This is a mechanism of disease map for Down syndrome, covering the etiology, pathophysiology, and manifestations.
ADDITIONAL TAGS:
Behavioral
+ intellectual disability
Risk factors / SDOH
Cell / tissue damage
Ion channel physio
Down syndrome (trisomy 21)
Medicine / iatrogenic
Infectious / microbial
Biochem / molecular bio
Other medical conditions
Signs / symptoms
Tests / imaging / labs
Development / intellectual
Genetics / hereditary
Behavioral / psychiatry
Pathophysiology
Etiology
Manifestations
Excess genetic material from chromosome 21
Full trisomy 21 (∼95%): three complete copies of chr 21
Karyotype:
♀: 47,XX,+21
♂: 47,XY,+21
Spontaneous maternal nondisjunction occurs during meiosis I (70%) or meiosis II (20%)
Spontaneous paternal nondisjunction during spermatogenesis, usually meiosis II (5%)
High parental age
Translocation trisomy 21 (3-4%): third copy of chr 21 is attached to another chr, usually chr 14 → unbalanced Robertsonian translocation
By Original from DataBase Center for Life Science (DBCLS)Derivative by Mikael Häggström, M.D. Author info- Reusing images- Conflicts of interest:None Mikael Häggström, M.D. - File:202208 Chromosomal structural abnormality robertsonian translocation icon.svg, CC BY 4.0,commons.wikimedia.org/w/index...
Parent with balanced Robertsonian translocation of long arm of chr 21 to long arm of chr 14 → normal phenotype
Karyotype:
♀: 45,XX,t(14;21)
♂: 45,XY,t(14;21)
Child with normal karyotype
Miscarriage
Mosaic trisomy 21 (1-2%): both trisomy 21 cell lines and normal cell lines are present → phenotypes range according to normal:affected ratio
Nondisjunction during mitosis that occurs after fertilization
Karyotype:
♀: 46,XX/47,XX,+21 ♂: 46,XY/47,XY,+21
Characteristic appearance
Organ malformations
Endocrine disorders
Increased risk of malignancy
By Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities - www.cdc.gov/ncbddd/birthdefec..., Public Domain, commons.wikimedia.org/w/index...
Eyes: upslanting palpebral fissures, epicanthal folds, Brushfield spots (white/gray in iris);
+/- strabismus, cataracts, refractive errors
Mouth: small mouth + large tongue = protruding tongue; small teeth with gaps
ENT: hypoplastic nasal bones; broad, flat nasal bridge; small round low-set ears w adherent earlobes; short neck, OSA
Extrem: transverse palmar crease; sandal gap; clinodactyly (inward curve of 5th finger); short
By Loranchet - Own work, CC BY 3.0, commons.wikimedia.org/w/index...
Heart: atrioventricular septal defect (endocardial cushion defect); +/- ASD, VSD, PDA, ToF
GI: duodenal atresia / stenosis; annular pancreas; anal atresia; rectal prolapse; Hirschsprung disease; megacolon; Celiac
GU: hypogonadism; cryptorchidism; impaired spermatogenesis → decreased fertility
Hypothyroidism
Type 1 diabetes
↓ metabolism, ↑ leptin levels, ↓ physical activity → ↑ obesity
Delayed motor development, muscle hypotonia
Varying intellectual disability (average IQ is 50)
Delayed developmental milestones (twice the normal age)
Attention deficit hyperactivity disorder; +/- conduct disorder
Amyloid precursor protein (on chr 21) → generates amyloid beta -- early onset Alzheimer
Autism spectrum disorder
Risk of acute lymphoblastic leukemia, acute myeloid leukemia
Karyotype:
♀: 46,XX,+21,t(14;21) ♂: 46,XY,+21,t(14;21)