2 cases of congenital abnormality

Lent term year 1

Case 1• A 27 year old woman becomes pregnant

and undergoes a triple test at 14 weeks gestation

• The results showed:

AFP 56.7 kU/l 0.6 MoM

hCG 32.2 IU/ml 3.97 MoM

uE3 2.9 nmol/L 0.56 MoM

• i.e. Risk for Down syndrome 1:100

The analytes:

• AFP: alphafetoprotein. Produced by yolk sac and fetal liver. Excreted into amniotic fluid via fetal urine. Crosses placenta into maternal circulation

• hCG: human chorionic gonadotrophin. Glycoprotein produced by trophoblast. Beta sub-unit specific for pregnancy

• UE3: unconjugated oestriol. Synthesised in placenta

Then….

• She undergoes amniocentesis, which confirms the baby has Down syndrome

Down syndrome

• Features of Down syndrome

• Screening: triple test/ultrasound

• Diagnosis: chromosome tests

• Outcome

What is Down syndrome?• Clinical syndrome described by John

Langdon Down in 1866

• Trisomy 21 in 90% cases identified by Prof Lejeune in 1959

Clinical features• Epicanthic folds

• Single palmar crease

• Flat occiput

• Macroglossia

• Cardiac murmur (1:3 congenital heart disease)

• Poor muscle tone/feeding/weight gain

• Developmental and learning delay

Assessing the risk for Down syndrome pregnancy

• Maternal age

• “Triple test”

• ultrasound

Maternal age at term

• <25 1:1500

• 27 1:1200

• 30 1:910

• 35 1:380

• 40 1:110

• 45 1:30

The “triple test”• Introduced to improve sensitivity and

specificity of testing

• Uses 3 analytes: AFP(alphafetoprotein), hCG (human chorionic gonadotrophin) and uE3 (uncongugated Oestriol)

• Combines with maternal age to give risk

In Down syndrome:

• AFP lower – on average 0.7 MoM

• hCG higher

• uE3 lower

• Offered as part of NHS Antenatal and Newborn Screening Programme

• http://www.screening.nhs.uk/downs/home.htm

Ultrasound: Nuchal translucency

Assessing risk

• Offer amniocentesis if risk >1:250

• May combine triple and nuchal screening test to improve sensitivity and specificity of risk

Amniocentesis

Chromosome tests

• Culture and staining

• PCR (polymerase chain reaction)

• FISH (Fluorescent in situ hybridisation)

Normal PCR

FISH (offered if risk>1:30)

outcome• In practice most parents opt for

termination of pregnancy• Individuals vary greatly in level of disability• High incidence of congenital heart

disease, duodenal atresia• Some children attend mainstream school

with help• Increased incidence of leukaemia and

Alzheimer’s disease in later life

Case 2• A 27 year old undergoes a triple test at 14

weeks gestation in her first pregnency

• The results showed:

AFP 126.7 kU/l 3.20 MoM

hCG 32.2 IU/ml 0.97 MoM

uE3 2.9 nmol/L 1.16 MoM

• She goes on to have an ultrasound at 16 weeks

What can cause a raised AFP?

Causes of a raised AFP (>2.0 MoM)

• Lab error/wrong gestational age• Multiple pregnancy• Hydatidiform mole (trophoblastic tumour)• Intrauterine death• Anencephaly• Other open neural tube defects: spina

bifida• Omphalocele/gastroschisis

“snowstorm effect”

Neural tube defects• Due to incomplete development of neural

tube from ectoderm• May present at different sites and different

grades of severity• Often associated with hydrocephalus• Not usually linked with chromosome

abnormality• Evidence that folic acid supplemants

reduce the incidence

In this case• The patient was referred for ultrasound

which showed a meningocele in the lumbar spine

What is the likely outcome in this pregnancy?

• Natural history difficult to predict from ultrasound

• Anencephaly incompatible with life after birth

• 50% babies with open SB survive after 5y

• Majority of survivors have major degree of disability: lower limb/bladder paralysis/hydrocephalus/learning disability

How would you manage these pregnancies?

• The majority of patients request termination

• In England, Scotland and Wales legal to 24 weeks under Abortion Act

• 2 doctors required to sign for clause E, which states: “there is a substantial risk that if a child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped”