Genetic aspects of
craniofacial disorders
Craniofacial disorders
 may be accompanied by considerable
discomfort and stress on the side of the
patient,because it may be associated with
a noticeable cosmetic problem,which is
individually perceived
 The role of genetic counseling is
necessary in the diagnostic process with
respect to possible recurrence
Disorders of teeth, jaws and
periodontium
Teeth
 Numerous defects of the teeth
 Hypodontia/oligodontia
 Hyperodontia
Hypodontia
 is the condition at which the patient has missing
teeth as a result of their failure to develop.
 Most common anomaly of human dentition in a
population
 Hypodontia: 1-6 missing teeth
 Oligodontia: more then 6 missing teeth
 anodontia : missing all teeth- rare
Hypodontia- prevalence
 In caucasians, the most common missing teeth are the
wisdom teeth (25-35%), the upper lateral incisors (20%)
,the lower or the upper second premolars (30%), with a
4:1 female to male ratio.
 The prevalence of missing primary teeth is found at 0,1-
0,9%, with a 1:1 male to female ratio. Excluding the
third molars, missing permanent dentition accounts for
3-6%.
 30-50% of people with missing primary teeth will have
missing permanent teeth, as well.
Hypodontia-etiology
 Among the possible causes are genetic, hormonal, environmental
and infectious factors during dental development.
 missing teeth have been reported in association with increased
maternal age, low birth weight, infection during embryonic life
 Hypodontia can be associated with genetic disorders such as
ectodermal dysplasia or Down syndrome and can also been seen in
people with cleft lip and palate.
 Etiology due to hormonal defects: idiopathic hypoparathyroidism
and pseudohypoparathyroidism.
 Environmental causes involving exposure to PCBs (ex.dioxin),
radiation,anticancer chemotherapeutic agents, allergy and toxic
epidermal necrolysis after drugs.
Genetic causes of hypodontia
 isolated
Several genes are known in assotiation
PAX9(14q12),MSX1(4p16), WNT10A(2q35),
AXIN2(17q24.1) (ovarian and CRC cancer susceptibility)
Inheritance: autosomal dominant or recesive(rare)
 syndromic
Ectodermal dysplasia
Orofaciodigital syndrome,etc.
IRF6(1q32.3),TGFA(2p13),FGFR1(8p11.23),
EDA(Xq13.1),EDARADD(1q42),LTBP3(11q13.1),
Ectodermal dysplasia
 there are abnormalities of two or more ectodermal structures such
as the hair, teeth, nails, sweat glands, cranial-facial structure, digits
and other parts of the body.
 more than 150 different syndromes have been identified
 Ectodermal dysplasia,anhidrotic
hypotrichosis, fine-brittle-scanty hair, absent or scanty
eyelashes,eyebrows, hypodontia /anodontia, hypoplastic or absent
mucous glands
danger of overheating
 Genetic heterogenity XR, AR,AD
 Heterozygous females show variable expressivity (mild
manifestations) including hypodontia, conical teeth, reduction in
scalp/body hair
Genes: EDA, EDAR, EDARADD
Hyperodontia
 Hyperdontia is the condition of having supernumerary teeth, or
teeth which appear in addition to the regular number of teeth.
Supernumerary teeth can be classified by shape and by position.
• The atypical shapes include:supplemental tuberculate , conical ,
compound odontoma (multiple small tooth-like forms),complex
odontoma (a disorganized mass of dental tissue)
• By position a supernumerary tooth may be referred to as a
mesiodens, a paramolar, or a distomolar.
The most common supernumerary tooth is a mesiodens, which is a malformed,
peg-like tooth that occurs between the maxillary central incisors.
Fourth and fifth molars that form behind the third molars are another kind of
supernumerary teeth.
Hyperodontia-causes
 there is evidence of hereditary factors along with some evidence of
environmental factors leading to this condition-multifactorial
inheritance
 Many supernumerary teeth never erupt, but they may delay
eruption of nearby teeth or cause other dental or orthodontic
problems. Dental X-rays are often used to diagnose hyperdontia.
 Supernumerary teeth in deciduous (baby) teeth are less common
than in permanent teeth.
