Down Syndrome

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In 1866, Down described clinical characteristics of the syndrome that now bears his name. In 1959, Lejeune and Jacobs et al. independently determined that Down syndrome is caused by trisomy 21.

Down syndrome is by far the most common and best-known chromosome disorder in humans. Mental retardation, dysmorphic facial features and other distinctive phenotypic traits char- acterize the syndrome. Frequency is estimated to be 1 in 800 live births. Approximately 6000 children are born with Down syndrome annually in the US.

GENETICS/BASIC DEFECTS

1. Caused by an extra chromosome 21 a. Affect almost every organ system

b. Result in a wide spectrum of phenotypic consequences

i. Life-threatening complications

ii. Significant alteration of life course (e.g., mental retardation)

iii. Dysmorphic physical features iv. Decreased prenatal viability

v. Increased prenatal and postnatal morbidity 2. Typical physical phenotype due to an extra copy of the

proximal part of 21q22.3 a. Mental retardation

b. Characteristic facial features c. Hand anomalies

d. Congenital heart defects

3. 21q22.1-q22.3 region containing the gene(s) responsible for the congenital heart disease observed in Down syndrome

4. The new gene (DSCR1), identified from region 21q22.1- q22.2 is highly expressed in the brain and the heart and is a candidate for involvement in the pathogenesis

5. Types of trisomy 21 a. Full trisomy 21 (94%) b. Mosaicism (2.4%) c. Translocations (3.3%)

i. De novo (75%)

ii. Familial translocation (25%) d. Isochromosome 21

6. Origin of nondisjunction: maternal nondisjunction in the first meiotic division (75%, most common)

7. Well-documented risk factor for maternal meiotic nondisjunction: advanced maternal age

8. Majority of mosaic cases result from a trisomic zygote with mitotic loss of one chromosome 21

CLINICAL FEATURES

1. Growth and development a. Short stature

b. Hypotonia which improves with age

c. Moderate-to-severe mental retardation with IQ range of 20–85 (mean IQ is approximately 50)

d. Articulatory problems

e. Sleep apnea occurring when inspiratory airflow from the upper airway to the lungs is impeded for 10 seconds or more, often resulting in hypoxemia or hypercarbia f. Seizure disorder (5–10%)

i. Infantile spasms (most common type of seizures seen in infancy)

ii. Tonic–clonic seizures (most commonly seen in older patients)

g. Visual and hearing impairments in addition to the presence of mental retardation further limiting the child’s overall function and may prevent the child from participating in significant learning processes and obtaining appropriate language development and interpersonal skills

h. Obesity during adolescence i. Premature aging

i. Decrease in skin tone ii. Early graying or loss of hair iii. Hypogonadism

iv. Cataracts v. Hearing loss

vi. Age-related increase in hypothyroidism vii. Seizures

viii. Neoplasms

ix. Degenerative vascular disease x. Loss of adaptive abilities

xi. Increased risk of senile dementia of Alzheimer type 2. Behavior

a. Natural spontaneity b. Genuine warmth c. Cheerful d. Gentleness e. Patience

f. Tolerance g. Anxiety h. Stubbornness 3. Psychiatric disorders

a. Prevalence among children (17.6%) b. Prevalence among adults (27.1%)

c. Children and adolescents at a higher risk for i. Autism

ii. Attention deficit hyperactivity disorder iii. Conduct disorder

iv. Obsessive-compulsive disorder v. Tourette syndrome

vi. Depressive disorder during the transition from adolescence to adulthood

4. Skull

a. Brachycephaly b. Microcephaly 295

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c. Sloping forehead

d. Vertical creases on the forehead when crying (“Woolley” sign, named after the late mentor, Dr. Woolley)

e. Flat occiput

f. Large fontanels with late closure g. Patent metopic suture

h. Absence of frontal and sphenoid sinuses i. Hypoplasia of the maxillary sinuses 5. Eyes

a. Up-slanting palpebral fissures b. Bilateral epicanthal folds c. Brushfield spots (speckled iris) d. Refractive errors (50%) e. Strabismus (44%)

f. Nystagmus (20%) g. Blepharitis (33%) h. Conjunctivitis

i. Tearing from stenotic nasolacrimal ducts j. Congenital cataracts (3%)

