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Genetics > Lecture 8: Craniofacial Disorders > Flashcards

Lecture 8: Craniofacial Disorders Flashcards

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1
Q

whole cranium development takes place in:

A

about 4 weeks

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2
Q

most common malformations are caused by

A

abnormal developmental processes and involve closure of structures and oral clefting

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3
Q

what can we learn from genetic studies?

A
  • 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
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4
Q

monogenic

A

mutation in one gene cause one disorder

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5
Q

multigenic

A

caused by an accumulation of mutations on different genes

ex: CL/P

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6
Q

mutigenic with environmental factors

A

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

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7
Q

genetic heterogeneity

A

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

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8
Q

allelic

A

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

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9
Q

modifier genes

A

same mutations in the same gene can cause different phenotypes

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10
Q

what is cleft lip and/ or palate ?

A

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

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11
Q

what causes a unilateral cleft?

A

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

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12
Q

mechanical cause for the formation of CL/P?

A

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

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13
Q

environmental factors that can cause CL/P?

A
  • alcohol
  • cigarettes
  • medications
  • retanoic acid
  • environmental toxins
  • insufficient blood supply during critical developmental period
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14
Q

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

A

mutigenic disorder

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15
Q

genes involved in palate development that can cause CL/P

A
  • 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
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16
Q

van der Woude syndrome

A
  • 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
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17
Q

what is IRF6?

A

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

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18
Q

CL/P risk factors

A
  • MSX1
  • associations near genes involved in craniofacial development: MAFB, PAX7, VAX1, ARHGAP29, IRF6
  • growth factors (TGFB)
  • environmental factors
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19
Q

what can a mutation in MSX1 lead to?

A
  • mutations lead to tooth agencies with or without cleating

- Witkop (tooth/ nail) syndrome

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20
Q

what is MSX1 in charge of?

A
  • 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
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21
Q

what do growth factors (TGFB) do ?

A

genes involved in metabolism of xenobiotics; metabolism; immune response

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22
Q

MSX1 and VEGD are involved in:

A

palatal shelf growth/ differentiation

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23
Q

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

A

palate elevation/ depression of tongue

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24
Q

TGF-b3 and PVRL1 are involved in:

A

palatal fusion, formation and disappearance of midline seam

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25
Q

rare facial clefts

A
  • majority are sporadic cases

- hereditary in trreacher collins and goldenhar syndrome (hemifacial microsomia)

26
Q

lateral facial clefts

A

macrostomia often associated with hemifacial microsomia

27
Q

hemifacial microsomia

A

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

28
Q

Treacheer-Collins syndrome

A
  • 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
29
Q

TCOF1 gene

A

-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

30
Q

craniosynostosis

A

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

31
Q

trigonocephaly

A

premature closure of the metopic structure (forehead)

32
Q

craniosynostosis: boston type

A
  • kleblattschaedel (leaf skull)
  • frontal bossing (protruding forehead)
  • occasional limb and eye anomalies (like short first metatarsals)
  • mutation in the MSX2
33
Q

mutation in MSX2

A

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

34
Q

can mutations in the same gene cause different disorders?

A

YES

35
Q

protein tyrosine kinases (receptro kinases)

A

regulate transcription and intracellular ion concentration

36
Q

fibroblast growth factor 2 receptor (FGFR2)

A

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

37
Q

most mutations in FGFR2 accumulate in:

A

exon 7 and exon 9

38
Q

FGFR2 mutations in exon 7 and exon 9 can cause:

A

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

39
Q

a mutation in the transmembrane domain of FGFR2 can cause:

A

baere-stevenson syndrome with cutis gyrate

40
Q

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

A

YES

41
Q

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

A

pfeiffer or crouzon syndrome

42
Q

crouzon syndrome

A
  • 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)
43
Q

asper syndrome

A
  • 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
44
Q

hypodontia

A

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

45
Q

oligodontia

A 
(>30 conditions)
Msx1 Ser202X (Witkop Syndrome), 11-28 congenitally missing teeth
46
Q

anodontia

A

(~25 conditions)

Pax9 KO mice; anhydrotic ectodermal dysplasias (ED1, PVRL1)

47
Q

supernumerary teeth

A 
(>35 conditions)
cleidocranial dysplasia (CBFA1=RUNX2)
48
Q

osteoscleroris

A

increased trabecular bone density

49
Q

hyperostosis

A

increased cortical bone thickening

50
Q

craniometaphyseal dysplasia (CMD)

A
  • characterized by increased bone deposition
  • disrupted bone homeostasis
  • monogenic disorder
51
Q

cherubism (CBM)

A
  • characterized by increased bone resorption
  • disrupted bone homeostasis
  • monogenic disorder
52
Q

craniometaphyseal dysplasia (CMD) genetics

A
  • autosomal dominant caused by mutations in transmembrane protein ANKH
  • autosmal recessive unknown
  • incidence is rare
  • penetrance 100%
  • expressively is variable
53
Q

craniometaphyseal dysplasia (CMD) phenotypic features

A
  • wide nasal bridge
  • craniofacial hyperostosis
  • flared undertraberculated long bone (metaphyses)
54
Q

craniometaphyseal dysplasia (CMD) clinical features

A
  • 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
55
Q

ANKH

A

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

56
Q

cherubism (CBM) genetics

A
  • autosomal dominant caused by mutation isn the adaptor protein SH3BP2
  • rare
  • variable expressivity
57
Q

cherubism (CBM) clinical features

A
  • 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
58
Q

SH3BP2

A

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

59
Q

how to study a genetic disorder?

A
  • 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
60
Q

how to verify a mutation?

A
  • 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)

Genetics (2 decks)

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