DOWN SYNDROME
DEFINITION:
A chromosomal disorder resulting in a syndrome characterized by
specific dysmorphic features (facies) and organ malformations.
EPIDEMIOLOGY:
- incidence: 1/800 live births
- 75% of fetuses with Trisomy 21 abort spontaneously
- most common autosomal chromosomal disorder causing mental
retardation
- age of onset:
- risk factors:
- increased maternal age (although 80% are born to mothers <35
years)
HISTORY:
- 1865 - John Langdon Down
- first detailed description
- 1930 - Brewster and Cannon
- first to report an association between Down's & acute
leukemia
- 1954 - Schunk and Lehman
- first to report an association between Down's & transient
leukemia
- 1959 - Lejeune
- first to associate Down's with Trisomy 21
GENETICS/PATHOGENESIS:
- due to non-disjunction during meiosis
- 80-90% due to maternal non-disjunction
- 10-20% " paternal "
- 1% recurrence risk
2. Unbalanced Translocation (3-4%)
- 50% are sporadic (de novo)
- 50% are due to a balanced translocation in one parent
- recurrence risk:
- 100% in parent with a 21:21 translocation
- 16% in mother with a 21:acrocentric chrom. transloca.
- 5% in father "
3. Mosaicism (1-2%)
- due to nondisjunction after meiosis
- ? recurrence risk
2. Pathogenesis
- trisomy of only the bottom 1/3 of chromosome 21 is
sufficient to account for Down's phenotype
- chrom. 21: the 800 genes in the 21q22 band appear to be
those responsible for the pathogenesis
- trisomy results in a 50% increased "dose" of certain
proteins:
3. Pathogenesis (of Transient Leukemia)
- proposed mechanisms:
CLINICAL FEATURES:
- 100% contain at least 4 of these
- 89% contain at least 6 of these:
- flat facial profile (90%)
- poor Moro reflex (85%)
- infantile hypotonia (80%)
- hyperflexibility of joints (80%)
- excess skin on neck (80%)
- slanted palpebral fissures (80%)
- dysplasia of pelvis (70%)
- anomalous auricles (60%)
- dysplastic 5th midphalanx (60%)
- 45 simian crease (45%)
2. Diagnostic Index (J. Peds. 100(6): 903 (1982))
- hallucal pattern
- forefinger pattern
- palmar triradius
2. Physical Traits
- ear length
- internipple distance ratio
3. Clinical Findings
- wide-spaced first toe
- excess skin on back of neck
- brushfield spots
3. Neurologic Manifestations
- at birth, in infancy, and as a toddler
- may delay motor milestones but improves with age
2. Seizures (5-10%)
- generalized, myoclonic most common type
3. Learning Disabled
- borderline to moderate IQ range (from 80 -> 40)
- processing problems:
- better at visual than auditory processing
- better at simultaneous than sequential processing
4. Global Developmental Delays
- gross motor due to hypotonia
- fine motor "
- speech and language delay
- 75% have an expressive language disability
- behavioural problems
- aggression, depression, inappropriate
5. Alzheimers
- may affect 15-20% of adults with Down's
- mean age of onset is 51 years (range 46-57 years)
4. Respiratory Manifestations
- increased incidence of pulmonary hypoplasia and elevated
pulmonary vascular resistence (+/- congenital heart defects) may
lead to an increased risk of:
- respiratory tract infections
- acute and chronic airway obstruction
- sleep apnea (small airways, large tonsils/adenoid,
obesity)
- cor pulmonale
5. Cardiovascular Manifestations (40%)
- complete AV canal (49%)
- VSD (22%)
- ASD(secundum)- 14%
- ASD(primum) - 8%
2. Others
- 3 PDA (3%)
- ToF (3%)
- AV valve malformation (prolapse)
- aberrant subclavian artery
2. Complications
- elevated pulmonary blood flow -> irreversible pulmonary
hypertension -> cor pulmonale
- structural anomalies and complications are usually
detected in the newborn period or in the first 6 weeks of life
6. Gastrointestinal Manifestations (12%)
- duodenal atresia most common problem (+/- polyhydramnios,
double bubble)
