Down syndrome (trisomy 21 syndrome)

Page most recently updated 7 September 2026

This page focuses on the reported psychiatric associations, which may be the initial presenting manifestation, and on other clinical features that may assist the psychiatrist or primary care physician in identifying the underlying diagnosis, considered through the lenses of the diagnostic lenses framework.

Down syndrome (trisomy 21 syndrome) is a genetic disorder that can affect neurodevelopment, mental health, and multiple organ systems. It can occur as a de novo genetic condition or, less commonly, as an inherited condition when caused by a familial chromosomal translocation; therefore, absence of a relevant family history does not exclude the diagnosis. A distinctive presentation may include the combination of a flat face, upslanted palpebral fissures, small ears, and hypotonia.

It can present with psychiatric features such as anxiety, depression, obsessive-compulsive symptoms, behavioural changes, social withdrawal, psychosis, and catatonia. Psychiatric manifestations can emerge during adolescence or adulthood, including psychosis and regression with loss of previously acquired functional, social, or language abilities. This pattern has been described as Down syndrome regression disorder. Later in adulthood, cognitive decline and dementia related to Alzheimer disease may also occur.

From a morphologic lens perspective, features include (but are not limited to):

  • Flat occiput

  • Flat face

  • Short neck

  • Epicanthus

  • Upslanted palpebral fissures

  • Depressed nasal bridge

  • Brachydactyly

  • Clinodactyly of fifth fingers

  • Single transverse palmar crease

Other characteristic features include developmental delay, intellectual disability, characteristic cognitive and learning difficulties, hypotonia, seizures in some individuals, and an increased risk of Alzheimer disease at a relatively young age.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

  • Cardiovascular: congenital heart disease, particularly atrioventricular septal defects, ventricular septal defects, atrial septal defects, and patent ductus arteriosus; pulmonary hypertension may also occur.

  • Respiratory: obstructive sleep apnoea, recurrent respiratory infections, and airway abnormalities.

  • Gastrointestinal: gastroesophageal reflux, constipation, coeliac disease, and congenital gastrointestinal abnormalities such as duodenal atresia and Hirschsprung disease.

  • Endocrine: hypothyroidism, diabetes mellitus, obesity, and other endocrine abnormalities.

  • Hematologic: increased susceptibility to hematologic malignancies, particularly acute lymphoblastic and acute myeloid leukaemia; transient abnormal myelopoiesis may occur in infancy.

  • Musculoskeletal: atlantoaxial instability, joint laxity, scoliosis, hip abnormalities, osteoporosis, and other skeletal abnormalities.

  • Dermatologic: alopecia areata and vitiligo may occur, reflecting the increased autoimmune susceptibility associated with Down syndrome.

Early diagnosis is important to identify potentially treatable medical contributors to psychiatric and cognitive presentations, recognize congenital and acquired multisystemic complications, distinguish psychiatric illness from regression, catatonia, or neurodegenerative disease, guide appropriate surveillance, and enable timely treatment of psychiatric and other comorbidities.

Selected references and further reading — Morphologic lens

Jones KL, Jones MC, del Campo M. Smith's recognizable patterns of human malformation. 8th ed. Philadelphia: Elsevier; 2021.

Reardon W. The bedside dysmorphologist: a guide to identifying and assessing congenital malformations. 2nd ed. Oxford: Oxford University Press; 2016.

Allanson JE, Biesecker LG, Carey JC, Hennekam RCM. Elements of morphology: introduction. Am J Med Genet A. 2009;149A(1):2-5. doi:10.1002/ajmg.a.32601.

Hennekam RCM, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, Carey JC; Elements of Morphology Consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A. 2013;161A(11):2726-2733. doi:10.1002/ajmg.a.36249.

Selected references and further reading — Multisystemic lens

Cardinal RN, Bullmore ET. The diagnosis of psychosis. Cambridge: Cambridge University Press; 2011.

Sachdev PS, Keshavan MS, editors. Secondary schizophrenia. Cambridge: Cambridge University Press; 2010.

Levenson JL, editor. The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. 3rd ed. Washington (DC): American Psychiatric Association Publishing; 2019.

Stern TA, Beach SR, Smith FA, Freudenreich O, Vranceau AM, Fava M, editors. Massachusetts General Hospital handbook of general hospital psychiatry. 8th ed. Philadelphia: Elsevier; 2025.

Arciniegas DB, Yudofsky SC, Hales RE, editors. The American Psychiatric Association Publishing textbook of neuropsychiatry and clinical neurosciences. 6th ed. Washington (DC): American Psychiatric Association Publishing; 2018.

Agrawal N, Faruqui R, Bodani M, editors. Oxford textbook of neuropsychiatry. Oxford: Oxford University Press; 2020.

Boland R, Verduin M, editors. Kaplan and Sadock's comprehensive textbook of psychiatry. 11th ed. Philadelphia: Wolters Kluwer; 2024.

Loscalzo J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison's principles of internal medicine. 22nd ed. New York: McGraw Hill; 2025.