3. Embryology

Question 1

Early stages limb development:

1. In which week does it begin?
2. Begins after activation of which cells?
3. T/F: usually upper limb bud develops before lower limb bud.
4. Which genes regulate patterning?

Answer 1

1. Their formation begins near the end of 4th week.
2. Begins with the activation of mesenchymal cells in the somatic layer of lateral plate mesoderm.
3. True. Upper limb bud appears around day 24. Lower limb bud usually lags around 1-2 days.
4. HOX genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals.

Question 2

HOX genes:

1. How do they determine development of upper limbs?
2. What determine HOX gene expression?
3. Which ones are expressed in upper limb development?

Answer 2

1. Different HOX genes are expressed at different times in the developing limb bud and pattern the fine structure of the limb.
   Structures are determined in a proximal>distal direction with time, i.e. proximal structures such as the humerus bone are laid down first.
2. HOX gene expression results from a combination of the expression of SHH (sonic hedgehog), FGF’s (fibroblast growth factor) and WNT-7a.
3. HOXd 9-13. If you remove HOXa 11 and HOXd 11 then the radius and ulna do not form.

Question 3

Limb buds develop opposite which part of the vertebrae?

Answer 3

Upper limb buds develop opposite the caudal cervical segments (C5-C8).

Lower limb buds form opposite the lumbar and sacral segments (L3-L5).

Question 4

Describe limb bud development initially.

Answer 4

Limbs are initially undifferentiated mesenchyme (mesoderm) with an epithelial (ectoderm) covering. Elongation occurs through proliferation of the underlying mesenchyme core, in which the AER plays a crucial role in ensuring that the mesenchyme immediately underneath it remains undifferentiated. As growth proceeds, the proximal mesenchyme loses signals from the AER and begins to differentiate into the constituent tissues of the limb.

Question 5

What is apical ectodermal ridge (AER)?

Answer 5

At the apex of each bud the ectoderm thickens to form an apical ectodermal ridge (AER). AER exerts an inductive influence on the limb mesenchyme.

Question 6

What happened to mesenchyme immediately below and proximal to AER?

Answer 6

The mesenchyme adjacent to the AER consist of undifferentiated, rapidly proliferating cells whereas mesenchymal cells proximal to it differentiate into blood vessels and cartilage bone models.

Question 7

Describe development of hand and foot plates.

Answer 7

• The distal ends of the limb buds flatten into paddle-like hand plates and flipper- like foot plates.
• By the end of 6th week, mesenchymal tissue in hand plates has condensed to form digital rays.
• During the 7th week digital rays are formed in the foot plates.
• Notches between digital rays form.
• Webbed fingers and toes appear
• separate digits of fingers and toes appear

Programmed cell death (apoptosis) is responsible for the tissue breakdown in the interdigital regions –mediated by bone morphogenetic proteins.

Question 8

Development of hands and feet happens during which week?

Answer 8

Development of hands and feet between the 4th and 8th weeks.

Question 9

Final stages of limb development:

When does cartilaginous precursors of the limb bones develop?

Answer 9

Cartilaginous precursors of the limb bones develop by chondrification within the mesoderm in the 6th week. Chondrification (aka chondrogenesis) is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the ECM.
Early in foetal development, the greater part of the skeleton is cartilaginous. This temporary cartilage is gradually replaced by bone (Endochondral ossification), a process that ends at puberty. In contrast, the cartilage in the joints remains un-ossified during the whole of life and is, therefore, permanent.

Question 10

Final stages of limb development:

When do primary centres of ossification appear?

Answer 10

Primary centres of ossification appear in weeks 8 to 12 in response to growth factors. Primary centres occur in the middle of diaphysis (shaft). Around time of birth secondary ossification centre appears in each end (epiphysis) of long bones.

Question 11

T/F: all bones go through endochondral ossification.

Answer 11

False. Endochondral ossification for all limb bones except the clavicle (membranous).

