Malformations

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Malformations

  1. 1. PATHOLOGY OF CONGENITAL MALFORMATIONS Professor EEU Akang, MBBS FMCPath FWACP, Department of Pathology, University College Hospital, Ibadan
  2. 2. OUTLINE DEFINITIONS- Malformation, Disruption, Deformation, Sequence, Syndrome, Association AETIOLOGY AND PATHOGENESIS SELECTED CHROMOSOMAL DISORDERS SELECTED ORGAN MALFORMATIONS
  3. 3. CONGENITAL MALFORMATIONS- Definition Morphological defects present at birth. May sometimes manifest in later adult life  Due to an intrinsically abnormal developmental process  May either be inherited or acquired  3% of neonates have a major anomaly  Up to 20% of (post)neonatal deaths 
  4. 4. CONGENITAL MALFORMATIONSDifferential diagnosis-1 DISRUPTIONSecondary destruction of normally developed tissue by extrinsic factors Will not recur e.g. amniotic bands
  5. 5. 1 in 2000 live births DISRUPTION- Amniotic band 2 THEORIES 1. Partial rupture of amniotic sac forms amniotic strands that encircle and trap part of the foetus 2. Intrinsic defect of blood circulation Characterised by constriction of digits, arms and legs Accompanied by lymphoedema Auto amputation may occur
  6. 6. CONGENITAL MALFORMATIONSDifferential diagnosis- 2  DEFORMATION- Localised/generalised compression of foetus by extrinsic forces such as 1st pregnancy, small uterus, bicornuate uterus, leiomyoma, oligohydramnios, multiple pregnancy, abnormal presentation e.g. talipes
  7. 7. Pathomechanism of malformations, disruptions and deformations (Queiβer-Luft and Spranger, 2006)
  8. 8. DEFORMATIONTalipes equinovarus Club foot may be classified as 1. structural (hereditarye.g. Edward’s syndrome, Ehlers-Danlos syndrome) 2. Postural (intrauterine compression) Against the classical, widely accepted teaching of postural club foot, this anomaly also occurs in the absence of restriction of the intrauterine space
  9. 9. CONGENITAL MALFORMATIONSTerminology SEQUENCEPattern of cascade anomalies (malformations, disruptions or deformations) due to a single localised abnormality in organogenesis e.g. Oligohydramnios (Potter) sequence
  10. 10. OLIGOHYDRAMNIOS SEQUENCE
  11. 11. OLIGOHYDRAMNIOS SEQUENCEPotter facies, talipes and lung hypoplasia
  12. 12. PLACENTA IN OLIGOHYDRAMNIOSAmnion nodosum a localized accumulation of amorphous material (vernix caseosa) with embedded desquamated foetal skin cells to produce small nodules
  13. 13. CONGENITAL MALFORMATIONSTerminology SYNDROMEConstellation of congenital anomalies that are pathologically related and not due to a single localised initiating defect. May be caused by single agent (virus, alcohol, etc.)- e.g. Congenital Rubella syndrome
  14. 14. CONGENITAL RUBELLA SYNDROME
  15. 15. ASSOCIATION A group of anomalies that occur more frequently together than would be expected by chance alone but that do not have a predictable pattern of recognition and/or a suspected unified underlying aetiology. Examples include • VACTERL (Vertebral, Anal, Cardiac, TE fistula, Renal, Limb defects) and • MURCS (Mullerian duct aplasia, Renal aplasia, Cervical Somite dysplasia
  16. 16. AGENESIS AGENESISComplete absence of an organ and its primordium
  17. 17. APLASIA APLASIAAbsence of an organ due to failure of development of its primordium
  18. 18. HYPOPLASIA HYPOPLASIAIncomplete development of an organ with decreased numbers of cells
  19. 19. ATRESIA Failure of luminal development in a hollow organ- e.g. oesophageal atresia
  20. 20. CONGENITAL MALFORMATIONSOther Terms HYPOTROPHYAbnormally small cells HYPERTROPHYAbnormally large cells
