Genetic aspects of craniofacial disorders Craniofacial disorders n nmay 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 nThe role of genetic counseling is necessary in the diagnostic process with respect to possible recurrence n Disorders of teeth, jaws and periodontium ANd9GcQanZr4wL23vSseYIrt09Zil2f-0SUWN87cXZzxUWkZe2-Hy0-FxmQOTw Teeth nNumerous defects of the teeth v vHypodontia/oligodontia vHyperodontia n Hypodontia nis the condition at which the patient has missing teeth as a result of their failure to develop. nMost common anomaly of human dentition in a population n vHypodontia: 1-6 missing teeth vOligodontia: more then 6 missing teeth vanodontia : missing all teeth- rare Hypodontia- prevalence nIn 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. nThe 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%. n30-50% of people with missing primary teeth will have missing permanent teeth, as well. n n Hypodontia-etiology n nAmong the possible causes are genetic, hormonal, environmental and infectious factors during dental development. nmissing teeth have been reported in association with increased maternal age, low birth weight, infection during embryonic life nHypodontia 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. nEtiology due to hormonal defects: idiopathic hypoparathyroidism and pseudohypoparathyroidism. nEnvironmental causes involving exposure to PCBs (ex.dioxin), radiation,anticancer chemotherapeutic agents, allergy and toxic epidermal necrolysis after drugs. n Genetic causes of hypodontia nisolated nSeveral genes are known in assotiation nPAX9(14q12),MSX1(4p16), WNT10A(2q35), nAXIN2(17q24.1) (ovarian and CRC cancer susceptibility) nInheritance: autosomal dominant or recesive(rare) nIRF6(1q32.3),TGFA(2p13),FGFR1(8p11.23), nEDA(Xq13.1),EDARADD(1q42),LTBP3(11q13.1), nsyndromic nEctodermal dysplasia nOrofaciodigital syndrome,etc. n Ectodermal dysplasia nthere 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. nmore than 150 different syndromes have been identified nEctodermal dysplasia,anhidrotic n hypotrichosis, fine-brittle-scanty hair, absent or scanty eyelashes,eyebrows, hypodontia /anodontia, hypoplastic or absent mucous glands n danger of overheating nGenetic heterogenity XR, AR,AD nHeterozygous females show variable expressivity (mild n manifestations) including hypodontia, conical teeth, reduction in scalp/body hair nGenes: EDA, EDAR, EDARADD Hyperodontia nHyperdontia is the condition of having supernumerary teeth, or teeth which appear in addition to the regular number of teeth. n nSupernumerary 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. n nThe most common supernumerary tooth is a mesiodens, which is a mal-formed, peg-like tooth that occurs between the maxillary central incisors. nFourth and fifth molars that form behind the third molars are another kind of supernumerary teeth. n n Hyperodontia-causes nthere is evidence of hereditary factors along with some evidence of environmental factors leading to this condition-multifactorial inheritance n nMany 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. n nSupernumerary teeth in deciduous (baby) teeth are less common than in permanent teeth. n nHyperdontia is seen in a number of genetic disorders, including Cleidocranial dysostosis or Gardner´s syndrome n n n Cleidocranial dysplasia npersistently 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 nOccurence 1:100 000 nInheritence AD,variable expressivity nLocation 6p21, gene CBFA1(RUNX2) nOne third of patients represent new mutations Cleidocranial dysplasia-unfavorable effects n n18% scoliosis n28% coxa vara, coxa valga n57% pedes plani n34% inflammation of the paranasal sinuses frequently n70% oral