Handbook of Genetic Counseling/Down Syndrome - Trisomy 21-2

Down Syndrome - Trisomy 21

Genetics

• 3 possible etiologies:
  • Full trisomy 21 (95% of the cases)
    • Due to nondisjunction during meiosis
    • Usually maternal nondisjunction (90-95% of these cases)
• 75% of maternal nondisjunction occurs during meiosis 1
  • • 1% recurrence risk, unless the mother's age related risk is higher than 1%, in which case the age-related risk is quoted
  • Unbalanced translocation (3-4% of cases)
    • 50% of cases a parent carries a balanced translocation
    • 50% of the unbalanced translocations are de novo and occur during fertilization
    • Recurrence risk is 100% for a parental 21:21 translocation
    • For a 21:14 translocation, recurrence is 16% if in the mother and 5% if in the father
  • Mosaicism (1-2% of cases)
    • Due to nondisjunction during mitosis, early in embryonic development
    • Only cells that descend from that specific cell where nondisjunction occurred will be trisomy 21
    • Usually associated with a less severe phenotype
• Molecular Genetics
  • Ongoing effort to define Chromosome 21 critical region
  • Narrowed to 21q22
  • DSCR1 is a candidate gene suspected to be involved in the pathogenesis of DS

Incidence

• One in every 650-1,000 children is born with down syndrome

Clinical Features

• Intelligence
  • Mild to moderate mental retardation seen in most individuals (ranges from ~40-80)
  • Language delays
• Cardiac
  • >40% are born with congenital heart defects
    • Av canal and VSD are common
• Gastrointestinal
  • Duodenal atresia is the most common
  • Duodenal web (partial obstruction)
  • Tracheoesophageal fistula
  • Pyloric stenosis
  • Omphalocele
  • Hirschprung's disease
  • Imperforate anus
  • Annular pancreas
  • Celiac disease
  • Associations with vomiting, diarrhea, constipation, and feeding difficulties may be associated
• Auditory
  • Recurrent otitis media
  • Some degree of hearing loss is present in ~90% of patients
  • Conductive hearing loss due to fluid accumulation
  • Sensorineural hearing loss is also seen
• Craniofacial
  • Macroglossia (60%)
    • May cause feeding difficulty
  • Dental malocclusions (100%)
  • Constellation of characteristic facial features
    • Brachycephaly
    • Low nasal root, flat nasal bridge
    • Epicanthic folds
    • Small and occasionally overfolded ears
    • Short neck sometime seen with redundant skin at the nape
    • Brushfield spots
• Skeletal
  • 14% have increased mobility of the cervical spine at the level of the 1st and 2nd vertebrae (atlantoaxial instability)
• other
  • Respiratory problems can be due to midfacial hypoplasia which results in narrow airways
    • Infections (recurrent croup due to narrow trachea)
    • Obstructive airway disease
    • Sleep apnea
  • Leukemia
    • Risk of developing leukemia is 15-30 times higher in Down syndrome patients than in the general population
  • Hypothyroidism (15%)
    • Common during adolescence
    • Yearly monitoring of TSH and T(subscript)4 levels recommended
  • Alzheimer's Disease
    • 15% of adults with average age of onset ~50 yrs
  • Eye problems
    • Strabismus
    • cataracts
  • Seizures (5-10%)
    • Correlation between age and prevalence
    • Peaks at infancy and 4th-5th decade of life
  • Short stature (average at 3rd percentile)
  • Obesity
  • Wide gap between first and second toes
  • Hypotonia
  • Clinodactyly of the 5th fingers

Natural History/Prognosis

• Life expectancy has significantly increased
  • No congenital heart defects: >60 yrs old
  • Congenital heart defects: 30-35 yrs old
• Causes of death
  • Leukemia (malignancy)
  • Infections

Treatment and Management

• Echocardiograms, EKG, chest X-rays to monitor heart defects
  • Surgery may be required
• Ophthalmology exams
• Hearing exams
• Abdominal X-rays, barium swallow or enema to follow digestive problems
• TSH levels to detect hypothyroidism
• Early intervention for MR and developmental delays
• Physical therapy for gross and fine motor skills
• Speech therapy

References

• Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company
• Jorde LB, Carey JC, Bamshad MJ, White RL (1999). Medical Genetics. 2nd ed.

Philadelphia: Mosby.

• Cohen WI (1999). Health Care Guidelines for Individuals with Down Syndrome: 1999 Revision (Down Syndrome Preventive Medical Check List). Down Syndrome Quarterly.
• Web References: OMIM Entry #190685

Notes

The information in this outline was last updated in 2000.