Craniofacial Disorders Flashcards
Describe the embryonic mechanism that is disrupted in cleft lip and palate.
around week 10 the face as we know it is fully formed, so the defect happens prior to then
lack of fusion between the maxillary swellings and the intermaxillary process
Describe the embryonic mechanism that is disrupted in cleft lip.
around week 10 the face as we know it is fully formed, so the defect happens some time prior to then
lack of fusion between the lateral nasal process
How can you subphenotype cleft lip and/or palates?
lip prints
obicularis oris defects (using US of the surrounding muscles of the mouth)
dental abnormalities
speech problems
What are microforms?
small defects in the muscles around the mouth that result from a minimally apparent cleft lip (even if there are multiple defects)
normally associated with BMP4 mutations
Describe the gender ratios for cleft lip and/or palate.
cleft lip and or palate occurs 2:1 male to female
cleft palate occurs 1:2 male to female
Cleft lip occurs __:__ left to right.
2:1
What prenatal factors contribute to development of a cleft lip and/or palate?
exposures (smoking, alcohol, retinoic acid, trimethidone and related anticonvulsants)
deficiencies (folate)
What is the recurrence risk for non-syndromic cleft lip and palate in patients with an affected first degree relative?
3.5%
What is the recurrence risk for non-syndromic cleft lip and palate in patients with an affected second degree relative?
0.8%
What is the recurrence risk for non-syndromic cleft lip and palate in patients with an affected third degree relative?
0.6%
What is the recurrence risk for non-syndromic cleft lip and palate in patients with an affected first degree relative?
4.6%
What is the recurrence risk for unilateral non-syndromic cleft lip and palate in patients with an affected first degree relative?
2.5%
What is the recurrence risk for cleft lip and palate as well as cleft lip in a future child when no parents are affected by one child is?
- 4% (CLP)
2. 5% (CL)
What is the recurrence risk for cleft lip and palate as well as cleft lip in a future child when one parent is affected?
- 2% (CLP)
6. 8% (CL)
What is the recurrence risk for cleft lip and palate as well as cleft lip in a future child when one parent and one child are already affected?
- 8% (CLP)
14. 9% (CL)
What feeding considerations are required for newborns with cleft lip and palate?
since palate is protective of food going into the nasal cavity and eustachean tube newborns typically have trouble feeding and require special nipples (bigger opening to increase the gravity of the milk and longer to direct the milk downwards
this prevents food from entering the eustachian tube and causing otitis media
When are repairs done for clefting?
cleft lip is cosmetic and typically done in the first few years of life
cleft palate requires sufficient surrounding tissue growth and must be done later in life
____ of CL/P patients have a syndrome and _____ of CP patients have a syndrome.
30%
50%
Name the syndromes most commonly associated with celfting.
DiGeorge/ Velocardiofacial Syndrome
Stickler Syndrome
Treacher Collins Syndrome
What are the clinical features of DiGeorge/ Velocardiofacial Syndrome?
cleft palate
medial displacement of internal carotid arteries
velopharyngeal insufficiency
ear abnormalities
cardiac abnormalities
slender hands and feet
learning disabilities, ID, and psychiatric disorders
What is DiGeorge/Velocardiofacial Syndrome?
AD
mutations to the TBX1 gene normally due to a 22q11 deletion
75% detectable by FISH
What are the clinical features of Stickler Syndrome?
cleft palate *nearsightedness* deafness midface hypoplasia; small chin mitral valve prolapse arthropathy spondyloepiphyseal disease
What is Stickler Syndrome?
AD
mutations of the COL2A1 gene (encodes type II collagen) mostly and COLIIA2 gene (encodes type XI collagen) among others
pathogenesis: abnormality of skin, vitreous, tendon, and bone
What are the clinical features of Treacher Collins Syndrome?
cleft palate *coloboma of lower eyelids* *microtia and ear deformities* palatopharyngeal insufficiency mid face hypoplasia (bilateral and symmetrical) palpebral fissures (downslanting) small chin conductive hearing loss
What is Treacher Collins Syndrome?
AD
mutations in the TCOF1 gene (though mosaicism and non-penetrance possible) which codes for treacle
mutations are loss of function to nucleolar phosphoprotein involved in ribosomal gene (the C-terminal, which is required for the localization to the nucleolas, is missing, making it unable to traffic)
treacher is expressed in the developing neural folds and mandibular arch
What is Miller Syndrome/Postaxial Acrofacial Dysostosis?
AR
rare
mutations in dihydroorotate dehydroenase (intermediate in the pyrimidine de novo biosynthesis)
What are the clinical features of Miller Syndrome/Postaxial Acrofacial Dysostosis?