disorders n19% difficulty breathing n39% deafness Cleidocranial dysplasia- oral symptoms nCleft palate(submucous ) Narrow, high-arched palate nDelayed eruption of deciduous teeth Delayed eruption of permanent teeth Supernumerary teeth Retention cysts Enamel hypoplasia nDelayed closure mandibular symphysis, prognathia relative-normal mandibular growth and limited growth of praemaxila Teeth- disorders of enamel namelogenesis imperfecta -presents with abnormal formation of the enamel or external layer of teeth. n inheritance: AD, AR, X-linked nSyndromic association (trichodentoosseous syndrome – TDO-AD, Kohlschutter syndrome –AR -epilepsy,mental retardation,amelogenesis imp.) nNon-genetic forms abnormal enamel (fluorosis, the use of tetracycline antibiotics,etc) Teeth- dentin disorders nDentinogenesis imperfecta vNon-syndromic AD inheritence v syndromic assotiation-diffrent forms of osteogenesis imperfecta- brittle bone disease, defective connective tissues(AD,AR, defects of collagen I)- COL1A1,COL1A2 genes vDisorders of dentin in number of systemic diseases associated with impaired metabolism of calcium and phosphate n (eg. Hypophosphatemic rickets ,hypoparathyroidism etc) Teeth nCaries- multifactorial, interaction between environmental and genetic factors - n susceptibility of tooth tissue, composition of oral microflora, eating habits, oral hygiene Periodontal diseases nFrequent cause of tooth loss nMultifactorial nSyndromic assotiation nPapillon-Lefévre syndrome vInheritence autosomal recessive voccurence 1-4/1 000 000 vKeratosis palmoplantaris vperiodontopathia Anomalies of jaws nPrognathia(excessive growth of maxilla) affects about 14% population, multifactorial probably, with high correlation between siblings. n nProgenia(excessive growth of mandibula, often in all three dimensions) n affects 3-9% population n polygenic (multifaktorial) n familial cases with AD inherritence have been reported(the best known is the case of the Habsburgs) n Facial cleft defects Zobrazit obrázek v plné velikosti Cleft lip and palate-CLP n n nCL- incidence : 1/500-1/1000 n nCP- incidence: 1/2500 Cleft defects-clasification nclefts typical lip (cheiloschisis) lip + palate (cheilognathoschisis) palate-isolated(palatoschisis) total (cheilognathopalatoschisis). nclefts 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). n Facial clefts -pathogenesis n nCleft lip and palate: failure of fusion of the maxillary and medial nasal processes (formation of the primary palate). n nCleft palate: failure of fusion of the lateral palatine processes, the nasal septum, and/or the median palatine processes n (formation of the secondary palate) Cleft lip and palate- cause nMultifactorial with significant inheritance component nEnviromental factors: viruses , toxoplasmosis, CMV,hypervitaminosis A + D, ATB(tetracyclines, erythromycine), AEDs, corticoids, X-ray, drugs, organic solvents ,other teratogens nCongenital chromosomal aberration nSyndromes asociated with CL/CP/CLP n Cleft lip and palate-ethnic differences n nmost common in Caucasians and Japanese nleast frequently in Negroid race n Cleft lip and palate- empiric risks(Harper) Empirical risk according to severity of defect n nDefect risk for sibs nBilateral CLP 5,7 % n nUnilateral CLP 4,2 % n nUnilateral CL 2,5 % Chromosomal aberration associated with CLP/CP ntrisomy 13 ntrisomy 18 nStructural aberrations autosomes nvelocardiofacial syndrome 22q11microdeletion syndrome Patau syndrome n47,XX(XY), +13 n1 in 5000-10 000 newborns, n1 in 90 SA n nCLP bilateral, congenital defects of the brain, eyes, postaxial hexadaktyly…) Edwards syndrome n47,XX(XY),+18 n1in 5000 newborns nIUGR nmicrocephaly ndolichocephaly nCP nrethrognathia n Wolf-Hirschhorn