Down Syndrome

Down syndrome is the commonest autosomal trisomy compatible with survival to adulthood. It results from an additional, third copy of chromosome 21 (trisomy 21). It produces a characteristic constellation of dysmorphic features, a broad range of medical comorbidities, and variable intellectual disability.

Full, structured, lifelong multidisciplinary care substantially improves both survival and quality of life. Intellectual disability is generally present to some degree.

The mechanisms are:

• Meiotic non-disjunction, which accounts for the great majority of cases. Risk increases substantially with advancing maternal age.
• Robertsonian translocation involving chromosome 21, which is less common. It carries distinct implications for recurrence risk in future pregnancies, particularly where a parent is a balanced translocation carrier.
• Mosaicism, which is less common and generally associated with a milder overall phenotype, reflecting a mixture of normal and trisomic cell lines.

Pathophysiology and genetics

• The additional copy of chromosome 21 produces a genetic dosage imbalance affecting expression of the numerous genes on this chromosome. The downstream effects on development and physiology account for the characteristic, broad phenotypic pattern. The precise mechanisms linking the dosage imbalance to each clinical manifestation remain an area of ongoing research.
• Standard trisomy 21 reflects non-disjunction during meiotic division of either the egg or, less commonly, the sperm. It accounts for the substantial majority of cases. The well established relationship between advancing maternal age and risk of meiotic non-disjunction underlies the rising incidence with maternal age.
• In Robertsonian translocation, the additional chromosome 21 material is attached to another chromosome (most commonly chromosome 14) rather than existing as a separate, free chromosome. It accounts for a small proportion of cases. It is particularly important where a parent is found to carry a balanced form of the same translocation. Recurrence risk for future pregnancies is then substantially elevated, compared with the generally lower risk for standard, non-disjunction related trisomy 21.
• Mosaic trisomy 21 reflects a post-zygotic non-disjunction event, producing a mixture of normal and trisomic cell lines in the same individual. It is generally, though not invariably, associated with a somewhat milder phenotype, reflecting the variable proportion of trisomic cells across tissues.

• Characteristic dysmorphic facial features typically prompt clinical suspicion at or shortly after birth. They include upslanting palpebral fissures, epicanthic folds, a flat nasal bridge, a small mouth with relative macroglossia, small ears, and a single palmar crease. Generalised hypotonia is a particularly notable, common finding in the newborn period.
• Congenital heart defects occur in a substantial proportion of affected individuals (approximately half). Atrioventricular septal defect is the most characteristic associated lesion, and the incidence of various other congenital heart defects is also increased. Full cardiac assessment, including echocardiography, is an essential component of initial evaluation in every newly diagnosed infant.
• Gastrointestinal anomalies include duodenal atresia, which presents with the characteristic "double bubble" radiographic sign and bilious vomiting shortly after birth. Hirschsprung disease occurs with substantially increased incidence. Coeliac disease also occurs with increased incidence later in childhood and warrants periodic screening.
• Hypothyroidism is more common, both congenital and acquired. It warrants routine newborn screening and ongoing, periodic surveillance throughout life.
• Atlantoaxial instability is an important consideration for certain physical activities and for anaesthetic and surgical positioning. Together with the comorbidities above, it requires proactive, structured surveillance.
• Susceptibility to infection is increased, reflecting relative immune dysfunction. The risk of leukaemia is substantially increased, both acute lymphoblastic and, particularly, acute megakaryoblastic leukaemia, which shows a striking, specific association with this condition.
• Obstructive sleep apnoea is more common, reflecting the combined effect of relative macroglossia, midface hypoplasia, and hypotonia on upper airway patency. These associations warrant clinical awareness and, where relevant, proactive screening.
• Intellectual disability is a universal feature, though its severity varies highly between individuals. The incidence of autism spectrum disorder and attention deficit hyperactivity disorder is increased.
• With advancing age, the risk of early-onset Alzheimer disease is substantially increased. The amyloid precursor protein gene is located on chromosome 21, and the additional copy increases production of this protein through a genetic dosage effect. This is an important consideration for long-term care planning for adults.

• Antenatal screening identifies a substantial proportion of cases before birth. It combines first-trimester screening with, increasingly, non-invasive prenatal testing using cell-free fetal DNA analysis.
• Non-invasive testing is a screening rather than a diagnostic approach. Definitive confirmation requires invasive diagnostic testing (chorionic villus sampling or amniocentesis, with karyotype or chromosomal microarray analysis).
• Postnatal diagnosis is generally suspected clinically from the characteristic dysmorphic features. Definitive confirmation is by karyotype analysis, which also identifies the underlying mechanism (standard trisomy, translocation, or mosaicism). This is directly relevant to genetic counselling about future reproductive risk.
• Initial newborn assessment following diagnosis includes full assessment for associated structural anomalies and comorbidities. This comprises echocardiography and thyroid function testing, and, where clinically indicated, assessment for duodenal atresia or Hirschsprung disease.
• Structured, ongoing surveillance continues throughout childhood and into adulthood, following established, published guidelines specific to this condition. Periodic, scheduled assessment addresses the associated comorbidities:
  • Regular thyroid function testing.
  • Audiological and ophthalmological assessment, given the increased incidence of hearing and visual impairment.
  • Periodic assessment for coeliac disease and, in adulthood, cognitive decline.

• Standard care is coordinated multidisciplinary management. It combines paediatric medical care for the full range of associated comorbidities with early intervention services, including physiotherapy, occupational therapy, and speech and language therapy. These are ideally started early in infancy, given evidence of benefit from early, proactive developmental support.
• Surgical management of any identified structural anomaly (cardiac defect, duodenal atresia, or Hirschsprung disease) follows the standard principles detailed under the relevant individual conditions. Down syndrome itself is not generally a contraindication to indicated surgical intervention. Outcomes for congenital heart defect repair are now generally comparable to those in children without Down syndrome.
• Structured educational support is tailored to the individual child's abilities and needs. Ongoing developmental and behavioural support addresses any associated autism spectrum disorder or attention deficit hyperactivity disorder features where present.
• Where atlantoaxial instability is identified or clinically relevant, take precautions regarding activities with a particular risk of neck injury or hyperextension. Position the patient carefully during any anaesthetic or surgical procedure.
• Routine, universal screening radiography for atlantoaxial instability in asymptomatic individuals is no longer generally recommended, given evolving evidence and guidance. Assessment is instead directed by any relevant clinical symptom or sign.
• Surveillance continues throughout adulthood. It addresses age-related comorbidities including early-onset Alzheimer disease, with continued monitoring for the other associated medical conditions. Structured support for the transition from paediatric to adult healthcare services underpins lifelong management of this common condition.
• Family support and genetic counselling are essential from the point of initial diagnosis and throughout the individual's life. They address the practical and emotional aspects of caring for a child with this condition, and the implications for future reproductive risk, which are directly informed by the underlying genetic mechanism identified on karyotype analysis. Connection to relevant support organisations and resources is part of family-centred care.