Lecture 8: Craniofacial Disorders

Question 1

whole cranium development takes place in:

Answer 1

about 4 weeks

Question 2

most common malformations are caused by

Answer 2

abnormal developmental processes and involve closure of structures and oral clefting

Question 3

what can we learn from genetic studies?

Answer 3

• 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

Question 4

monogenic

Answer 4

mutation in one gene cause one disorder

Question 5

multigenic

Answer 5

caused by an accumulation of mutations on different genes

ex: CL/P

Question 6

mutigenic with environmental factors

Answer 6

caused by an accumulation of mutations on different genes and succeptibility
ex: CL/P

Question 7

genetic heterogeneity

Answer 7

mutations in more than one gene can cause the same phenotype
ex: crouzon

Question 8

allelic

Answer 8

different mutations in the same gene can cause different disorders
ex: FGFR2, FGFR3

Question 9

modifier genes

Answer 9

same mutations in the same gene can cause different phenotypes

Question 10

what is cleft lip and/ or palate ?

Answer 10

it is a malformation of the upper lip (and/ or palate) and may be unilateral or bilateral

Question 11

what causes a unilateral cleft?

Answer 11

unilateral cleft results from failure of the maxillary process of one side to fuse with the medial nasal process

Question 12

mechanical cause for the formation of CL/P?

Answer 12

a small oral cavity or disproportionately large tongue may prevent the elevation of the palatal shelves (no elevation = no fusion)

Question 13

environmental factors that can cause CL/P?

Answer 13

• alcohol
• cigarettes
• medications
• retanoic acid
• environmental toxins
• insufficient blood supply during critical developmental period

Question 14

unequal incidence of CL/P between different ethnic groups indicates that CL/P is in most cases a:

Answer 14

mutigenic disorder

Question 15

genes involved in palate development that can cause CL/P

Answer 15

• 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

Question 16

van der Woude syndrome

Answer 16

• 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

Question 17

what is IRF6?

Answer 17

it is a transcription factor that contains DNA and protein binding domains

Question 18

CL/P risk factors

Answer 18

• MSX1
• associations near genes involved in craniofacial development: MAFB, PAX7, VAX1, ARHGAP29, IRF6
• growth factors (TGFB)
• environmental factors

Question 19

what can a mutation in MSX1 lead to?

Answer 19

• mutations lead to tooth agencies with or without cleating

- Witkop (tooth/ nail) syndrome

Question 20

what is MSX1 in charge of?

Answer 20

• 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

Question 21

what do growth factors (TGFB) do ?

Answer 21

genes involved in metabolism of xenobiotics; metabolism; immune response

Question 22

MSX1 and VEGD are involved in:

Answer 22

palatal shelf growth/ differentiation

Question 23

collagen XI, VEGF, EGFR, TGF-a, and Hoxa2 are involved in:

Answer 23

palate elevation/ depression of tongue

Question 24

TGF-b3 and PVRL1 are involved in:

Answer 24

palatal fusion, formation and disappearance of midline seam

Question 25

rare facial clefts

Answer 25

- majority are sporadic cases | - hereditary in trreacher collins and goldenhar syndrome (hemifacial microsomia)

Question 26

lateral facial clefts

Answer 26

macrostomia often associated with hemifacial microsomia

Question 27

hemifacial microsomia

Answer 27

condition in which the lower half of one side of the face is underdeveloped and does not grow normally

Question 28

Treacheer-Collins syndrome

Answer 28

- 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

Question 29

TCOF1 gene

Answer 29

-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

Question 30

craniosynostosis

Answer 30

caused by premature closure of one or more calvarial structures, which leads to abnormal skull and facial shape and can increase intracranial pressure

Question 31

trigonocephaly

Answer 31

premature closure of the metopic structure (forehead)

Question 32

craniosynostosis: boston type

Answer 32

- kleblattschaedel (leaf skull) - frontal bossing (protruding forehead) - occasional limb and eye anomalies (like short first metatarsals) - mutation in the MSX2

Question 33

mutation in MSX2

Answer 33

leads to lack of indication of cell proliferation and structure maintenance mutation which causes mesenchyme degredation

Question 34

can mutations in the same gene cause different disorders?

Answer 34

YES

Question 35

protein tyrosine kinases (receptro kinases)

Answer 35

regulate transcription and intracellular ion concentration

Question 36

fibroblast growth factor 2 receptor (FGFR2)

Answer 36

transmembrane proteins consists of extracellular ligand binding domains, a transmembrane domain, and and intracellular domain

Question 37

most mutations in FGFR2 accumulate in:

Answer 37

exon 7 and exon 9

Question 38

FGFR2 mutations in exon 7 and exon 9 can cause:

Answer 38

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

Question 39

a mutation in the transmembrane domain of FGFR2 can cause:

Answer 39

baere-stevenson syndrome with cutis gyrate

Question 40

can the same mutation on the same gene cause different phenotypes?

Answer 40

YES

Question 41

cys342tyr and cys342arg mutation in the extracellular Ig-G like domain of FGFR2 have been found in patients with:

Answer 41

pfeiffer or crouzon syndrome

Question 42

crouzon syndrome

Answer 42

- 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)

Question 43

asper syndrome

Answer 43

- 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

Question 44

hypodontia

Answer 44

(~70 conditions) Msx1 Arg31Pro – agenesis of second premolar and third molar Dlx1 and Dlx2 mice lack maxillary molars

Question 45

oligodontia

Answer 45

``` (>30 conditions) Msx1 Ser202X (Witkop Syndrome), 11-28 congenitally missing teeth ```

Question 46

anodontia

Answer 46

(~25 conditions) | Pax9 KO mice; anhydrotic ectodermal dysplasias (ED1, PVRL1)

Question 47

supernumerary teeth

Answer 47

``` (>35 conditions) cleidocranial dysplasia (CBFA1=RUNX2) ```

Question 48

osteoscleroris

Answer 48

increased trabecular bone density

Question 49

hyperostosis

Answer 49

increased cortical bone thickening

Question 50

craniometaphyseal dysplasia (CMD)

Answer 50

- characterized by increased bone deposition - disrupted bone homeostasis - monogenic disorder

Question 51

cherubism (CBM)

Answer 51

- characterized by increased bone resorption - disrupted bone homeostasis - monogenic disorder

Question 52

craniometaphyseal dysplasia (CMD) genetics

Answer 52

- autosomal dominant caused by mutations in transmembrane protein ANKH - autosmal recessive unknown - incidence is rare - penetrance 100% - expressively is variable

Question 53

craniometaphyseal dysplasia (CMD) phenotypic features

Answer 53

- wide nasal bridge - craniofacial hyperostosis - flared undertraberculated long bone (metaphyses)

Question 54

craniometaphyseal dysplasia (CMD) clinical features

Answer 54

- 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

Question 55

ANKH

Answer 55

transmembrane protein implicated in pyrophosphate trasport but also has other unknown features --> pyrophosphate is associated with mineralization

Question 56

cherubism (CBM) genetics

Answer 56

- autosomal dominant caused by mutation isn the adaptor protein SH3BP2 - rare - variable expressivity

Question 57

cherubism (CBM) clinical features

Answer 57

- 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

Question 58

SH3BP2

Answer 58

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

Question 59

how to study a genetic disorder?

Answer 59

- 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

Question 60

how to verify a mutation?

Answer 60

- 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)