syndrome, 4p- n1:50 000 n8% de novo deletion n13% due to familial translocation nF:M 2:1 n nsymptoms n-dwarfism n-microcefaly, craniofacial stigmatisation n- CL,CP,CLP n-heart defects n image004 Di George syndrome – velocardiofacial n nMicrodeletion 22q11 n nSymptoms: n - heart defects n - facial stigmatisation n - CP( submucous too) n - hypoplasia of thymus and parathyroids) n ( immunodefects, hypocalcemia) n n n n n Fig6-28 Syndromes without Mendelian inheritance n nPierre-Robin sequence -Mandibular hypoplasia -Glossoptosis -Cleft of palate n n nMay be part of a variety of n skeletal or muscular syndromes, nsome mendelian (e.g. Stickler sy, nCongenital myotonic dystrophy) AD hereditary syndromes with CLP n nvan der Woude syndrome n EEC syndrome n Stickler syndrome n Larsen syndrome n van der Woude syndrome n -Autosomal dominant, incomplet penetrance n variable expressivity !!! n -Mouth lower lip pits -Cleft lip -Cleft palate -Cleft uvula -Hypodontia -Molecular Basis - caused by mutations in the interferon regulatory factor 6 gene (IRF6) n- EEC syndrome n-Ectrodaktyly-deformities of hands and feet n-Ectodermal dysplasia-skin ,hair,nails n-Cleft lip/palate n-other defects-kidneys,eyes,teeth nGenetic heterogenity nTwo loci described – EEC1(7q11) n and EEC3 (3q28) nMajority of EEC cases appear to be nto TP63 mutations n n Stickler syndrome n nIncidence 1 in 10 000 nMutation in COL11A1,COL11A2,COL2A1 genes nSymptoms n-Pierre-Robin sequence n-eye:glaucoma,cataracts, retinal detachment n-sensorineural hearing loss n-artropathy, scoliosis,mitral valve prolaps Larsen syndrome nIncidence 1 in 100 000 nCaused by mutation in the nfilamin B gene (FLNB)-3p14.3 n nMultiple joint dislocation nDeformities of feet nFacial stigmatisation nOthers: dwarfism, skeletal defects , heart defects, CP, deafness, mental retardation n nRare AR inheritance AR hereditary syndromes with CLP nFryns syndrome nRoberts syndrome( pseudothalidomid) nDiastrophic dysplasia nSmith-Lemli-Opitz syndrome nOrofaciodigital syndrome II nMeckel-Gruber syndrome n n Fryns syndrome - -Diaphragmatic hernia -Abnormal face, and distal limb anomalies -Cleft lip/palate Roberts syndrome nPseudothalidomid 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 n- dwarfism, adult high 100-120 cm n-short limbs n-short, thick tubular bone, with n broad metaphyses and flattened, n irregular epiphyses n-cleft palate n-ear abnormalities n-joint deformities n-hip contractures n-hands deformities(„ hitchhiker thumb“) n-vertebral deformities nSLC26A2 gene (5q32) - Smith-Lemli-Opitz syndrome -pre- and postnatal growth deficiency -Microcephaly -Facial stigmatisation -Cleft palate -Mental retardation -Hypospadias,ambiguous genitalia,micropenis -Syndaktyly of second and third toes of feet -Mutation in DHCR gene, locus 11q12-q13 -low cholesterol,elevated 7-dehydrocholesterol Orofaciodigital syndrome, type II n nMohr syndrome -Medial cleft of upper lip -micrognathia -Cleft and lobation of tongue, -hypertelorism -Bilateral postaxial hexadactyly of hands, bilateral polysyndaktyly of hallux n Meckel-Gruber syndrome -microcephaly, encephalocele -Microphtalmia -Cleft lip and/or palate -Congenital defect of heart -Postaxial polydactyly -Polycystic kidneys nA lethal disorder, with death occuring in the perinatal period nHeterogenity:loc.17q21-24,11q13 and 8q24 n n X-linked hereditary syndromes with CLP nOrofaciodigital syndrome, type I nOtopalatodigital syndrome nIsolated X-linked cleft of palate with ankyloglossia Orofaciodigial syndrome,type I nPapillon-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 nType 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 nType II n- + other multiple skeletal anomalies n n n Cleft