Down’s syndrome (DS), also known as trisomy 21, is the most common congenital chromosomal abnormality, occurring in about 1 in 800 to 1 in 1000 live births.1,2 The presence of additional genetic material from chromosome 21 results in characteristic phenotypic features and increased morbidity through its effect on multiple organ systems. The major cause of early mortality in Down’s syndrome is congenital heart disease.3,4 Despite this, many people with Down’s syndrome live happy and fulfilling lives, developing at their own pace and receiving coordinated care to manage comorbidities.
Trisomy 21 typically occurs via one of the following mechanisms:4,5
Meiotic non-disjunction of the maternal chromosome 21 (95%)
Robertsonian translocation of unbalanced chromosomal material, usually between chromosome 14 and chromosome 21 (4%)
Maternal age is the strongest risk factor for Down’s syndrome.23
Table 1. Risk of Down’s syndrome (live births) in relation to maternal age at delivery, prior to screening in pregnancy.4
Maternal age (years)
Risk of Down’s syndrome
1 in 650
1 in 1530
1 in 900
1 in 385
1 in 240
1 in 110
1 in 37
Dysmorphic features which may be noted in neonates with Down’s syndrome are described below.2,7
Hypotonia: this may cause difficulties with feeding
Oblique palpebral fissures
Flat nasal bridge
Brachycephaly (flat occiput)
Dysplastic, low-set, small ears
Open mouth with protruding or furrowed tongue
High arched palate
Short neck with excessive skin at the nape of the neck
Transverse palmar crease (Simian crease)
Short and incurved little finger
Large gap between the first and second toes (“sandal toe deformity”)
Congenital heart defects
Approximately 50% of neonates with DS will have associated congenital heart disease.
The most common forms of congenital heart disease are: 2-4,7,10
Complete atrioventricular septal defect (37%)
Ventricular septal defect (31%)
Atrial septal defect (15%)
Developmental delay and intellectual disability
Developmental milestones are frequently delayed in Down’s syndrome.
Intellectual disability is an almost universal feature of Down’s syndrome which can vary significantly in severity.
Autism, attention deficit hyperactivity disorder (ADHD) and aggressive behaviour are also more prevalent in Down’s syndrome.20
Alzheimer’s disease develops in up to 75% of DS patients by the sixth decade of life.8,9,20.
Asthma and obstructive sleep apnoea are more common in Down’s syndrome.1
Gastrointestinal tract anomalies requiring surgery occur in about 12% of patients with Down’s syndrome.1 The most characteristic anomaly is duodenal atresia caused by a failure of the intestine to recanalize during development.7,11 Other structural gastrointestinal anomalies may include imperforate anus and/or tracheo-oesophageal fistula.
Down’s syndrome is also associated with an increased risk of Hirschsprung disease.7
Endocrine diseases most commonly associated with Down’s syndrome include hypothyroidism and type 1 diabetes mellitus.
Down’s syndrome is associated with an increased risk of developing several different haematological disorders including:1,7,14,15
Transient myeloproliferative disorder
Acute megakaryoblastic leukaemia
Acute lymphoblastic leukaemia
Other clinical features
Other clinical features associated with Down’s syndrome include (but are not limited to):
Short stature and obesity
Ophthalmological disorders including cataracts, refractive disorders, nystagmus, strabismus and glaucoma
Orthopaedic disorders such as atlanto-axial instability, hyperflexibility, hip dislocation and foot deformities
Recurrent acute otitis media 1
Benign skin disorders such as hyperkeratosis and seborrhoeic dermatitis
Urological abnormalities such as hypospadias and cryptorchism
Juvenile idiopathic arthritis
Differential diagnosis of Down’s syndrome includes, but is not limited to: 5,24
49 XXXXY chromosome and high-order X chromosome disorders
Zellweger syndrome (or other peroxisomal disorders)
Screening for Down’s syndrome
Pre-natal screening is currently the most common means through which Down’s syndrome is identified and eventually diagnosed. Screening tests along with other data such as maternal age, weight, family origin and gestation are combined in software to calculate the probability of a fetus having Down’s syndrome. The screening test is considered positive if the risk of a fetus having Down’s syndrome is greater than 1 in 150. If the screening test returns a positive result, women are offered diagnostic testing.
