Download Teeth and syndromes

Teeth and syndromes
A. BLOCH-ZUPAN
Faculté de Chirurgie Dentaire, Université de Strasbourg; Centre de Référence pour les manifestations bucco-dentaires des maladies rares;
Pôle de
Médecine et Chirurgie Bucco-Dentaires, Hôpitaux Universitaires Strasbourg, France; IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire),
INSERM U964, UMR7104 CNRS, Illkirch; ICS, Illkirch, France
Orodental anomalies are one aspect of rare diseases or syndromes
Prevalence
< 1/2000
80%
genetic
Rare
diseases
4 millions
people in
France
7000
syndromes
8000
25 millions
people in
Europe
+900
with orodentofacial
anomalies
750 with cleft
lip and/or
palate
è Few information
è Adequate care and management, diagnostic issues
è The oral cavity a door towards diagnosis treatment and patient management
65 % rare diseases are severe
Williams syndrome
- 1/10 000
- Cardiac Malformation
- Facial Dysmorphism
Osteogenesis Imperfecta
- 1/100 000
- DI
Lesch-Nyhan Disease
- 1/1 000 000
- Enzymatic deficit
(purine)
-Motor deficit
- Self mutilation
Specific orodental manifestations
Non specific caries, periodontal diseases, specific management
The oral cavity : a door towards
development and pathology
Odontogenesis
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Origin of dental cells
Determination of tooth region
Determination of tooth identity
Determination of tooth shape
Cytodifferentiation of Od and Am
Dentin and Enamel
Root development, Eruption
Alveolar bone formation
Stem cells
Palatogenesis
EMT
Bone formation and metabolism
Anomalies
• 
• 
• 
Number
Shape
Size
• 
• 
Structure
Colour
• 
• 
Root
Eruption
Cleft L/P
Embryonic origin of dental cells
•  Enamel organ oral
ectoderm, ameloblasts
•  Dental mesenchyme
(dental papilla,
odontoblasts,
periodontium, bone of
attachement cells) derives
from cranial neural crest
–  Prosencephalon + rostral
mesencephalon populating the
periocular and frontonasal regions
contributes to the upper incisors
–  Rostral rhombencephalon
(Rhombomeres 1 and 2) and
caudal mesencephalon populates
the first maxillo-mandibular
pharyngeal arch thus contributing
to the lower incisors, the lower and
upper molars.
MES
RHO
PRO
*
*
A. TUCKER, P. SHARPE, (5) 2004
Tummers and Thesleff, J Exp Zool (Mol dev Evol) 312B, 2009
Molar Incisor Molar Premolar Canine Incisor
Fleischmannova J. et al.,
Eur J Oral Sci. Feb;116(1):1-10. (2008)
Osteopetrosis / Ae2
- Increased bone density
- Diffuse and focal sclerosis of varying severity
- Modelling defects at metaphyses
- Pathological fractures
- Osteomyelitis
- Dental abnormalities: tooth eruption defects
INTERREG Offensives sciences A27
France
INTERREG
European
project
Germany
Switzerland
Translational Research
Patient
centred
Reference
Centre
Genetic
INSERM U 1112
Helène Dollfus
- Phenotype
analysis
- Clinical data
- Database
D4/phenodent
- Treatment
- Salivary
samples
- Genotype
- Exome
analysis
- Hight
throughput
sequencing
- Validation
Preclinical
IGBMC
Organoculture
Molecular
biology
Transcriptomic
- Proteomic
- Mice model
- Gene
validation
- Mice model
analysis by
microCT
- SEM
Région Alsace, Ministerium für
Wissenschaft, Forschung und
Kunst Baden Württemberg,
Ministerium für Bildung,
Wissenschaft, Weiterbildung und
Kultur des Landes RheinlandPfalz, Université de Strasbourg,
Hôpitaux Universitaires de
Strasbourg, CERBM – IGBMC,
EA3949 - Laboratoire de
Génétique Médicale,
Universitätsklinikum Freiburg,
Universität Heidelberg,
Hypophosphatasie Europe,
O b e r r h e i n i s c h e
Zahnärtztegesellschaft
Genes transcribed at mouse E14.5
cap stage - Transcriptome atlas
19872 genes
expressed at cap
stage E14.5
387 genes involved in a
disease with « teeth
abnormalities »
OMIM, Manteia
405 different
diseases
Among 19872 genes expressed at mouse tooth cap stage, 387
were encountered in 405 diseases with «teeth abnormalities »
Molars and incisors: show your microarray IDs.
