O.14.1 Chromosomal Abnormalities 1 of 2 - PowerPoint.pdf

ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 1 2 Chromosomal Abnormalities textbook reference Module O.14 Abnormal Fetal Karyotype • • Rumack 5th Edition Chapter 31 Chromosomal Abnormalities – Part 1 3 4 Chromosomal Abnormalities –...

ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 1 2 Chromosomal Abnormalities textbook reference Module O.14 Abnormal Fetal Karyotype • • Rumack 5th Edition Chapter 31 Chromosomal Abnormalities – Part 1 3 4 Chromosomal Abnormalities – Part 1 • Chromosomes • Congenital anomalies • Aneuploidy • Syndromes • Risk factors • Screening Chromosomal Abnormalities – Part 2 • 5 Ultrasound screening 6 Chromosomes Chromosomes Definition Microscopic structures in the nucleus of a cell that contain genes (genetic information) • Humans have 46 chromosomes (23 pairs) • 22 pairs of autosomes • 1 pair of sex chromosomes (XX or XY) Textbook of Diagnostic Sonography, 7th Edition (Hagen‐Ansert fig 53‐4) 1 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 7 8 Abnormal chromosomes • May be structurally abnormal • May be numerically abnormal • May be due to environmental causes • Drugs, viruses, etc. • Cause congenital anomalies Congenital Anomalies youtu.be/mBq1ULWJp_M 9 10 Congenital Anomalies AKA birth defects Congenital anomalies – causes Definition Structural or functional abnormalities existing at birth • Develop during intrauterine life Ultrasonography in Obstetrics and Gynecology, 5th Edition (Callen fig 6‐52) 11 12 Aneuploidy Aneuploidy Definition An abnormal number of chromosomes • e.g. 45 or 47 chromosomes • Have associated syndromes NORMAL = 46 Ploidy Number of complete sets of chromosomes in a cell; Humans are diploid (23 pairs) with a total of 46 chromosomes Ova and sperm are haploid with 23 chromosomes each 2 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 13 14 Polyploidy • Cells contain more than two sets of chromosomes • Described in multiples of the haploid number (n) • 3n = 69 chromosomes (triploidy) • 4n = 92 chromosomes (tetraploidy) • Etc. Haploid (n) One set of chromosomes (derived from one parent); 23 chromosomes in humans Diploid (2n) – NORMAL Two sets of chromosomes (one set from each parent); 46 chromosomes in humans 15 Aneuploidy Trisomy 21 Trisomy 18 Trisomy 13 45, X0 Triploidy Syndrome Down Edwards Patau Turner Chromosomes 47 47 47 45 69 Prevalence Most common Uncommon Least common Uncommon Uncommon Trisomy A single extra chromosome 16 Aneuploidy – sonographic markers • Sonographic features associated with aneuploidy • Some of these features not very reliable on their own • Also seen in “normal” fetuses non‐specific • Also seen with other abnormalities – transient • May come and go during a pregnancy • Less reliable markers are called “soft markers” 17 Syndromes 18 Syndromes • Trisomy 21 • Trisomy 18 • Trisomy 13 • Turner • Triploidy Trisomy 21 3 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 19 20 Trisomy 21 MOST COMMON ANEUPLOIDY AKA Down syndrome • Presence of all or part of a third 21st chromosome • Mild to moderate developmental disabilities • Can be severely disabled • Survival rate dependent on severity of anomalies • Heart defects are the main cause of death • Ultrasound alone identifies 25% of trisomy 21 fetuses 21 Trisomy 21 – 1st trimester sonographic marker • Increased nuchal translucency (NT) • ≥ 2.5 mm abnormal • Measured from 11 – 14 weeks GA • Considered very accurate 22 Trisomy 21 – markers Trisomy 21 – 2nd trimester sonographic markers • • • • • • Nuchal fold thickening Absent/hypoplastic nasal bone Short femur Short humerus Echogenic bowel Echogenic intracardiac focus • • • • • • • Pyelectasis Cardiac defects Mild ventriculomegaly Hypoplasia of fifth digit Wide iliac angle Shortened ear length Frontothalamic distance (brachycephaly) 23 Diagnostic Medical Sonography: Obstetrics & Gynecology, 3rd Ed. (Raatz Stephenson fig 28‐30) 24 Trisomy 21 – making sense of the markers • We’ll organize the markers into categories: • MOST COMMON 2nd trimester markers • Most common STRUCTURAL markers • SOFT markers routinely evaluated • SOFT markers NOT routinely evaluated Trisomy 21 – MOST COMMON 2nd trimester markers • Thickened nuchal fold • Absent/hypoplastic nasal bone • Shortened femur • Shortened