202406301420

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Tags: Paed

Down's syndrome

Down syndrome is the most common chromosomal disorder with an incidence of 1 per 700 live births

T21 is caused by errors of cell division. There are three main cytogenetic forms:

1. Free T21 results from failure of separation of chromosome 21 during gametogenesis, leading to an extra chromosome in every cell.
2. Translocation T21 occurs when there is an extra chromosome 21, or part of chromosome 21, attached to another chromosome. A parent can carry a translocation and transmit it to their child, or translocation can occur de novo during maternal meiosis in a parent with a normal karyotype.
3. Mosaic T21 is caused by an error of cell division that occurs after fertilisation resulting in two cell lineages, one with two copies of chromosome 21, another with an extra copy

T21 is disorder of gene dosage imbalance. The genes themselves are normal, as are the gene products, but the altered expression of genes plays a key role in the manifestations of T21

Clinical features

Cardiovascular

Cardiovascular disease is a leading cause of morbidity and mortality in patients with T21

CHD

Atrioventricular septal defects (AVSDs) are the most common congenital heart defects in patients with T21, with 65% of all AVSDs being associated with T21. Other commonly occurring lesions include tetralogy of Fallot (13%), combined tetralogy of Fallot and AVSD (9%) and isolated ventricular septal defects (VSDs) (4–17%)

Patients with T21 develop pulmonary hypertension (PH) to a greater severity and at an earlier age than patients without T21 with similar cardiac lesions

The aetiology of early-onset PAH in T21 is uncertain but may be related to the genetic disease itself or to associated respiratory comorbidities

Post-tricuspid shunts (e.g. VSD) are high-pressure, left-to-right shunts that place a volume load on the left ventricle and the pulmonary vasculature. If these defects are large enough, the pulmonary vasculature is exposed to systemic blood pressure, which if left untreated, leads to the development of suprasystemic pulmonary vascular resistance (PVR)

pretricuspid shunts (e.g. ASD) are low-pressure, left-to-right shunts that place a volume load on the right atrium and right ventricle, and do not usually pose the same time-critical threat to PVR

Respiratory

Airway

• Micrognathia/retrognathia
• Macroglossia: absolute or relative to a micrognathic mandible
• Narrow nasopharynx and oropharynx
• Obstructive adenoids and tonsils, owing to hypertrophy or relative to a narrow nasopharynx and oropharynx
• Midface hypoplasia
• Subglottic stenosis
  • ↑ incidence of congenital SGS
  • ↑ likelihood of requiring surgical intervention therefore intubation
    • → acquired SGS
• Laryngomalacia
  • high prevalence ∵ generalised hypotonia & high prevalence of GORD

The anatomical features, combined with generalised hypotonia and an increased prevalence of obesity, result in a high prevalence of OSAS

Central sleep apnoea is also more common in children with T21, especially younger children and infants, than in non-syndromic children

Vocal cord palsy, secondary to recurrent laryngeal nerve injury during congenital cardiac surgery, may also be present

Respiratory tract infections (RTIs) are more common and more severe in patients with T21.

RTIs are one of the most common reasons for hospital and ICU admissions in children with T21
Congenital abnormalities of the respiratory tract, chronic aspiration and inherent immunodeficiencies are contributing factors. Recurrent RTIs can contribute to the development of established PH

Neurocognitive

T21 is the commonest genetic cause of intellectual disability

Children with T21 have more behavioural problems and psychiatric comorbidities than other children

Hearing and visual impairments are common, which can compound learning and communication difficulties

Chronic otitis media and chronic middle ear effusions are common and can lead to hearing loss if left untreated

Ocular manifestations of T21 include strabismus, amblyopia, cataracts, glaucoma, optic nerve disease, and retinal disease

There is a higher prevalence of epilepsy in children with T21 than in the general population

C spine

Instability of the cervical spine is a well-known manifestation of T21 and results from a combination of ligamentous laxity and osseous abnormalities

Laxity of the transverse ligament predisposes to the subluxation of the odontoid away from the atlas, thereby decreasing the neural canal width
Bony abnormalities including a hypoplastic posterior arch of C1 or body of C2 can occur.

Cervical instability:

• atlantoaxial
• atlanto-occipital
• craniocervical

There is a predisposition to inflammatory arthritis (often called Down syndrome-associated arthritis), predominantly a polyarticular disease that further compounds instability

GI

GORD ∵

• generalised hypotonia
  • delay in being able to sit upright
  • ↓ tone of gastroesophageal sphincter
    May lead to aspiration → recurrent resp tract infection

Haematological

T21 is one of the genetic conditions most strongly associated with childhood leukaemia.

Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with T21.
TAM usually resolves within 3 or 4 months. Treatment is usually supportive.
About 10–20% of children with TAM will develop myeloid leukaemia

Endocrine

References

Associated Medical Conditions in Children - A&ICM