Down syndrome

Down syndrome, also known as trisomy 21, is the most common autosomal chromosome aberration, occurring in approximately 1:700 live births. The risk of a trisomy 21 pregnancy rises with increasing maternal age. Clinically, trisomy 21 manifests as a syndrome involving a characteristic appearance, organ malformations, and mental disability. Typical facial features include upward slanting palpebral fissures, epicanthus, a small oral cavity with a large tongue, a flattened nose. Other typical features are disproportionate short stature, a single crease across the palm of the hand (transverse palmar crease), and an enlarged gap between the first two toes (sandal gap). Common organ malformations include heart defects, duodenal stenosis, and a hypoplastic thyroid. Further associated conditions, such as diabetes mellitus, susceptibility to infections, and a higher incidence of leukemia may shorten life expectancy. The degree of intellectual disability varies greatly and may range from mild manifestations to severe impairment with dependence on caregivers. Children with Down syndrome present with a typical appearance at birth although the disease is often detected in prenatal tests. These include ultrasound measurement of nuchal translucency and maternal blood tests for human gonadotropin, estriol, and alpha-fetoprotein. Fetal karyotyping through chorionic villus sampling and amniocentesis confirm the diagnosis but are associated with an increased risk of fetal injury or loss due to the invasive nature of these tests.

• Most common autosomal chromosome aberration (∼ 1:700 live births).
• The risk of a Down syndrome pregnancy rises with maternal age

Maternal age (years)	Incidence of trisomy 21
20	∼ 1:1500
30	∼ 1:900
40	∼ 1:100
45	∼ 1:30
50	∼ 1:6

The general risk of trisomy 21 rises with maternal age. This does not, however, apply to translocation trisomies!

Down syndrome is the most common genetic cause of intellectual disability. Fragile X syndrome is the most common heritable cause of intellectual disability.

References:^{[1][2][3][4][5][6][7][8]}

Epidemiological data refers to the US, unless otherwise specified.

Full trisomy 21 (∼ 95% of cases)

• Full trisomy 21 is not a hereditary disease, as the chromosomal aberration occurs spontaneously.
• Meiotic non-disjunction
  • Non-disjunction occurs in approx. 70% of cases in meiosis I and in approx. 20% of cases in meiosis II.
  • May occur due to paternal non-disjunction during spermatogenesis (approx. 5% of cases)
• Karyogram
  • Three copies of chromosome 21; are present in all cells, with a total of 47 chromosomes
  • Karyotype: ♀: 47,XX,+21 or ♂: 47,XY,+21

Translocation trisomy 21 (3–4% of cases)

• Definition: three copies of chromosome 21 are present, of which one is attached to another chromosome (usually chromosome 14)
• Occurrence: independent of maternal age; increased familial incidence (approx. 3–4%); occurs as a spontaneous translocation
• Pathogenesis
  • In approx. 50% of cases a balanced translocation is inherited from a parent, usually the mother, who does not suffer from trisomy 21. The other 50% of cases are caused by new mutations during meiosis.
    • Balanced Robertsonian translocation
      • Translocation of the long arm of chromosome 21 to the long arm of chromosome 14 with elimination of the respective short arms (fusion of the chromosomes)
      • The karyogram shows a total number of 45 chromosomes and may be expressed as either ♀: 45,XX,t(21;14) or ♂: 45,XY,t(21;14).
      • Affected individuals only have 45 chromosomes, but possess complete genetic information and therefore a normal phenotype
    • Unbalanced translocation: clinical features of trisomy 21 caused by inheritance of a translocation chromosome and a normal chromosome
      • Although there are only 46 chromosomes present, three copies of genetic material from chromosome 21 exist; . This results in the karyotypes ♀: 46,XX,+21,t(21;14) and ♂: 46,XY,+21,t(21;14).

Mosaicism (1–2%)

• Mosaic trisomy is caused by non-disjunction during mitosis; . In these cases two cell lines are present, the trisomy 21 cell line and the normal cell line. The resulting karyotypes are either ♀: 46,XX/47,XX,+21 or ♂: 46,XY/47,XY,+21.
• Depending on the timing of the mitotic error, there is a variable proportion of trisomic and normal cells
  • Phenotypic expression may vary according to the ratio of healthy to trisomic cells

References:^[1][9][10]

Facial and cranial features (craniofacial dysmorphia)

• Eyes
  • Upward slanting of the eyelids, epicanthal folds, hypertelorism
  • Brushfield spots; (aggregation of connective tissue in periphery of iris, visible as white or grayish-brown spots)
  • Refractive errors (e.g., short-sightedness, astigmatism), strabismus
  • Cataracts (congenital, infantile, or juvenile)
• Mouth
  • Small oral cavity, large tongue
  • High arched palate
  • Abnormal teeth
• Further features
  • Brachycephaly
  • Hypoplastic nasal bones, broad and flat nasal bridge
  • Ear anomalies (small, round low-set ears, adherent earlobes)

Extremities, soft tissue, and skeletal features

• Extremities
  • Single transverse palmar crease; : crease across the palm, which runs along the metacarpophalangeal joints perpendicular to the fingers
  • Sandal gap: large space between the first and second toe
  • Clinodactyly, camptodactyly, brachydactyly
• Soft tissue: connective tissue deficiency → ↑ increased risk of umbilical and inguinal hernias; marked hyperextension of joints may occur
• Atlantoaxial instability