Laugel-Haushalter V, Paschaki M, Thibault-Carpentier C, Dembelé D, Dollé P, Bloch-Zupan A.
BMC Res Notes. 2013 Mar 26;6:113.
Vrolik Museum. Amsterdam.
Abnormalities of tooth number
•  Fewer teeth
–  Hypodontia (≤ 6 missing teeth (permanent)
–  Oligodontia (>6 congenitally missing teeth)
–  Anodontia (no teeth)
•  More teeth
–  Supernumerary
–  Hyperdontia
Frequencies
•  Hypodontia
•  Primary dentition
•  Permanent dentition
– Maxillary lateral incisor
– Maxillary second premolar
– Mandibular second premolar
– Third molar
– Maxillary central incisor
– Ca, 1st PreMo, 1st Mo, 2nd Mo
0.1-0.7%
2.3-9.6%
27%
15%
32%
25%
0.05%
1%
•  Missing of a primary tooth is followed by the absence of the
permanent successor in 75-80% of cases
Mucchielli ML, Mitsiadis TA, Raffo S, Brunet JF, Proust JP, Goridis C. Dev Biol. 1997 Sep 15;189(2):275-­‐84. Missing teeth and MSX1 mutations
AD, 4p16.1
2
1 3
3 1
2nd premolar > 3rd molar > 1st premolar >
2
Van den Boogaard et al., 2000
§  CL/P
The same MSX1 mutation can cause teeth agenesis and CL/P
Jumlongras et al., 2001
§ Witkop syndrome : AD missing teeth and nail defects
Stockton
et al.,
2000
V.5 (13 ans)
Missing teeth and PAX9 mutations
1 2 3
3rd molar > 2nd molar > 1st molar>
3 2 1
Rieger syndrome
II:2
R
PITX2, AD, 4q25-q26
III:2
FOXC1, AD, 6p25
IV:1
IV:1 A
III:2 D
B
E
C
F
A novel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes.
Idrees F, Bloch-Zupan A, Free SL, Vaideanu D, Thompson PJ, Ashley P, Brice G, Rutland P, Bitner-Glindzicz M, Khaw PT, Fraser S, Sisodiya SM, Sowden JC.
Am J Med Genet B Neuropsychiatr Genet. 2006 Mar 5;141B(2):184-91.
Pathway
http://david.abcc.ncifcrf.gov/kegg.jsp?path=hsa04310$Wnt signaling p...
Pathway:Wnt signaling pathway
Pathway information generated by KEGG.
List genes are shown in red
DAVID Gene Name
C-terminal binding protein 1
C-terminal binding protein 2
Stop Blinking
Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal
cancer. Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thesleff I, Pirinen S,
Nieminen P. Am J Hum Genet. 2004 May;74(5):1043-50.
WNT10A missense mutation associated with a complete odonto-onycho-dermal dysplasia
syndrome (AR, 2q35 ). Nawaz S, Klar J, Wajid M, Aslam M, Tariq M, Schuster J, Baig SM,
Dahl N. Eur J Hum Genet. 2009 Dec;17(12):1600-5. Epub 2009 May 27.
WNT10A non syndromic hypodontia 16% of patients with 1-3 missing teeth and 51.6 %
(16/31) of patients with 4 or more missing teeth
Song et al, Hum Genet. 2013
:
The Ectodysplasin and NFkappaB signalling pathways in odontogenesis.
