Embryology of the Skeletal System

Question 1

Bones can develop either from mesenchyme or cartilage. How does bone develop from mesenchyme?

Answer 1

Intramembranous Ossification - Flat bones, such as those that make up the skull, develop directly from the mesenchyme in preexisting membranes

Question 2

Bones can develop either from mesenchyme or cartilage. How does bone develop from cartilage?

Answer 2

Endochondral ossification - Most bones, including long bones, develop from mesenchyme as well but this mesenchyme has already condensed into cartilage first.

Question 3

Discuss, in the endochondral ossification model, the difference between primary and secondary centers of ossification

Answer 3

The primary center of ossification forms the shaft, or diaphysis, of the long bone. This occurs for several years before secondary ossification begins in the epiphyses, or ends of the bone.

Question 4

Discuss secondary centers of ossification in bone

Answer 4

The ends of the bones remain cartilaginous for several years after birth, during which time the secondary centers of ossification appear. It continues at the E-D junction (epiphyseal plate) until it ossifies by about age 20

Question 5

Discuss the etiology behind osteogenesis imperfecta and what it leads to in patients that have it

Answer 5

OI is caused by a deficiency in Type I collagen, usually secondary to an autosomal dominant gene defect affecting collagen synthesis. There are 8 different types that differ in the amount of Type I available as well as different qualities of that produced.

Patients with thishave extremely fragile bones, poor wound healing, hearing loss and blue sclerae, which is pathognomonic for the disease

Question 6

Achondroplasia is the most common type of dwarfism, and is caused by what type of genetic abnormality?

Answer 6

Autosomal Dominant Disorder (Dwarfs Dominate) caused by a mutation in the gene for fibroblast growth factor FGF-3 receptor on chromosome 4p. Constitutive activation of this receptor leads to inhibition of chondrocyte proliferation.

Question 7

What mechanism leads to the short stature and effects we see in dwarfism (achondroplasia)

Answer 7

Endochondral ossification is impaired due to limited chondrocyte proliferation secondary to FGF receptor constantly activating.

The epiphyseal plate becomes small and disorganized, preventing proper bone growth. This leads to disproportionately large head and trunk.

Question 8

The rarer cause of dwarfism is due to what?

Answer 8

Proportional dwarfism occurs in growth hormone deficiency due to the pituitary.

Question 9

This disease is often confused with child abuse. Why is that?

Answer 9

OI - because exuberant healing of fractures created calluses

Question 10

What mutation/deficiency leads to Marfan Syndrome?

Answer 10

Marfan syndrome is an autosomal dominant mutation in the gene for the protein fibrillin (fib-1 on 15q21.1)

This leads to abnormal elastin fibers that affect the skeletal, cardiac, and ocular systems.

Question 11

So Marfan occurs due to these abnormal elastin fibers that affect multiple systems. How does it present in the clinic (as far as structural bone stuff right off the bat)?

Answer 11

Tall stature, long limbs, hyperextendable joints, long tapering digits, excavated pectus area, and scoliosis (like an old alien)

Question 12

What is Larson syndrome and how is it linked to the other forms of dwarfism?

Answer 12

Proportional dwarfism is due to a defect in GH. Larson’s is due to a defect in the GH receptor. You can tell the difference because GH influx does not fix the problem.

Question 13

We’ve talked about issues that lead to deficiciency of GH or its receptor. What if we have an overactive pituitary?

Answer 13

Causes extra GH that can lead to gigantism in infants and acromegaly in adults (weird bone growth in the jaw hands and feet and organs/soft tissue).

Question 14

What kind of labwork will we see with excess pituitary activity?

Answer 14

IGF-1 levels are usually up secondary to excess GH, seen usually in adolescence.

Also, you will have a failed Oral Glucose Tolerance test (Glucose decreases GH normally, so when it doesn’t, it’s a pituitary thing)

Question 15

How does cretinism present and why?

Answer 15

Mental retardation, short stature and impaired bone growth , as well as neurological disorders of muscle tone and coordination all because of a deficiency in fetal thyroid hormone.

Question 16

Pathognomonic cause of Cretinism

Answer 16

Biggest cause is a lack of dietary iodine

Can also caused by mutations in TH synthesis and agenesis of the thyroid gland.

Question 17

Marfan leads to many ocular conditions, one of which is ectopia lentis. What is this condition, and where else do we see it?