Organ malformations and associated conditions

• Heart: congenital heart defects; in ∼ 50% of cases – atrioventricular septal defect (∼ 40%); , ventricular septal defect; (∼ 30%), atrial septal defects (∼ 15%), tetralogy of Fallot (∼ 5%)
• Gastrointestinal tract: duodenal atresia/stenosis; , annular pancreas, imperforate anus; , enlargement of the colon, rectal prolapse; , Hirschsprung disease
• Urogenital system: hypogonadism, cryptorchidism, decreased fertility in men
• Further features: hypothyroidism; , celiac disease, sleep apnea; , hearing loss; due to recurrent otitis media, ↑ risk of leukemia (acute lymphoblastic leukemia, acute myeloid leukemia); , ↑ risk of early-onset of Alzheimer disease (75% of individuals affected by age of 40 years), ↑ risk of developing epilepsy

Height and development

• Motor skills
  • Delayed motor development
  • Muscle hypotonia
• Height: reduced growth with shortening of long bones → average adult height 150 cm (4 ft 11 in)
• Obesity: prevalence approx. 50% higher than in general population
• Intelligence
  • Varying levels of intellectual disability (average IQ: 50)
  • Apparent within first 12 months: developmental milestones (e.g., sitting, walking, talking) achieved at approx. twice the age of healthy children

Although symptoms may be less severe in mosaic trisomies, the clinical manifestation generally provides no indication of the underlying genetic mutation!

5 A's of Down syndrome: Advanced maternal age, duodenal Atresia, Atrioventricular septal defect, AML/ALL, Alzheimer disease

References:^{[11][10][12][13]}

Diagnostic approach

• The diagnostic approach in Down syndrome is dependent on the week of gestation. It involves an initial screening test
  • Standard tests
    • First trimester combined test (11-13 weeks)
    • Second trimester quadruple test (15-18 weeks)
  • Additional tests (usually performed optionally in high-risk pregnancies (e.g, maternal age > 35 years, history of prior pregnancy with trisomy, presence of ultrasound features suggesting aneuploidy) ^[14][15]
    • Integrated tests over the first and second trimesters
    • Cell-free DNA (10-20 weeks)
• If any of the above screening tests yield an abnormal result, one of the following confirmatory diagnostic tests is performed:
  • Amniocentesis (15–22 weeks)
  • Chorionic villus sampling (9–14 weeks)
  • Percutaneous umbilical cord sampling (18-22 weeks)
• See prenatal diagnostics for further information.

Prenatal screening

Counseling

• Precedes screening procedures
• Provides information that screening is voluntary
• Explains option of terminating the pregnancy if trisomy 21 is diagnosed

Screening procedures

• Recommended for all women prior to the 20^th week of gestation
• First trimester combined test (11–13 weeks)
  • First trimester combined test can detect 90% of cases ^[16]
  • Maternal serum
    • ↑ Beta human chorionic gonadotropin (β-hCG)
    • ↓ Pregnancy-associated plasma protein-A (PAPP-A)
  • Ultrasound
    • Nuchal translucency; measurement: nuchal translucency increases due to the high amount of fluid collecting behind the neck ^[10]
    • Absent or hypoplastic nasal bone
    • Shortened middle phalanges of the fifth digits with clinodactyly
    • Shortened long bones (humerus, femur)
• Second trimester quadruple test (15–18 weeks)
  • ↓ Free estriol
  • ↓ Alpha-fetoprotein (AFP)
  • ↑ Inhibin A
  • ↑ β-hCG
• Additional screening tests: these tests are optionally performed in addition to the above tests and are evaluated along with the results of second trimester quadruple test
  • Sequential integrated test
  • Full integrated test (10–13 weeks)
  • Cell-free fetal DNA (10–20 weeks): Fetal DNA is isolated from a maternal blood specimen and evaluated for chromosomal abnormalities. ^[17]
    • Non-invasive (to the fetus) but expensive test
    • More predictive in high-risk women
    • The test is currently available but not guideline-recommended

Fetal karyotyping (confirmatory test)

• Indications
  • Positive screening test
  • Previous trisomy 21 pregnancy
  • Parent with known chromosomal translocation or aberration
• Procedures ^[18]
  • Chorionic villus sampling (9–14 weeks)
  • Amniocentesis (15–22 weeks)
  • Percutaneous umbilical cord sampling (18-22 weeks) ^[19]
  • Complications
    • Bleeding
    • Infection
    • Fetal injury
    • Amniocentesis has a lesser risk of fetal loss (0.1%-0.3%) compared to chorionic villus sampling (0.7%-2%) ^[20][21]

In the quadruple test, hCG and Inhibin A are both HIgh up (↑) and Estriol and α-fEtoprotein are both dEficient (↓).

Postnatal diagnostics

• Chromosome analysis
• Screening for associated conditions (see “Clinical findings” above), e.g., echocardiography to detect heart defects

Typical features and malformations are an important indicator, but, on their own, are insufficient for diagnosis!

References:^{[11][10][22][7][23][24]}

• Treatment of the symptom complex and malformations as necessary (e.g., heart surgery for cardiac malformations)
• Early, targeted intervention, educational programs and support (e.g., encourage physical activity to decrease risk of obesity and improve motor control)

References:^[13]