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UNSW Embryology

Abnormal Development - Trisomy 18 (Edwards Syndrome)

© Dr Mark Hill (2011)

Acknowledgements

Introduction

First recognized as a specific clinical entity by the discovery of an extra chromosome 18 in babies with a particular pattern of malformation by three independent groups (Edwards et al., Patau et al., Smith et al.).

Page Links: Introduction | Some Recent Findings | Mother's Age and Risk of Having a Baby With a Chromosomal Abnormality | Screening strategies for Down's syndrome | Checking your baby's health before birth | References | WWW Links | Glossary

Some Recent Findings

Prenatal Diagnosis

Chitty LS, Kagan KO, Molina FS, Waters JJ, Nicolaides KH. Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ. 2006 Feb 13

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME. First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-2011. A large team of clinical researchers have compared the effectiveness of first and second trimester screening methods for this chromosome 21 trisomy disorder "First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates." First-trimester combined screening - nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], free beta subunit of hCG (10 weeks 3 days through 13 weeks 6 days of gestation) Second-trimester quadruple screening - alpha-fetoprotein, total hCG, unconjugated estriol, and inhibin A at (15 through 18 weeks of gestation). (NEMJ Nov 10) NEMJ - Down's Syndrome Screening Article

This entry from Pedbase (click here to see original internet entry)

Pediatric Database (PEDBASE) Last Updated: 11/12/93

TRISOMY 18 SYNDROME

DEFINITION: A chromosomal disorder resulting in a syndrome characterized by specific (small) dysmorphic features and organ malformations.

EPIDEMIOLOGY:

HISTORY:

PATHOGENESIS:

1. Genetics

1. Trisomy 18

  • 90% of cases
  • due to meiotic nondisjunction
  • less than 1% recurrence rate

2. Mosaicism

  • 10% of cases
  • due to postzygotic (postfertilization) mitotic nondisjunction
  • leads to the partial clinical expression of Trisomy 18 with a longer survival

3. Translocations

  • very rare
  • give rise to partial trisomy 18 syndromes
  • short arm:
    • causes non-specific clinical features with mild or no mental deficiency
  • long arm:
    • entire:
      • clinically indistinguishable from trisomy 18
    • distal 1/3 -> :
      • partial clinical picture of trisomy 18 with a longer survival and less profound mental retardation

CLINICAL FEATURES:

1. Dysmorphic Features

1. Facial

  • microcephaly with prominent occiput
  • narrow bifrontal diameter
  • short palpabral fissures
  • low-set malformed ears
  • cleft lip +/- palate
  • narrow palatal arch
  • micrognathia

2. Skeletal

  • neck
  • webbed
  • chest
    • short sternum
    • widely spaced nipples
  • hips:
    • small pelvis, congenital dislocation of the hips, limited hip abduction
  • extremities:
    • phocomelia
    • rockerbottom feet or equinovarus
    • short dorsiflexed big toes
    • fixed flexion deformity of the fingers (overlapping of the 2nd and 5th fingers over the 3rd and 4th fingers)
    • simple arch pattern of the fingers and toes
    • hypoplasia of fingernails
    • single crease of 5th finger or all fingers (absence of interphalangeal flexion creases)
    • simian crease

2. Organ Malformations

1. Central Nervous System

  • severe mental retardation
  • hypotonia -> hypertonia
  • neural tube defects
  • poor suck and weak cry
  • failure to thrive
  • ocular anomalies

2. Respiratory

  • apnea

3. Cardiovascular( >95%)

  • major: VSD, ASD, PDA
  • minor: transposition, ToF, coarctation, anomalous coronary artery, dextrocardia, aberrant subclavian artery, arteriosclerosis, PS, bicuspid aortic and/or pulmonic valves

4. Gastrointestinal

  • inguinal, umbilical, and/or diaphragmatic hernia
  • congenital defects:
    • diastasis recti, heterotopic pancreas, malrotation, Meckel's, tracheoesophageal fistula

5. Genitourinary

  • cryptorchidism
  • congenital defects:
    • double ureter, ectopic kidney, horseshoe kidney, hydronephrosis, polycystic kidney

