Lecture 8: Craniofacial Disorders Flashcards
whole cranium development takes place in:
about 4 weeks
most common malformations are caused by
abnormal developmental processes and involve closure of structures and oral clefting
what can we learn from genetic studies?
- etiology: cause of disorder
- nosology: classification
- diagnostics: molecular diagnosis, personalized medicine
- intervention: conventional; small molecules; gene therapy
- proactive/ preventative health care: diet, lifestyle, pharmaceutics, molecular or cell therapy
monogenic
mutation in one gene cause one disorder
multigenic
caused by an accumulation of mutations on different genes
ex: CL/P
mutigenic with environmental factors
caused by an accumulation of mutations on different genes and succeptibility
ex: CL/P
genetic heterogeneity
mutations in more than one gene can cause the same phenotype
ex: crouzon
allelic
different mutations in the same gene can cause different disorders
ex: FGFR2, FGFR3
modifier genes
same mutations in the same gene can cause different phenotypes
what is cleft lip and/ or palate ?
it is a malformation of the upper lip (and/ or palate) and may be unilateral or bilateral
what causes a unilateral cleft?
unilateral cleft results from failure of the maxillary process of one side to fuse with the medial nasal process
mechanical cause for the formation of CL/P?
a small oral cavity or disproportionately large tongue may prevent the elevation of the palatal shelves (no elevation = no fusion)
environmental factors that can cause CL/P?
- alcohol
- cigarettes
- medications
- retanoic acid
- environmental toxins
- insufficient blood supply during critical developmental period
unequal incidence of CL/P between different ethnic groups indicates that CL/P is in most cases a:
mutigenic disorder
genes involved in palate development that can cause CL/P
- migration/ differentiation of neural crest cells: multiple genes
- palatal shelf growth/ differentiation: MSX1, VEGD
- palate elevation/ depression of tongue: collagen XI, VEGF, EGFR, TGF-a, Hoxa2
- palatal fusion, formation and disappearance of midline seam: TGF-b3, PVRL1
van der Woude syndrome
- autosomal dominant
- cleft lip with or without palate
- hypodontia
- pits on lower lip
- mutations in IRF6 ( interferon regulatory factor 6) sufficient for CL/P; haploinsufficiency
what is IRF6?
it is a transcription factor that contains DNA and protein binding domains
CL/P risk factors
- MSX1
- associations near genes involved in craniofacial development: MAFB, PAX7, VAX1, ARHGAP29, IRF6
- growth factors (TGFB)
- environmental factors
what can a mutation in MSX1 lead to?
- mutations lead to tooth agencies with or without cleating
- Witkop (tooth/ nail) syndrome
what is MSX1 in charge of?
- expressed in anterior palatal mesenchyme, required for Bmp4 maintenance
- controls network of growth factors mediating epithelial mesenchymal interactions including Bmp2, Bmp4, Shh ; controls cell proliferation
what do growth factors (TGFB) do ?
genes involved in metabolism of xenobiotics; metabolism; immune response
MSX1 and VEGD are involved in:
palatal shelf growth/ differentiation
collagen XI, VEGF, EGFR, TGF-a, and Hoxa2 are involved in:
palate elevation/ depression of tongue
TGF-b3 and PVRL1 are involved in:
palatal fusion, formation and disappearance of midline seam
rare facial clefts
- majority are sporadic cases
- hereditary in trreacher collins and goldenhar syndrome (hemifacial microsomia)
lateral facial clefts
macrostomia often associated with hemifacial microsomia
hemifacial microsomia
condition in which the lower half of one side of the face is underdeveloped and does not grow normally
Treacheer-Collins syndrome
- madibulofacial dysostosis
- antimongoloid slant of the eyes
- coloboma of the lower lip
- micrognathis (small jaw)
- microtia and other deformities of the ears
- hypoplastic zygomatic arches
- macrostomia
- mutation in gene: TCOF1
- inherited in autosomal dominant
- not associated with mental disabilities
TCOF1 gene
-involved in nuclear trafficking
-important for neural crest cell development
nuclear phosphoprotein, regulates ribosome biogeneis
-200 mutations: premature stop codon–> loss of function–> nonsense mediated mRNA decay–> impairment of metabolic needs –> high levels of cell death–> 25% less neural crest cell migrate
-acts through p53 activation
craniosynostosis
caused by premature closure of one or more calvarial structures, which leads to abnormal skull and facial shape and can increase intracranial pressure
trigonocephaly
premature closure of the metopic structure (forehead)
craniosynostosis: boston type
- kleblattschaedel (leaf skull)
- frontal bossing (protruding forehead)
- occasional limb and eye anomalies (like short first metatarsals)
- mutation in the MSX2
mutation in MSX2
leads to lack of indication of cell proliferation and structure maintenance mutation which causes mesenchyme degredation
can mutations in the same gene cause different disorders?
