Sri. Marker USG dugaan kelainan kromosomal final.pptx

pembelajaran USG

1. Marker Ultrasonografi Dugaan Kelainan Kromosom Sri Pudyastuti RSUP Persahabatan

2. Ultrasonographic Markers of Chromosomal Anomalies Second trimester First trimester Nuchal translucency Nasal bone Ductus venosus Tricuspid regurgitation Fetal heart rate Fetal facial angle Nuchal Fold Thickening Echogenic Bowel Short Long Bones Echogenic Intracardiac Foci Choroid Plexus Cysts Mild Pyelectasis Soft Markers and Aneuploidy Risk Assessment Sonogenetics aneuploidies trisomy 13, 18, monosomy X, and triploidy .

3. Nuchal Translucency FMF : 40 countries, 107 multicenter studies (1995-2004) Total 200,868 patients Successfull measurement 99,8% Cut-off > 95 th False positives 4,2% T21 detection rate 76,8% (71-90,9%) Nicolaides, 2004

4. Nuchal Translucency 45 < CRL < 8 5mm F etal sagittal view , head and thorax Magnification maximal C lear separation between F etal skin and amnion Largest thickness N eutral position A void the amnion and nuchal cord C alipers “ in ner - t o - in ner “ Minimum 5 MHz probe Caliper setting at least 0.1 mm

5. Nuchal Translucency Nicolaides, 2004

6. Nuchal Translucency Nicolaides, 2004

7. Screening for chromosomal defects First trimester screening (FTS) Karyotype Median nuchal translucency (mm) Median-free beta-hCG (MoM) Median PAPP-A (MoM) Normal 2.0 1.0 1.0 Trisomy 21 3.4 2.0 0.5 Trisomy 18 5.5 0.2 0.2 Trisomy 13 4.0 0.5 0.3

8. NT thickness Trisomy 21/18/13 (%) Other chromosomal defects (%) Submicroscopic defects (%) Single-gene disorders (%) Structural defects (%) 95th–3.4 13 1 1 1 6 3.5–4.9 25 3 3 1 11 5.0–6.4 44 13 4 6 11 6.5–7.9 51 9 3 3 17  > 8.0 34 22 1 7 14 Table 2 Risk of chromosomal and structural defects according to the NT thickness (submicroscopic defects = those defects not detectable by routine karyotyping) Open in a separate window

9. Nasal Bone Sandikciouglu , J Craniofac Genet Dev Biol 1993 Abnormal nasal bone Absent of nasal bone : < 2,5 mm Hypoplastic of nasal bone Nasal b ones are formed by intramembranous ossification of connective tissue of the nasal capsule Ossification of n asal b ones first appears at a CRL of 42 mm and increases linearly with gestation.

10. FRONTAL BONE SKIN NASAL BONE maximal echogenicity CARTILAGINOUS TIP OF THE NOSE ORBIT ZYGOMATIC BONE

11. 90 45 -50 NO YES I M P O R T A N T ! ANGLE OF INSONATION

12. ULTRASO NOGRAPHY OF NASAL BONE GAIN REDUCING

13. Nasal Bone In 5/6 (83%) fetuses with Fragile X, n asal b one was absent at X-ray Keeling , 2002 Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation : An observational study . Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Nasal bone absent in 43/59 (73%) trisomy 21 fetuses Nasal bone absent in 3/603 (0,5%) normal fetuses

14. Nasal bone Normal 1-3% Trisomy 21 65% Trisomy 18/13 50% Gestation 11-14 wks CRL 45-8 5 mm S ize : Caliper movement 0.1 mm Mid-sagittal view First line: Nasal skin Second line: Hyperechoic bone Third line: Cartilaginous tip Angle of resonance : 90 o No; 45-50 o Yes

15. Nasal Bone The true mid sagittal view Nicolaides, 2004

16. Nasal bone GAIN REDUCING 90 o : NO 45-50 o : Yes

17. Ductus Venosus At 11-14 weeks abnormal ductal flow is : 5% of chromosomally normal fetuses 80% of fetuses with trisomy 21 ( Nicolaides 2004 )

18. Ductus Venosus

19. INCREASED NUCHAL TRANSLUCENCY CONGENITAL HEART DEFECT FETAL ANEUPLOIDY DUCTUS VENOSUS ABNORMALITIES DUCTUS VENOSUS SCREENING