k. Pseudopapilledema l. Spasm nutans

m. Acquired lens opacity (30–60%) n. Keratoconus

6. Nose

a. Hypoplastic nasal bone b. Flat nasal bridge 7. Mouth

a. Open mouth

b. Tendency of tongue protrusion c. Fissured and furrowed tongue d. Mouth breathing

e. Drooling

f. Chapped lower lip g. Angular cheilitis 8. Teeth

a. Partial anodontia (50%) b. Tooth agenesis

c. Malformed teeth d. Delayed eruption

e. Microdontia (35–50%) in both the primary and secondary dentition

f. Hypoplastic and hypocalcified teeth g. Malocclusion

h. Taurodontism (0.54–5.6%) i. Increased periodontal destruction 9. Ears

a. Small

b. Over-folded helix c. Chronic otitis media

d. Hearing loss common. Between 66–89% of children have hearing loss of greater than 15–20 dB in at least one ear by auditory brainstem response

10. Neck

a. Atlantoaxial instability (14%) resulting from laxity of transverse ligaments that ordinarily hold the odontoid process close to the anterior arch of the atlas

b. Laxity causing backward displacement of the odontoid process, leading to spinal cord compression

11. Chest

a. Narrow chest

b. Decreased internipple distance 12. Congenital heart defects

a. Common (40–50%)

b. Frequently seen in hospitalized Down syndrome patients (62%)

c. Common cause of death in the first two years of life d. Endocardial cushion defect/atrioventricular canal (43%,

most common type): About 70% of all endocardial cushion defects are associated with Down syndrome e. Ventricular septal defect (32%)

f. Secundum atrial septal defect (10%) g. Tetralogy of Fallot (6%)

h. Isolated patent ductus arteriosus (4%)

i. Multiple cardiac defects (30%) The most common associated lesions are patent ductus arteriosus (16%) and pulmonic stenosis (9%)

13. Abdomen a. Diastasis recti b. Umbilical hernia 14. Gastrointestinal (12%)

a. Duodenal atresia or stenosis b. Hirschsprung disease (less than 1%) c. TE fistula

d. Meckel diverticulum e. Imperforate anus

f. Omphalocele 15. Genitourinary

a. Renal malformations b. Hypospadias c. Micropenis d. Cryptorchidism 16. Skeletal

a. Atlantoaxial (and atlantooccipital) instability i. Occurring in approximately 15% of individuals

(<21 year old)

ii. Mildest asymptomatic form

iii. Severe symptomatic subluxation or dislocation at the atlantoaxial joint may injure the spinal cord. Neurologic manifestations include:

a) Easy fatigability b) Difficulties in walking c) Abnormal gait d) Neck pain

e) Limited neck mobility f) Torticollis (head tilt)

g) Incoordination and clumsiness h) Sensory deficits

i) Spasticity j) Hyperreflexia k) Clonus

l) Extensor-plantar reflex

m) Other upper motor neuron and posterior col- umn signs and symptoms

n) Rarely progressing to paraplegia, hemiple- gia, quadriplegia, or death

b. Short and broad hands

c. Clinodactyly of the fifth fingers with a single flexion crease (20%)

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d. Hyperextensible finger joints

e. Increased space between the great toe and the second toe

f. Acquired hip dislocation (6%) 2. Endocrine

a. Thyroid disease

i. Primarily autoimmune disorder with a lifetime prevalence of 13–63%

ii. Congenital hypothyroidism: about 28 times more common among infants with Down syndrome than in the general population with an incidence of 1% detected by newborn screening a) 0.7% permanent congenital hypothyroidism b) 0.3% transient congenital hypothyroidism iii. Hypothyroidism in 16–20% of young patients b. Diabetes

c. Decreased fertility

i. Almost invariably infertile in males ii. Decreased fertility in females 3. Hematologic

a. Neonatal leukemoid reactions (i.e., pseudoleukemia) common and distinguishing this from true leukemia is frequently a diagnostic challenge

b. 10- to 15-fold increased risk of developing leukemia in children with Down syndrome. Approximately 1 in 150 patients develops leukemia

c. Uniquely predisposed to clonal disorders affecting the megakaryocyte lineage in children with Down syndrome

i. Transient myeloproliferative disorder (also known as transient leukemia)

c) Resolves spontaneously in most cases d) Develops acute megakaryoblastic leukemia

in up to 30% of cases ii. Acute megakaryoblastic leukemia

d. An increased risk of hepatitis B carrier status if previ- ously institutionalized

