CFD 3 - Treacher Collins syndrome Flashcards
What is the incidence of Treacher Collins Syndrome (TCS)?
1:50,000 live births
What causes TCS?
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
Genetically, what causes TCS?
- 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
Mutations to what proteins cause TCS?
- TCOF1 - most cases, encodes Treacle
- POLR1D and POLR1C - encodes subunits of RNA Polymerase I and III
In most cases of TCS, what bones are underdeveloped?
facial bones, particularly the cheek bones, eye sockets and a very small jaw and chin (micrognathia)
What are some of the facial features of TCS?
eyes that slant downwards, sparse eyelashes, eye life coloboma
What ear problems can TCS also be characterised by?
- absent, small, or unusually formed ears.
- hearing loss occurs in about half of all affected individuals
What is the main concern for a newborn TCS patient?
respiratory failure due to airway narrowing from craniofacial malformation
Why is early intervention needed for a newborn with TCS?
- clear and maintain airway
- enable feeding
- protect the eyes
- improve hearing and speed development
What treatment may be given later in life (not a newborn) to a TCS patient?
aesthetic and functional reconstructions of the mouth, face and external ear may occur
What do 50% of TCS patients suffer from?
abnormalities of the middle ear and may have a smaller middle ear cavity, leading to possible bilateral conductive hearing loss
What is usually used to improve the hearing of TCS patients with hearing loss?
bone conduction hearing aids or middle ear surgery
How many distinct mutations have been reported in TCOF1?
200 distinct mutations
What percentage of TCS cases are caused by TCOF1 mutations?
70-93%
How are TCOF1 mutations inherited?
via an autosomal dominant pattern
(autosomal = not on a sex chromosome)
What percentage of TCS patients have POLR1D and POLR1C mutations been found in?
11-23%
How are POLR1D and POLR1C mutations inherited?
POLR1D = autosomal dominant
POLR1C = autosomal recessive
Are mutations always inherited?
no, some may occur spontaneously
What are the majority of TCOF1 mutations?
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
What may TCOF1 mutations result in?
a truncated Treacle protein which is small and non-functional
When is Treacle protein active?
during early embryonic development in structures that become bones and other tissues in the face
What kind of protein is Treacle?
nucleolar phosphoprotein
What does Treacle play a key role in?
pre-ribosomal processing and make of the ribosome
In mice, what does haploinsufficiency of tcof1 result in?
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