20. Tricuspid Regurgitation Tricuspid regurgitation

21. DV and or Tricuspid?

22. The face is flat …….

23. The others ultrasound marker of chromosomal abnormalities Fetal growth : CRL Heart rate Umbilical cord diameter Single umbilical artery/ SUA Maxillary length Humerus length Ear length Micrognatia Wrist contracture Exomphalos Choroid plexus cyst Holoprosencephaly Megacystis Pyelectasis Cardiac echogenic foci

24. Crown Rump Length In the first trimester the measurement of CRL Is useful to detect this finding Drugan et al, reported that a fetal CRL smaller more than 7 mm indicate a three time higher risk for chromosome abnormalities Trisomy 18 and triploidy are associated with moderately severe growth restriction Trisomy 13 and Turner syndrome are associated with mild growth restriction Trisomy 21 growth is essentially normal

25. CRL Ekstensi Pembesaran cukup / zoom Puncak kepala sampai bokong , tidak termasuk ekstremitas dan yolk sac Shapeless embryo ( 8 minggu ) Trisomi 8 Trisomi 16 Triploidi Embryonic disc : C- shape, three dimensional 6 weeks limb bud by 8-9 weeks Movement by 9-10 weeks Normal rhombencephalon

26. Harris Birthright Research Centre for Fetal Medicine 10–14-week Ultrasound Study. In 787 chromosomally abnormal pregnancies, where the women were certain of their dates and had regular menstrual cycles of 26–30 days, the difference in gestation between that estimated by measurement of fetal crown–rump length and menstrual dates was calculated trisomy 18 triploidy

27. Micrognathia The term micrognathia describes a small mandible Micrognathia is associated with a vast array of other congenital anomalies which include: aneuploidic syndromic, non- aneuploidic syndromic and non-syndromic non- aneuploidic A small mandible occurs secondary to abnormalities of the first branchial arch which in turn are caused by deficient or insufficient migration of neural crest cells and usually occur around the 4 th week of gestation

28. Wrist Contracture

29. Heart Rate 100 beats per minute at 6 weeks 160-170 beats per minute at 9 weeks 150 beats per minute at 14 weeks Trisomy 13 and Turner : Tachycardia Trisomy 18 and triploidy : Bradycardia ( A.W. Liao et col, 2000)

30. Umbilical Cord Diameter Easy identification in late 1 st trimester ( 10-14 weeks ) An increase diameter (the 95 th centile ) is more frequent among abnormal karyotype fetuses than in normal fetuses Ghezzi et al : 784 cases with CRL of 45-85 mm 17 cases chromosomal abnormal Trisomy 21 : The extracellular matrix of nuchal skin is much richer in glucosaminenoglycans , especially hyaluronan, compared with chromosomally normal Trisomy 18 : The distribution and organization of collagen types I and III are different from normal fetuses Trisomy 13 : Most dermal fibroblasts are collagen type IV Turner syndrome might have thicker than normal umbilical cord

31. Single umbilical artery SUA in one percent of deliveries 717 fetuses 3.3% normal karyotype 77.8% trisomy 18

32. Maxillary length At 11-13 +6 weeks : Mid sagittal view ( Cicero et al 2004) In chromosomally normal fetuses maxillary length increases liniarly with gestation by about 0,1 mm for each 1 mm increase in CRL In the trisomy 21 fetuses, the median maxillary length is significantly below the normal median for CRL by 0,7 mm Fetuses with other chromosomal defect, there are no different significances from normal in maxillary length.

33. Maxillary length - T21

34. Humerus length Trisomy 21 is characterised by short stature during second trimester At 11-13 +6 weeks in trisomy 21 fetuses, the median femur and humerus lengths are significantly below normal median for CRL But it is too small for these measurements to be useful in screening ( Longo et al 2004)

35. Humerus length Trisomy 21 is characterised by short stature during second trimester At 11-13 +6 weeks in trisomy 21 fetuses, the median femur and humerus lengths are significantly below normal median for CRL But it is too small for these measurements to be useful in screening ( Longo et al 2004)

36. Ear Length EAR LENGTH 6% 85%

37. Choroid plexus cyst At 11-14 weeks the prevalence of choroid plexus cyst was 2,2% At 16-24 weeks : 2% More than 95% of cases they resolve by 26-28 weeks There is an association with chromosomal defect, particularly trisomy 18 They concluded that the presence of CPCs increases the risk for aneuploidy 1.5 times, mainly trisomy 18.

