Cleft Lip and Palate

Question 1

What occurs at a molecular level to cause CLP?

Answer 1

o Mutations in Hox genes, including homeobox genes (subtype of hox genes)
§ Hox genes code for Hox proteins that act as transcription factors that bind to enhancers to either activate or repress genes
§ Act on 3 levels
· Regulate genes that regulate other genes
· Directly regulate the effectors genes that form the tissues, structures, and organs
· Regulate cell division and adhesion, apoptosis, and cell migration
§ Responsible for regulating embryonic cell differentiation by altering the concentration of morphogens to create morphogenetic field
§ E.g., MSX 1 homeobox gene, which is required for the expression of BMP2 and BMP4 in the palatal mesenchyme. Insufficient mesenchyme proliferation is believed to impact the elevation of the palatal shelves cleft palate
§ Mutations in fibroblast growth factor 9, which is responsible for palatal growth and fusion, and timely elevation by regulating cell proliferation and accumulation
o Cytokines IL-2 and IFN gamma are highly correlated in promoting mesenchymal cell death

Question 2

What occurs at a cellular level to cause CLP?

Answer 2

NCC failure to migrate from the crests of the neural folds to form mesenchyme (due to inappropriate signalling events at a molecular level): failure to undergo epithelial mesenchymal transition to give rise to the relevant tissues

Question 3

What occurs at a tissue layer to cause CLP?

Answer 3

Failure of fusion of the palatal shelves due to incomplete breakdown of the epithelium

Question 4

What occurs at an organ level to cause CLP?

Answer 4

o Failure of tongue depression, preventing the shelves from contacting and fusing together
o Failure for structure to contact: can be due to failure of mesenchyme proliferation, leading to the shelves not being long enough to contact
o Rupture post-fusion

Question 5

Environmental factors that contribute to CLP

Answer 5

o Lack of folic acid is associated with neural tube defects
o Rubella virus
Heavy alcohol use during pregnancy

Question 6

What can mutations in Hox genes result in? How is this the case?

Answer 6

CLP
o Mutations in Hox genes, including homeobox genes (subtype of hox genes)
§ Hox genes code for Hox proteins that act as transcription factors that bind to enhancers to either activate or repress genes
§ Act on 3 levels
· Regulate genes that regulate other genes
· Directly regulate the effectors genes that form the tissues, structures, and organs
· Regulate cell division and adhesion, apoptosis, and cell migration
§ Responsible for regulating embryonic cell differentiation by altering the concentration of morphogens to create morphogenetic field
§ E.g., MSX 1 homeobox gene, which is required for the expression of BMP2 and BMP4 in the palatal mesenchyme. Insufficient mesenchyme proliferation is believed to impact the elevation of the palatal shelves cleft palate
§ Mutations in fibroblast growth factor 9, which is responsible for palatal growth and fusion, and timely elevation by regulating cell proliferation and accumulation

Question 7

How do Hox genes work?

Answer 7

§ Hox genes code for Hox proteins that act as transcription factors that bind to enhancers to either activate or repress genes
§ Act on 3 levels
· Regulate genes that regulate other genes
· Directly regulate the effectors genes that form the tissues, structures, and organs
· Regulate cell division and adhesion, apoptosis, and cell migration
§ Responsible for regulating embryonic cell differentiation by altering the concentration of morphogens to create morphogenetic field

Question 8

Examples of Hox genes which can cause CLP

Answer 8

§ E.g., MSX 1 homeobox gene, which is required for the expression of BMP2 and BMP4 in the palatal mesenchyme. Insufficient mesenchyme proliferation is believed to impact the elevation of the palatal shelves cleft palate
§ Mutations in fibroblast growth factor 9, which is responsible for palatal growth and fusion, and timely elevation by regulating cell proliferation and accumulation

Question 9

Consequences of CLP

Answer 9

Speech
Suckling/ swallowing/ mastication
Hearing problems
Dental Defects
Psychosocial impacts

Question 10

How does CLP cause speech impairments?

Answer 10

o Difficulty pronouncing vowels, labial consonants, and nasal/ oral sounds, due to communication between nasal and oral cavities
o Hypernasality
o An impacted pitch of voice if their vocal folds are impacted by the cleft palate
o Increased difficulty when communicating with their caregivers about their needs + difficulty understanding speech from others

Question 11

How does CLP cause suckling/ swallowing/ mastication problems? What impact does this have on the individual?

Answer 11

o In those with cleft lip: difficult to achieve a vacuum (negative pressure) due to the consolidation of the nasal and oral cavities and the incompetency of the lips. Makes it difficult to withdraw milk
o Swallowing: the food originally aimed to be swallowed to end up in the nasal cavity through nasal cavity through nasal regurgitation choking/ coughing

Can lead to dietary malnutrition

Question 12

How does CLP cause hearing problems?

Answer 12

Due to middle effusion and related infection

Question 13

What dental defects are associated with CLP?

Answer 13

Agenesis and crowding
Can lead to malocclusion

Question 14

Normal suckling process in infants

Answer 14

1. • Levator veli palatini muscle and tensor veli palatini muscle elevate and tense the soft palate to block the nasopharynx and protect the airway
   • Orbicularis oris muscle allows lips to surround bottle or breast
   • Lateral pterygoid muscle allows depression on mandible
2. • Expression of milk suckling from the bottle/ nipple occurs next as the tongue presses the bottle or breast against the hard palate
   • Glossopharyngeal muscle elevates the tongue
   • When liquid reaches palatoglossal arch, soft palate remains elevated blocking the nasal cavity, vocal folds close, pharynx elevates and moves anterior by suprahyoid muscle, pharyngeal constrictor muscles move liquid inferior towards the upper oesophageal sphincter
3. • Upper oesophageal sphincter opens through thyrohyoid contraction, cricopharyngeal relaxation and distension from the liquid
     Once into the oesophagus, liquid travels inferiorly towards the stomach by gravity. Upper oesophageal sphincter will close while lower oesophageal sphincter will open: enter stomach