 Hyperdontia is seen in a number of genetic disorders, including
Cleidocranial dysostosis or Gardner´s syndrome
Cleidocranial dysplasia
 persistently open skull sutures with bulging
calvaria, hypoplasia or aplasia of the clavicles
permitting abnormal facility in opposing the
shoulders, wide pubic symphysis, short middle
phalanx of the fifth fingers, dental anomalies,
and often vertebral malformation
 Occurence 1:100 000
 Inheritence AD,variable expressivity
 Location 6p21, gene CBFA1(RUNX2)
 One third of patients represent new mutations
Cleidocranial dysplasiaunfavorable
effects
 18% scoliosis
 28% coxa vara, coxa valga
 57% pedes plani
 34% inflammation of the paranasal sinuses frequently
 70% oral disorders
 19% difficulty breathing
 39% deafness
Cleidocranial dysplasiaoral
symptoms
 Cleft palate(submucous )
Narrow, high-arched palate
 Delayed eruption of deciduous teeth
Delayed eruption of permanent teeth
Supernumerary teeth
Retention cysts
Enamel hypoplasia
 Delayed closure mandibular symphysis, prognathia
relative-normal mandibular growth and limited growth of
praemaxila
Teeth- disorders of enamel
 amelogenesis imperfecta -presents with
abnormal formation of the enamel or external
layer of teeth.
inheritance: AD, AR, X-linked
 Syndromic association (trichodentoosseous
syndrome – TDO-AD, Kohlschutter syndrome –
AR -epilepsy,mental retardation,amelogenesis
imp.)
 Non-genetic forms abnormal enamel (fluorosis,
the use of tetracycline antibiotics,etc)
Teeth- dentin disorders
 Dentinogenesis imperfecta
 Non-syndromic AD inheritence
 syndromic assotiation-diffrent forms of
osteogenesis imperfecta- brittle bone disease,
defective connective tissues(AD,AR, defects of
collagen I)- COL1A1,COL1A2 genes
 Disorders of dentin in number of systemic
diseases associated with impaired metabolism of
calcium and phosphate
(eg. Hypophosphatemic rickets
,hypoparathyroidism etc)
Teeth
 Caries- multifactorial, interaction between
environmental and genetic factors susceptibility
of tooth tissue, composition
of oral microflora, eating habits, oral
hygiene
Periodontal diseases
 Frequent cause of tooth loss
 Multifactorial
 Syndromic assotiation
Papillon-Lefévre syndrome
 Inheritence autosomal recessive
 Caused by mutation in the cathepsin C gene (CTSC,
11q14.2)
 occurence 1-4/1 000 000
 Keratosis palmoplantaris
 periodontopathia
Anomalies of jaws
 Prognathia(excessive growth of maxilla) affects about
14% population, multifactorial probably, with high
correlation between siblings.
 Progenia(excessive growth of mandibula, often in all
three dimensions)
affects 3-9% population
polygenic (multifaktorial)
familial cases with AD inherritence have been
reported(the best known is the case of the Habsburgs)
Facial cleft defects
Cleft lip and palate-CLP
 CL- incidence : 1/500-1/1000
 CP- incidence: 1/2500
Cleft defects-clasification
 clefts typical
lip (cheiloschisis)
lip + palate (cheilognathoschisis)
palate-isolated(palatoschisis)
total (cheilognathopalatoschisis).
 clefts atypical
Cross
upper middle (nose, upper lip, upper lip defect with defect of
praemaxilla)
lower middle (lower lip, lower lip + jaw)
oblique (lip + face, + faces of the lower lid, with cleft palate typical
+ atypical).
Facial clefts -pathogenesis
 Cleft lip and palate: failure of fusion of the
maxillary and medial nasal processes
(formation of the primary palate).
 Cleft palate: failure of fusion of the lateral
palatine processes, the nasal septum,
and/or the median palatine processes
(formation of the secondary palate)
Cleft lip and palate- cause
 Multifactorial with significant inheritance
component
Enviromental factors: viruses , toxoplasmosis,
CMV,hypervitaminosis A + D, ATB(tetracyclines,
erythromycine), AEDs, corticoids, X-ray, drugs, organic
solvents ,other teratogens
 Congenital chromosomal aberration
 Syndromes asociated with CL/CP/CLP
Cleft lip and palate-ethnic differences
 most common in Caucasians and
Japanese
 least frequently in Negroid race
Cleft lip and palate- empiric risks(Harper)
Relationship to index case CLP CP
Sibs (overall risk) 4% 1,8%
Sib (no other affected) 2.2%
Sib(2 affected sibs) 10% 8%
Sib and parent affected 10%
Children 4,3% 3%
Second-degree relatives 0,6%
Empirical risk according to severity of defect
Defect risk for sibs
Bilateral CLP 5,7 %
Unilateral CLP 4,2 %
Unilateral CL 2,5 %
Chromosomal aberration associated with
CLP/CP
 trisomy 13
 trisomy 18
 Structural aberrations autosomes
 velocardiofacial syndrome
22q11microdeletion syndrome
Patau syndrome
 47,XX(XY), +13
 1 in 5000-10 000
newborns,
 1 in 90 SA
 CLP bilateral,
congenital defects of
the brain, eyes,
postaxial
hexadaktyly…)
Edwards syndrome
 47,XX(XY),+18
 1in 5000 newborns
 IUGR
 microcephaly
 dolichocephaly
 CP
 rethrognathia
Wolf-Hirschhorn syndrome, 4p-
1:50 000
80% de novo deletion
13% due to familial translocation
F:M 2:1
symptoms
-dwarfism
-microcefaly, craniofacial stigmatisation
- CL,CP,CLP
-heart defects
Di George syndrome
– velocardiofacial
 Microdeletion 22q11
 Symptoms:
- heart defects
- facial stigmatisation
- CP( submucous too)
- hypoplasia of thymus and parathyroids)
( immunodefects, hypocalcemia)
Syndromes without Mendelian inheritance
 Pierre-Robin sequence
- Mandibular hypoplasia
- Glossoptosis
- Cleft of palate
May be part of a variety of
skeletal or muscular syndromes,
some mendelian (e.g. Stickler sy,
Congenital myotonic dystrophy)
AD hereditary syndromes with CLP
 van der Woude syndrome
 EEC syndrome
 Stickler syndrome
 Larsen syndrome
van der Woude syndrome
-Autosomal dominant, incomplet penetrance
variable expressivity !!!