INVESTIGATIONS:

1. Imaging Studies

2. Karyotyping

MANAGEMENT:

1. Supportive

Mother's Age and Risk of Having a Baby With a Chromosomal Abnormality

(see references)

Age of Mother

Risk of Down Syndrome

Risk of Any Chromosomal Abnormality

20

1 in 1667

1 in 526

21

1 in 1667

1 in 526

22

1 in 1429

1 in 500

23

1 in 1429

1 in 500
24

1 in 1250

1 in 476

25

1 in 1250

1 in 476

26

1 in 1176

1 in 476

27

1 in 1111

1 in 455

28

1 in 1053

1 in 435

29

1 in 1000

1 in 417

30

1 in 952

1 in 384

31

1 in 909

1 in 384

32

1 in 769

1 in 323

33

1 in 625

1 in 286

34

1 in 500

1 in 238

35

1 in 385

1 in 192

36

1 in 294

1 in 156

37

1 in 227

1 in 127

38

1 in 175

1 in 102

39

1 in 137

1 in 83

40

1 in 106

1 in 66

41

1 in 82

1 in 53

42

1 in 64

1 in 42

43

1 in 50

1 in 33

44

1 in 38

1 in 26

45

1 in 30

1 in 21

46

1 in 23

1 in 16

47

1 in 18

1 in 13

48

1 in 14

1 in 10

49

1 in 11

1 in 8

References

Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstetrics and Gynecology 58:282-285, 1981 (Data USA sourced)

Hook EB, Cross PK, Schreinemachers DM.Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983 Apr 15;249(15):2034-8.

Schreinemachers DM, Cross PK, Hook EB. Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births. Hum Genet. 1982;61(4):318-24.

Screening strategies for Down's syndrome

Procedure

Detection rate

First trimester screening (10 to 14 weeks):

  Maternal age

  Nuchal translucency measurement (by ultrasound)

  First trimester double test (PAPP-A, HCG)

  First trimester combined test (nuchal translucency, PAPP-A, HCG)

 

32%

74%

63%

86%

Second trimester screening (15 to 19 weeks):

  Maternal age

  Second trimester double test (AFP, HCG)

  Triple test (AFP, HCG, uE3)

  Quadruple test (AFP, HCG, uE3, inhibin A)

  Integrated test (first trimester: nuchal translucency, PAPP-A; second trimester: quadruple test)

 

32%

60%

68%

79%

95%

Prenatal diagnosis:

  Amniocentesis (15 weeks)

  Chorionic villus sampling (11-14 weeks)

 

100%

100%

Data from United Kingdom: Gilbert etal., British Medical Journal 2001; 323: 423)

AFP = fetoprotein, HCG = human chorionic gonadotrophin, PAPP-A = pregnancy associated plasma protein A, uE3 = unconjugated oestriol.

Termination: Surgical dilatation, evacuation (11 to 13 weeks), Medical with mifepristone (14 weeks)

Checking your baby's health before birth.

Below is the NSW State Health Publication Checking your baby's health before birth. This Pamphlet is an example of the information made available to the general public on the diagnostic testing that can be carried out to check the genetic/physical status of the fetus.

Links: Ultrasound | Chorionic Villus Sampling (CVS)Amniocentesis

PRENATAL DIAGNOSIS

Every couple wants to have a healthy baby. For most couples, that will come true. However, there are some couples who have a greater chance than others of having a baby with a birth defect.

Special tests are available which are carried out during pregnancy to determine if the baby has a particular problem. These tests are generally referred to as prenatal diagnosis.

Some reasons why you should ask your doctor about prenatal diagnosis:

Can all birth defects be detected by prenatal diagnosis?

How is prenatal testing done?

Ultrasound

Chorionic Villus Sampling (CVS)

Amniocentesis

What happens if the results of the test show a birth defect?

How can I find out more about prenatal diagnosis?

