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Craniofacial > Genetics > Flashcards

Genetics Flashcards

1
Q

Which synostosis has the highest prevalence of SMAD6 variants?

A

Metopic (5.8%). Not sagittal is 1.7% and combined metopic and sagittal have a SMAD6 variant in 20%

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2
Q

What % of craniosynostosis patients overall have an underlying genetic cause found?

A

24% overall. (88% in bicoronal and 8% in sagittal synostosis)

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3
Q

What other conditions have been found to be associated with SMAD6 mutations?

A

Congenital heart disease, bicuspid aortic valve, ascending thoracic aortic aneurysms, intellectual disability and radioulnar synostosis

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4
Q

What proportion of non-syndromic and syndromic patients have a SMAD6 mutation?

A

2% and 3.4%

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5
Q

What is the underlying mechanism for SMAD6 variants in craniosynostosis?

A

SMAD6 is an inhibitor of BMP. Mutations in SMAD6 reduce the inhibition, resulting in an increase in activity in BMP signalling that results in craniosynostosis.

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6
Q

What is the incidence of craniosynostosis?

A

1 in 2500 live births

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7
Q

What proportion of craniosynostosis is syndromic?

A

15%

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8
Q

What proportion of craniosynostosis is non-syndromic?

A

85%

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9
Q

What mutation is seen in Muenke syndrome?

A

Point mutation of Pro250Arg in the immunoglobulin like II-III linker region of FGFR3 Ch4p16.3

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10
Q

What mutations are seen with Apert syndrome?

A

FGFR2 mutations Ch10q26 missense mutations of Pro253Arg, Ser252Trp and 2 Alu insertion mutations

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11
Q

What mutation is found in unicoronal synostosis that was previously thought to be non-syndromic?

A

Muenke syndrome

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12
Q

What proportion of mutations in craniosynostosis are sporadic?

A

85%

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13
Q

What is the embryonic origin of the calvarial bones?

A

Noden and Trainor used a retroviral lineage tracing approach to show that the facial bones, sphenoid, temporal and frontal bones are from Neural Crest origin whilst the remaining bones are exclusively Mesodermal origin

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14
Q

What is the classical phenotype seen with Muenke syndrome?

A

Unicoronal or bicoronal synostosis
Brachydactylyl
Thimble like middle finger
Carpal and tarsal fusions
Sensorineural hearing loss
Developmental delay

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15
Q

What types of joints are the cranial sutures?

A

Fibrous (synarthroses)

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16
Q

What are the features of Saethre-Chotzen?

A

Coronal synostosis
Bifid hallux
Syndactyly of second and third digits
Facial asymmetry
Low frontal hairline
Ptosis
Small ears with prominent ear crura
Enlarge parietal foramina

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17
Q

What is the mutation that leads to Saethre-Chotzen?

A

TWIST1 autosomal dominant loss of function mutation

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18
Q

What is the triad of Crouzon’s syndrome?

A

Bicoronal synostosis
Exophthalmos
Midface hypoplasia

19
Q

What proportion of Muenke syndrome patients have developmental delay?

A

2/3 - usually mild

20
Q

What mutation cause Crouzon’s syndrome?

A

FGFR2 autosomal dominant missense mutation of the Ig 3 domain

21
Q

How many types of Pfeiffer syndrome are there?

A

3
Type 1 is mild
Type 2 & 3 are severe with early death

22
Q

What are the clinical features of Pfeiffer syndrome?

A

Coronal and multi-suture synostosis
Broad fingers and toes with partial syndactylyl
Maxillary hypoplasia
Small nose with low nasal bridge
Hypertelorism
Proptosis
Radio-humeral synostosis
Strabismus

23
Q

What mutation caused Pfeiffer type 1?

A

Autosomal dominant FGFR1 mutation Pro252Arg

24
Q

What mutation caused Pfeiffer type 2 & 3?

A

FGFR2

25
Q

What are the clinical features of Apert syndrome?

A

Coronal synostosis
Severe syndactyly of hands and feet
Symphalangism (fusion of the joints of the hands and feet)
Radiohumeral fusion
Mental retardation

26
Q

What are the clinical features of Jackson-Weiss syndrome?

A

Craniosynostosis
Broad toes with medial deviation on hallux
2nd and 3rd toe syndactyly
Tarsal-metatarsal fusion
Broad short metatarsals and phalanges
Midface hypoplasia
Hypertelorism
Proptosis
Normal intelligence

27
Q

What mutation is found in Jackson-Weiss syndrome?

A

FGFR2 autosomal dominant

28
Q

Which craniosynostosis syndromes are autosomal recessive?

A

Baller-Gerold syndrome
Carpenter syndrome
Antley-Bixler syndrome

29
Q

Which FGF-receptors are highly expressed in midface ossification centres?

A

FGFR1 & 2
(FGFR 3 is NOT i.e. why Muenke does not have midface retrusion)

30
Q

What is the cause of most de novo Apert mutations?

A

Advanced paternal age

31
Q

What is the prevalence of Pfeiffer syndrome?

A

1 in 100,000 live births

32
Q

What are the clinical subtypes of Pfeiffer syndrome?

A

Described by Cohen in 1993:
Type 1: Mild craniofacial and skeletal abn with normal intellect
Type 2: Cloverleaf skull, proptosis causing visual impairment, finger and toe deformity, elbow ankylosis and developmental delay.
Type 3: Same as type 2 but without Clover leaf

33
Q

What mutation is most common in Pfeiffer type 1?

A

FGFR1 (Pro252Arg)

34
Q

What mutation is associated with Crouzon syndrome with acanthosis nigricans?

A

FGFR3

35
Q

What are the additional features of Crouzons with acanthosis nigricans?

A

Hydrocephalus
Dermatological features
Choanal atresia
Short vertebral bodies
Broad and short metacarpals and phalanges

36
Q

What proportion of patients with syndromic craniosynostosis have a continuous tracheal sleeve?

A

20%

37
Q

What is a continuous tracheal sleeve?

A

Where the normal c shaped tracheal rings are continuous: this means they do not grow and result in tracheal stenosis. Without a tracheostomy there is a 90% risk of death by age 2!

38
Q

What is the action of the SMAD6 gene?

A

This is an inhibitor of BMP2 (bone morphogenic protein-2). A mutation in SMAD6 leads to increased BMP-2 action. This found in 2% of isolated sagittal synostosis, 8% of isolated metopic synostosis and 20% of combined saggital and metopic synostosis.

39
Q

What is the implication of TCF-12 mutation in coronal craniosynostosis?

A

In comparison with Muenke or Saethre-Chotzen, TCF-12 associated coronal synostosis has a more benign course

40
Q

What are the features of ERF-associated craniosynostosis?

A
  1. Multisutural synostosis with predilection for pansynostosis, sagittal and lamboid synostosis ** Late fusion with relatively normal head shape **
  2. Facial dysmorphism with mild Crouzonoid phenotype
  3. Chiari 1
  4. Behavioural problems
  5. Speech and language delay

ERF mutation was found in 2013

41
Q

What gene should you test for in a patient with a mild Crouzon phenotype that is negative for FGF mutation?

A

ERF mutation

42
Q

What is the functional matrix theory by Moss?

A

Pressure from the brain is the primary source of tensile strength that causes the suture to deposit bone

43
Q
A

Craniofacial (4 decks)

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