-Mouth lower lip pits
-Cleft lip
-Cleft palate
-Cleft uvula
-Hypodontia
- Molecular Basis - caused by mutations in the
interferon regulatory factor 6 gene (IRF6)
EEC syndrome
-Ectrodaktyly-deformities of hands and feet
-Ectodermal dysplasia-skin ,hair,nails
-Cleft lip/palate
-other defects-kidneys,eyes,teeth
Genetic heterogenity
Two loci described – EEC1(7q11)
and EEC3 (3q28)
Majority of EEC cases appear to be
to TP63 mutations
Stickler syndrome
Incidence 1 in 10 000
Mutation in COL11A1,COL11A2,COL2A1 genes
Symptoms
-Pierre-Robin sequence
-eye:glaucoma,cataracts, retinal detachment
-sensorineural hearing loss
-artropathy, scoliosis,mitral valve prolaps
Larsen syndrome
Incidence 1 in 100 000
Caused by mutation in the
filamin B gene (FLNB)-3p14.3
Multiple joint dislocation
Deformities of feet
Facial stigmatisation
Others: dwarfism, skeletal defects , heart defects, CP,
deafness, mental retardation
Rare AR inheritance
AR hereditary syndromes with CLP
 Fryns syndrome
 Roberts syndrome( pseudothalidomid)
 Diastrophic dysplasia
 Smith-Lemli-Opitz syndrome
 Orofaciodigital syndrome II
 Meckel-Gruber syndrome
Fryns syndrome
- Diaphragmatic hernia
- Abnormal face, and distal limb anomalies
- Cleft lip/palate
Roberts syndrome
 Pseudothalidomid syndrome
- Pre-/postnatal growth deficiency
- Cleft lip/ palate( bilat.)
- cataracta
- Oligodactyly
- Phocomelia
- Radial hypoplasia
- Mental retardation
- Caused by mutations in ESCO2 gene (8p21)
Diastrophic dysplasia
- dwarfism, adult high 100-120 cm
-short limbs
-short, thick tubular bone, with
broad metaphyses and flattened,
irregular epiphyses
-cleft palate
-ear abnormalities
-joint deformities
-hip contractures
-hands deformities(„ hitchhiker thumb“)
-vertebral deformities
SLC26A2 gene (5q32)
Smith-Lemli-Opitz syndrome
- pre- and postnatal growth deficiency
- Microcephaly
- Facial stigmatisation
- Cleft palate
- Mental retardation
- Hypospadias,ambiguous genitalia,micropenis
- Syndactyly of second and third toes of feet
- Mutation in DHCR gene, locus 11q12-q13
- low cholesterol,elevated 7-dehydrocholesterol
Orofaciodigital syndrome, type II
 Mohr syndrome
- Medial cleft of upper lip
- micrognathia
- Cleft and lobation of tongue,
- hypertelorism
- Bilateral postaxial hexadactyly of hands,
bilateral polysyndaktyly of hallux
Meckel-Gruber syndrome
- microcephaly, encephalocele
- Microphtalmia
- Cleft lip and/or palate
- Congenital defect of heart
- Postaxial polydactyly
- Polycystic kidneys
A lethal disorder, with death occuring in the
perinatal period
Heterogenity:loc.17q21-24,11q13 and 8q24
X-linked hereditary syndromes with CLP
 Orofaciodigital syndrome, type I
 Otopalatodigital syndrome
 Isolated X-linked cleft of palate with
ankyloglossia
Orofaciodigial syndrome,type I
 Papillon-Léage-Psaume syndrome
- Hyperplasia of fraenulum
- Multiply lobulated tongue
- Hypoplasia of lateral nasal cartilages
- Medial pseudocleft of upper lip
- Asymetrical cleft of palate
- Variable malformation of digits
- Moderate mental retardation
Otopalatodigital syndrome
 Type I
- A characteristik face(prominent supraorbital arches, joined
eyebrows,antimongoloid position of eye slits, hypertelorism, a
broad and flat root of the nose)
- Cleft palate
- Conductive hearing loss
- Mental retardation
- Somatic retardation
 Type II
- + other multiple skeletal anomalies
Cleft palate and ankyloglossia
X-linked inheritance
- Cleft of uvula- heterozygot female
- Incomplet cleft of palate
- Incompetention of palate
- ankyloglossia
Craniosynostoses
Craniosynostoses
 Premature closing of cranial sutures
 This early fusion affects the shape of the head
and face.
