

Answer 18

Babies being born hips first rather than head first

Question 19

Developmental Dysplasia of the Hip

Answer 19

Hip is loose, unstable and easily dislocated at birth

RFs: breech position, overcrowding (multiple foetuses or big foetus), small mother or uterus

Treatment: Pavlik Harness which is an abdutcion brace - successful

Question 20

Perthe’s Disease

Answer 20

Affects the hip in growing children

most commonly 4-10 year old boys

reduced blood supply to femoral head causes softening and collapse of bone

re-establishment of blood supply occur but remodelling results in inflammation and limping

Treatment: broomstick plasters (legs wide appart with stick across)
In older children, reduce weight bearing and maintain fitness

Question 21

Club foot (Talipes)

Answer 21

constriction of the feet leads to twist downwards and inwards

most common MSK defect

Treatment: Ponseti technique of boots that slowly turn feet outwards over weeks- successful
Most need minor surgery later to correct Achille’s

Question 22

Calcaneal apophysitis (Sever’s disease)

Answer 22

inflammation of the calcaneal growth plate in one or both heels

Caused by pulling or tightness of the Achille’s tendon

Could be caused by toewalking or lead to toewalking