4. Immunodeficiency: patients have about 12-fold increased risk of developing infectious diseases, especially pneu- monia, secondary to impaired cellular immunity

5. Upper airway obstruction a. Causes

i. Large tonsils and adenoids ii. Lingual tonsils

iii. Choanal stenosis iv. Glossoptosis b. Consequences

i. Serous otitis media ii. Alveolar hypoventilation iii. Arterial hypoxemia

iv. Cerebral hypoxia

v. Pulmonary artery hypertension vi. Cor pulmonale

vii. Heart failure 6. Skin

a. Xerosis

b. Localized hyperkeratotic lesions c. Elastosis serpiginosa

d. Alopecia areata (up to 10%) e. Vitiligo

f. Folliculitis g. Abscess formation h. Recurrent skin infections 7. Dermatoglyphics

a. Distal axial triradius in the palms b. Transverse palmar creases

c. A single flexion crease in the fifth finger d. Ulnar loops (often 10) in the digital patterns

e. A pattern present in hypothenar and interdigital III regions

8. Significant health problems observed in adults with Down syndrome

a. Untreated congenital heart anomalies b. Acquired cardiac disease

c. Pulmonary hypertension

d. Recurrent respiratory infections/aspiration leading to chronic pulmonary interstitial changes

e. Presenile dementia/Alzheimer-type disease f. Adult-onset epilepsy

g. Osteoarthritic degeneration of the spine

h. Osteoporosis with resultant fractures of the long bones or vertebral bodies

i. Untreated atlantooccipital instability j. Acquired sensory deficits

k. Loss of vision due to early onset of adult cataracts, recurrent keratitis or keratoconus

l. Significant hearing loss m. Behavioral problems 9. Prognosis

a. Life expectancy

i. Approximately 75% of conceptuses die in embryonic or fetal stage

ii. Approximately 85% of infants survive to 1 year iii. About 50% can be expected to live beyond the

age 50 years b. Mobility and mortality

i. Presence of congenital heart disease (most significant factor that determines survival)

ii. Esophageal atresia with or without TE fistula, Hirschsprung disease, duodenal atresia, infec- tion, and leukemia adding to mortality

iii. Higher mortality rate later in life secondary to premature aging

c. Phenotype of mosaic individuals: depends on the frequency and distribution of trisomic cells, with typical Down syndrome as the worst phenotype

DIAGNOSTIC INVESTIGATIONS

1. Serum triple screen a. α-fetoprotein b. Unconjugated estriol

c. Human chorionic gonadotrophin 2. Cytogenetic studies

a. Clinical diagnosis should be confirmed with cytogenetic studies

b. Karyotyping is essential for determination of recurrence risk

i. Free trisomy 21 (93–96%)

ii. Robertsonian translocation (2–5%)

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iii. Reciprocal translocation (<1%) iv. Isochromosome (<1%)

v. Mosaicism (2–4%)

c. In translocation or isochromosome Down syndrome, karyotyping of the parents and other relatives is required for proper genetic counseling

3. Interphase fluorescence in situ hybridization (FISH) a. Used for rapid diagnosis

b. Successfully applied to both prenatal diagnosis and diagnosis in the newborn period

4. Extraction of fetal cells from maternal circulation: after fetal nucleated red blood cells have been sorted using dif- ferent cell transferrin and glycophorin-A receptors on the cell surface, interphase FISH can determine chromosome constitution. Chromosome-specific probes for X, Y, 13, 18, and 21 permit diagnosis. The FISH finding should be confirmed by standard cytogenetic techniques

5. Thyroid function tests: TSH and T4 should be obtained at birth and annually thereafter

6. Measurement of IgG

a. Used to identify deficiency of IgG subclass 2 and 4 b. A significant correlation between decreased IgG sub-

class 4 and bacterial infections

c. Cellular immunity deficits documented in individuals with gingivitis and periodontal disease

7. Skeletal radiography

a. Craniofacial anomalies include i. Brachycephalic microcephaly ii. Hypoplastic facial bones and sinuses

b. Cervical spine x-rays (lateral flexion and extension views)

c. Required to measure the atlanto-dens distance for excluding atlantoaxial instability at 3 years of age d. Used prior to anesthesia if there are signs suggesting

spinal cord compression

e. Reduced iliac and acetabular angles in the young infant

f. Short hands with shortened digits and clinodactyly due to hypoplastic middle phalanx of the fifth finger 8. Echocardiography: this test should be performed on all

infants with Down syndrome for identification of congenital heart disease, regardless of findings on physical examination