Answer 17

Lens dislocation seen in half of Marfan patients. Usually, the dislocation is upward and towards the temples.

This is in contrast to ectopia lentis in homocystinuria, which is usually downward and into the anterior chamber.

Question 18

Marfan as we discussed makes you look like an old alien. But there are more sinister effects on organs like the heart and brain. Discuss these findings.

Answer 18

1. Ascending aortic dissection
2. Mitral Valve Prolapse
3. Brain - Cerebral Berry Aneurysms

Question 19

Mesenchyme around the fetal brain develops into the skull, which can be divided into two parts. What are they and what do they include?

Answer 19

Neurocranium, which includes the flat bones and the base of the skull

and

Viscerocranium, which includes the bones of the face and laryngeal cartilage.

Question 20

Where do most bones of the neurocranium come from embryologically?

Answer 20

Most are derived from neural crest cells

Exceptions:

• Base of the occipital bone comes from the mesoderm of the occipital sclerotomes
• Laryngeal cartilage - derived from pharyngeal arches 4 and 6

Question 21

How many fontanelles do we have and when do they close?

Answer 21

6 of them:

• Anterior - Last to close, at the end of the second year
• Posterior
• Sphenoid (one on each side)
• Mastoid (one on each side)

Question 22

10 types of cartilage and what they are associated with

Answer 22

1. Skin, tendon, bone, dentin
2. Cartilage and vitreous body
3. Skin, muscle, blood vessels, and usually with type 1
4. Basement membranes
5. Fetal tissues, placenta, skin, bone, interstitial tissues
6. Connective tissues (most)
7. Epithelia
8. Endothelium
9. Cartilage and Vitreous body (same as 2)
10. Hypertrophic cartilage

Question 23

What are craniosyntoses?

Answer 23

Premature closure of the sutures may lead to abnormal shapes of the skull

Question 24

At week 4 of embryonic development , what happens around the notochord?

Answer 24

Each sclerotome consists of a layer of loosely arranged cells cranially and a layer of densely arranged cells caudally.

Some of those dense caudal cells move cranially to make the intervertebral disk. The rest of the dense ones fuse with the loose ones to make the centrum, which will become the body of the vertebrae. Once these vertebrae finish, the notochord will degenerate.

Question 25

Between the vertebral bodies, the notochord develops into the ______. It is joined by the ______ to make ______.

Answer 25

Between the vertebral bodies, the notochord develops into the nucleus pulposus of the intervertebral disk. Surrounding the nucleus pulposus is the annulus fibrosus, which develops from sclerotomal cells.

Question 26

In week 4, its not just the notochord that gets some development. What happens around the neural tube and what happens in the body wall?

Answer 26

Around the neural tube: Mesenchymal cells from the vertebral arch

In the body wall: Mesenchymal cells from the costal processes that then develop into the ribs.

Question 27

What three things occur during week 6 of development?

Answer 27

1. Mesenchyme forms a cartilaginous vertebra
2. Chondrification centers appear in the centrum to form a cartilaginous body
3. Chondrification centers in the vertebral arch (originally from the neural tube) fuse with the centrum and each other, giving rise to the spinous and transverse processes

Question 28

Discuss what makes the atlas and axis special during development

Answer 28

Atlas (C1) has no vertebral body

Axis (C2) has a dens (odontoid process) that is the developmental remnant of the body of the atlas

Question 29

What causes a chondroma and how does it present in patients?

Answer 29

Chondromas are remnants of the notochord. One third of them develop into slow-growing, malignant tumors that infiltrate surrounding tissues, including bone.

They often form at the base of the skull, extending into the nasopharynx, but many can form lower, in the lumbosacral area or sacrococcygeal areas.

If higher up, we see diplopia and headache.

If lower, we see lower back and leg pain.

Only one half of patients survive past 5 years.

Question 30

What is Klippel-Feil syndrome and what does it lead to in patients?

Answer 30

Also known as Brevicollis, Klippel-Feil Syndrome has an unclear etiology, but results in the fusion of the cervical vertebrae.

Leads to reduced ROM in the cervical spine and defects in the thoracic and lumbar spine causing scoliosis.

Patients also have renal anomalies, hearing loss, and a short neck with a low hairline.

Question 31

Spina bifida is caused by what?

