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Genetic aspects of craniofacial disorders

Explore the genetic aspects of craniofacial disorders such as hypodontia and hyperdontia, which affect teeth development. Understand the causes, prevalence, inheritance patterns, and associated syndromes, as well as the impacts on oral health and overall well-being.

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Genetic aspects of craniofacial disorders

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  1. Geneticaspectsofcraniofacialdisorders

  2. Craniofacialdisorders • maybeaccompanied by considerablediscomfortand stress on thesideofthepatient,becauseitmaybeassociatedwith a noticeablecosmeticproblem,whichisindividuallyperceived • The role ofgeneticcounselingisnecessary in thediagnosticprocesswithrespect to possiblerecurrence

  3. Disorders of teeth, jaws and periodontium

  4. Teeth • Numerousdefectsoftheteeth • Hypodontia/oligodontia • Hyperodontia

  5. 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

  6. Hypodontia- prevalence • In caucasians, the most common missing teeth are the wisdom teeth (25-35%), the upper lateral incisors (20%) ,the lower ortheuppersecond 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.

  7. Hypodontia-etiology • Among the possible causes are genetic, hormonal, environmental and infectiousfactorsduringdentaldevelopment. • 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 syndromeand 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.

  8. Geneticcausesofhypodontia • isolated Severalgenes are known in assotiation PAX9(14q12),MSX1(4p16), WNT10A(2q35), AXIN2(17q24.1) (ovarian and CRC cancer susceptibility) Inheritance: autosomal dominant orrecesive(rare) IRF6(1q32.3),TGFA(2p13),FGFR1(8p11.23), EDA(Xq13.1),EDARADD(1q42),LTBP3(11q13.1), • syndromic Ectodermaldysplasia Orofaciodigital syndrome,etc.

  9. Ectodermaldysplasia • 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 • Ectodermaldysplasia,anhidrotic hypotrichosis, fine-brittle-scantyhair, absentorscantyeyelashes,eyebrows, hypodontia /anodontia, hypoplasticorabsentmucousglands dangerofoverheating • 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

  10. 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 atypicalshapes include:supplemental tuberculate, conical, compoundodontoma (multiple small tooth-like forms),complexodontoma (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 mal-formed, 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.

  11. Hyperodontia-causes • there is evidence of hereditary factors along with some evidence of environmental factors leading to this condition-multifactorialinheritance • 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 geneticdisorders, including CleidocranialdysostosisorGardner´s syndrome

  12. Cleidocranialdysplasia • persistently open skullsutureswithbulgingcalvaria, hypoplasiaoraplasiaoftheclaviclespermittingabnormalfacility in opposingtheshoulders, widepubicsymphysis, shortmiddlephalanxofthefifthfingers, dentalanomalies, andoftenvertebralmalformation • Occurence 1:100 000 • Inheritence AD,variableexpressivity • Location 6p21, gene CBFA1(RUNX2) • One third of patients represent new mutations

  13. Cleidocranialdysplasia-unfavorableeffects • 18% scoliosis • 28% coxavara, coxavalga • 57% pedesplani • 34% inflammationoftheparanasalsinusesfrequently • 70% oral disorders • 19% difficultybreathing • 39% deafness

  14. Cleidocranialdysplasia- oral symptoms • Cleft palate(submucous )Narrow, high-arched palate • Delayed eruption of deciduous teethDelayed eruption of permanent teethSupernumerary teethRetention cystsEnamel hypoplasia • Delayedclosuremandibularsymphysis, prognathiarelative-normalmandibulargrowthand limited growthofpraemaxila

  15. Teeth- disordersofenamel • amelogenesisimperfecta -presents with abnormal formation of the enamel or external layer of teeth. inheritance: AD, AR, X-linked • Syndromicassociation (trichodentoosseous syndrome – TDO-AD, Kohlschutter syndrome –AR -epilepsy,mentalretardation,amelogenesisimp.) • Non-geneticformsabnormalenamel (fluorosis, the use oftetracyclineantibiotics,etc)

