Down's Syndrome

Synonym: trisomy 21

It is a common genetic disorder characterised by learning difficulty, dysmorphic facial features and a host of structural abnormalities. It is named after John Langdon Haydon Down - an English physician, 1828-1896.

Incidence

One of the commonest genetic disorders, affecting 1 in 800 live births.^1,2

• The underlying genetic defect is trisomy 21 in 94% of cases.
• Mosaicism (2.4%) and translocations (3.3%) also occur.
• 75% of these translocations are de novo errors.

Risk factors

• Family history.
• Age of mother:
  • 1:385 risk at 35
  • 1:106 at 40
  • 1:30 at 45 years

At birth there is a wide range of associated physical features. Not all babies have typical facies. Frequently the first feature noticed is hypotonia.

Cardiological disorders

Commonest cardiac abnormalities are:

• Atrioventricular canal defects (45%)
• Ventricular septal defect (35%)
• Isolated secundum atrial septal defects (8%)
• Isolated persistent patent ductus arteriosus (7%)
• Fallot's tetralogy (4-6%)

Adult patients, without known congenital heart disease, may develop mitral valve prolapse (46%) or aortic regurgitation (17%). A second assessment in early adulthood may be appropriate.

Ear, nose and throat disorders

• Patients with Down's syndrome may have conductive, sensorineural, or mixed hearing loss.
• They are more susceptible to otitis media, sinusitis and pharyngitis.
• Obstructive sleep apnoea may develop.

Ophthalmological disorders

Most commonly:

• Cataracts
• Refractive errors (35-76%)
• Strabismus (27-57%)
• Nystagmus (20%)
• Congenital glaucoma
• Keratoconus

Gastro-intestinal disorders

• Oesophageal atresia or tracheo-oesophageal fistula
• Duodenal atresia
• Pyloric stenosis
• Meckel's diverticulum
• Hirschsprung's disease
• Imperforate anus
• Gastro-oesophageal reflux
• Dental problems - delayed and unusual patterns of eruption, missing teeth
• Coeliac disease occurs frequently enough for screening to be recommended

Orthopaedic disorders

• Atlanto-axial instability (13%)*
• Hyperflexibility
• Scoliosis
• Hip dislocation after 2 years
• Patellar subluxation or dislocation
• Foot deformities

*Only 1-2% need treatment.⁷ This presents as neck pain, limited movements or symptoms/signs suggestive of cord compression. Less specific symptoms, e.g. bladder problems, gait abnormalities or clumsiness may also indicate need for further investigation.

Endocrine disorders

These are common, particularly hypothyroidism. Annual TFTs are indicated.⁸

Neurological and psychiatric disorders

• Mental retardation (ranges from severe retardation to "low normal").
• Behavioural problems.
• Seizures occur in 5-10%.
• In older patients an Alzheimer's-type picture develops in > 60% of those over 60 years of age.

Haematological disorders

• Patients have approximately 12 x greater risk of infections, e.g. pneumonia due to impaired cellular immunity.
• They also have increased risk of acute myeloblastic leukaemia (AML), acute lymphoblastic leukaemia (ALL) and acute megakaryoblastic leukaemia (AMegL).
• Polycythaemia and transient myeloproliferative disorder (a self-limiting type of leukaemia which regresses spontaneously by the age of 2 months) may occur in newborns.

• There is a large amount of published research on Down's syndrome screening. It looks at combinations of markers ± ultrasound (nuchal translucency (NT) scans measure the thickness of skin at the nuchal fold at around 10-12 weeks' gestation) used in the first or second trimesters. Screening aims to identify women at higher risk than that predicted on the basis of age alone. If the woman chooses, she may proceed to invasive testing after counselling on associated risks (e.g. chorionic villus sampling or amniocentesis). These establish fetal karyotype.
  • The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester.⁹ This test comprises NT scanning and pregnancy-associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy and alpha-fetoprotein, unconjugated oestriol (uE3), free beta or total human chorionic gonadotrophin (hCG) and inhibin-A in the early second trimester. With this method at an 85% detection rate, it has been estimated that there would be six amniocentesis-caused miscarriages of unaffected fetuses per 100,000 women screened, compared with 35% using the combined test or 45% with the quadruple test.
  • If PAPP-A, hCG and NT scanning are used as a first-trimester screening test, it is commonly referred to as the combined test.
  • When hCG and AFP are used between 14 to 20 weeks as a screening test this is often called the double test.
  • If uE3 is added to the double test combination it becomes known as the triple test.
  • The addition of inhibin A to the triple test comprises the quadruple test.
• First trimester prenatal screening using a combination of maternal serum biochemistry and fetal NT thickness has been shown to achieve detection rates over 90%.^10,11
• A disintegrin and metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta. It has been shown to be a potential first-trimester maternal serum marker for Down's syndrome (DS).¹² ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks has been predicted to give a detection rate of 97% at a 5% false-positive rate.
• First trimester screening for trisomy 21 in twin pregnancies is possible and practical using a combination of NT thickness and maternal serum biochemistry.¹³
• Amniocentesis (at 14-16 weeks) is 99.5% accurate. Chorionic villus sampling (CVS) can be performed earlier (10-13 weeks) but accuracy is less (96-98%). Both procedures have an operator specific miscarriage risk.