38. Holoprosencephaly Prevalence 1: 10,000 Unknown First trimester alobar holoprosencephaly 30% : Trisomy 18 and trisomy 13 Mid-facial abnormalities

39. Megacystis Visualization of the fetal bladder 10 weeks : 50% 11 weeks : 80% 13 weeks : 100% Normal diametar is < 6mm 7 – 15mm : 20% chromosomal abnormalities trisomy 13, and trisomy 18 ≥ 15mm : 10% chromosomal abnormalities Spontaneous resolution in normal kariotype is 90% Megacystis increases the likelihood for trisomy 13 or 18 by a factor of 6.7

40. Nuchal edema in the second trimester between 15 and 23 weeks is known as the nuchal fold The cerebellum, cisterna magna, and occipital bone should be seen. Soft tissue is measured from the outer echogenic line of occipital bone to the outer echogenic skin line. Initial studies suggested a cutoff of 6 mm The predominant reason for measuring the nuchal fold is that it is a soft marker for  aneuploidy . As an isolated finding, it has a  likelihood ratio  of 3.25 for  Down syndrome

41. Pyelectasis The results of these studies suggest that in the absence of other structural anomalies or soft markers or risk factors for aneuploidy, amniocentesis for isolated mild pyelectasis does not seem to be warranted. fetal pyelectasis is considered present if the anterior to posterior diameter of the renal pelvis measures: >4 mm up to 28 weeks or >7 mm at or after 28 weeks gestation isolated fetal renal pyelectasis is not considered to increase the risk of aneuploidies, however, in combination with other soft markers, the risk will increase  1

42. Echogenic bowel Fetal echogenic bowel refers to the presence of hyperechoic bowel, as compared with the echogenicity of the adjacent iliac bone Sagittal image of fetal abdomen shows echogenic bowel. The image should include fetal bowel, liver and iliac bone for comparison. Bowel is considered echogenic if the echogenicity of the bowel is more or equal to that of adjacent iliac bone. Technical factors are very important, and the frequency of the transducer should be 5 MHz or lower.  It is associated with normal fetuses , fetuses with aneuploidy, intrauterine growth retardation (IUGR), bleeding, cystic fibrosis (CF), congenital viral infections, and thalassemia. trisomy 21  (~15%)  12 less commonly associated with  trisomy 13 ,  trisomy 18 , and  Turner syndrome  

43. Cardiac echogenic foci EIF are described as discrete areas of echogenicity comparable to bone in the region of papillary muscle in either cardiac ventricle The most common locations for identification of spurious EIF were in the moderator band, endocardial cushion, and tricuspid valve annulus isolated EIF in women aged 18 to 34 years was not associated with increased risk for trisomy 21 in midgestation .

44. To evaluate nasal bone length (NBL), maxilla– nasion –mandible (MNM) angle, fetal profile (FP) line, prenasal thickness (PT), prenasal thickness to nasal bone length (PT:NBL) ratio and prefrontal space ratio (PFSR) as markers of trisomy 18 in the second and third trimesters of pregnancy A total of 43 trisomy-18 fetuses were included in the analysis. At initial examination, median gestational age was 21 + 2 weeks. NBL and PT were correlated with gestational age ( P  < 0.001), but the other markers were not. Mean NBL, MNM angle, PT, PT:NBL ratio and PFSR were 3.76 mm, 16.67°, 4.25 mm, 1.39 and 0.87, respectively. The FP line was zero (normal) in 53.7% of cases and negative (abnormal) in 46.3%. All markers were significantly associated with trisomy 18, with the PT:NBL ratio yielding the highest detection rate (88.4%) followed by NBL (83.7%), MNM angle (56.4%), FP line (46.3%), PT (27.9%) and the PFSR (20.5%) (for a 5% false-positive rate for the continuous variables). Various combinations of the four best markers (NBL, FP line, MNM angle and PT:NBL ratio) yielded detection rates of between 72% and 95%. Structural anomalies were not detected in 22% of fetuses at the initial scan and in 2% at the advanced scan.