Courtney JM, Blackburn J, Sharpe PT.
Arch Oral Biol. 2005 Feb;50(2):159-63. Review.
X linked
Hypohydrotic
ectodermal
dysplasia with
EDA gene
mutation
(exons 4-9
deletion).
F Clauss
CR
Hypohydrotic
ectodermal
dysplasia with
EDAR gene
mutation
F Clauss
CR
Incontinentia Pigmenti
NEMO, IKKgamma, Xq28
EEC (ED, Ectrodactyly, CP)
P63, 3q27
Missing:
83,12,13,14,14,22,23,24,25,41,42,4344
45,47,31,32,33,34,35,37
EEC
M Holder-Espinasse Lille, France
Nicolas Chassaing, Toulouse, France
Mutations in different components of FGF signaling in LADD syndrome. Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nürnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, UlubilEmeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yüksel-Apak M, Nürnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Nat Genet. 2006 Apr;38(4):414-7
Kallman syndrome, FGFR1, 8p11.2-p11.1
Central
hypogonadism
Lack of sense of
smell
Renal aplasia
Deafness
Syndactyly
Cleft lip/palate
Tooth agenesis
I Bailleul-Forestier
Toulouse
Isolated tooth
agenesis, PreMo
Viera, 2007
Modulation of Fgf3
dosage in mouse
and men mirrors
evolution of
mammalian
dentition
Cyril Charles,
Vincent Lazzari,
Paul Tafforeau,
Thomas
Schimmang,
Mustafa Tekin,
Ophir Klein
and Laurent Viriot
PNAS, 106, 52,
2009
Fgf3+/+
Fgf3+/–
Fgf3–/–
Oral-facial-digital syndrome Type I
OFD1(Cxorf5/71-7a), Xp22
M-C
Manière
CR
Oligodontia in Johanson-Blizzard
syndrome, UBR1, AR, 15q15.2
•  Characteristic facies, severe mental and somatic
retardation, sensorineural hearing loss,
malabsorption due to pancreatic insuficiency
• Microdontia
• All permanent
teeth absent
except for the
first permanent
molars, incisors
Bloom syndrome
•  #210900 - 15q26.1 - RECQL3
•  DNA helicase -ATP-dependent RNA or DNA unwinding
Cockayne
syndrome
(Type A – CSA; or CS Type
I OMIM #216400)
(Type B – CSB; or CS Type
II OMIM #133540)
ERCC6, ERCC8
A possible cranio-oro-facial phenotype in
Cockayne syndrome.
Bloch-Zupan A, Rousseaux M, Laugel V,
Schmittbuhl M, Mathis R, Desforges E, Koob M,
Zaloszyc A, Dollfus H, Laugel V.
Orphanet J Rare Dis. 2013 Jan 14;8(1):9.
Unique phenotype
6q27
3Mb
Affected Rela+ves Non affected Haplotypes / A single shared homozygous region
Bioinformatics
Phenotype
Bibliography
Hypothèses
69 Genes
Transcriptome Atlas
Homozygous area
Genes
Functions
Phylogeny
Proteins
Expression pattern
Interactions
Candidates
2 Genes
SMOC2, SPARC related modular calcium binding 2 – 226kb - 13 Exons
DACT2, dapper, antagonist of beta-catenin, homolog 2 –26.93 kb - 4 Exons
SMOC2: Exon1, c.84+1G>T, c.84+1G>T
Mutation affecting the splice donor site – abnormal splicing
I
II
III
IV
IV:3
IV:9
IV:4
V
V:1
V:2
V:4
V:3
IV:4
IV:3
V:1
V:2
V:3
IV:10
V:5
V:6
IV:9
V:4
IV:10
V:5
V:6
SMOC2
SPARC related modular calcium binding 2
This gene is coding for
- a member of the SPARC (secreted protein acidic and rich in cysteine/
osteonectin/BM-40) family
- expressed during embryonic development
-  an extracellular matrix protein binding calcium
-  facilitating matrix formation, proliferation, cell migration (endothelial) and
angiogenesis
SMOC proteins family
The domain structure of SMOC1 and SMOC2 is
composed of 5 domains, one KAZAL domain (a
serine protease inhibitor), two thyroglobulin type I
repeats (predicted to be inhibitors of cysteine
proteases and binding partners of heparin) and a
calcium-binding domain, which is conserved
throughout the evolution.