9. Auditory brainstem response (ABR), also known as brainstem auditory evoked response (BAER), to demon- strate hearing loss. Evaluation of ABR in 47 unselected children with Down syndrome, age between 2 months and 3 1/2 years, demonstrated some degree of hearing loss in 66% of the children examined (28% unilateral, 38% bilateral)

10. Speech evaluation

11. Pediatric vision screening for ophthalmologic disorders 12. Modified Denver Developmental Screening Test chart for

noninstitutionalized children for assessing the developmental milestones

13. Growth charts available for children with Down syndrome

14. Prenatal ultrasonography

a. Thickened nuchal fold (major marker) b. Cystic hygroma

c. Slightly shortened femora d. Hyperechogenic bowel e. Pyelectasis

f. Echogenic intracardiac focus g. Wider lateral flare of the iliac bones h. Other subtle sonographic signs

i. Short ears

ii. Hypoplasia of the middle phalanx of the 5th fingers (clinodactyly)

iii. Choroid plexus cyst

iv. Delayed fusion of the amnion and chorion v. Simian crease of the hand

vi. Separation of the great toe (‘sandal gap foot’)

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. Nondisjunction type: 1% or less

ii. De novo Robertsonian translocation type: 2–3%

b. Familial Robertsonian translocation type

i. Theoretical recurrence risk for a Robertsonian carrier parent to have a liveborn Down syndrome offspring: 1 in 3

ii. The actual risks to future offspring depend on parental sex:

a) Mother with rob(Dq;21q): 10–11%

b) Father with rob(Dq;21q): 2.4%

c) Mother with rob(21q;22q): 14%

d) Father with rob(21q;22q): 1–2%

c. A carrier parent with a 21q21q translocation or isochromosome: a 100% recurrence risk

d. Gonadal mosaicism postulated for having more than one trisomic child in the family with apparently normal parents

e. Patient’s offspring

i. Affected individuals rarely reproduce

ii. Females with trisomy 21: about 15–30% are fer- tile and have a 50% risk of having an affected child

iii. Males with trisomy 21: no evidence of fathering a child

2. Prenatal screening

a. Advanced maternal age

i. The first prenatal diagnosis of Down syndrome made in 1968

ii. Gradual introduction of screening women on the basis of advanced maternal age with amniocentesis into medical practice

b. Maternal serum biochemical markers

i. Low maternal serum alpha-fetoprotein (MSAFP) shown to be associated with Down syndrome in 1983

ii. Later, elevated human chorionic gonadotropin (hCG) and low unconjugated estriol (uE3) found to be the additional markers for Down syndrome iii. By 1988, the three biochemical markers, together with maternal age were accepted as a method of prenatal screening for Down syndrome in the general population

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iv. Estimated detection rate when ultrasound is used to estimate gestational age: 20% when using only the MSAFP test, 59% using the double test (MSAFP and hCG), and 69% using the triple test (MSAFP, hCG, uE3). The false positive rate is 5%. Other factors for adjustment are maternal age and weight, insulin-dependent diabetes mellitus, multiple pregnancy, ethnic origin, previous Down syndrome pregnancy, and first or repeat test in a pregnancy. A positive screening test suggests only an increased risk for having a Down syndrome fetus and that definitive testing by amniocentesis with chromosome analysis is indicated c. First-trimester free beta-hCG and pregnancy-associ-

ated plasma protein A retrospective screening study achieved rates as high as those associated with MSAFP, hCG or uE3 in the second trimester.

