Dr Cédric Le Caignec Service de Génétique Médicale

1. Frequent chromosome disorders Dr Cédric Le Caignec Service de Génétique Médicale

2. Frequent chromosome disorders Numerical abnormalities (aneuploidies) Primary trisomies 21, 18, 13 Homogeneous Mosaic Turner and Klinefelter syndromes Structural abnormalities Trisomy with Robertsonian translocation Unbalanced reciprocal translocations de novo deletions or duplications

3. TRISOMY 21 Down syndrome

4. Epidemiology • Frequency • Most frequent cause of learning disability • Most frequent chromosomal anomaly • Responsible for frequent miscarriages

5. Epidemiology • Equal frequency in different ethnic and socio-economic groups

6. Epidemiology • Frequency: • 1/700 newborns, today 1/1500 newborns • Sex ratio: 1,2 • In France, 300-500 trisomy 21 newborns each year • Risk factor • Major risk factor: advanced maternal age

7. 38 years Epidemiology Frequency Maternal age 20 years

8. Estimation of the risk depending on the maternal age

9. DIAGNOSTIC • PRENATAL DIAGNOSIS • Chromosomal rearrangement involving the chromosome 21 in a parent • Family history of trisomy 21 • Echographic fetal anomaly • 11-12 SA: thickened nuchal translucency >3 mm

10. Thickened nuchal translucency at 12 SA

11. Hygroma colli

12. Hygroma colli

14. DIAGNOSTIC • PRENATAL DIAGNOSIS • Chromosomal rearrangement involving the chromosome 21 in a parent • Family history of trisomy 21 • Echographic fetal anomaly • 11-12 SA: thickened nuchal translucency >3 mm • 20-22 SA: congenital heart defects, renal anomaly…

15. DIAGNOSTIC • PRENATAL DIAGNOSIS • First trimester screening with biological markers • Risk estimation > 1/250 • ß HCG • PAPPA

16. Different methods to get fetal samples • Depends on the term • 3 methods : • CVS : chorionic villus sample • Amniotic fluid • Fetal blood • Risk: • miscarriage

17. Chorionic villus sample 11-13 WG

18. Chorionic villus sample • Miscarriage : 1-3 % • Risk of infection • Short term culture : 24-48 h • Long term culture : 2-3 weeks

19. Amniotic fluid sample • 15-39 WG • Miscarriage : 0,5 % • Risk of infection • Maternal contamination • 2-3 weeks

20. Fetal blood sample • After 21 WG • Miscarriage : 3-4 % • 3-5 days

21. DIAGNOSTIC Clinical diagnostic: Most often obvious but no specific features

22. DIAGNOSTIC • Cranio-facial dysmorphism • Microcephaly • Flat and round face

23. DIAGNOSTIC • Cranio-facial dysmorphism • Flat and thickened neck

24. DIAGNOSTIC • Cranio-facial dysmorphism • Short nose • Epicanthic folds

25. DIAGNOSTIC • Cranio-facial dysmorphism • Upslanting palpebral fissures

26. DIAGNOSTIC • Cranio-facial dysmorphism • Small ears, narrow auditory canal

27. DIAGNOSTIC • Cranio-facial dysmorphism • Small mouth, thickened lips • Macroglossia, protruding tongue • Abnormal teeth

28. DIAGNOSTIC • Short and large fingers • Brachymesophalangy and clinodactyly of the fifth fingers

29. DIAGNOSTIC • Single transverse palmar crease -> bilateral in 25% of the cases

30. DIAGNOSTIC • Short, large and flat feet with gap between the first and second toes

31. DIAGNOSTIC • Muscular hypotonia and hyperlaxity --> always present Abdominal distention (hypotonia) • Frequent umbilical hernia • Normal genitalia

32. DIAGNOSTIC • Learning disability • Constant • Variable among the patients • Gets worse with the age • IQ: 50 on average at 5 years, 38 at 15 years !!!!

33. DIAGNOSTIC • Milestones: • Delayed walk: 30 months on average • Delayed language • Affectivity and sociability preserved

34. DIAGNOSTIC • Associated congenital malformations • Congenital heart defects – 40% of the patients • Atrio-ventricular canal

35. DIAGNOSTIC • Associated congenital malformations • Congenital heart defects – 40% of the patients • Atrio-ventricular canal • Others: ASD, VSD, tetralogy of Fallot…

36. DIAGNOSTIC • Associated congenital malformations • Congenital heart defects – 40% of the patients • Atrio-ventricular canal • Others: ASD, VSD, tetralogy of Fallot… • Cardiac echography is required at birth • Surgical operation

37. DIAGNOSTIC • Associated congenital malformations • Digestives • Duodenal atresia (30%?)

38. DIAGNOSTIC • Associated congenital malformations • Digestives • Duodenal atresia (30%?) • Imperforate anus…

39. DIAGNOSTIC • CYTOGENETIC Karyotype to confirm the clinical diagnosis and to define the type of the chromosomal rearrangement • Primary and homogeneous trisomy 21

40. DIAGNOSTIC • CYTOGENETIC Karyotype to confirm the clinical diagnosis and to define the type of the chromosomal rearrangement Primary and homogeneous trisomy 21 • 92% of the patients • Non-disjunction of chromosome 21 in meiosis, most often of maternal origin • 47,XX,+21 or 47,XY,+21 • Most of the time, meiosis error • Risk factor: advanced maternal age • Estimated risk: 1%

41. DIAGNOSTIC • CYTOGENETIC • Robertsonian translocation trisomy 21 • 5% of the patients • Most often t(14;21) • Inherited in 45% of the cases • Ex. 45,XY,rob(14;21)(q10;q10)

42. DIAGNOSTIC 45,XY,rob(15;21)(q10;q10)

43. DIAGNOSTIC • CYTOGENETIC • Robertsonian translocation trisomy 21 • 5% of the patients • Most often t(14;21) • Inherited in 45% of the cases • Ex. 45,XY,rob(14;21)(q10;q10)

44. DIAGNOSTIC • CYTOGENETIC • Robertsonian translocation trisomy 21 • 5% of the patients • Most often t(14;21) • Inherited in 45% of the cases • Ex. 45,XY,rob(14;21)(q10;q10) child: 46,XY,der(14;21)(q10;q10),+21 Which risk for the offspring ?

45. DIAGNOSTIC der (14;21)(q10;q10) 14 21

46. DIAGNOSTIC • pachytene

47. normal balanced DIAGNOSTIC • pachytene • alternate segregation gametes normal balanced zygotes

48. DIAGNOSTIC • adjacent segregation gametes disomy 21 nullosomy 21 zygotes trisomy 21 monosomy 21

49. 46,XY,der(14;21)(q10;q10),+21 trisomy21

50. DIAGNOSTIC • Adjacentsegregation gametes disomy 14 nullosomy 14 zygotes trisomy 14 monosomy 14