SMART, eggNOG, Orthoinspector, AQUA, GBLOCK, PhyML, ReadSEQ, iTOL
14q24.2
A
C
B
P
P
P
T
Mo
T
Mo
MC
S
D
S
E
Mo1
Mo2
Mo1
F
G
★
H
★
Inc
Inc
Tooth development Zebrafish versus Mouse
[Borday-Birraux et al (2006) Evol Dev 8: 130-141]
Christelle ETARD et Uwe STRAHLE, Karlsruher Institut für Technologie (KIT), Institut für Toxikologie und Genetik (ITG),
Allemagne
SMOC2 exome sequencing
IntegraGen exome :
69 genes analyzed using VaRank (V. Geoffroy)
- 81 substitutions (47 intronic, or in the untranslated regions; 22 synonymous; and 12
missense, of which all were SNPs)
- 7 deletions (all intronic and four SNPs)
- 1 insertion (all intronic and one SNP).
Good coverage of other SMOC2 exons
SMOC2 Exome
CTRL
Affected
No coverage of the mutation region
c.84+1G>T
Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects.
Bloch-Zupan A, Jamet X, Etard C, Laugel V, Muller J, Geoffroy V, Strauss JP, Pelletier V, Marion V, Poch O, Strahle U, Stoetzel C, Dollfus H.
Am J Hum Genet. 2011 Dec 9;89(6):773-81.
Recessive oligodontia linked to a homozygous loss-of-function mutation in the
SMOC2 gene. Alfawaz S, Fong F, Plagnol V, Wong FS, Fearne J, Kelsell DP.Arch
Oral Biol. 2013
a homozygous mutation, NM_022138.2: c.681T>A, in the SMOC2 gene changing a cysteine to a premature
stop termination codon at codon 227 (p.C227X) in exon 8
Abnormalities of tooth number +
•  0.3-0.8% primary
dentition
•  1-3.5% permanent
dentition
•  98% maxillary region
•  Cleidocranial
dysplasia
•  Gardner syndrome
Cleidocranial dysplasia,
Runx2, AD, 6p21
Gardner syndrome
Familial adenomatous polyposis , APC,
negative regulator of Wnt, AD, 5q21-q22
several well-defined opacities around the periphery of the mandible
Gardner's syndrome - a case report. Payne M, Anderson JA, Cook J. Br Dent J.
2002 Oct 12;193(7):383-4.
Nance-Horan syndrome, NHS, Xp22.13
•  X-linked cataract with dental anomalies
•  Number
–  Supernumerary
–  Agenesis
•  Shape
–  Inc screwdriver-shaped, tapering
–  Cingular cusps
–  Premolars, molars rounded
–  Taurodontism, wide pulp chambers
•  Eruption, Impacted teeth
Abnormalities of tooth shape
•  Double formation
•  0.14-3%
•  0.2%
• KBG
Abnormalities of tooth shape
•  Talon cusp (T cingulum)
•  OFDII, Rubinstein Taybi syndromes
Tooth shape/size anomalies
•  Dens invaginatus, dens in dente
•  0.25-10%, 12 or 22 6-10%, bilateral
43%
•  Dens invaginatus and deafness
•  Taurodontism, microdontia and dens
invaginatus
•  Postaxial polydactyly-dental vertebral
syndrome
Taurodontism
•  Enlarged body of the tooth
Reduced length of the root
•  Taurodontism, oligodontia,
sparse hair syndrome
•  Trichodento-osseous
syndrome
•  Ackerman syndrome
•  Sauk Delaney syndrome
•  Klinefelter syndrome
Klinefelter syndrome XXY
Case report: Macrodont mandibular second premolars, a hereditary dental anomaly.