  16. Teeth- dentin disorders • Dentinogenesisimperfecta • Non-syndromic AD inheritence • syndromicassotiation-diffrentformsofosteogenesisimperfecta- brittle bone disease, defectiveconnectivetissues(AD,AR, defectsofcollagen I)- COL1A1,COL1A2 genes • Disordersof dentin in number of systemic diseases associated with impaired metabolism of calcium and phosphate (eg. Hypophosphatemicrickets ,hypoparathyroidismetc)

  17. Teeth • Caries- multifactorial, interaction between environmental and genetic factors - susceptibility oftoothtissue, compositionof oral microflora, eatinghabits, oral hygiene

  18. Periodontaldiseases • Frequent cause oftoothloss • Multifactorial • Syndromicassotiation Papillon-Lefévre syndrome • Inheritenceautosomalrecessive • occurence 1-4/1 000 000 • Keratosispalmoplantaris • periodontopathia

  19. Anomaliesofjaws • Prognathia(excessivegrowthofmaxilla) affectsabout 14% population, multifactorialprobably, withhighcorrelationbetweensiblings. • Progenia(excessivegrowthof mandibula, often in allthreedimensions) affects 3-9% population polygenic (multifaktorial) familialcaseswith AD inherritencehavebeenreported(the best known is the case of the Habsburgs)

  20. Facial cleft defects

  21. Cleft lip andpalate-CLP • CL- incidence : 1/500-1/1000 • CP- incidence: 1/2500

  22. Cleftdefects-clasification • clefts typicallip (cheiloschisis)lip + palate (cheilognathoschisis)palate-isolated(palatoschisis)total (cheilognathopalatoschisis). • clefts atypicalCrossupper 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).

  23. Facialclefts -pathogenesis • Cleft lip andpalate: failure of fusion of the maxillary and medial nasal processes (formation of the primary palate). • Cleftpalate: failure of fusion of the lateral palatine processes, the nasal septum, and/or the median palatine processes (formationofthesecondarypalate)

  24. Cleft lip andpalate- cause • Multifactorialwithsignificant inheritance component Enviromentalfactors:viruses , toxoplasmosis, CMV,hypervitaminosis A + D, ATB(tetracyclines, erythromycine), AEDs, corticoids, X-ray, drugs, organicsolvents ,otherteratogens • Congenitalchromosomalaberration • SyndromesasociatedwithCL/CP/CLP

  25. Cleft lip andpalate-ethnicdifferences • most common in Caucasians and Japanese • leastfrequently in Negroidrace

  26. Cleft lip andpalate- empiricrisks(Harper)

  27. Empirical risk according to severityofdefect Defect risk forsibs Bilateral CLP 5,7 % Unilateral CLP 4,2 % Unilateral CL 2,5 %

  28. Chromosomalaberrationassociatedwith CLP/CP • trisomy 13 • trisomy 18 • Structuralaberrationsautosomes • velocardiofacial syndrome 22q11microdeletion syndrome

  29. Patau syndrome • 47,XX(XY), +13 • 1 in 5000-10 000 newborns, • 1 in 90 SA • CLP bilateral, congenitaldefectsofthebrain, eyes, postaxialhexadaktyly…)

  30. Edwards syndrome • 47,XX(XY),+18 • 1in 5000 newborns • IUGR • microcephaly • dolichocephaly • CP • rethrognathia

  31. Wolf-Hirschhorn syndrome, 4p- 1:50 000 8% de novo deletion 13% due to familialtranslocation F:M 2:1 symptoms -dwarfism -microcefaly, craniofacialstigmatisation - CL,CP,CLP -heartdefects

  32. DiGeorge syndrome– velocardiofacial • Microdeletion 22q11 • Symptoms: - heartdefects - facialstigmatisation - CP( submucoustoo) - hypoplasiaofthymusandparathyroids) ( immunodefects, hypocalcemia)

  33. SyndromeswithoutMendelian inheritance • Pierre-Robin sequence • Mandibularhypoplasia • Glossoptosis • Cleftofpalate May be part of a variety of skeletalormuscularsyndromes, somemendelian (e.g. Sticklersy, Congenitalmyotonicdystrophy)

  34. AD hereditarysyndromeswith CLP • van der Woude syndrome • EEC syndrome • Stickler syndrome • Larsen syndrome

  35. van der Woude syndrome -Autosomal dominant, incomplet penetrance variableexpressivity !!! -Mouthlower lip pits-Cleft lip-Cleftpalate-Cleft uvula-Hypodontia • Molecular Basis - caused by mutations in the interferon regulatoryfactor 6 gene (IRF6) -