Question 12

Compare endochondral ossification with intramembranous ossification.

Answer 12

During intramembranous ossification, compact and spongy bone develops directly from sheets of mesenchymal (undifferentiated) connective tissue. In endochondral ossification, bone develops by replacing hyaline cartilage.

Question 13

Which ways do the limbs rotate?

Answer 13

Upper limbs rotate 90o laterally so that extensors are on the lateral and posterior surfaces (and the thumb is lateral).

Lower limbs rotate 90o medially so that the extensors are on the anterior surface (and the big toe is medial).

Limb rotation happens during 8th week.

Question 14

Development of dermatomal patterns of the limbs happened during which week and from what?

Answer 14

During the 5th week, peripheral nerves grow from the developing limb plexus (brachial and lumbosacral) into the mesenchyme of the limbs.

Question 15

Define amelia.

Answer 15

Amelia – complete absence of a limb.

Question 16

Define meromelia.

Answer 16

Meromelia – partial absence of one or more limb structures.

Question 17

Define phocomelia.

Answer 17

Some long bone absence

Question 18

Define micromelia.

Answer 18

A condition characterized by abnormally small and imperfectly developed extremities but all parts are present.

Question 19

What is the critical period of limb development?

Answer 19

24-36 days after fertilization

Question 20

T/F: Lobster claw foot can be inherited as

an autosomal dominant trait.

Answer 20

True. Lobster claw foot = deficiency or absence of one or more central digits of the hand or foot.

Question 21

What is polydactyly?

Answer 21

• Presence of more than 5 digits on the hands or feet
• Extra digit is incompletely formed and lacks muscular development
• May be inherited or teratogen induced
• extra digit can be surgically removed.

Question 22

Syndactyly:

1. T/F: Common birth defect of the hand or foot.
2. T/F: More frequent in the hand than in the foot.
3. Name two types of it.

Answer 22

1. True
2. False. More frequent in the foot than in the hand.
3. Cutaneous Syndactyly (simple webbing between the digits due to a lack of apoptosis between the digits during development) is a common limb defect. Osseous Syndactyly (fusion of bones) occurs when notches between the digital rays fail to develop.

Question 23

Thalidomide:

1. What was it used for?
2. What birth defects did it cause?
3. Mode of mechanism?
4. What is it used for now?

Answer 23

1. 1957-1962 used as a sleeping tablet and anti-nauseate.
2. Absence or deformity of long bones (meromelia/phocomelia) (intestinal atresia and cardiac anomalies). ‘Sensitive’ period 4-8wks.
3. Acts by disrupting cell adhesion and angiogenesis.
4. Now used to help cancer, leprosy and AIDS patients

Question 24

Congenital club foot:

1. What is it?
2. What causes it?

Answer 24

1. Aka TALIPES EQUINOVARUS (Club foot) is a relatively common birth defect in which the sole of the foot is turned medially and the foot is inverted.
2. Multifactorial (genetic and environmental factors) - — Abnormal positioning or restricted movement of the foetus’s lower limb in the utero – Evidence is inconclusive.

Question 25

Developmental Dysplasia of the Hip (DDH):

1. What is it?
2. What is acetabulum?
3. How common is abnormal development of acetabulum and what are the risk factors for it?
4. What is generalized joint laxity?

Answer 25

1. Developmental dysplasia of the hip (DDH) is a spectrum of anatomical abnormalities of the hip joint in which the femoral head has an abnormal relationship with the acetabulum.
2. The acetabulum is a concave surface of a pelvis where the head of the femur meets with the pelvis forming the hip joint.
3. 15% of infants with congenital dislocation of the hip. Common after breech(buttocks) deliveries -? Breech posture during late part of pregnancy (abnormal development of acetabulum and head of femur
4. Generalized joint laxity is characterized by increased length and elasticity of normal joint restraints, resulting in a greater degree of translation of the articular surfaces. Multifactorial. Associated with congenital dislocation of hip (DDH).