Genetics Flashcards
Which synostosis has the highest prevalence of SMAD6 variants?
Metopic (5.8%). Not sagittal is 1.7% and combined metopic and sagittal have a SMAD6 variant in 20%
What % of craniosynostosis patients overall have an underlying genetic cause found?
24% overall. (88% in bicoronal and 8% in sagittal synostosis)
What other conditions have been found to be associated with SMAD6 mutations?
Congenital heart disease, bicuspid aortic valve, ascending thoracic aortic aneurysms, intellectual disability and radioulnar synostosis
What proportion of non-syndromic and syndromic patients have a SMAD6 mutation?
2% and 3.4%
What is the underlying mechanism for SMAD6 variants in craniosynostosis?
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.
What is the incidence of craniosynostosis?
1 in 2500 live births
What proportion of craniosynostosis is syndromic?
15%
What proportion of craniosynostosis is non-syndromic?
85%
What mutation is seen in Muenke syndrome?
Point mutation of Pro250Arg in the immunoglobulin like II-III linker region of FGFR3 Ch4p16.3
What mutations are seen with Apert syndrome?
FGFR2 mutations Ch10q26 missense mutations of Pro253Arg, Ser252Trp and 2 Alu insertion mutations
What mutation is found in unicoronal synostosis that was previously thought to be non-syndromic?
Muenke syndrome
What proportion of mutations in craniosynostosis are sporadic?
85%
What is the embryonic origin of the calvarial bones?
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
What is the classical phenotype seen with Muenke syndrome?
Unicoronal or bicoronal synostosis
Brachydactylyl
Thimble like middle finger
Carpal and tarsal fusions
Sensorineural hearing loss
Developmental delay
What types of joints are the cranial sutures?
Fibrous (synarthroses)
What are the features of Saethre-Chotzen?
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
What is the mutation that leads to Saethre-Chotzen?
TWIST1 autosomal dominant loss of function mutation
What is the triad of Crouzon’s syndrome?
Bicoronal synostosis
Exophthalmos
Midface hypoplasia
What proportion of Muenke syndrome patients have developmental delay?
2/3 - usually mild
What mutation cause Crouzon’s syndrome?
FGFR2 autosomal dominant missense mutation of the Ig 3 domain
How many types of Pfeiffer syndrome are there?
3
Type 1 is mild
Type 2 & 3 are severe with early death
What are the clinical features of Pfeiffer syndrome?
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
What mutation caused Pfeiffer type 1?
Autosomal dominant FGFR1 mutation Pro252Arg
What mutation caused Pfeiffer type 2 & 3?
FGFR2
What are the clinical features of Apert syndrome?
Coronal synostosis
Severe syndactyly of hands and feet
Symphalangism (fusion of the joints of the hands and feet)
Radiohumeral fusion
Mental retardation
What are the clinical features of Jackson-Weiss syndrome?
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
What mutation is found in Jackson-Weiss syndrome?
FGFR2 autosomal dominant
Which craniosynostosis syndromes are autosomal recessive?
Baller-Gerold syndrome
Carpenter syndrome
Antley-Bixler syndrome
Which FGF-receptors are highly expressed in midface ossification centres?
FGFR1 & 2
(FGFR 3 is NOT i.e. why Muenke does not have midface retrusion)
What is the cause of most de novo Apert mutations?
Advanced paternal age
What is the prevalence of Pfeiffer syndrome?
1 in 100,000 live births
What are the clinical subtypes of Pfeiffer syndrome?
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
What mutation is most common in Pfeiffer type 1?
FGFR1 (Pro252Arg)
What mutation is associated with Crouzon syndrome with acanthosis nigricans?
FGFR3
What are the additional features of Crouzons with acanthosis nigricans?
Hydrocephalus
Dermatological features
Choanal atresia
Short vertebral bodies
Broad and short metacarpals and phalanges
What proportion of patients with syndromic craniosynostosis have a continuous tracheal sleeve?
20%
What is a continuous tracheal sleeve?
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!
What is the action of the SMAD6 gene?
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.
What is the implication of TCF-12 mutation in coronal craniosynostosis?
In comparison with Muenke or Saethre-Chotzen, TCF-12 associated coronal synostosis has a more benign course
What are the features of ERF-associated craniosynostosis?
- Multisutural synostosis with predilection for pansynostosis, sagittal and lamboid synostosis ** Late fusion with relatively normal head shape **
- Facial dysmorphism with mild Crouzonoid phenotype
- Chiari 1
- Behavioural problems
- Speech and language delay
ERF mutation was found in 2013
What gene should you test for in a patient with a mild Crouzon phenotype that is negative for FGF mutation?
ERF mutation
What is the functional matrix theory by Moss?
Pressure from the brain is the primary source of tensile strength that causes the suture to deposit bone