humerus • Mild pyelectasis • Echogenic bowel • Echogenic intracardiac foci • Some sort of structural anomaly (e.g. heart defect) 4 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 25 26 Trisomy 21 – most common STRUCTURAL markers Trisomy 21 – SOFT markers routinely evaluated • Cardiac anomalies (septal defects) • Choroid plexus cysts • Duodenal atresia • Echogenic intracardiac foci • Mild ventriculomegaly • Renal pyelectasis • Hydrops • Echogenic bowel Most common Not specific to trisomy 21 27 Controversial findings Higher risk with additional sonographic findings, increased maternal age, and abnormal maternal serum screening 28 Trisomy 21 – SOFT markers NOT ROUTINELY evaluated • Short humerus • Shortened/absent nasal bone • • Trisomy 21 – THAT WAS A LOT OF LISTS! But, what do sonographers typically find? • Increased nuchal fold thickening Fifth finger clinodactyly • Mild pyelectasis Increased iliac angle • Short femur • Small ear length • Cardiac anomalies • Sandal gap toes Look for this one!! 29 Most common 30 Trisomy 21 – images • See part 2 of “Chromosomal Abnormalities” for many examples Trisomy 18 5 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 31 32 Trisomy 18 AKA Edwards syndrome 18th • Presence of all or part of a third • Severe mental and physical disabilities • Low survival rate • Few live born infants survive their first year (5‐10%) Trisomy 18 – most common sonographic markers Most common • IUGR • Clenched hands Very common • Cardiac anomalies • Choroid plexus cysts • Neural tube defects • Hydrocephalus • Omphalocele • Diaphragmatic hernia chromosome (50% of live infants reach 2 months, 1% reach age 10) 33 34 Trisomy 18 – markers Trisomy 13 Diagnostic Medical Sonography: Obstetrics & Gynecology, 3rd Ed. (Raatz Stephenson fig 28‐27) 35 36 Trisomy 13 AKA Patau syndrome • Presence of a third 13th chromosome • Spontaneous abortion rate is high • Embryos that survive to birth present with multiple anomalies (usually die within days or weeks) • Severe neurological problems • Complex heart defects Trisomy 13 – most common sonographic markers • Cardiac anomalies • Including echogenic intracardiac foci • Central nervous system anomalies • Holoprosencephaly (± facial defects) • Ventriculomegaly • Microcephaly • IUGR • Abnormal hands or feet 6 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 37 38 Trisomy 13 Turner Diagnostic Medical Sonography: Obstetrics & Gynecology, 3rd Ed. (Raatz Stephenson fig 28‐25) 39 40 Turner • Affects females • Part or all of one X chromosome is absent (45,X0) • Characteristic physical abnormalities • Short stature, lymphedema, low‐set ears, webbed neck, broad chest, low hairline, and streak ovaries • 98% abort spontaneously • May have significant associated medical problems 41 Turner – most common sonographic markers • Cystic hygroma • Non‐immune hydrops • Edema • Pleural effusions • Ascites • Cardiac anomalies Most common 42 Turner – markers Triploidy Diagnostic Medical Sonography: Obstetrics & Gynecology, 3rd Ed. (Raatz Stephenson fig 28‐18) 7 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 43 44 Triploidy • • • A complete third set of chromosomes • Total of 69 chromosomes (rather than 46) Cause of triploidy Result Spermatocyte fails to divide in meiosis I or II Extra set of paternal chromosomes Majority abort spontaneously (> 99%) Oocyte fails to divide in meiosis I or II Extra set of maternal chromosomes Survivors to birth will have severe IUGR and multiple birth defects • Incompatible with life – die hours to days after birth Ovum fertilized by two sperm (dispermy) Extra set of paternal chromosomes 45 • In 60‐75% of cases the extra set is paternally derived • 69XXY – 60% • 69XXX – 37% • 69XYY – 3% 46 Triploidy – a cause of GTD (partial mole) Triploidy – most common sonographic markers • Molar placenta (before 20 weeks GA) Most common • Thick, abnormal placenta formation • NB: normal placenta often seen (especially in 2nd/3rd trimester) • Severe asymmetric IUGR • Abnormal hands and feet • Heart anomalies x Triploidy from paternal source (maternal triploidy does not cause GTD) Ultrasonography in Obstetrics and Gynecology, 5th Edition, (Callen fig 29‐2) 47 48 Triploidy – markers Diagnostic Medical Sonography: Obstetrics & Gynecology, 3rd Ed. (Raatz Stephenson fig 28‐23) 