Kyriazidou A, Haider D, Mason C, Parekh S, Bloch-Zupan A.
Eur Arch Paediatr Dent. 2013 Jun 5.
Ekman-Westborg and
Julin syndrome
Multiple macrodontic multituberculism. Benjamin MR, Rodrigo FS, Gorlin RJ. Am
J Med Genet A. 2003 Jul 15;120A(2):283-5.
Otodental syndrome
• 
• 
• 
• 
• 
Sensorineural hearing loss
Large globe shaped molars (globodontia)
Supernumerary microdont teeth
Taurodontism
Delayed development and eruption
Oto-dental pedigrees
UK
Belgium
Brazil
SNP genome scanning localizes
oto-dental syndrome to
chromosome 11q13 and
microdeletions at this locus
implicate FGF3 in dental and
inner-ear disease and FADD in
ocular coloboma.
Gregory-Evans CY, Moosajee M,
Hodges MD, Mackay DS, Game
L, Vargesson N, Bloch-Zupan A,
Rüschendorf F, Santos-Pinto L,
Wackens G, Gregory-Evans K.
Hum Mol Genet. 2007 Oct
15;16(20):2482-93.
Otodental syndrome.
Bloch-Zupan A,
Goodman JR.
Orphanet J Rare Dis.
2006 Mar 21;1:5.
Review.
Abnormalities of tooth
structure/Dentin
•  Dentinogenesis imperfecta with or
without progressive hearing loss, DSPP
•  Osteogenesis imperfecta, with
dentinogenesis imperfecta COL1A1,
COL1A2, CRTAP, LEPRE1,
SERPINF1, SERPINH1, SP7, OSX …
–  Type I (B) and (C) 10%
–  Type III 50%
–  Type IV 80%
OI
Dentin dysplasia type I (short roots), AD
Dentin dysplasia type II, AD
Kantaputra P, Tanpaiboon P, Porntaveetus T,Ohazama A, Sharpe P, Rauch A, Hussadaloy
A, Thiel CT. 2011. The smallest teeth in the world are caused by mutations in the PCNT gene.
Am J Med Genet Part A 9999A: 1–6.
Goldblatt syndrome: #184260
SPONDYLOMETAPHYSEAL DYSPLASIA WITH DENTINOGENESIS IMPERFECTA – Short stature, narrow thorax, pectus carinatum, Joint
hyperextensibility, mesomelia
48
Gorlin Collection. Ehlers Danlos syndrome.
Type VII (dermatosparaxis). Patient at 12 years.
Oral cavity showing prolapse of lips and
discolored permanent teeth.
ADAMTS2, procollagen protease, AR , 5q35.3
49
Gorlin Collection. Ehlers Danlos syndrome.
Type VII (dermatosparaxis). Patient at 12 years.
Oral cavity showing prolapse of lips and
discolored permanent teeth.
ADAMTS2, procollagen protease, AR , 5q35.3
Amelogenesis imperfecta Hypoplasia
Hypomineralised
Hypomature
From: J Dent Res. 2010 October; 89(10): 1024–1038.
doi: 10.1177/0022034510375829
Copyright/License ►
<< Prev
Figure 8.
Next >>
Amelogenesis and proteins
Request permission to reuse
Figure 8.