45. Facial profile markers in second‐ and third‐trimester fetuses with trisomy 18 Ultrasound in Obstet & Gyne , Volume: 46, Issue: 1, Pages : 66-72, First published: 05 September 2014, DOI: (10.1002/uog.14662) Variable DR (%) (95% CI) FPR (%) (95% CI) LR+ (95% CI) LR– (95% CI) NBL 83.7 (68.6–93.0) 5.0 (1.7–11.3) 16.7 (7.0–39.6) 0.17 (0.09–0.35) MNM angle 56.4 (38.3–71.4) 5.0 (1.7–11.3) 11.3 (4.5–27.2) 0.46 (0.33–0.67) FP line 46.3 (29.3–61.5) 0.0 (0.0–3.7)  ∞ 0.54 (0.42–0.73) PT 27.9 (13.9–42.0) 5.0 (1.7–11.3) 5.6 (1.9–14.2) 0.76 (0.65–0.94) PT:NBL ratio 88.4 (74.4–96.0) 5.0 (1.7–11.3) 17.7 (7.4–41.7) 0.12 (0.05–0.29) PFSR 20.5 (9.6–37.3)  5.0 (1.7–11.3) 4.1 (1.5–12.1) 0.84 (0.70–0.99) Table 2.  Performance of nasal bone length (NBL), maxilla– nasion –mandible (MNM) angle, fetal profile (FP) line, prenasal thickness (PT), PT:NBL ratio and prefrontal space ratio (PFSR) as markers for trisomy 18 in the second and third trimesters

46. Ultrasound finding Initial scan ( n  = 27) Advanced scan ( n  = 43) Soft markers 29  and abnormal findings (besides profile markers) Choroid plexus cyst 44 70 Single umbilical artery 26 33 Short femur 11 12 Nuchal fold * 11 11 Overlapping fingers 7 60 Renal pyelectasis † 4 5 Echogenic bowel — 7 Clinodactyly — 5 Echogenic intracardiac focus — — Short humerus ‡ — — Other 4 26 Structural anomalies Heart 52 77 Growth restriction ‡ 11 37 Skeletal (including facial cleft and anomalies of the feet) 7 67 Central nervous system 7 35 Chest 7 16 Abdomen 7 16 Genitourinary — 9 Cystic hygroma — — Average number of soft markers observed ( n ) 1.1 2.3 Average number of structural anomalies observed ( n ) 0.9 2.1 ≥ One soft marker observed 100 100 No structural anomaly observed 22 2 Table 4.  Abnormal ultrasound findings at initial and advanced second-trimester ultrasound examination in fetuses with trisomy 18 Ultrasound finding Initial scan ( n  = 27) Advanced scan ( n  = 43) Soft markers 29  and abnormal findings (besides profile markers) Choroid plexus cyst 44 70 Single umbilical artery 26 33 Short femur 11 12 Nuchal fold * 11 11 Overlapping fingers 7 60 Renal pyelectasis † 4 5 Echogenic bowel — 7 Clinodactyly — 5 Echogenic intracardiac focus — — Short humerus ‡ — — Other 4 26 Structural anomalies Heart 52 77 Growth restriction ‡ 11 37 Skeletal (including facial cleft and anomalies of the feet) 7 67 Central nervous system 7 35 Chest 7 16 Abdomen 7 16 Genitourinary — 9 Cystic hygroma — — Average number of soft markers observed ( n ) 1.1 2.3 Average number of structural anomalies observed ( n ) 0.9 2.1 ≥ One soft marker observed 100 100 No structural anomaly observed 22 2

47. In conclusion, this study shows that when gross anomalies are absent at the second-trimester ultrasound scan, trisomy 18 can be detected effectively by the combination of markers for micrognathia (MNM angle and FP line) and a small NB (NBL and PT:NBL ratio). We prefer a combination of PT:NBL ratio and FP line; the PT:NBL ratio is in fact the strongest marker for trisomy 18 (and Down syndrome), while the FP line can differentiate between trisomy 18 and Down syndrome. Furthermore, both markers are independent of gestation and therefore a fixed cut-off can be used. Data are given as percent except where indicated. Nuchal fold abnormal if > 5 mm before 20 weeks' gestation and if > 6 mm at or after 20 weeks. † Renal pyelectasis abnormal if 5–10 mm in second trimester and 10–15 mm in third trimester. ‡ < 5 th   percentile.

