Embryology: What Can Go Wrong?

Question 1

What are the three theories of digit patterning?

Answer 1

1. Turing Patterning Theory
2. Radial-ulnar acid and the Sonic Hedgehog Pathway
3. Evo-Devo Theory

Question 2

Describe the Turing Pattern.

Answer 2

Alan Turing 1952 described the Reaction-Diffusion Pattern

Mathematician in Manchester published a paper on the chemical basis of morphogenesis.

Turing proposed a model wherein two homogeneously distributed substances (P and S) interact to produce stable patterns during morphogenesis. These patterns represent regional differences in the concentrations of the two substances. Their interactions would produce an ordered structure out of random chaos.

In Turing’s model, substance P promotes the production of more substance P as well as substance S. However, substance S inhibits the production of substance P; if S diffuses more readily than P, sharp waves of concentration differences will be generated for substance P.

Explains the formation of zebra stripes - random. Digit formation is thought to be similar.

Question 3

Describe how the radial-ulnar axis and the Sonic Hedgehog Pathway may influence digit patterning.

Answer 3

Diffusion gradient of the SHH creates an ulnarizing effect. By the time the SHH reaches the radial aspect of the limb bud there is very little SHH so the thumb doesn’t get any SHH.

May explain why the thumb is smaller.

Question 4

How could combining Turing Patterning Gand Sonic Hedgehog Pathway describe digit patterning?

Answer 4

After the humerus is formed

Ulna forms first (under SHH influence)
Radius forms next (Turing Pattern)

Digits start developing starting with the little finger under SHH influence then the remaining fingers branch out by Turing Pattern.

Thumb is the smallest - probably because SHH effect has worn off but fatter with more muscles (?due to evo-devo theory)

Question 5

What is the Evo-Devo theory?

Answer 5

Diogo et al 2019

At the beginning of gestation there are many more muscles in the hand than at birth.

Thumb naturally most evolved digit, more dextrous, retains most of it’s muscles

Question 6

How is the human hand unique?

Answer 6

Thumb is dextrous and larger in proportion to the rest of the digits

Question 7

What are the common congenital hand conditions?

Answer 7

1. Cleft hand
2. Triphalangeal thumb
3. Thumb polydactyly
4. Forearm anomalies
5. Macrodactyly
6. Vascular anomalies

Question 8

Cleft hand insights

Answer 8

Guero and Holder 2019 - All tendons are present, even to the missing fingers

Duiif 2003 - AER failure results in failure of digit formation

Moved in the OMT classification - Proximal-distal axis

Question 9

Macrodactyly insights

Answer 9

Ezaki et al 2019 - high staining for Desert Hedgehog and Ptc receptors

Thought to be due to a mutation in the PIK3CA/AKT/mTOR pathway

Surgery with targeted application of drugs to modify this pathway and manage the condition

Question 10

What are the broad types of thumb deformities?

Answer 10

1. Thumb polydactyly (too many)
2. Thumb hypoplasia (too small)
3. Thumb aplasia (missing)

Question 11

How does thumb polydactyly (split or extra thumb) happen?

Answer 11

Excess Sonic Hedgehog

Explains why the majority of patients have a dominant ulnar duplicate - because the ulnar duplicate is formed first with a larger amount of SHH present. A smaller radial duplicate is formed with the remaining SHH left.

Don’t have to reconstruct the UCL for the thumb for these patients.

Question 12

Can all thumb conditions be part of the same spectrum?

Answer 12

We Lam et al 2015
Experimental evidence that pre-axial polydactyly and forearm radial deficiencies may share a common developmental origin

Ectopic SHH was added to the chicken embryos limb bud and following happened:

Low strength: Pre-axial polydactyly
Moderate strength: Radial dysplasia (in humans and on measuring of all forearms of patients with thumb hypoplasia, a discrepancy was found)
Strong strength: Mirror hand deformity (two ulnae and mirror image digits)

In humans we get the following sequence:
1. Normal thumb
2. Thumb duplication
3. Triphalangeal thumb
4. Hypoplastic thumb with forearm abnormalities (radial dysplasia)
5. Mirror hand deformity (thumb replaced by digits)

Question 13

What does an early increase in SHH cause?

Answer 13

Radial and Thumb hypolasia

OMT: Malformation
Entire upper limb
Radial-ulnar axis

Question 14

What does a late increase in SHH cause?

Answer 14

Thumb polydactyly

OMT: Malformation
Hand Plate
Radial-ulnar axis

Question 15

What does a half-way sustained increase in SHH cause?

Answer 15

Mirror Hand deformity

OMT: Malformation
Hand Plate
Radial-ulnar axis

Question 16

Pre-axial polydactyly with radial hypoplasia or ulnar dimelia

Question 17

Radial dysplasia/Radial club hand management

Answer 17

Douglas Lam 1977
Centralisation of the ulna however high recurrence rate - one way around that is through ulnocarpal fusion (less recurrence)

Buck Garmcko 1985 in Germany
Pre-operative distraction to prevent damage to the growing physis by radialisation - stretch the soft tissue so there is less force when the carpus is positioned over the ulna
Always recurred

Radial dysplasia is an unsolved problem - inability to achieve a straight wrist

Question 18

What did Murphy et al 2018 “Radial Dysplasia; intrinsic changes in the soft tissues and their effect on disease progression” find?

Answer 18

Tissue fibroblasts from fascia of radial dysplasia patients is significantly less organised than control fascia fibroblasts

Fascia and ECM may contribute to recurrence

May need to excised AND replaced with healthy growing tissue

Question 19

What is fate mapping? And how is it done?

Answer 19

Trace the origin of tissues from the developing limb bud

• Use of dyes
• Nonspecific and crude
• Focused only on digits

In Edinburgh, to determine the origin of the radius and try to understand why radial dysplasia happens, genetically modified embryos with cells capable of fluorescence. These cells are labelled with an enzyme that lights up in the presence of certain cells. These cells’ location is then visualised as they grow - determine the origin and path of the radius.

Through this we can look at the different bones, muscles and surrounding soft tissue as they develop to understand what happens to them in the different stages of development

Question 20

What happens to muscles in radial dysplasia?

Answer 20

Muscles follow the path of the radius proximally then congregate on the ulnar path distally.

Surgical findings:
1. Hypoplastic radial muscles +/- abnormal insertion
2. Preserved ulnar muscles

Experimental findings:
1. Proximal and distal abnormalities need addressing
2. Normal muscles proximally but subsequently disappear
3. May be muscular elements proximally that need releasing - brachiocarpalis at the elbow

MRI needed to diagnose