- others: TEF, annular pancreas, Meckel's diverticulum,
Hirschsprung's disease, imperforate anus
2. Complications
- vomiting (bilious), constipation, failure to thrive,
feeding difficulties and intolerance
- structural anomalies and complications are usually
detected in the newborn period or in the first 6 weeks
7. Genitourinary Manifestations
8. Hematologic Manifestations
- risk is 10-30x that of general population
- in newborns AML > ALL (2-4:1)
- in children ALL > AML (2:1)
2. Transient (Congenital) Leukemia
- presence of a large number of blasts (megakaryoblasts) in
the peripheral blood
- may be variable leukocytosis +/- thrombocytopenia +/-
anemia
- clinically may be associated with lymphadenopathy and/or
hepatomegaly/hepatosplenomegaly
- 100% spontaneous remission rate within 1st weeks of life
- occurs exclusively in Down's (82% in newborn period)
- some cases may give rise to acute megakaryoblastic
leukemia (AMKL) or other forms of leukemia during the first 3
years
- - diagnosis is retrospective
3. Autoimmune Disorders
- higher than average likelihood of developing:
- thyroiditis
- alopecia areata (in 10-15%)
- diabetes mellitus
- rheumatoid-type arthropathy
- autoimmune hemolytic anemia
9. Endocrine Manifestations
10. Dermatologic Manifestations
- with secondary itching, eczema, and infections (i.e.,
recur-rent follicular skin infections)
2. Syringomas
- benign sweat gland tumors
- F > M; onset at beginning of puberty
- yellow or skin-coloured, soft 2-3 mm raised papules
occur-ring singly or in groups
- most commonly found around eyes but also on neck and
thor-acic, axillary, umbilical, and pubic areas
3. Others
- alopecia areata (in 10%)
- rapid aging of skin
- increased risk of sunburn
11. Musculoskeletal Manifestations
- bony anomalies of the cervical spine
- subluxation or dislocation of hips and/or knees
- pronation of feet at ankles, pes pannus, short broad
hands, short sternum, decreased acetabular and iliac angle (CDH,
dysplastic hips), see "Clinical features in Newborn"
- hypotonia & ligamentous laxity predisposes to these
problems
12. Ocular Manifestations
- congenital nystagmus or alternating esotropia
- congenital cataracts and glaucoma
- 60% with strabismus
- 50% with refractive errors
2. Minor
- epicanthal folds, oblique palpebral fissures
- blepharitis, keratoconus, Brushfield spots
13. Oral and Dental Manifestations
- delays and alterations in the sequence of tooth eruption
- 100% with malocclusions (mandibular overjet, post. cross
bite)
- 60% with relative macroglossia
- 50% with missing teeth
- 37-60% with fissuring tongue, enlargement of vallate
papillae
14. Otorhinolaryngologic Manifestations
- 75% with sensorineuronal conductive hearing loss due to an
accumulation of fluid in the middle ear space
2. Midface Hypoplasia
- nasolacrimal duct obstruction (in 20%)
- obstructive sleep apnea
- sinusitis and purulent rhinitis
INVESTIGATIONS:
- chorionic villus sampling at 9-12 weeks
- amniocentesis at 16-18 weeks
- indications for:
- advanced maternal age (>35 years)
- previous child with Trisomy 21
- balanced translocation in parent
- prenatal U/S findings suggestive of Trisomy 21
- altered maternal serum markers
- decreased alpha fetoprotein
- " human chorionic gonadotropin
- " unconjugated estriol (uE3)
2. Imaging Studies
- 2D-Echo, chest x-ray, EKG
2. Gastrointestinal
- abdominal x-ray, barium swallow/enema
3. Renal
4. Skeletal X-Rays
- bone age for short stature
- C-spine - an atlanto-dens space >5 mm is suggestive of
atlantoaxial instability
- sinusitis
3. Serum
- compensated respiratory acidosis (due to COPD)
- elevated urea, creatinine, uric acid, decreased creatinine
and uric acid clearance
- CBC with blasts
- TSH, T3, T4, thyroid antibodies
- ? GH stimulation tests
4. Others
MANAGEMENT:
- Neurology consult, EEG, anticonvulsant medications
2. Learning Disabilities
- teaching methods which emphasize visual over auditory
information
3. Developmental Delays
- early intervention
- gross/fine motor - physiotherapy
- speech/language - total communication techniques (signing
or computers), speech therapy, special education
- behaviour - mental health assistance, family counsel
2. Respiratory Manifestations
- decrease weight, repositioning during sleep, nasal CPAP,
remove tonsils and adenoids
2. Cor Pulmonale
- early surgical correction of congenital heart disease (CHD)
3. COPD
3. CVS Manifestations
- all Down's patients should have a Cardiology consult and an
echo done within the first few weeks of life
- surgical correction of CHD
4. Gastrointestinal Manifestations
- surgical correction of malformations
- treat functional problems, i.e., constipation
- feeding team for problems
5. Genitourinary Manifestations
- follow serum urea, creatinine, uric acid
- follow uric acid and creatinine clearance rates
- ? role of imaging studies for screening for anomalies
- surgical correction of hypospadia, undescended testes
6. Hematologic Manifestations
- state of the art therapy noting increased risk of
infec-tion and sensitivity to anti-folate chemotherapy
- lower remission rate and a higher mortality with ALL in
- Down's than general population
- similar remission rate and mortality with AML in Down's
and general population
2. Transient Leukemia
- moniter blasts in peripheral blood
- spontaneous remission but risk of leukemia (ie. AMKL)
3. Autoimmune Disorders
- screen for manifestations i.e., TSH, blood sugar
- ? role of pneumococcal and influenzae vaccines
7. Endocrine Manifestations
- screen for clinical s/s of hypothyroidism (dry hair/skin,
lethargy, cold intolerance, constipation, hoarse voice)
- screen TFT (TSH, T3, T4) annually +/- thyroid antibodies
2. Growth
- moniter growth on charts for Down's
- true GH deficiency is rare but may respond to GH
supplements
- obesity - caloric restriction, increase activity/exercise
3. Reproduction
- birth control and reproductive health issues need to be
addressed (i.e., sterilization)
8. Dermatology Manifestations
- moisturizers, hypoallergenic creams for dry skin
- steroid creams for eczema
- topical or systemic antibiotics for infection
- preventive measures to avoid sunburn
- topical steroids, minoxidil for alopecia areata
9. Musculoskeletal Manifestations
- see the Canadian Down's Society Guidlines
- initially assessed at 2-4 years and repeated between 8-10
years
- earlier assessment if indicated - neurologic findings:
- loss of motor skills
- asymmetric hypertonicity in lower limbs
- increased clumsiness or tripping
- widely-spaced stiff-legged gait
- any upper motor neuron signs
- loss of fine motor skills
- torticollis, neck pain, headaches
- if abnormal then must restrict activities - tumbling, div-ing,
butterfly, collision sports
2. Spinal Cord Compression
- may require surgical stabilization (skeletal fixation) of
cervical spine
- ortho, neuro, neurosurg consults
10. Ocular Manifestations
- initial screen should occur in early infancy with follow-up
at
- 18 months and 5 and 15 years
11. Oral and Dental Manifestations
- routine preventive dental care
- relative macroglossia may be corrected by oral or plastic
sur-gery if indicated
12. Otorhinolaryngologic Manifestations
- audiologic evaluation by sound field testing or auditory
brain-stem responses (ABR) should begin at 6 months and be
repeated q6-12m during the preschool years
- antibiotics for recurrent OM, sinusitis, or purulent
rhinitis
- myringotomy tubes for recurrent otitis media (OM)
13. Genetics
- genetic counselling if plans for another child
- 80% survive to age 30 or beyond
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