Down’s syndrome screening most commonly involves:
Serum screening: assessment of a range of biomarkers in the serum between 10-14 weeks + 1 day of gestation.
Nuchal translucency scanning: ultrasound is used to assess the translucency of the nuchal pad at the nape of the fetal neck between 11 weeks + 2 days and 14 weeks + 1 day gestation. Increased nuchal translucency is associated with Down’s syndrome.
Serum screening and nuchal translucency scanning are typically used in combination (known as ‘the combined test‘).
The standard serum screen measures the following biomarkers:
Beta-hCG: raised in Down’s syndrome
PAPPA-A: decreased in Down’s syndrome
If a woman engages with antenatal care later in pregnancy when nuchal translucency scanning is less reliable, a different set of biomarkers are assessed (known as ‘the quadruple test‘):
Beta-hCG: raised in Down’s syndrome
AFP: low in Down’s syndrome
Inhibin A: raised in Down’s syndrome
Unconjugated estriol (uE3): low in Down’s syndrome
The quadruple test is less reliable than the combined test.
Non-invasive prenatal testing (NIPT)
During pregnancy, the placenta sheds cell-free DNA (cfDNA) into the mother’s bloodstream. As a result, the mother’s blood contains a mixture of placental and maternalcfDNA. By evaluating the cfDNA in the blood and combining this with the mother’s background chance of a trisomy (mother’s age or the combined test results), a likelihood ratio is obtained to predict whether or not the baby is more likely to have a chromosomal condition such as Down’s, Edward’s or Patau’s syndrome. It is possible from around 10 weeks gestation and has a sensitivity of around 99%.17-20
This test is not currently part of the routine screening pathway.
Confirming the diagnosis of Down’s syndrome
Karyotype analysis of fetal cells via chorionic villus sampling (9–12 weeks gestation) or amniocentesis (15–19 weeks gestation) is the gold standard for diagnosing Down’s syndrome, with equal detection rates of around 99%. There is a higher risk of pregnancy loss with chorionic villus sampling compared to amniocentesis.19
Given the association of Down’s syndrome with a wide range of pathologies, it is essential that comprehensive screening is performed in the post-natal period to allow early identification and management of these complications.
Some examples of post-natal investigations include:
Echocardiography: to screen for congenital cardiovascular abnormalities
Red reflex testing: to screen for congenital cataracts
TFTs: to screen for congenital thyroid disease
FBC: to screen for myeloproliferative disorders and polycythaemia
Hearing assessment: to screen for congenital hearing issues
Radiographic swallowing assessment: performed if feeding difficulties are present to screen for gastrointestinal abnormalities (e.g. duodenal atresia)
Management of Down’s syndrome requires a tailored multidisciplinary approach to screen, diagnose and treat complications. Patients with Down’s syndrome often require ongoing regular review from relevant specialists.
If a newborn is diagnosed with Down’s syndrome, parents should be referred for genetic counselling to discuss the risk of further children having Down’s syndrome.
Down’s syndrome is caused by the presence of additional genetic material from chromosome 21.
Clinical features of Down’s syndrome are wide-ranging including dysmorphic features, cognitive impairment and a multitude of other medical conditions.
The biggest risk factor for Down’s syndrome is maternal age.
Prenatal screening provides a method for assessing the risk of Down’s syndrome through the assessment of serum biomarkers and nuchal translucency.
Prenatal diagnosis of Down’s syndrome can be achieved through chorionic villus sampling or amniocentesis.
Post-natal screening investigations are essential to allow early identification of Down’s syndrome complications.
Management of Down’s syndrome requires a tailored multidisciplinary approach to screen, diagnose and treat complications.
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