AMELX
ENAM
MMP20
KLK4
WDR72
FAM83H
DLX3
FAM20A
TP63
CNNM4
ROGDI
C4orf26
SLC24A4
Xp22.3-p22.1
4q21
11q22.3-q23
19q13.3-q13.4
15q21.3
8q24.3
17q21.3-q22
17q24.2
3q27-q29
2q11.2
16p13.3
4q21.1
14q32.12
LAMB3
1q32
Major activities of maturation stage ameloblasts. (A) Calcium (Ca2+) and phosphate
(H2PO4- and HPO42-) ions are transported and add to the width and thickness of existing
calcium hydroxyapatite crystals generating hydrogen ions (H+). (B) Enamel proteins are
cleaved by kallikrein (KLK4) and reabsorbed into the cells, possibly with the assistance of
WDR72. (C) Magnesium ions (Mg2+) are potentially removed from the matrix by
CNNM4. (D) Carbonic anhydrase II (CA2) catalyzes the combination of carbon dioxide
(CO2) and water (H2O) to form a bicarbonate ion (HCO3-) and a hydrogen ion. The H+ is
removed from the cell, possibly by the action of a sodium (Na+) and hydrogen ion
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086535/figure/fig8-0022034510375829/
Regulation of dental enamel shape and hardness.
Simmer JP, Papagerakis P, Smith CE, Fisher DC, Rountrey AN, Zheng L, Hu JC.
J Dent Res. 2010 Oct;89(10):1024-38.
Page 1 sur 2
Amelogenin, X-linked
Enamelin
Matrix metalloprotéinase 20
Kallikreine 4
WD repeat domain 72
Family with sequence similarity 83 member H
Distalless Homeobox 3
Family with sequence similarity 20 member A
Transformation-related protein 63
Cyclin M4
Rogdi homolog (Drosophila)
Chromosome 4 open reading frame 26
Potassium dependent sodium/calcium
exchanger
A subunit of Laminin-5
AMEL
X
AI
hypoplasia
- Thin enamel
Rough surface
- Pits
- Stripes
- Normal and abnormal enamel
- Banding pattern
- Normal Dentine
- Deletions and Mutations in the
signal peptide coding region
J Dent Res. 2004 May;83(5):378-83. Amelogenin p.M1T
and p.W4S mutations underlying hypoplastic X-linked
amelogenesis imperfecta.Kim JW, Simmer JP, Hu YY,
Lin BP, Boyd C, Wright JT, Yamada CJ, Rayes SK,
Feigal RJ, Hu JC.
Am J Med Genet A. 2009 Aug;149A(8):1698-705. A large X-chromosomal deletion is associated
with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI).Hobson
GM, Gibson CW, Aragon M, Yuan ZA, Davis-Williams A, Banser L, Kirkham J, Brook AH.
• 
deletion encompassing the entire AMELX gene, female patient
MMP20 Homozygous mutation c.389C>T
444C>T ; c.389C>T ; p.T130I
Homozygous and compound heterozygous MMP20 mutations in
amelogenesis imperfecta.
Gasse B, Karayigit E, Mathieu E, Jung S, Garret A, Huckert M, Morkmued
S, Schneider C, Vidal L, Hemmerlé J, Sire JY, Bloch-Zupan A.
J Dent Res. 2013 Jul;92(7):598-603.
Homozygous and compound heterozygous MMP20 mutations in
amelogenesis imperfecta.
Gasse B, Karayigit E, Mathieu E, Jung S, Garret A, Huckert M, Morkmued
S, Schneider C, Vidal L, Hemmerlé J, Sire JY, Bloch-Zupan A.
J Dent Res. 2013 Jul;92(7):598-603.
A: Normal enamel in a control tooth
showing characteristic HunterSchreger bands.
B: AI enamel of the first upper molar
from the hypoplastic area. The
darker layer corresponds to prenatal
enamel.
C: Enlargement of the prenatal
enamel from the darker area in B. D:
Enlargement of the postnatal enamel
from the darker area in B.
E: Enamel crystal alignment within
the enamel rods of the control tooth.
F: Enamel crystal perpendicular
direction within the rods in the AI
tooth.
G: Presence of inter-rod enamel in
the normal tooth.
H: Absence or loss of interprismatic
enamel in the AI tooth.
Scale bars: A,B: 500 µm; C-H: 20 µm.
Homozygous and compound heterozygous MMP20 mutations in
amelogenesis imperfecta.
