Craniofacial Abnormalities

Question 1

What is oro-facial clefting?

Answer 1

Abnormal development of the lip and palate

Question 2

What types of clefting can we have?

Answer 2

Cleft lip +- palate

Cleft palate

Question 3

What gender is more likely to get cleft lip?

What side of the face is more common?

Answer 3

Males

Left

Question 4

What % of cleft lip is associated with syndromes?

Answer 4

10%

Question 5

Explain the process in the face during development

Answer 5

Have brachial arches present.

Frontonasal process at the top bound by the maxillary and mandibular processes below.

The cardiac bulge sits underneath this.

Within the frontonasal process there is a thickening of the ectoderm called the nasal placodes.

These start to sink into the underlying mesenchyme.

Question 6

What happens during development within the frontonasal process?

Answer 6

As the nasal pits form due to sickening of the nasal placed, thickening occur around the nasal pit called the medial and lateral nasal processes.

Below this are 2 maxillary processes and a continuous mandibular process.

Within 6 weeks, the medial nasal process moves towards rehab midline and the lateral nasal processes bound the nasal pits.

Question 7

Explain what origin each of these have:

1) Upper lip
2) Alae and sides of nose
3) Cheek

Answer 7

1) Medial nasal processes in middle, maxillary processes laterally
2) Lateral nasal processes
3) Maxillary processes, lateral nasal processes

Question 8

How does the palate form?

Answer 8

Palate is derived from primary and secondary palate.

The primary palate gives rise to the middle portion of the lip (philtrum) and the incisor teeth.

Secondary palate gives rise to the rest of the hard and soft palate and the maxillary dentition.

The primary palate is is derived from the merged medial nasal processes.
The secondary palate is derived from the maxillary processes.

The maxillary process gives rise to palatine shelves.
These sit either side of the tongue and then elevate above the tongue and grow towards each other in the midline.

They fuse in the midline and the nasal septum above and the primary palate anteriorly to form the secondary palate.
This takes place within 6-10 weeks of development.

Question 9

What is a conditional knock-out?

Answer 9

Lacking function of a gene in certain tissues.

Question 10

What can go wrong in the formation of the palate?

Answer 10

The shelves could fail to form

Shelves can fuse inappropriately with other regions of the embryo

They can fail to elevate above the tongue

They can fail to grow towards each other in the midline

They can fail to fuse when they meet each othe

Question 11

How do we manage patients with facial clefts?

Answer 11

Main objectives of treatment is to improve appearance, maximise function of speech, hearing and swallowing.
Want to enhance well-being and self esteem.

It involves a team approach.

Lip repair = within 3 months of life

Placate repair = within 9 months of lip as we dont want to limit maxillary growth.

Question 12

When would a clefting patient need a alveolar graft and why?

Answer 12

Prior to canon eruption.

This graft will allow canine eruption through the bone, periodontal support, stabilises maxillary segment, allows orthodontic space closure if laterals absent, suppers the alar base and closes fistulae.

Question 13

What is an osteotomy and when is it needed?

Answer 13

Need an advancement of the maxilla and set back of mandible to correct the class 3 malocclusion.

Question 14

How many CLP and CP are associated with syndromes?

Answer 14

CLP = 10%

CP = 30%

Question 15

What are the main 2 causes associated with non-syndromic clefting?

Answer 15

FGF signalling pathway

Transcription factors

Question 16

What is a syndrome?

Answer 16

A group of physical signs and symptoms that occur together and are characteristic of a disease.

Question 17

What are craniofacial syndromes usually caused by?

Answer 17

Single gene defects (dominant or recessive)
Structural abnormalities
Tetatogens (maternal smoking, drug or alcohol intake usually)

Question 18

Why does fetal alcohol syndrome occur?

Answer 18

Ethanal is toxic to neural crest cells which are importune for forming skeletal tissues of the face.

Question 19

Does CP or CLP have more syndromic conditions?

Answer 19

CP

Question 20

What are the two main conditions with CLP and explain them?

Answer 20

1. Van der Woude syndrome
   - Autosomal dominant condition
   - Tend to get fusion between fingers and depressions of lower lip
   - IRF6 is the transcription factor causing this : transcription factor that regulates differentiation of epithelial cells in the embryo and without the normal function, the epithelium fo the facial processes become abnormally sticky so premature fusion between regions causes clefting
2. CLP ectodermal dysplasia
   - Autosomal recessive conditon
   - Lack od development of ectodermal appendages such as skin and teeth

Question 21

What are the 4 main conditions associated with CP?

Answer 21

1. Treacher Collins
   - Autosomal dominant
   - Derived from 1st and 2nd brachial arch
   - Craniofacial syndrome
   - Lack of development of mid 1/3 of the face and the mandible
   - Down slanting eyes
   - Can be deaf
   - Cleft palate
   - Absent parotid glands
   - Due to the TCOF-1 gene mutation needed for ribosomal synthesis in neural crest cells causing these cells to die
2. Apert
   - Carniosynostotis and fused fingers
   - Midline defects
   - Likely to get cleft palate
   - Down slanting features
   - Small maxillas, lots of crowing and anterior overbites
3. Crouzon
   - Craniosynososis
   - Midface affected
   - Shallow orbits
   - Dental crowding and overbites
   - Normal hands
4. Holoprosencephaly
   - Abnormality in separation of the forebrain and eye field splitting
   - Can get a single orbit
   - Often get cleft palate
   - Caused by hedgehog signalling mutations
5. Pierre Robin Syndrome
   - Commonest one
   - 50% cleft palates are due to this condition
   - Low small jaw, large U shaped cleft palate, tongue sits at the back of the upper oropharynx which prevents the palatal shelves from rising up towards each other
   - Can make respiration hard at birth

Question 22

How does craniosynotosis occur?

Answer 22

Sutures repsrent a balance between bone formation and resorption.
Can get hole in skull of premature fusion if this is disrupted.

The bone edges or Osteogenic Fronts are the sites of osteogenesis & therefore bony expansion.

Mesenchymal cells will condense, differentiate into proliferative osteoprogenitor cells which will differentiate into preosteoblasts and finally mature to fully functional osteoblasts.
The suture presents us with a relative simple model of osteogenesis, an uncomplicated by cartilage.

So this intramembranous bone growth differs from endochondral long bones in not having a cartilage anlagen,
no growth plates

Due to mutations in fibroblast growth factor receptors of transcription factors.
- Get increased FGF signalling.
Ligands bings to the mutated receptor and get a gainer function effect.
The ligands binds to the receptor and stimulates the pathway and then the pathway doesn’t switch off.
Increased signalling means lots of bone formation so early suture closing

Question 23

What is nevoid basal cell carcinoma?

Answer 23

Autosomal dominant condition.
Associated with skin defects, epidermal cysts of the skin, craniofacial defects, intercranial calcifications.

Due to mutations in Patched-1.
This is the receptor for sonic hedgehog.

Question 24

What is cleidocranial dysplasia?

Answer 24

Autosomal dominant skeletal dysplaysia,

Associated with bone ossification not occurring in flat bone of the skull and clavicles.

Failure of eruption of tooth.

Dwarf-like appearance

Cleinocranial displasia is caused in mutations in Runx2 (transcription factor needed for terminal differentiation of osteoblasts). Bone does not mineralise without this factor.