Answer 31

Two halves of the vertebral arch fail to fuse, usually in L5/S1 region

• Occulta - Small tuft of hair, mildest version
• Meningocele - Sac containing memninges and CSF protrudes, but spinal cord still not affected
• Meningomyelocele - Same as above, but the sac also has spinal cord in it, leading to neurological issues
• Rachischisis - Most severe, open neural tube due to a week 4 failure of the neuropore to close. Spinal cord is open, often fatal.

Question 32

What labs/causes are associated with spina bifida?

Answer 32

It is linked to elevated AFP and low Folic Acid/

It can be caused by genetic changes, EtOH during pregnancy, and drugs like Valproic Acid, which is an anticonvulsant

Question 33

Spondylolysis vs. spondylolisthesis

Answer 33

The vertebral arch pedicles fail to fuse with the vertebral body (spondylolysis) which may lead to displacement of the vertebral body below is (spondylolisthesis). It can move anteriorly or posteriorly, leading to anterolisthesis or posterolisthesis respectively.

Question 34

Where do our ribs come from?

Answer 34

Mesenchymal cells from the sclerotomes of the somites that aurround the body wall form the costal processes that develop into ribs. Only the thoracic vertebrae develop ribs

Question 35

How many ribs do we have and what types are there?

Answer 35

True ribs are the first 7 that attach to the sternum
False ribs, 8 - 12, attach to the sternum by attaching to other ribs.
The last two just float there at the bottom not attaching to the sternum.

Question 36

What can an extra cervical rib do to a patient?

Answer 36

The interscalene triangle is bounded anteriorly by the anterior scalene and posteriorly by the middle scalene. Inferiorly is the medial surface of the first rib.

An accessory cervical rib can compress this small area, causing thoracic outlet syndrome, compression of the thoracic outlet neurovascular bundle.

This leads to tingling in the ulnar nerve distribution (lower roots affected) or radial nerve distribution (upper roots affected)

The subclavian vein can also be compressed leading to swelling and cyanosis in the upper extremity of the affected side. Subclavian artery being affected leads to pallor, pulselessness, low BP, and small infarcts in the upper extremity.

Question 37

Discuss what is happening in each week (4 - 12 and then as an adult) for limb development.

Week 4 and 5, go.

Answer 37

4: Early limb buds form
5: Mesodermal cells from the lateral plate migrate to the bud.

A thickened region of ectoderm called the apical ectodermal ridge (AER) develops at the edge of the limb bud. It makes FGF which causes the mesodermal cells to grow outward and form cartilage. But its not just the bud tip. The base of the bud starts churning out sonic hedgehog protein in the zone of polarizing activity. This activates Hox genes to direct patterned organization of the limbs and digits.

Question 38

Discuss what is happening in each week (4 - 12 and then as an adult) for limb development.

Week 6 - 12, go.

Answer 38

6: Digital rays develop in the hands and feet. Digit formation involves selective apoptosis within the AER. By the end of week 6, cartilage models for the bones are complete.

7 - 12: Time tot urn that cartilage into bone.

Question 39

Amelia and the most common cause

Answer 39

Absence of one or more limbs, usually secondary to ingested teratogen like thalidomide

Question 40

Meromelia

Answer 40

Partial absence of one or more limbs

Question 41

Cleft hand and foot

Answer 41

Lobster claw deformities due to the digital rays failing to form in week 6 in the central areas. The lateral digits fuse, leading to claw shaped hands and/or feet

Question 42

Skin is associated with what type of collagen?

Answer 42

1, 3, 5, 7 (7 is specifically epithelia)

Question 43

Tendons are associated with what collagen types?

Answer 43

1

Question 44

Bone is associated with what collagen type?

Answer 44

1, some of 5

Question 45

Most connective tissue comes from what collagen type?

Answer 45

6

Question 46

Cartilage comes from what collagen type?

Answer 46

2, 9

Question 47

Dentin comes from what collagen type?

Answer 47

1

Question 48

Vitreous body comes from what collagen type?

Answer 48

2 and 9, which make the same things

Question 49

Muscle comes from what collagen type?

Answer 49

3

Question 50

Basement membrane comes from what collagen type?

Answer 50

4

Question 51

Fetal tissues and the placenta come from what collagen type?

Answer 51

5

Question 52

Endothelium comes from what collagen type?

Answer 52

8

Question 53

Blood vessels come from what collagen type?

Answer 53

3

Question 54

Interstitial tissue comes from what collagen type?

Answer 54

5

Question 55

Hypertrophic cartilage comes from what collagen type?

Answer 55

10