13th March 2024

Down’s syndrome

Pathophysiology

Down’s syndrome is the most common genetic cause of cognitive disability worldwide and occurs as a result of individuals having an extra copy of chromosome 21 (trisomy 21). It is associated with a range of dysmorphic features and a higher prevalence of medical conditions, including congenital heart defects. Around 95% of those with trisomy 21 are caused by chromosome non-disjunction. Less commonly, trisomy 21 is a result of chromosome translocation or mosaicism.

Diagnosis is most often through prenatal screening, although individuals may be diagnosed after birth through phenotypic features and genetic testing.

Clinical manifestations

Down’s syndrome is associated with a number of characteristic facial features, including up-slanting palpebral fissures and epicanthic folds around the eyes, a flat nasal bridge, low-set ears, brachycephaly, and protruding tongue. Other dysmorphic features include a sandal gap between the first and second toes and transverse palmar crease. 

It affects a range of body systems, with individuals being more likely to experience gastrointestinal conditions, including duodenal atresia and coeliac disease, endocrine conditions, typically thyroid disease or type 1 diabetes mellitus.

The majority of individuals with Down’s syndrome will have some level of cognitive impairment and have a higher risk of developing dementia. 

Others with Down’s syndrome may experience haematological conditions such as polycythaemia and leukaemia and respiratory conditions, including obstructive sleep apnoea.

Cardiovascular manifestations

Around half of those with Down’s syndrome will have congenital heart disease. The most common congenital heart defect is atrioventricular septal defect. Other anomalies include ventricular septal defect, atrial septal defect, tetralogy of Fallot and patent ductus arteriosus. 

Individuals with Down’s syndrome can develop cardiac valve problems, most commonly mitral valve prolapse or aortic regurgitation.

Atrioventricular septal defect

In normal development, there is a canal connecting the atria and ventricles known as the AV canal. Typically, at 4 weeks gestation, the endocardial cushions which form the canal fuse and create the atrioventricular (AV) valves and septum. Incorrect fusion of the endocardial cushions results in an AV septal defect (AVSD) and left to right shunt. 

AVSD can be divided into complete and partial. A complete AVSD results in an ostium primum atrial septal defect (ASD), a ventricular septal defect (VSD) and a single AV valve due to complete failure of the endocardial cushions to fuse. Complete AVSD is more common than partial AVSD in Down’s syndrome. A partial AVSD is a result of incomplete fusion of the endocardial cushions and leads to an ostium primum ASD and a VSD but with separate AV valves with a cleft mitral valve. ASVD may present with the following: 

• Tachypnoea
• Tachycardia
• Pallor
• Poor feeding and weight gain

Diagnostics

Down’s syndrome can be diagnosed before birth through antenatal screening followed by amniocentesis or chorionic villus sampling. It may also be diagnosed postnatally based on physical characteristics and confirmed by genetic testing in the form of chromosomal karyotype.

A paediatric cardiologist should review all newborn babies diagnosed with Down’s syndrome and have an echocardiogram to assess for congenital heart defects.

Management

Children with complete AVSD will require surgical repair, typically performed between ages 3-6 months. Life-long follow-up is required due to the risk of AV valve regurgitation or LVOT obstruction.

Continued clinical monitoring in adolescence and adulthood is required to monitor for mitral valve prolapse and aortic regurgitation.

References

• UpToDate – Down syndrome: Clinical features, diagnosis and management
• BMJ Best Practice – Down’s syndrome
• BMJ Best Practice – Congenital heart disease
• StatPearls – Atrioventricular Septal Defect – https://www.ncbi.nlm.nih.gov/books/NBK562194/