CFD 3 - Treacher Collins syndrome

Question 1

What is the incidence of Treacher Collins Syndrome (TCS)?

Answer 1

1:50,000 live births

Question 2

What causes TCS?

Answer 2

TCS is caused by abnormal formation of the first and second branchial arches during the 5th to 8th weeks of human fetal development, leading to profound facial dysmorphism

Question 3

Genetically, what causes TCS?

Answer 3

• most cases caused by loss-of-function mutations in the gene TCOF1 which encodes the protein Treacle
• other TCS cases caused by mutations to the gene POLR1D and POLR1C which encode subunits of the enzymes RNA Polymerase I and III, important in RNA synthesis

Question 4

Mutations to what proteins cause TCS?

Answer 4

• TCOF1 - most cases, encodes Treacle
• POLR1D and POLR1C - encodes subunits of RNA Polymerase I and III

Question 5

In most cases of TCS, what bones are underdeveloped?

Answer 5

facial bones, particularly the cheek bones, eye sockets and a very small jaw and chin (micrognathia)

Question 6

What are some of the facial features of TCS?

Answer 6

eyes that slant downwards, sparse eyelashes, eye life coloboma

Question 7

What ear problems can TCS also be characterised by?

Answer 7

• absent, small, or unusually formed ears.
• hearing loss occurs in about half of all affected individuals

Question 8

What is the main concern for a newborn TCS patient?

Answer 8

respiratory failure due to airway narrowing from craniofacial malformation

Question 9

Why is early intervention needed for a newborn with TCS?

Answer 9

• clear and maintain airway
• enable feeding
• protect the eyes
• improve hearing and speed development

Question 10

What treatment may be given later in life (not a newborn) to a TCS patient?

Answer 10

aesthetic and functional reconstructions of the mouth, face and external ear may occur

Question 11

What do 50% of TCS patients suffer from?

Answer 11

abnormalities of the middle ear and may have a smaller middle ear cavity, leading to possible bilateral conductive hearing loss

Question 12

What is usually used to improve the hearing of TCS patients with hearing loss?

Answer 12

bone conduction hearing aids or middle ear surgery

Question 13

How many distinct mutations have been reported in TCOF1?

Answer 13

200 distinct mutations

Question 14

What percentage of TCS cases are caused by TCOF1 mutations?

Answer 14

70-93%

Question 15

How are TCOF1 mutations inherited?

Answer 15

via an autosomal dominant pattern
(autosomal = not on a sex chromosome)

Question 16

What percentage of TCS patients have POLR1D and POLR1C mutations been found in?

Answer 16

11-23%

Question 17

How are POLR1D and POLR1C mutations inherited?

Answer 17

POLR1D = autosomal dominant
POLR1C = autosomal recessive

Question 18

Are mutations always inherited?

Answer 18

no, some may occur spontaneously

Question 19

What are the majority of TCOF1 mutations?

Answer 19

the majority are deletions, which range in size from 1 - 40 nucleotides

other mutations have been found which include splicing, insertions, and non-sense mutations

Question 20

What may TCOF1 mutations result in?

Answer 20

a truncated Treacle protein which is small and non-functional

Question 21

When is Treacle protein active?

Answer 21

during early embryonic development in structures that become bones and other tissues in the face

Question 22

What kind of protein is Treacle?

Answer 22

nucleolar phosphoprotein

Question 23

What does Treacle play a key role in?

Answer 23

pre-ribosomal processing and make of the ribosome

Question 24

In mice, what does haploinsufficiency of tcof1 result in?

Answer 24

depletion of neural crest cell precursors, through high levels of cell death

• this results in a reduced number of neural crest cells migrating into the developing craniofacial complex