 different patterns of growth of the skull include:
trigonocephaly (fusion of the metopic suture),
brachycephaly (fusion of the coronal suture)
dolichocephaly (fusion of the sagittal suture)
plagiocephaly (unilateral premature closure of lambdoid
and coronal sutures)
turicephaly(fusion of coronal and lambdoidal sutures)
Craniosynostoses
 Heterogenous group etiologically and
pathogenetically
 Isolated or part of syndrome units
 Syndromic- AD inheritance in most case
Apert syndrome
 AD inheritance
 turribrachycephaly
 Hypoplasia of the central part of the face,
 Mental defect- varying degree( also
normal intelligence)
 Glove-like asymetrical fusion of fingers
and toes
 Mutation in FGFR2 gene
Crouzon syndrome
 AD inheritance
 Craniosynostosis of coronal,sagital and
lambdoid sutures
 parrot-like nose
 hypoplastic maxilla
 exoftalmus, shallow orbits
 impressiones gyrorum
 Mutations in FGFR2 and FGFR3 gene
Pfeiffer syndrome
 AD inheritance
 Brachycephaly,plagiocephaly
 Hypoplasia of medial part of face
 Exophtalmus
 skin syndactyly of fingers
 Medial deviation of thumbs
 Mutation in FGFR1 gene
Seathre-Chotzen syndrome
 AD inheritance
 Brachycephaly
 Hypoplastic maxilla
 Facial asymetry
 Syndactyly, hallux valgus, brachydactyly
 Mutation in TWIST gene
Craniofacial syndromes
Carpenter syndrome
 AR inheritance
 Brachycephaly
 Midface hypopalsia
 hypertelorism, flat nasal bridge
 Obesity
 Mental retardation
 Brachydactyly, postaxial polydactyly, clinodaltyly,
syndaktyly, camptodactyly
 Locus 6p11
Goldenhar syndrome
 Hypoplastic face( often unilateral)
 Colobomas of upper eyelids
 Epibulbar dermoids
 Rudimentary auricles
 Accesory auricular apendages
 macrostomia
 Vertebral anomalies
 Inheritance : polygenic, AD, AR
Treacher Collins syndrome
 Antimongoloid slant of palpebral fissures
 colobomas of the lower eyelids,
 Partial absence of lower eyelashes
 macrostomia, microgenia,
 rudimentary auricles,conductive hearing
loss
 inheritance AD, with variable expressivity
 TCOF1 gene(5q32)
Hallermann-Streiff syndrome
Oculomandibulodyscrania
 Dyscrania with hypotrichosis
 Anomalies of the face , especially of the
eye(microftalmia, colobomas, strabism
catharacta)
 Dental anomalies- congenital teeth,
supernumerary teeth, maloclusion etc.
 Somatic retardation
 AD,AR,heterogenia, sporadic in most case
Orofaciodigital syndrome
 Dysmorphic face
 Oral symptoms( CLP, hyperplastic fraenulum,multiply
lobulated tongue)
 Digital anomalies( brachydacktyly,syndactyly,polydactyly,
clinodactyly)
 Heterogenia, 8 types
Type I : XD
Type II-VI: AR
Typ VIII: XR
Typ VII: AD/XD
Oculodentodigital syndrome
 narrow nose with hypoplastic wings and thin nostrils,
 microcornea with iridial anomalies,
 syndactyly and/or camptodaktyly of postaxial digits,
hypoplastic/aplastic middle phalanx of the fith toe
 Hypoplasia of enamel
 Inheritance AD, with as much 50%of the cases on the
basis of new mutations
Frontonasal dysplasia
 Median cleft face syndrome
 Hypertelorism
 brachycephaly, prominent forehead wit a broad ridge of
nose
 Sagitally lined up to cleft nose(often frontal cranium
bifidum occultum and/or medial cleft of the face)
 Widely opened fontanelle,sutura metopica ,synostosis of
coronal sutures
 Facial asymetry, high palate, diastematous teeth.
 Sporadic mostly, both AD or AR inheritance has been
reported
 Prevalence of female 6:1.