  21. 21. CONGENITAL MALFORMATIONS- Aetiology Idiopathic Multifactorial Cytogenetic (Chromosomal) Monogenic (Mendelian) Maternal diseases Transplacental infections  Drugs and chemicals Irradiation 40-60% 20-25% 10-15% 2-10% 6-8% 2-3% 1% 1%
  22. 22. Risk factors for major malformations Queiβer-Luft and Spranger, 2006
  23. 23. MULTIFACTORIAL CAUSES 20-25% of malformations  Interaction between several disease genes and multiple environmental factors  Subject to geographic and temporal variation  Congenital dislocation of the hip, neural tube defects
  24. 24. HEREDITARY CAUSES 12-25% of malformations  Chromosomal aberrations (Trisomy 21, 18, 13, Klinefelter, Turner)  Monogenic disorders (Autosomal recessive/dominant, X-linked recessive/dominant)
  25. 25. ENVIRONMENTAL CAUSES 10-13% of malformations  Maternal disease (DM, PKU, endocrine)  Infections (TORCHES/HIV)  Drugs/chemicals (alcohol, antifolates, androgens, phenytoin, thalidomide, warfarin, 13-cisretinoic acid)  Irradiation
  26. 26. PATHOGENESIS OF MALFORMATIONS Timing determines nature/severity of malformation (3-9 weeks)  Insults affect migration, proliferation, cellular interactions, cell-matrix associations, apoptosis  Homeobox genes, Paired box genes, cytokines, growth factors, adhesion molecules, hormones, mechanical forces 
  27. 27. KARYOTYPING 1. Incubate cell suspension with phytohaemagglutinin 2. Add colchicine (arrests cell division in metaphase) 3. Stain (i. Giemsa (G), ii. Reverse (R), iii. Centric (C), iv. Quinacrine (Q), v. Silver nucleolar organiser region (AgNOR) 4. Photograph and arrange chromosomes (A1-3; B4-5; C6-12; D13-15; E16-18; F19-20; G21-22; X/Y)
  28. 28. TRISOMY 21- Down syndromeKaryotype
  29. 29. TRISOMY 21- Phenotype
  30. 30. TRISOMY 21- Mongoloid facies
  31. 31. TRISOMY 18- Edward syndromeKaryotype
  32. 32. TRISOMY 18- Phenotype
  33. 33. TRISOMY 18- Facies
  34. 34. TRISOMY 13- Patau syndromeKaryotype
  35. 35. TRISOMY 13- Phenotype
  36. 36. TRISOMY 13- Facies
  37. 37. TURNER SYNDROMEKaryotype
  38. 38. TURNER SYNDROMEPhenotype
  39. 39. TURNER SYNDROMEWebbed neck
  40. 40. Ventricular septal defect
  41. 41. Atrial septal defect
  42. 42. Patent ductus arteriosus
  43. 43. Renal cystic dysplasia
  44. 44. Adult polycystic disease Autosomal dominant PKD1 (polycystin 1) and PKD2 (polycystin 2) Hepatic cysts, pancreatic cysts, berry aneurysms, colon diverticula
  45. 45. Infantile polycystic disease Autosomal recessive PKHD1 (fibrcocystin) Pancreatic cysts, hepatic biliary dysgenesis and fibrosis
  46. 46. CNS MALFORMATIONS      NEURULATION- wk 3 (anencephaly, spina bifida) TELENCEPHALISATION- wk 5-6 (arrhinencephaly, holoprosencephaly) PROLIFERATION- 2-4 mos (micrencephaly) MIGRATION- 3-5 mos (lissencephaly (MillerDieker syndrome), pachygyria, polymicrogyria, heterotopia) MATURATION- 3rd trim.-post natal (megalencephaly, Arnold-Chiari, Dandy-Walker)
  47. 47. ANENCEPHALY
  48. 48. MYELOMENINGOCELE
  49. 49. HOLOPROSENCEPHALY
  50. 50. ARNOLD-CHIARI MALFORMATION Hydrocephalus Cerebellar tonsil herniation Z-shaped kinking of brainstem Spina bifida
  51. 51. Congenital cytomegalovirus infection
  52. 52. HYDROPS FETALIS Iso-immunisation  Turner syndrome  Parvovirus infection  Twin-twin transfusion  syndrome
  53. 53. Summary • An overview of processes that can result in acquired or inherited structural malformations manifesting at the time of birth or in some cases later in life has been presented • Malformations arise from insults occurring during the critical period of organogenesis and may range from minor to severe, life threatening conditions • Many cases are preventable by the avoidance of teratogenic exposure, immunisation and genetic 56 counselling in selected cases
  54. 54. THANKS FOR LISTENING!

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