Gasse B, Karayigit E, Mathieu E, Jung S, Garret A, Huckert M, Morkmued
S, Schneider C, Vidal L, Hemmerlé J, Sire JY, Bloch-Zupan A.
J Dent Res. 2013 Jul;92(7):598-603.
An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta.
Michaelides M, Bloch-Zupan A, Holder GE, Hunt DM, Moore AT.
J Med Genet. 2004 Jun;41(6):468-73.
Mutations in CNNM4 cause Jalili
syndrome, consisting of autosomalrecessive cone-rod dystrophy and
amelogenesis imperfecta.
Parry DA, Mighell AJ, El-Sayed W,
Shore RC, Jalili IK, Dollfus H, BlochZupan A, Carlos R, Carr IM, Downey
LM, Blain KM, Mansfield DC,
Shahrabi M, Heidari M, Aref P, Abbasi
M, Michaelides M, Moore AT, Kirkham
J, Inglehearn CF.
Am J Hum Genet. 2009 Feb;84(2):
266-73.
AI and nephrocalcinosis
Dr Marie-Claude ADDOR, Service de Génétique Médicale, CH-1011 CHUV Lausanne
• 
• 
• 
Nephrocalcinosis (enamel renal
syndrome) caused by autosomal
recessive FAM20A mutations.
Jaureguiberry G, De la Dure-Molla
M, Parry D, Quentric M, Himmerkus
N, Koike T, Poulter J, Klootwijk E,
Robinette SL, Howie AJ, Patel V,
Figueres ML, Stanescu HC, Issler N,
Nicholson JK, Bockenhauer D, Laing
C, Walsh SB, McCredie DA, Povey
S, Asselin A, Picard A, Coulomb A,
Medlar AJ, Bailleul-Forestier I,
Verloes A, Le Caignec C, Roussey
G, Guiol J, Isidor B, Logan C, Shore
R, Johnson C, Inglehearn C, AlBahlani S, Schmittbuhl M, Clauss F,
Huckert M, Laugel V, Ginglinger E,
Pajarola S, Spartà G, Bartholdi D,
Rauch A, Addor MC, Yamaguti PM,
Safatle HP, Acevedo AC, MartelliJúnior H, dos Santos Netos PE,
Coletta RD, Gruessel S, Sandmann
C, Ruehmann D, Langman CB,
Scheinman SJ, Ozdemir-Ozenen D,
Hart TC, Hart PS, Neugebauer U,
Schlatter E, Houillier P, Gahl WA,
Vikkula M, Bloch-Zupan A, Bleich
M, Kitagawa H, Unwin RJ, Mighell A,
Berdal A, Kleta R.
Nephron Physiol. 2012;122(1-2):1-6.
Epileptic encephalopathy and amelogenesis imperfecta
(Kohlschütter-Tönz syndrome)
ROGDI on chromosome 16p13.3
Schossig-Zschocke AJHG 2012
Tuberous sclerosis, TSC1 9q34,
TSC2 16p13.3, AD
Tooth eruption/resorption anomalies
Pycnodysostosis CTSK
cathepsin K, AR, 1q21
Short stature
Deformity of the
skull (including
wide sutures),
maxilla and
phalanges
(acroosteolysis),
osteosclerosis, and
fragility of bone
Micrognathia
Narrow palate
Delayed eruption of
deciduous teeth
Persistence of
deciduous teeth
Delayed eruption of
permanent teeth
Hypodontia
Caries, enamel
hypoplasia
Primary failure of tooth eruption,
PTHR1, parathyroid hormone
receptor-1 gene, AD, 3p22-p21.1
- Hypodontia
- Posterior
openbite
- Ankylosis of
deciduous teeth
- No responsive
to orthodontic
treatment
Keratinisation defect
•  Papillon Lefevre syndrome
•  #245000 – 11q14.1-q14.3 – Cathepsin C
Homozygous for the R272P mutation
likely to cause a problem in protein folding
parents are heterozygous for the same mutation
Hypophosphatasia
ALPL
Childhood form
- Mutation A 159T (c.526G>A),
heterozygous, from paternal
origin, moderate forms
- Mutation c.648+1G>A,
heterozygous, from maternal
origin, severe forms
Orodental phenotype and genotype findings in all subtypes of hypophosphatasia.