palate and ankyloglossia n n X-linked inheritance n- Cleft of uvula- heterozygot female n- Incomplet cleft of palate n- Incompetention of palate n- ankyloglossia n n n Craniosynostoses metopic-craniosynostosis Craniosynostoses nPremature closing of cranial sutures nThis early fusion affects the shape of the head and face. ndifferent patterns of growth of the skull include: ntrigonocephaly (fusion of the metopic suture), nbrachycephaly (fusion of the coronal suture) ndolichocephaly (fusion of the sagittal suture) nplagiocephaly (unilateral premature closure of lambdoid and coronal sutures) nturicephaly(fusion of coronal and lambdoidal sutures) n Craniosynostoses nHeterogenous group etiologically and pathogenetically nIsolated or part of syndrome units n nSyndromic- AD inheritance in most case n n Apert syndrome nAD inheritance nturribrachycephaly nHypoplasia of the central part of the face, nMental defect- varying degree( also normal intelligence) nGlove-like asymetrical fusion of fingers and toes nMutation in FGFR2 gene Crouzon syndrome nAD inheritance nCraniosynostosis of coronal,sagital and lambdoid sutures n parrot-like nose n hypoplastic maxilla n exoftalmus, shallow orbits nimpressiones gyrorum nMutations in FGFR2 and FGFR3 gene n Pfeiffer syndrome nAD inheritance nBrachycephaly,plagiocephaly nHypoplasia of medial part of face nExophtalmus n skin syndactyly of fingers nMedial deviation of thumbs nMutation in FGFR1 gene Seathre-Chotzen syndrome nAD inheritance nBrachycephaly nHypoplastic maxilla nFacial asymetry nSyndactyly, hallux valgus, brachydactyly nMutation in TWIST gene Carpenter syndrome nAR inheritance nBrachycephaly nMidface hypopalsia nhypertelorism, flat nasal bridge nObesity nMental retardation nBrachydactyly, postaxial polydactyly, clinodaltyly, syndaktyly, camptodactyly nLocus 6p11 Craniofacial syndromes OK_Oblicej Goldenhar syndrome nHypoplastic face( often unilateral) nColobomas of upper eyelids nEpibulbar dermoids nRudimentary auricles nAccesory auricular apendages n macrostomia nVertebral anomalies nInheritance : polygenic, AD, AR n Treacher Collins syndrome nAntimongoloid slant of palpebral fissures n colobomas of the lower eyelids, nPartial absence of lower eyelashes n macrostomia, microgenia, n rudimentary auricles,conductive hearing loss n inheritance AD, with variable expressivity nTCOF1 gene(5q32) n Hallermann-Streiff syndrome nOculomandibulodyscrania nDyscrania with hypotrichosis nAnomalies of the face , especially of the eye(microftalmia, colobomas, strabism catharacta) nDental anomalies- congenital teeth, supernumerary teeth, maloclusion etc. nSomatic retardation nAD,AR,heterogenia, sporadic in most case Orofaciodigital syndrome nDysmorphic face nOral symptoms( CLP, hyperplastic fraenulum,multiply lobulated tongue) nDigital anomalies( brachydacktyly,syndactyly,polydactyly, n clinodactyly) nHeterogenia, 8 types nType I : XD nType II-VI: AR nTyp VIII: XR nTyp VII: AD/XD n Oculodentodigital syndrome nnarrow nose with hypoplastic wings and thin nostrils, n microcornea with iridial anomalies, n syndactyly and/or camptodaktyly of postaxial digits, hypoplastic/aplastic middle phalanx of the fith toe nHypoplasia of enamel nInheritance AD, with as much 50%of the cases on the basis of new mutations Frontonasal dysplasia nMedian cleft face syndrome nHypertelorism nbrachycephaly, prominent forehead wit a broad ridge of nose nSagitally lined up to cleft nose(often frontal cranium bifidum occultum and/or medial cleft of the face) nWidely opened fontanelle,sutura metopica ,synostosis of coronal sutures nFacial asymetry, high palate, diastematous teeth. n Sporadic mostly, both AD or AR inheritance has been reported nPrevalence of female 6:1.