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Down syndrome Short notes

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"Down syndrome" trisomy 21

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Down Syndrome (Trisomy 21) - Short Notes

Definition & Epidemiology

Down syndrome is the most common chromosomal disorder and the single most common genetic cause of intellectual disability. Incidence is approximately 1 in 700 live births (15 per 10,000). About 6,000 babies are affected annually in the USA. The risk rises sharply with maternal age - from about 1 in 100 after age 32, approaching 1 in 10 in the oldest maternal age group. However, because younger mothers have higher birth rates, more than half of all affected newborns are born to mothers under 35 years.
First described by the English physician Langdon Down in 1866 based on characteristic physical features.

Chromosomal Basis

Three distinct karyotypic mechanisms cause Down syndrome:
TypeMechanismFrequencyKaryotype
Trisomy 21Non-disjunction during maternal meiosis~95%47 chromosomes (+21)
TranslocationFusion of chromosomes 21 & 14 (or 15); inherited~4%46 chromosomes (extra 21 attached)
MosaicismNon-disjunction after fertilization; some normal, some trisomic cells~1%Mixed 46/47 cell lines
Key points:
  • Trisomy 21: maternal karyotype is normal; caused by non-disjunction; risk increases with maternal age
  • Translocation type: NOT age-related; familial; asymptomatic carrier parents have only 45 chromosomes; recurrence risk ~1 in 3
  • Mosaic type: milder phenotype; variable intellectual disability
  • Only ~20-25% of trisomy 21 conceptuses survive to birth

Phenotypic Features

Child with Down syndrome showing characteristic facial features - upslanting eyes, flat nasal bridge, epicanthal folds, and short fingers
Typical phenotype of Down syndrome - note upslanting palpebral fissures, flat nasal bridge, epicanthal folds (Thompson & Thompson Genetics, 9th ed.)

Facial/Head

  • Hypotonia (often the first sign noticed in the newborn)
  • Brachycephaly with flat occiput
  • Upslanting palpebral fissures (eyes slant upward)
  • Epicanthal folds
  • Flat nasal bridge
  • Brushfield spots (speckled iris)
  • Protruding tongue (macroglossia relative to small oral cavity)
  • Short neck with loose skin at the nape
  • Small, low-set ears

Limbs & Hands

  • Short stature
  • Short, broad hands
  • Single transverse palmar crease (simian crease)
  • Fifth finger clinodactyly (incurved fifth digit)
  • Wide sandal gap between 1st and 2nd toes

Associated Complications & Clinical Features

1. Intellectual Disability

  • Present in all; ranges from mild to moderate (most have IQ 40-70)
  • Delay usually becomes obvious by end of first year
  • Minority have IQ above 50; most can attend school with support
  • Behavioral phenotype: generally social, friendly, but rates of ADHD and autism elevated

2. Congenital Heart Disease (~50% of liveborns)

  • Most common anomaly overall
  • Especially endocardial cushion defects (AV septal defects), ASD, VSD
  • ~25% of liveborn infants with heart defects die before their first birthday
  • Risk of cerebral embolism and stroke

3. Gastrointestinal Malformations

  • Duodenal atresia ("double bubble" sign on X-ray) - much more common than in other disorders
  • Tracheoesophageal fistula
  • Hirschsprung disease

4. Alzheimer's Disease / Dementia

  • Gene encoding amyloid precursor protein (APP) is located on chromosome 21
  • By age 40: virtually all individuals have beta-amyloid plaques and tau tangles
  • ~30% develop dementia by age 60; ~50% by age 70
  • Early signs may be behavioral change, loss of enthusiasm, or withdrawal rather than memory loss

5. Leukemia

  • 15-fold increased risk for leukemia (particularly AML and ALL)
  • Down syndrome-associated AML: megakaryoblastic differentiation, increased chemosensitivity (to methotrexate), relatively favorable prognosis
  • Transient myeloproliferative disorder in neonates

6. Atlantoaxial Instability

  • Present in ~10-20% of individuals due to generalized ligamentous laxity (collagen defect)
  • ~1/3 of these develop premature cervical spondylosis
  • ~1-2% develop symptomatic spinal cord dysfunction
  • Screening recommended before general anesthesia and contact sports

7. Endocrine & Other

  • Hypothyroidism (increased risk; must screen and treat)
  • Epilepsy
  • Moyamoya syndrome (progressive carotid vasculopathy causing stroke)
  • Obstructive sleep apnea
  • Recurrent otitis media (small Eustachian tubes)
  • Visual problems (cataracts, refractive errors)

Prenatal Diagnosis & Screening

Biochemical Markers (maternal serum)

  • AFP - reduced (~25% lower than unaffected pregnancies)
  • hCG - elevated
  • Inhibin A - elevated
  • Estriol - reduced
  • Triple test (AFP + hCG + estriol) or quadruple test (add inhibin A)

Ultrasound Markers

  • Increased nuchal translucency (first trimester)
  • Short femur, short humerus
  • Absent/hypoplastic nasal bone
  • Echogenic bowel, choroid plexus cysts, single umbilical artery

Definitive Tests

  • Chorionic villus sampling (CVS) - 10-13 weeks
  • Amniocentesis - 15-20 weeks
  • Cell-free fetal DNA (cfDNA) / NIPT (non-invasive prenatal testing) - high sensitivity/specificity

Diagnosis

  • Clinical diagnosis at birth based on characteristic phenotype
  • Confirmed by karyotyping - essential for:
    1. Confirmation
    2. Identifying the karyotypic type (trisomy vs translocation vs mosaic)
    3. Genetic counseling and recurrence risk calculation

Management

No targeted therapy currently exists. Management is multidisciplinary and supportive:
  • Cardiac evaluation at birth (echocardiography); surgical correction of defects
  • Thyroid function testing - regular screening; treat hypothyroidism
  • Cervical spine X-rays before anesthesia and contact sports participation
  • Hearing and vision assessments
  • Developmental and educational support - special education programs, speech therapy, occupational therapy
  • Leukemia surveillance
  • Dementia monitoring in adulthood (baseline cognitive assessment)
  • Supportive family environment; most individuals can lead enjoyable, semi-independent lives
Prognosis has improved considerably with better management of cardiac disease, spine defects, and leukemia.

Genetics Counseling - Recurrence Risk

TypeRecurrence Risk
Trisomy 21 (non-disjunction)~1% above age-related risk (or age-specific risk, whichever is higher)
Translocation (maternal carrier)~10-15%
Translocation (paternal carrier)~5%
21q21q translocation carrier~100% (all viable offspring affected)
Mosaic Down syndrome~1% above baseline
Sources: Thompson & Thompson Genetics and Genomics in Medicine (9th ed.); Goldman-Cecil Medicine International Edition; Kaplan & Sadock's Synopsis of Psychiatry; Quick Compendium of Clinical Pathology (5th ed.)
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