Reibel A, Manière MC, Clauss F, Droz D, Alembik Y, Mornet E, Bloch-Zupan A.
Orphanet J Rare Dis. 2009
Hypophosphatasia ALPL, Infantile form
Familial expansile osteolysis
TNFRSF11A, RANK, AD 18q21.1-22
Genodermatosis/Cancer
Gorlin syndrome
•  #109400 – 9q31, 9q22.3 - PTCH
Quality of care
• 
• 
• 
• 
• 
• 
• 
Multidisciplinary teams
Baby to Adults
Prevention
Evidence based dentistry
Guidelines
Chair side management and
care to general anaesthesia or
conscious sedation
Partnership with local treating
dental practitioners
http://mediad4.u-strasbg.fr/register.php
IGBMC
Virginie LAUGEL, Marie PASCHAKI, Julia MARRIE, Arnaud LANGER, Pascal DOLLE
André HANAUER, Raymond RIPP, Guillaume BERTHOMMIER, Olivier POURQUIE
La plate-forme technologie: Biopuces Christelle THIBAULT
La plateforme de Bioinformatique Intégrative et Génomique Jean MULLER, Olivier POCH
ICS C. PILGRAM, J.L. MANDEL, T SORG, P. CHAMBON, S MULLER, Y HERAULT
ICH, UCL Patrizzia FERRETTI, Patimaporn PUNGCHANCHAIKUL
Collaborations
Hélène DOLLFUS, Corinne STOETZEL, Mégana PRASAD, Mathilde HUCKERT,
Laboratoire de génétique médicale, INSERM-UMR 1112, Université de Strasbourg Faculté de Médecine
Uwe STRAHLE, Cristelle ETARD Karlsruher Institut für Technologie (KIT), Institut für Toxikologie und Genetik (ITG), Germany
Jean Yves SIRE, Research group "Evolution & Développement du Squelette-EDS", UMR 7138-SAE, Université
Pierre et Marie Curie, Paris, France
Ann HUYSSEUNE, Université de Ghent, Belgique
HUS – API - PHRC 2008-2013 Amélogenèse imparfaite
Centre de référence des manifestations odontologiques des maladies rares
Marie Cécile MANIÈRE, François CLAUSS, Sébastien TROESTER, Marzena SWITALA, Elodie FEISTHAMMEL
Service de Biophysique et Médecine Nucléaire
P. CHOQUET, A. CONSTANTINESCO
Service de génétique médicale
Hélène DOLLFUS
DRC Hélène KUISSU, Naoual YAHMI
Egide PHC France KKU Thaïlande Patimaporn PUNGCHANCHAIKUL, Morkmued SUPAWICH
IFRO Institut Français de Recherche en Odontologie
INTERREG, Offensive Sciences A27, Orodental manifestations of rare diseases, Vanessa STOEHR, Ute Moog, Anna
WOLFF, Unikinikum Heidelberg, Stéphanie FEIERABEND, Uniklinikum Freiburg
Fondation maladies rares
Région Alsace, Ministerium für
Wissenschaft, Forschung und
Kunst Baden Württemberg,
Ministerium für Bildung,
Wissenschaft, Weiterbildung und
Kultur des Landes RheinlandPfalz, Université de Strasbourg,
Hôpitaux Universitaires de
Strasbourg, CERBM – IGBMC,
EA3949 - Laboratoire de
Génétique Médicale,
Universitätsklinikum Freiburg,
Universität Heidelberg,
Hypophosphatasie Europe,
O b e r r h e i n i s c h e
Zahnärtztegesellschaft
[email protected]