8 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 49 50 Textbook of Diagnostic Sonography, 7th Edition (Hagen‐Ansert box 53‐2) 51 e.g. Aneuploidy acrostic • Can someone actually remember all of these markers? • It has been done! • Try making acronyms • A word where each letter stands for something • e.g. colours of the rainbow: ROY‐G‐BIV • Try making acrostics • A sentence where the first letter in each word stands for something • e.g. taxonomic classification system: Dumb King Philip Came Over From Great Spain 52 Trisomy 21 markers Need Nine Fish Here, Please Buy It Shoes Nuchal fold – thickened Nasal bone – short/absent Femur – short Humerus – short Pyelectasis – mild Bowel – echogenic Intracardiac foci Structural anomalies 53 Risk Factors for Aneuploidy 54 Risk Factors for Aneuploidy Advanced maternal age (> 35 years) Most common • Risk of a trisomy increases as maternal age increases • Risk of Turner or triploidy not affected by maternal age Advanced maternal age • Increased risk of trisomy 13, 18, and 21 • Previously affected child • • Abnormal triple screen plus PAPP‐A and dimeric inhibin A Turner and triploidy risk not affected by age • Most common Diagnostic Ultrasound, 5th Edition (Rumack fig. 31.1) 9 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 55 56 Screening for Aneuploidy • Majority of children with chromosome abnormalities are born to patients under 35 years of age • This population has more babies • Trisomy 21 is most common BUT most difficult diagnosis • Biochemical serum markers identify most but not all fetuses at risk • Invasive testing too expensive to offer to all patients • Also has a slight risk of fetal loss Screening for Aneuploidy 57 58 Screening for aneuploidy – tests • Maternal blood tests • Ultrasound Screening for Aneuploidy Maternal Blood Tests O.14.2 59 60 Maternal Blood Tests • Triple screen • Triple screen plus (5 screen) • Cell‐free DNA Maternal Blood Tests Triple Screen 10 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 61 62 Maternal Blood Tests Triple screen Maternal blood test that evaluates AFP, estriol, ß‐hCG • Triple screen 1. MSAFP 60% detection rate of chromosomal abnormalities • Note: trisomy 13 shows no characteristic patterns 63 • Alphafetoprotein detected in maternal blood • Protein produced by fetal liver • Decreased with trisomy 21 and 18 64 Triple screen Triple screen 2. Estriol 3. ß‐hCG • Estrogen produced by the placenta • Decreased with trisomy 21 and 18 65 • Human chorionic gonadotropin • Hormone produced by the placenta • Increased with trisomy 21 • Decreased with trisomy 18 66 Maternal Blood Tests Maternal Blood Tests Triple Screen Plus Triple screen plus (5 screen) Maternal blood test that evaluates AFP, estriol, ß‐hCG plus dimeric inhibin A, and PAPP‐A 11 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 67 68 Maternal Blood Tests Triple screen plus (5 screen) Triple screen plus (5 screen) 4. Dimeric inhibin A 5. PAPP‐A • Glycoprotein produced by the placenta • Pregnancy associated plasma protein A • Produced by embryo and placenta • 1st trimester levels: • Decreased from 8‐14 weeks GA suggest a risk of IUGR and trisomy 21 • 2nd • trimester levels: Double the normal level with trisomy 21 Dimeric inhibin A Used as part of a “quad” screen in Manitoba 69 70 Maternal blood tests – summary of results Trisomy Trisomy Trisomy 13 18 21 TRIPLE Test PLUS Screening for Down in Manitoba • Prior to 1987 – age only • 25% detection • 10% false positives • 1987‐1999 – age OR age & MSAFP • 35‐60% detection • Current – triple screen plus • >70% detection • 10% false positives MSAFP Estriol ß‐hCG Dimeric inhibin A PAPP‐A ↓ ↓ ↓ ‐ ‐ ↓ ↓ ↑ ↑ ↓ 71 2nd trimester 8‐14 weeks GA 72 Maternal Blood Tests Maternal Blood Tests Cell Free DNA Cell‐free DNA AKA Non‐invasive Prenatal Test (NIPT) AKA Harmony Prenatal Test • “99% accurate” bit.ly/3rVbWHi 12 ULTR‐3014 OBGYN Sonography 3 Module O.14: Abnormal Fetal Karyotype 1 Chromosomal Abnormalities – Part 1 73 74 Cell‐free DNA • Tests maternal blood for fetal DNA • Provides limited screening for chromosomes 21, 13, 18 and sex chromosomes • Must be ≥ 10 weeks GA • Results in about a week • Paid for by the patient in Manitoba ($495 in 2018) Module O.14 Abnormal Fetal Karyotype Chromosomal Abnormalities – Part 1 Continued in Part 2 13