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
Clinical Features
 * One in every 650-1,000 children is born with down syndrome
 * 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