Treacher Collins like features cleft palate downslanting eyes eyelid coloboma cupped ears malar hypoplasia ulnar hypoplasia absence of 5th digit
What is Nager Syndrome/Preaxial Acrofacial Dysostosis?
both AD and AR forms
rare
mutations in SF3B4 (component of pre-mRNA spliceosomal complex)
What are the clinical features of Nager Syndrome/Preaxial Acrofacial Dysostosis?
micrognathia downslanting eyes cleft palate dysplastic ears malar hypoplasia thumb hypoplasia upper lip
What is Mandibulofacial Dysostosis with Microcephaly?
AD
rare
mutations to EFTUD2 (component of the spliceosome)
What is Pierre Robin Syndrome?
AR
mutations to the SOX9 enhancer (normally deletions about 2Kb upstream)
What is the progression of clinical symptoms for Pierre Robin Syndrome?
begins with having a small chin –> thrusting of the tongue upward –> no fusion of the maxillary swellings –> cleft palate
What is Van der Woude Syndrome?
AD
accounts for 27% of all CLP (but <1% of non-syndromic CLP)
70% due to mutations in IF6 gene
5% due to mutations in the GRHL3 gene (which also has variants that are associated with non-syndromic CLP)
allelic with popliteal pterygium syndrome
What are the clinical features of Van der Woude Syndrome?
CLP
lip pits
webbing of legs (if presence of popliteal pterygium syndrome)
What is GLASS Syndrome?
AD
mutations to the SATB2 gene
What are the clinical features of GLASS Syndrome?
cleft palate micrognathia downslanting eyes crowding teeth seizures joint laxity arachnodactyly happy demeanor
What is Catel-Manzke Syndrome?
AR
mutations to the TGDS gene
What are the clinical features of Catel-Manzke Syndrome?
cleft palate
Pierre Robin anomaly
glossoptosis
hyperphalangy
What gene is associated with cleft palate and ankyloglossia?
TBX22
What gene is associated with Ectodermal Dysplasia, Ectrodactyly, CLP (EEC)?
TP63
What gene-environment correlations have evidence of associations with CLP?
MLLT and SMC2 plus maternal alcohol consumption (3 months prior through 1st trimester)
TBK1 and ZNF236 plus maternal smoking
BAALC plus multivitamin supplementation (decreases risk)
What genes are associated with Non-Syndromic orofacial clefting?
FOXE1 and MSX1
What results in scaphocephaly?
premature fusion of sagital suture
What results in brachycephaly?
premature fusion of coronal suture
What results in anterior plagiocephaly?
premature fusion of the coronal suture (asymmetrical)
What results in trigonocephaly?
premature fusion of the frontal suture
What results in posterior plagiocephaly?
premature fusion of the lambdoid suture (asymmetrical)
What is Saethre-Chotzen Syndrome?
AD
TWIST gene mutation (to the transcription factor, DNA binding domain, Helix-Loop-Helix dimerization, resulting in increased FGFR expression) resulting in loss of function
What are the clinical manifestations of Saethre-Chotzen Syndrome?
craniosynostosis and limb abnormalities (otherwise phenotypically variable)
What are FGFR Craniosynostosis Disorders?
mostly AD
normally gain of function mutations
phenotypic variability/genetic heterogeneity (mutations in FGFR1, FGFR2, and FGFR3 cause 14+ conditions)
involved in growth, development, and differentiation in many organs and tissues
List the FGFR Craniosynostosis Disorders?
Crouzon Jackson Weiss Apert Crouzonodermoskeletal Beare-Stevenson
What is Mueke Syndrome?
mutations to FGFR3 P250R
highly variable phenotype even in families
increases risk of need for subsequent surgeries after initial repair
What are the clinical features of Apert Syndrome?
prominent forehead midface hypoplasia depression of nasal bridge trapezoidal-shaped mouth common CT findings in infants (midline calvarial defect, large anterolateral fontanelles, coronal/lamboid synostosis) syndactyly of hands and feet
Describe oculo-auriculo-vertibral spectrum, Goldenhar Syndrome
genetic heterogeneity
facial asymmetry
external ear deformity, tags, sinuses
epibulbar dermoid, coloboma
What is Branchiootorenal Dysplasia?
AD
mutations in the EYA1 (eye-absent 1) gene
What are the clinical features associated with Branchiootorenal Dysplasia?
branchial cleft, fistula, cysts
hearing loss (accounts for 27% of all deafness)
renal dysplasia, aplasia, cystic