48. 1. The combined test 2. The quadruple test 3. Non-invasive prenatal testing (NIPT) 4. Markers used in the combined and quadruple tests 5. Laboratory information for the combined and quadruple tests 6. Ultrasound information for the combined and quadruple tests 7. Screening in twin pregnancies 8. Screening in in-vitro fertilisation (IVF) pregnancies 9. Screening results

49. Sonogenetics Soft marker Hard/strong marker

50. Sonographic Marker Isolated Appearance Combined Appearance Nuchal translucency > 3 mm (11-14 wks ) 29% 29% Echogenic intestine up to 7% up to 46% Umbilical cord cyst 7% 55% Early growth restriction (< 20 wks )  5% 40% Bilateral pylectasia 2 - 3% up to 30% Choroid plexus cysts (bilateral) 0.6 - 1.5% 4.5 - 45% Single umbilical artery (SUA) 0 - 2% 20 - 30% Ventricular enlargement (10-15 mm) 2% 17% Echogenic intracardiac focus 0 - 1.2% up to 12%

51. Sonographic marker T-21 T-18 T-13 ∙ Nuchal fold ≥ 6 mm. + + + ∙ Echogenic bowel + ∙ Echogenic foci in the fetal heart + ∙ Short femur (< 3 %- ile ) + ∙ Short humerus (< 3 %- ile ) + ∙ Dilated renal pelvis (> 5 mm) + + + ∙ Mild ventriculomegaly (10-15 mm) + + ∙ Single umbilical artery + +

52. Sonographic Scoring Index ∙ Nuchal fold ≥ 6 mm 2 ∙ Structural defect 2 ∙ Short femur (< 3%- ile ) 1 ∙ Short humerus (<3&- ile ) 1 ∙ Pyelectasis (> 5 mm) 1 ∙ Echogenic bowel 1 ∙ Choroid plexus cyst 1 * Amniocentesis should be performed when the score ≥ 2 (Nadel AS, et al. J Ultrasound Med. 1995; 14)

53. SONOGRAPHIC SCORING INDEX FOR DETECTING DOWN SYNDROME Nuchal fold ≥ 6 mm 2 ∙ Structural defect 2 ∙ Short femur (< 3%- ile ) 1 ∙ Short humerus (<3&- ile ) 1 ∙ Pyelectasis (> 5 mm) 1 ∙ Maternal age 35-39 years 1 ∙ Maternal age ≥ 40 years 2 * Score ≥ 2: sensitivity 86,8%; false-positive rate 27,1% (Bromley B, et al. Ultrasound Obstet Gynecol. 1997; 10)

54. SOFT MARKERS FOR DETECTING DOWN SYNDROME Isolated marker Sensitivity False (+) rates ∙ Nuchal translucency (> 3 mm) 75% 1.0% ∙ Nuchal thickening (> 6 mm) 39,4% 0.6% ∙ Absent of the nasal bone 81% 11% ∙ Echogenic bowel 20.6% 0.6% ∙ Shortened femur ( humerus ) 31.6% (21.9%) 5.2% (1.4%) ∙ Echogenic intracardiac focus 27.7% 4.4% ∙ Renal pyelectasis 13.5% 2.6% J Perinat Educ. 2006 Winter; 15

55. HARD MARKERS 1. Head abnormalities ∙ hydrocephalus (21, 18, triploidy ) ∙ microcephaly (13, 45X/O) ∙ holoprosencephaly (13) ∙ Dandy-Walker malformation (21, 18, 13) ∙ agenesis of the corpus callosum (18) 2. Face & neck abnormalities ∙ cleft lip & palate (18, 13) ∙ micrognathia (18) ∙ nuchal edema (21, 18, 13) ∙ cystic hygroma (45X/O)

56. 3. Thoracic cavity abnormalities ∙ diaphragmatic hernia (18, 13) ∙ congenital heart diseases (21, 18, 13, triploidy , 45X/O) 4. Abdominal wall & GI tract abnormalities ∙ esophageal atresia (21, 18) ∙ duodenal atresia (21) ∙ omphalocele (21, 18, 13)

57. 5. Genitourinary abnormalities ∙ cystic kidney dysplasia (21, 18, 13, triploidy ) ∙ hydronephrosis (21, 18, 13) 6. Skeleton abnormalities ∙ shortened femur/ humerus (21) ∙ clenched fist (18, triploidy ) ∙ club foot (18, 13)

58. 7. Others ∙ non-immune hydrops (21, 45X/O) ∙ fetal growth restriction (21, 18, 13, triploidy , 45X/O) ∙ polyhydramnios (21, 18, 13) ∙ oligohydramnios (18, 13)

59. terima kasih …….