Hereditary diseases. Congenital malformations.

1. Hereditary diseases. Congenital malformations. Dr. György Fekete

3. Congenital malformations • Conception – organogenesis - birth • Genetic causes • Environmental factors (teratogens) • Visible/ recognazible at birth • Later manifestation

4. Genetic conditions: causes of acute and chronic diseases • Onset of disease: fetus,infant, child, adult • Genetic abnormalities may produce: congenital malformations, metabolic disturbances,specific organ dysfunction, abnormalities of sexual differentiation

5. Monogenic diseases: 1% of newborn babies • Chromosomal aberrations: 0.5% • Multifactorial disorders: 1-3%

6. Monogenic diseases: 1% of newborn babies • Chromosomal aberrations: 0.5% • Multifactorial disorders: 1-3%

7. Inherited conditions • If a single allele has a detectable effect: dominant • If two functionally identical alleles cause the effect: recessive • XY males are hemizygous for genes on the X chromosome

8. Mendelian inheritance Autosomal dominant inheritance • If one parent displays a dominant condition and is heterozygous for the gene, each child has a 50% chance of receiving the single allele and of manifesting the condition • Not all individuals with the affected gene my be symptomatic • Penetrance: percentage of patients with the gene mutation who manifest symptoms

9. Expressivity: spectrum of severity in patiens having clinical manifestation • Examples:achondroplasia, Crouzon syndrome, neurofibromatosis type I, II, Marfan syndrome,hereditary angioneurotic edema (HANE)

10. Autosomal recessive (AR) inheritance • Consanguinity increases the risk • The risk of two carriers of gene mutation having a child with AR diseases is 1 in 4 : 25% • Examples:phenylketonuria, cystic fibrosis, congenital adrenal hyperplasia, sickle cell disease, Gaucher disease, Pompe disease

11. Sex – linked inheritance • The gene locus is on the X chromosome • When the mother is a carrier of the gene mutation, 50% of male offspring will have the disease, and 50% of female offspring will be carriers • All daughters of the ill father will be obligate carriers • Examples: Duchenne muscular dystrophy (DMD),hemophilia A and B, adrenoleukodystrophy, Fabry disease

12. Mitochondrial diseases

13. Importance • Prevalence in newborns: 46-50 %o • 25-40 per cent of infant mortality • One factor in prematurity and intrauterine dystrophy • Severe conditions • Burden: child, family, society

14. Classification • Severity: major and minor malformations • Major: hindering significant organ functions • Isolated (GI atresias, Fallot – tetralogy) • Multiple: two or more organs, organ systems • Genetic: chromosome aberration, monolocus, other mechanism (uniparental disomy, genomic imprinting, triplet expansion, mitochondrial) • Teratogens (TORCH, chemicals, drugs, irradiation) • Genetic + environmental (multifactorial, complex diseases)

15. Minor malformations • Informative morphogenetic variants • Non - functional, harmless, esthetical deviations - Epicanthus

16. Supernumerary nipple

17. Minor malformations • Bifid uvula • 4 digits crease

18. Hypertelorism

19. Low – set ears

20. Craniofacial dysmorphy („peculiar face”) • Elements of face are forming from the 4. embryonal week. Face of fetus: 8. gestational week

21. Ossification anomalies of sutures (craniostenosis) • Craniosynostosis (+ corpus callosum agenesia, hydrocephalus )

22. Craniofacial dysostosis type I Crouzon syndrome

23. Crouzon syndrome • AD, gene: 10q26

24. Crouzon syndrome • Apert syndrome (Acrocephalosyndactyly type I) • Gene: 10q26,fibroblast growth factor receptor-2 (FGFR-2) • Advanced paternal age ( >45 yrs) • Pfeiffer syndrome (Acrocephalosyndactyly type V) • Gene: 10q26, 8p11.2-11.1(FGFR-1)

25. Apert syndrome

26. Pfeiffer syndrome

27. Splits • Split lip / palate (cheilo- gnatho- palatoschisis)

28. Mandibulofacial dysostosis: Treacher - Collins syndrome

29. Steps of examination • Parents, sibs, grandparents: resemblance? (photos!) • Anatomical/ morphological deviation? • Isolated or multiple? • Psychomotor retardation? • Other minor malformations? Hidden malformations (internal organs) ? • Teratogenic exposition? • Special methods / investigations • Councelling: prognosis, therapy

30. Special methods • Laboratory data • Imaging techniques (CT, MRI) • Cytogenetics • DNA analysis • Biochemical studies

31. Recognizable malformations in newborn age • Down- syndrome • ( trisomy chromosome 21 ) 21q22

32. Patau -, Edwards- syndrome • Patau- syndrome (trisomy chromosome 13) • Edwards- syndrome (trisomy chromosome 18)

33. Prader – Willi syndrome

34. Turner syndrome (45,X):lymphedema on the back of the hand / feet, pterygium colli

36. DiGeorge syndrome

37. Isolated malformations / newborns • Anencephaly • Spina bifida • Hip dyslocation • Atresias of esophagus and bowels • Pyelectasy (obstructive uropathy) • Diaphragma hernia • Omphalokele • Hirschsprung disease (megacolon congenitum) • Congenital heart disease

38. Spina bifida

39. Congenital heart disease, pyloric stenosis

40. Club- foot, congenital dyslocation of the hip

41. Inguinal hernia , megacolon congenitum (Hirschsprung disease)

42. Retentio testis, hypospadiasis

43. Malformations, dysmorphisms of the skull and face (craniofacial dysmorphy) Mental retardation Multiorgan involvement Maternal age: 35 yrs or more Clinical signs and data of a possible chromosome aberration

44. Achondroplasia • 1:5000, gene mutacions of fibroblast growth factor receptor-3 gene, 4p16.3

46. Osteogenesis imperfecta

47. Neurofibromatosis type 1 (NF1) Prevalence: 1/ 2500 – 1/3000 Diagnosticcriteria: 2 or more of thefollowingpointsarepresent • 6 or more café- au -laitspots, diameter > 5 mm. (prepuberty), and > 15 mm. (postpuberty)

48. 2 or more neurofibromas (fibromatous tumors of the skin), or at least one plexiform neurofibroma

49. Plexiform neurofibromas • potential for transformation into malignant peripheral nerve sheath tumors (malignant schwannomas)

50. Axillary and/ or inguinal freckling