Down Syndrome (Trisomy 21)

Primer

Down Syndrome (Trisomy 21) is the most common identifiable genetic cause of intellectual disability. It is due to the presence of all or part of a third copy of chromosome 21. Individuals with Down syndrome have a characteristic facial appearance and hypotonia in infancy. About half are born with a heart defect.

Epidemiology
  • Typically, below the age of 10, individuals with Down syndrome are cheerful, placid, cooperative, and adapt easily at home.[1]
    • When adolescence is reached, however, social, emotional, and behavioural difficulties begin to emerge, and there is also an increased risk for psychotic disorders.[2]
  • The average prevalence of Down syndrome is 1 in 700 individuals
  • The risk for having an offspring with Down syndrome varies; it generally is much lower with younger maternal age, with a 1 in 1500 chance in women age <20. In women older than 45 years old the risk is 1 in 25.[3]
Prognosis
  • It is the most common viable chromosomal disorder, and most individuals are able to survive into adulthood.
  • Around 75% of adults with Down syndrome survive to age 50, and 25% will survive to age 60.
  • A core feature of aging in Down syndrome is the progressive accumulation of Alzheimer's brain pathology including senile plaques and neurofibrillary tangles. Almost all individuals will have these findings by age 40.[4]
Comorbidity
  • Individuals with Down syndrome have a significantly higher risk for developing early-onset Alzheimer's dementia.[5]
    • By age 40, up to 33% of individuals have a clinical diagnosis of dementia.[6] The incidence is as high as 77% by age 60.
Risk Factors
  • Advanced maternal age is a risk factor for the ofspring being born with Down Syndrome.[7]

Diagnosis

Mnemonic

The mnemonic the 5 A's of Down Syndrome can be used to remember the features associated with Down syndrome.
  • A - Advanced maternal age
  • A - Alzheimer's disease (early)
  • A - Acute Myeloid Leukaemia (AML)/Acute lymphocytic leukemia (ALL)
  • A - Atrioventricular septal defects
  • A - Atresia (duodenal)

Pathophysiology

  • In the majority of cases, Down syndrome is not hereditary.
  • 95% of cases are due to meiotic nondisjunction secondary to increased risk from maternal ageing. A minority (4%) of cases due to unbalanced Robertsonian translocation, usually between chromosomes 14 and 21. Even more rarely, about 1% of cases are due to post-fertilization mitotic errors.

Neuropsychiatric Symptoms

Investigations

  • Prior to birth, on first-trimester ultrasound will show nuchal translucency and hypoplastic nasal bone
  • Maternal serum will show elevated hCG and inhibin.[8]

Physical Exam

On examination, individuals will have:

  • Intellectual disability, flat facies, prominent epicanthal folds
  • Examination of the hands shows a single palmar crease, incurved fifth finger, and a gap between the first two toe digits
  • Cardiovascular: atrial septal defect, congenital heart disease
  • Gastrointestinal: duodenal atresia, Hirschsprung disease

Treatment

Resources

For Patients

For Providers

Articles
Research

References

1) Sadock, B. J., Sadock, V. A., & Ruiz, P. (2015). Kaplan & Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (Eleventh edition.). Philadelphia: Wolters Kluwer.
2) Sadock, B. J., Sadock, V. A., & Ruiz, P. (2015). Kaplan & Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (Eleventh edition.). Philadelphia: Wolters Kluwer.
3) Asim, A., Kumar, A., Muthuswamy, S., Jain, S., & Agarwal, S. (2015). Down syndrome: an insight of the disease. Journal of biomedical science, 22(1), 41.
4) Head, E., Powell, D., Gold, B. T., & Schmitt, F. A. (2012). Alzheimer's Disease in Down Syndrome. European journal of neurodegenerative disease, 1(3), 353–364.
5) Glasson, E. J., Sullivan, S. G., Hussain, R., Petterson, B. A., Montgomery, P. D., & Bittles, A. H. (2002). The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clinical genetics, 62(5), 390–393.
6) Head, E., Silverman, W., Patterson, D., & Lott, I. T. (2012). Aging and down syndrome.
7) Allen, E. G., Freeman, S. B., Druschel, C., Hobbs, C. A., O’Leary, L. A., Romitti, P. A., ... & Sherman, S. L. (2009). Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Human genetics, 125(1), 41-52.
8) Noble, P. L., Wallace, E. M., Snijders, R. J. M., Groome, N. P., & Nicolaides, K. H. (1997). Maternal serum inhibin‐A and free β‐hCG concentrations in trisomy 21 pregnancies at 10 to 14 weeks of gestation. BJOG: An International Journal of Obstetrics & Gynaecology, 104(3), 367-371.