YES
protein tyrosine kinases (receptro kinases)
regulate transcription and intracellular ion concentration
fibroblast growth factor 2 receptor (FGFR2)
transmembrane proteins consists of extracellular ligand binding domains, a transmembrane domain, and and intracellular domain
most mutations in FGFR2 accumulate in:
exon 7 and exon 9
FGFR2 mutations in exon 7 and exon 9 can cause:
craniosynotosis such as
- pfeiffer syndrome
- apert syndrome
- crouzon syndrom
- jackson-weiss syndrome
and are gain of function mutation affecting ligand binding in the extracellular domain
a mutation in the transmembrane domain of FGFR2 can cause:
baere-stevenson syndrome with cutis gyrate
can the same mutation on the same gene cause different phenotypes?
YES
cys342tyr and cys342arg mutation in the extracellular Ig-G like domain of FGFR2 have been found in patients with:
pfeiffer or crouzon syndrome
crouzon syndrome
- craniosynostosis
- hypoplastic maxilla
- proptosis (abnormal protrusion of the eyes)
- autosomal dominant
- FGFR2 mutation
- -> FGFR3 crouzon with acanthosis nigricans (dark, velvety patches in body folds and creases)
asper syndrome
- FGFR2 mutation
- could be considered a severe form of couzons
- craniosynoptosis (fibrous sutures in an infant skull prematurely fuses by turning into bone)
- exorbitism
- midfacial hypoplasia
- cleft of secondary palate
- symmetric syndarctyly of hands and feet
- single nail
hypodontia
(~70 conditions)
Msx1 Arg31Pro – agenesis of second premolar and third molar
Dlx1 and Dlx2 mice lack maxillary molars
oligodontia
(>30 conditions) Msx1 Ser202X (Witkop Syndrome), 11-28 congenitally missing teeth
anodontia
(~25 conditions)
Pax9 KO mice; anhydrotic ectodermal dysplasias (ED1, PVRL1)
supernumerary teeth
(>35 conditions) cleidocranial dysplasia (CBFA1=RUNX2)
osteoscleroris
increased trabecular bone density
hyperostosis
increased cortical bone thickening
craniometaphyseal dysplasia (CMD)
- characterized by increased bone deposition
- disrupted bone homeostasis
- monogenic disorder
cherubism (CBM)
- characterized by increased bone resorption
- disrupted bone homeostasis
- monogenic disorder
craniometaphyseal dysplasia (CMD) genetics
- autosomal dominant caused by mutations in transmembrane protein ANKH
- autosmal recessive unknown
- incidence is rare
- penetrance 100%
- expressively is variable
craniometaphyseal dysplasia (CMD) phenotypic features
- wide nasal bridge
- craniofacial hyperostosis
- flared undertraberculated long bone (metaphyses)
craniometaphyseal dysplasia (CMD) clinical features
- increased bone density in cranial and facial bones
- facial deformities
- closure of foramina due to increased bone depositions, neuronal compression
- tubular bone malformation which includes widening and less bone mass of metaphyses
ANKH
transmembrane protein implicated in pyrophosphate trasport but also has other unknown features
–> pyrophosphate is associated with mineralization
cherubism (CBM) genetics
- autosomal dominant caused by mutation isn the adaptor protein SH3BP2
- rare
- variable expressivity
cherubism (CBM) clinical features
- excessive bone resorption and replacement with fibrous tissues self limiting to mandible and maxilla
- tissue grows in tumor like manner and consists of a mass of osteoblastic stromal cells and clusters of mutinucleated osteoclastic cells
- submandibular lymph node enlargement
- tooth agenesis, delayed permanent teeth, root resorption, maloclusion and maldepositioned teeth
SH3BP2
adaptor proteins that bring signaling molecules together in protein complexes and therefore regulate signaling pathways
-mutation increases TNF alpha which is know to induce inflammation and osteoclastogenesis
how to study a genetic disorder?
- determination of disorders and trait: monogenic disorder with qualitative or quantitative trait
- pedigree selection or association study with unrelated individuals or sibling pairs
- candidate gene mapping or genome wide scan
- determination of disease gene locus (linkage analysis or non-parametric analysis )
- candidate gene or positional cloning
- mutation detection and verification
- functional studies
how to verify a mutation?
- testo for co-segregation of the mutation with disease phenotype
- test a large number of controls for this sequence variance
- show impact of mutations on function of protein/pathway
- re-create phenotype in cell culture (or cellular level)
- re-create phenotype in mouse model (transgenic, knock out, knock in)