  36. EEC syndrome -Ectrodaktyly-deformities of hands and feet -Ectodermaldysplasia-skin ,hair,nails -Cleft lip/palate -otherdefects-kidneys,eyes,teeth Genetic heterogenity Two loci described – EEC1(7q11) and EEC3 (3q28) Majority of EEC cases appear to be to TP63 mutations

  37. Incidence 1 in 10 000 Mutation in COL11A1,COL11A2,COL2A1 genes Symptoms -Pierre-Robin sequence -eye:glaucoma,cataracts, retinaldetachment -sensorineuralhearingloss -artropathy, scoliosis,mitralvalve prolaps Stickler syndrome

  38. Larsen syndrome Incidence 1 in 100 000 Caused by mutation in the filamin B gene (FLNB)-3p14.3 Multiple joint dislocation Deformitiesoffeet Facialstigmatisation Others: dwarfism, skeletaldefects , heartdefects, CP, deafness, mentalretardation Rare AR inheritance

  39. AR hereditarysyndromeswith CLP • Fryns syndrome • Roberts syndrome( pseudothalidomid) • Diastrophicdysplasia • Smith-Lemli-Opitz syndrome • Orofaciodigital syndrome II • Meckel-Gruber syndrome

  40. Fryns syndrome • Diaphragmatichernia • Abnormalface,anddistal limb anomalies • Cleft lip/palate

  41. Roberts syndrome • Pseudothalidomid syndrome • Pre-/postnatalgrowthdeficiency • Cleft lip/ palate( bilat.) • cataracta • Oligodactyly • Phocomelia • Radialhypoplasia • Mentalretardation • Caused by mutations in ESCO2 gene (8p21)

  42. Diastrophicdysplasia - dwarfism, adulthigh 100-120 cm -shortlimbs -short, thick tubular bone, with broad metaphyses and flattened, irregular epiphyses -cleftpalate -earabnormalities -joint deformities -hipcontractures -handsdeformities(„ hitchhikerthumb“) -vertebraldeformities SLC26A2 gene (5q32)

  43. Smith-Lemli-Opitz syndrome • pre- andpostnatalgrowthdeficiency • Microcephaly • Facialstigmatisation • Cleftpalate • Mentalretardation • Hypospadias,ambiguousgenitalia,micropenis • Syndaktylyofsecondandthirdtoesoffeet • Mutation in DHCR gene, locus 11q12-q13 • low cholesterol,elevated 7-dehydrocholesterol

  44. Orofaciodigital syndrome, type II • Mohr syndrome • Medialcleftofupper lip • micrognathia • Cleftandlobationoftongue, • hypertelorism • Bilateralpostaxialhexadactylyofhands, bilateralpolysyndaktylyofhallux

  45. Meckel-Gruber syndrome microcephaly, encephalocele Microphtalmia Cleft lip and/orpalate Congenitaldefectofheart Postaxialpolydactyly Polycystickidneys A lethaldisorder, withdeathoccuring in theperinatal period Heterogenity:loc.17q21-24,11q13 and 8q24

  46. X-linkedhereditarysyndromeswith CLP • Orofaciodigital syndrome, type I • Otopalatodigital syndrome • Isolated X-linkedcleftofpalatewithankyloglossia

  47. Orofaciodigial syndrome,type I • Papillon-Léage-Psaume syndrome • Hyperplasiaoffraenulum • Multiply lobulatedtongue • Hypoplasiaoflateralnasalcartilages • Medialpseudocleftofupper lip • Asymetricalcleftofpalate • Variablemalformationofdigits • Moderatementalretardation

  48. Otopalatodigital syndrome • Type I • A characteristikface(prominent supraorbitalarches, joinedeyebrows,antimongoloidpositionofeyeslits, hypertelorism, a broadandflatrootofthe nose) • Cleftpalate • Conductivehearingloss • Mentalretardation • Somaticretardation • Type II - + other multiple skeletalanomalies

  49. Cleft palate and ankyloglossia X-linked inheritance - Cleft of uvula- heterozygot female - Incomplet cleft of palate - Incompetention of palate - ankyloglossia

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