Definition: Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance.
Trisomy 21, also known as Down syndrome (DS), is a complex developmental disorder that affects many organs, including the brain, heart, skeleton and immune system.
A working hypothesis for understanding the consequences of trisomy 21 is that the overexpression of certain genes on chromosome 21, alone or in cooperation, is responsible for the clinical features of DS.
There is now compelling evidence that the protein products of two genes on chromosome 21, Down syndrome candidate region 1 (DSCR1) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), interact functionally, and that their increased dosage cooperatively leads to dysregulation of the signaling pathways that are controlled by the nuclear factor of activated T cells (NFAT) family of transcription factors, with potential consequences for several organs and systems that are affected in DS individuals.
Incidence, 1 in 650-1000 live births
Etiology:
trisomy 21
- Meiotic origin >95% maternal, mostly meiosis I - Increased recurrence risk with parental translocation
- Full trisomy 21: 94%
- Mosaic trisomy 21: 2.4%
- Translocation 21: 3.3%
Synopsis
systemic anomalies
head and neck anomalies
- brachycephaly
- excess nuchal skin
- flat facial profile
- small ears
- folded helix
- conductive hearing loss
- upslanting palpebral fissures
- epicanthal folds
- cleft lip/cleft palate
- cataracts
- iris brushfield spots
- protruding tongue
cardiovascular anomalies (50%)
-
cardiac malformations
- atrioventricular canal
- pulmonary hypertension
- pulmonary capillary dysplasia
- pulmonary vascular sclerosis
- coronary periarteritis nodosa
digestive anomalies
- oesophageal atresia (1%)
- duodenal stenosis/duodenal atresia (30%)
- imperforate anus and anorectal malformations (2%)
- Hirschsprung disease (congenital megacolon) (2%)
- annular pancreas (24%)
hepatic anomalies
- neonatal hemochromatosis +/- transitory leukemoid reaction
renal anomalies
rachis anomalies
- atlanto-axial instability
limbs anomalies
- hypoplastic iliac wings
- shallow acetabulum
- joint laxity
- short hands, broad hands
- fifth finger mid-phalanx hypoplasia
- single transverse palmar crease
- talipes equinovarus
neurological anomalies
- mental retardation
- Alzheimer disease
- hypotonia, poor Moro reflex
- meningomyelocele
endocrine anomalies
- hypothyroidism
hematological anomalies
- transient abnormal myelopoiesis (TAM) with severe fetal liver failure (15202167)
- leukemoid reaction +/- neonatal hemochromatosis
- leukemias (both ALL and AML)
- acute megakaryocytic leukemia
autoimmunity
- thyroid dysfunction (2149955)
Animal models
References
Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE. Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet. 2007 Aug;81(2):252-63. PMID: 17668376
Reviews
de la Luna S, Estivill X. Cooperation to amplify gene-dosage-imbalance effects. Trends Mol Med. 2006 Oct;12(10):451-4. PMID: 16919501
Antonarakis SE, Epstein CJ. The challenge of Down syndrome. Trends Mol Med. 2006 Oct;12(10):473-9. PMID: 16935027
Reeves RH. Down syndrome mouse models are looking up. Trends Mol Med. 2006 Jun;12(6):237-40. PMID: 16677859
Patterson D, Costa AC. Down syndrome and genetics - a case of linked histories. Nat Rev Genet. 2005 Feb;6(2):137-47. PMID: 15640809
Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer. 2005 Jan;5(1):11-20. PMID: 15630411
Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet. 2004 Oct;5(10):725-38. PMID: 15510164
Hernandez D, Fisher EM. Down syndrome genetics: unravelling a multifactorial disorder. Hum Mol Genet. 1996;5 Spec No:1411-6. PMID: 8875245