By Dr. Samuel ObasekiGPST2 2012

Background – Down’s SyndromeIs the most common and well studied

chromosomal autosomal disorder and a major cause of intellectual and physical disability with an incidence of about 1 in 700 births.

Mostly caused by trisomy of chromosome 21, leading to structural and functional defects in people born with the condition.

There is decreased prenatal, and postnatal viability and reduced life expectancy due to associated physical and health problems.

Genetics/etiology of Down’s Syndrome

Trisomy 21, 94% of cases. Occurs following nondysjunction during meiosis in one of the parents. Though this can occur with either parents’ advancing age, there is a stronger correlation with the maternal age.

Chromosomal translocation, 3.3%. When genetic material from chromosome 21 attaches to another chromosome (14, 21 or 22). Could be de novo (75%) or transmitted from the parents (25%).

Mosacism, 2.4%. Mostly from a trisomy zygote (after fertilization) that loses one chromosome leading to a mixture of trisomy 21 and normal karyotype autosomal cells. This results in a variety of phenotypes from near normal to classical trisomy 21 phenotype.

Genetics/epidermiology of Down’s Syndrome

Overall frequency 1 in 700 birthsA baby with down’s syndrome may be born to a mother at any age, but the risk increases with maternal age.Chances of having a baby with down’s syndrome is1 in 1600 < 20 years1 in 1500 at 20 years1 in 900 at 30 years1 in 270 at 35 years1 in 100 at 40 years1 in 50 if mum > 45 yearsA female patient with trisomy 21 has a 1 in 2 chance of having a child with down’s syndrome while male sufferers are usually infertile (those with mosacism being an exception).

Clinical features of Down’s syndromeThe physical and mental effects of Down’s syndrome are profound. General appearance - Short extremities and height, slanted eyes,

medial epicanthic folds, flat nasal bridge, protruding tongue, single simian crease etc

CNS - moderate to severe mental retardation, seizure disorders, and hypotonia in neonates.

Psychiatric – Usually very cheerful and gentle. ADHD, ASD, OCD, depression, early dementia.

Eyes - Brushfield spots (speckled iris), refractive errors, strabismus.

Facial features – Brachycephaly, large sutures with delayed closure, microcephaly, small ears with overfolded helix, flat facies, hypertelorism, anodontia, chronic otitis media and hearing loss,

Broad sort neck with antlantoaxial instability and possible cord compression.

CVS – Congenital defects like endocardial cushion defect, VSD, secundum ASD, TOF, PDA.

GUT – Duodenal atresia/stenosis, Hirschsprungs, omphalocele Hypothyroidism, leukaemia, Impaired cellular immunity.

UK screening criteria (Wilson & Jungner) The condition The condition should be an important health problem. The epidemiology and natural history of the condition, including development from latent

to declared disease, should be adequately understood and there should be a detectable risk factor, disease marker, latent period or early symptomatic stage.

All the cost-effective primary prevention interventions should have been implemented as far as practicable.

If the carriers of a mutation are identified as a result of screening, the natural history of people with this status should be understood, including the psychological implications.

The test There should be a simple, safe, precise and validated screening test. The distribution of test values in the target population should be known and a suitable

cut-off level defined and agreed. The test should be acceptable to the population. There should be an agreed policy on the further diagnostic investigation of individuals

with a positive test result and on the choices available to those individuals. If the test is for mutations the criteria used to select the subset of mutations to be

covered by screening, if all possible mutations are not being tested, should be clearly set out.

The treatment There should be an effective treatment or intervention for patients identified through

early detection, with evidence of early treatment leading to better outcomes than late treatment. There should be agreed evidence-based policies covering which individuals should be offered treatment and the appropriate treatment to be offered.

Clinical management of the condition and patient outcomes should be optimised in all healthcare providers prior to participation in a screening programme.

Down’s Syndrome ScreeningIs co-ordinated in the UK by the UK National

Screening Committee which provides advice through its antenatal and newborn screening programmes.

NHS Fetal Anomaly Screening Programme – Screening tests are offered to ALL pregnant women. Those at increased risk are then offered diagnostic tests.

NHS Newborn and Infant Physical Examination (NIPE) Programme – Examination of all infants within 72 hours of birth and around 6 – 8 weeks of life.

Down’s syndrome screening - AntenatalScreening tests – Offered to all women

Combined screening test - from 10 weeks + 0 days to 14 weeks + 1 day. Maternal serum levels of beta hCG and Pregnancy Associated Plasma Protein - A (PAPP-A) + Nuchal Transluscency (NT) scan done between 11weeks + 2 days and 14weeks + 1 day.

Quadruple test – from 14 weeks + 2 days to 20 weeks + 0 days. Maternal serum beta hCG, alphafetoprotein (AFP), inhibin A, and unconjugated oestriol (uE3).

Diagnostic tests – Offered to those with a risk between 1 in 2 and 1 in 150 Chorionic Villus Sampling (CVS). Ultrasound guided

transabdominal or transcervical aspiration of placenta from 11+0 weeks to 12+6weeks (up to 13+6weeks for transabdominal)

Amniocentesis. Ultrasound guided transabdominal aspiration of amniotic sac fluid for cytogenetics, from 15+0 weeks.

Down’s syndrome screening - NewbornAs part of the ‘Baby check’, the phenotypic

features of Down’s syndrome may be recognized and a diagnosis made at the Newborn Physical Examination or at the 6 – 8 week Infant Physical Examination. Note that those with mosacism may be quite difficult to recognize by just the physical examination.

Chromosomal analysis may be offered in suspected/recognized cases of Down’s syndrome. Presence of chromosomal translocation will suggest a much increased chance of recurrence if inherited from either parent.

All neonates with Down’s syndrome should be screened for congenital heart disease.

Down’s Syndrome screeningAbout a quarter of babies born with Down’s

syndrome are not detected by the screening tests.Results of diagnostic tests eg CVS and

amniocentesis may take between 3 and 18 days.1 in every 30 women screened will be offered a

diagnostic test.Foetal loss with CVS and amniocentesis is

approximately 1 – 2%. Other complications include preterm labour, bleeding and infection etc.

In 2% of diagnostic tests, sample may be deemed inadequate.

With multiple gestation pregnancies, there is a higher incidence of false positive screening tests and complications following diagnostic tests.

Down’s syndrome screening For affected pregnancies, offer the parents

support and specialized counselling services.Parents may be signposted to –

Antenatal Results and Choices (ARC)Contact a family (CAFAMILY)Down’s Syndrome AssociationDown’s Syndrome Medical Interest GroupNHS Fetal Anomaly Screening Programme

Down’s syndrome screeningReferences –

www.gpnotebook.com www.emedicine.com www.mapofmedicine.com www.arc-uk.org RCOG guidelines for Amniocentesis and CVS