Prospective studies are needed to further assess first- trimester screening

3. Prenatal diagnosis a. Ultrasonography

i. Nuchal fold thickening identifies 75% of Down syndrome fetuses

ii. Shortened humerus or femur length detect 31%

of cases iii. Cystic hygroma

iv. Duodenal atresia or stenosis (double-bubble sign) v. Cardiac defects

a) Endocardial cushion defect with atrial and ventricular septal defects

b) Abnormal mitral and tricuspid valves vi. Echogenic bowel

vii. Renal pyelectasis

b. Amniocentesis, CVS, or fetal blood sampling i. FISH analysis of interphase cells or metaphase

spreads

ii. Chromosome analysis 4. Management

a. Medical care

i. Early intervention programs a) Physical therapy b) Occupational therapy c) Speech therapy

d) Special education programs ii. Hearing evaluation

iii. Thyroid hormone for hypothyroidism

iv. Medical management of congenital heart defects a) Digitalis and diuretics usually required b) Subacute bacterial endocarditis prophylaxis v. Prompt treatment of respiratory tract infections

and otitis media

vi. Pneumococcal and influenza vaccines for children with chronic cardiac and respiratory disease vii. Anticonvulsants for seizures

viii. Provide pharmacologic agents, behavioral therapy, and psychotherapy for behavioral/psychiatric disorders

ix. Treat skin disorders a) Weight reduction b) Proper hygiene

c) Frequent baths

d) Application of antibiotic ointment e) Systemic antibiotics therapy

x. Prevent dental caries and periodontal disease a) Appropriate dental hygiene

b) Fluoride treatments c) Good dietary habits d) Restorative care

xi. Megadoses of vitamins and minerals supple- mented with zinc and/or selenium: have not shown benefits in a number of well-controlled studies

b. Surgical care

i. Presence of Down syndrome alone does not adversely affect the outcome of surgery in the absence of pulmonary hypertension

ii. Timely surgery of cardiac anomalies necessary to prevent serious complications

iii. Prompt surgical repair of the following gastrointestinal anomalies:

a) TE fistula b) Pyloric stenosis c) Duodenal atresia d) Annular pancreas e) Aganglionic megacolon f) Imperforate anus

iv. Adenotonsillectomies may be required for obstructive sleep apnea

v. Surgical intervention may be necessary to reduce the atlantoaxial subluxation and to stabilize the upper segment of the cervical spine if neurologic deficits are significant

vi. Extract congenital cataracts, which occur in about 3% of children, soon after birth with sub- sequent correction with glasses or contact lenses to assure adequate vision

vii. Anesthetic airway management

a) Adequate evaluation of the airway and neu- rological status

b) Cervical spine radiography (flexion and extension views) when any neurologic deficits suggest spinal cord compression c) Avoid hyperextension of the head during

laryngoscopy and intubation

d) Prescribe anticholinergics to control airway hypersecretion

e) Aware of other airway complications (sub- glottic stenosis and obstructive apnea resulting from a relatively large tongue, enlarged adenoids, and midfacial hypoplasia)

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Fig. 1. An infant with Down syndrome showing sloping forehead, upslanting palpebral fissures, “Woolley” sign, flat nasal bridge, small mouth, protruding tongue, narrow chest, and decreased internipple distance.

Fig. 2. An infant with Down syndrome showing microcephaly, sloping forehead, upslanting palpebral fissure, and “Woolley” sign

Fig. 3. Two infants with Down syndrome showing severe hypotonia in the neck and back (gibbus).

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Fig. 4. An infant with Down syndrome showing lymphedema in the cheeks and thickened nuchal fold.

Fig. 5. Two children with Down syndrome showing Brushfield spots of the iris.

Fig. 6. Two infants with Down syndrome showing typical small ear with overfolded helix.

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Fig. 7. Two infants with Down syndrome showing small hands, small fingers, Clinodactyly of the 5th finger with a single crease, and a transverse palmar crease.

Fig. 8. Two infants with Down syndrome showing a widened space between the 1st and the 2nd toes (‘sandal gap foot’).

Fig. 9. An adult patient with Down syndrome showing upslanting palpebral fissure and severe midfacial hypoplasia.

Fig. 10. An adult patient with mosaic Down syndrome showing rela- tively mild phenotype.

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Fig. 11. A brother and a sister with non-disjunction type of trisomy 21.

Fig. 12. A G-banded karyotype showing trisomy 21.

Fig. 13. A G-banded karyotype showing i(21q) type of trisomy 21.

Fig. 14. A G-banded karyotype showing a t(14q;21q) carrier.

Fig. 15. FISH using a probe cocktail for chromosomes 13 (green) and 21 (orange) on interphase cells. Three copies of the orange/chromosome 21 signal are seen with only two copies of the green signal/chromosome 13 (AneuVysion LSI 13/21, Vysis/Abbott).