Further information can be obtained front the following centres. They specialise in prenatal diagnosis and related genetic counselling:

Camperdown

King George V Hospital
Fetal Medicine Unit
Camperdown NSW 2050
Tel: (02) 9515 8258

Royal Alexandra Hospital for Children- This Hospital has now moved to Westmead Campus as The Childrens Hospital.

Westmead

Westmead Centre
Fetal Medicine Unit
Westmead NSW 2145
Tel: (02) 9633 6800

Paddington - Royal Hospital for Women - This Hospital has now moved to Prince of Wales Campus

Randwick

Prince of Wales Children's Hospital
Department of Medical Genetics
Randwick NSW 2031
Tel: (02) 93994591

St Leonards

Royal North Shore Hospital
Fetal Medicine Unit
St Leonards NSW 2065
Tel: (02) 9438 7280

Penrith

Nepean Hospital
Fetal Medicine Unit
Penrith NSW 2750 Tel: (047) 924 2114

Newcastle

John Hunter Hospital
Prenatal Diagnosis Unit
Newcastle NSW 2310
Tel: (049) 921 4694

For information on services in other areas:

Genetic Education Program, Tel: (02) 438 7324 (Note: phone numbers in NSW are now 9438 7324)


Written in association with the NSW Genetic Education Program

PO. Box 317, St Leonards, NSW 2065. Tel: (02) 9438 7324.

State Health Publication Number (PA) 94-090

NHMRC Recommendations

The Australian NHMRC(1988) recommends neonates be assessed for follow-up care under the following conditions.

(see the NHMRC WWW Page)

References

Reviews

Benn PA. Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin Chim Acta. 2002 Oct;324(1-2):1-11.

Maymon R, Jauniaux E. Down's syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod Biomed Online. 2002 May-Jun;4(3):285-93.

Souter VL, Nyberg DA. Sonographic screening for fetal aneuploidy: first trimester. J Ultrasound Med. 2001 Jul;20(7):775-90.

Jackson M, Rose NC. Diagnosis and management of fetal nuchal translucency. Semin Roentgenol. 1998 Oct;33(4):333-8. Review.

Menendez M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 2005 Jun;27(4):246-52.

FitzPatrick DR. Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. Trends Genet. 2005 May;21(5):249-53.

Articles

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME. First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-2011.

Hook EB, Cross PK, Schreinemachers DM.Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983 Apr 15;249(15):2034-8.

Schreinemachers DM, Cross PK, Hook EB. Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births. Hum Genet. 1982;61(4):318-24.

Checking your baby's health before birth. State Health Publication Number (PA) 94-090

New triple screen test for Down syndrome: combined urine analytes and serum AFP. Bahado-Singh RO, et al. [See Related Articles] J Matern Fetal Med. 1998 May-Jun;7(3):111-4.

Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies R E Gilbert, C Augood, R Gupta, A E Ades, S Logan, M Sculpher, J H P van der Meulen, Euan M Wallace, and Sheila Mulvey BMJ 2001; 323: 423 (link to paper)

Noninvasive means of identifying fetuses with possible Down syndrome: a review. Kubas C. J Perinat Neonatal Nurs 1999 Sep;13(2):27-46 Women who are 35 years or older are offered invasive prenatal testing because of the increased risk of chromosomal abnormalities, especially Down syndrome. In an attempt to increase the number of Down syndrome fetuses being detected and decrease the number of invasive procedures being performed on pregnancies not affected with a chromosome abnormality, both biochemical and ultrasound screening methods are being studied and are summarized in this article.

The ultrasound markers reviewed include increased nuchal thickness, increased nuchal lucency, shortened femur, shortened humerus, pyelectasis, hypoplastic ears, echogenic intracardiac focus, hypoplasia of the fifth middle phalanx, and echogenic bowel.

WWW Links

Trisomy Organization http://www.trisomy.org/

Better Health Victoria trisomy disorders

Support Organization for Trisomy 18, 13, and Related Disorders

S.O.F.T. Chicago

See also Virtual Hospital male Karyotype (Virtual Hospital inactive)

Glossary of Terms

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers

Where to Next?

You should look at Development Notes for early normal development. In particular, look at the first week of development following fertilization.

Quick Links

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