Down's Syndrome

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Down's syndrome (DS)\: also known as trisomy 21; most common congenital chromosomal abnormality (1 in 800-1000 live
births).
Pathophysiology\: additional genetic material from chromosome 21 causes phenotypic features and increased morbidity,
especially congenital heart disease.
Aetiology\:
Meiotic non-disjunction of maternal chromosome 21 (95%)
Robertsonian translocation (4%)
Mosaicism (1%)
Risk factor\: maternal age is the strongest risk factor (e.g., risk at age 35 is 1 in 385, at age 40 is 1 in 110).
Dysmorphic features\:
General\: hypotonia, hyper
Head\: oblique palpebral
protruding tongue, high arched palate
Neck\: short with excessive nape skin
Hands\: transverse palmar crease, short/in-curved little
Feet\: large gap between
Congenital heart defects\: present in ~50% of neonates; most common are complete atrioventricular septal defect (37%),
ventricular septal defect (31%), atrial septal defect (15%).
Neurological disease\:
Developmental delay, intellectual disability
Increased prevalence of autism, ADHD, aggressive behavior
Alzheimer's disease in up to 75% by the sixth decade
Respiratory disease\: higher rates of asthma, obstructive sleep apnoea.
Gastrointestinal disease\: 12% have anomalies like duodenal atresia, imperforate anus, tracheo-oesophageal
Hirschsprung disease.
Endocrine disease\: common issues include hypothyroidism, type 1 diabetes mellitus.
Haematological disease\: increased risk of immunode
megakaryoblastic leukaemia, acute lymphoblastic leukaemia.
Other clinical features\: short stature, obesity, various ophthalmological and orthopaedic disorders, recurrent otitis media,
benign skin disorders, urological abnormalities, juvenile idiopathic arthritis.
Di
syndrome.
Investigations\:
Prenatal\: combined test (serum screening and nuchal translucency), quadruple test, non-invasive prenatal testing (NIPT),
con
Post-natal\: echocardiography, red re
feeding di
Management\: tailored multidisciplinary approach, regular specialist reviews, genetic counselling for parents.Article 🔍
A comprehensive topic overview

Introduction

Down’s syndrome (DS), also known as trisomy 21, is the most common congenital chromosomal abnormality, occurring in
about 1 in 800 to 1 in 1000 live births. 1,2
The presence of additional genetic material from chromosome 21 results in
characteristic phenotypic features and increased morbidity through its e
of early mortality in Down's syndrome is congenital heart disease. 3,4
Despite this, many people with Down’s syndrome live
happy and ful

Aetiology

Trisomy 21 typically occurs via one of the following mechanisms\:
4,5
Meiotic non-disjunction of the maternal chromosome 21 (95%)
Robertsonian translocation of unbalanced chromosomal material, usually between chromosome 14 and chromosome 21
(4%)
Mosaicism (1%)

Risk factors

Maternal age is the strongest risk factor for Down's syndrome.
23
Table 1. Risk of Down’s syndrome (live births) in relation to maternal age at delivery, prior to screening in pregnancy.
4
Maternal age
(years)
Risk of Down’s
syndrome
All ages 1 in 650
20 1 in 1530
30 1 in 900
35 1 in 385
37 1 in 240
40 1 in 110
45 1 in 37

Clinical features

Dysmorphic features
Dysmorphic features which may be noted in neonates with Down’s syndrome are described below.
2,7
General\:
Hypotonia\: this may cause di
Hyper
Head\:
Oblique palpebral
Epicanthic folds
Flat nasal bridgeBrachycephaly (
Dysplastic, low-set, small ears
Open mouth with protruding or furrowed tongue
High arched palate
Neck\:
Short neck with excessive skin at the nape of the neck
Hands\:
Transverse palmar crease (Simian crease)
Short and incurved little
Feet\:
Large gap between the
Down's syndrome
Congenital heart defects
Approximately 50% of neonates with DS will have associated congenital heart disease.
The most common forms of congenital heart disease are\:
2-4,7,10
Complete atrioventricular septal defect (37%)
Ventricular septal defect (31%)
Atrial septal defect (15%)
Neurological disease
Developmental delay and intellectual disability
Developmental milestones are frequently delayed in Down's syndrome.
Intellectual disability is an almost universal feature of Down's syndrome which can vary signi
Autism, attention de
syndrome.
20
Alzheimer's disease
Alzheimer’s disease develops in up to 75% of DS patients by the sixth decade of life.
8,9,20.
Respiratory disease
Asthma and obstructive sleep apnoea are more common in Down’s syndrome.
1Gastrointestinal disease
1
Gastrointestinal tract anomalies requiring surgery occur in about 12% of patients with Down’s syndrome. The most
characteristic anomaly is duodenal atresia caused by a failure of the intestine to recanalize during development. 7,11
structural gastrointestinal anomalies may include imperforate anus and/or tracheo-oesophageal
Down’s syndrome is also associated with an increased risk of Hirschsprung disease.
7
Other
Endocrine disease
Endocrine diseases most commonly associated with Down’s syndrome include hypothyroidism and type 1 diabetes
mellitus.
Haematological disease
Down's syndrome is associated with an increased risk of developing several di
including\:
1,7,14,15
Immunode
Transient myeloproliferative disorder
Polycythaemia
Acute megakaryoblastic leukaemia
Acute lymphoblastic leukaemia
Other clinical features
Other clinical features associated with Down’s syndrome include (but are not limited to)\:
Short stature and obesity
Ophthalmological disorders including cataracts, refractive disorders, nystagmus, strabismus and glaucoma
Orthopaedic disorders such as atlanto-axial instability, hyper
Recurrent acute otitis media
1
Benign skin disorders such as hyperkeratosis and seborrhoeic dermatitis
Urological abnormalities such as hypospadias and cryptorchism
Juvenile idiopathic arthritis

Di

Di
5,24
Congenital hypothyroidism
49 XXXXY chromosome and high-order X chromosome disorders
Zellweger syndrome (or other peroxisomal disorders)
Aymé-Gripp syndrome

Investigations

Prenatal investigations
Screening for Down's syndrome
Pre-natal screening is currently the most common means through which Down’s syndrome is identi
diagnosed. Screening tests along with other data such as maternal age, weight, family origin and gestation are combined in
software to calculate the probability of a fetus having Down's syndrome. The screening test is considered positive if the risk
of a fetus having Down's syndrome is greater than 1 in 150. If the screening test returns a positive result, women are o
diagnostic testing.
Down's syndrome screening most commonly involves\:
Serum screening\: assessment of a range of biomarkers in the serum between 10-14 weeks + 1 day of gestation.Nuchal translucency scanning\: ultrasound is used to assess the translucency of the nuchal pad at the nape of the fetal
neck between 11 weeks + 2 days and 14 weeks + 1 day gestation. Increased nuchal translucency is associated with
Down's syndrome.
Serum screening and nuchal translucency scanning are typically used in combination (known as 'the combined test').
The standard serum screen measures the following biomarkers\:
Beta-hCG\: raised in Down's syndrome
PAPPA-A\: decreased in Down's syndrome
If a woman engages with antenatal care later in pregnancy when nuchal translucency scanning is less reliable, a di
set of biomarkers are assessed (known as 'the quadruple test')\:
Beta-hCG\: raised in Down's syndrome
AFP\: low in Down's syndrome
Inhibin A\: raised in Down's syndrome
Unconjugated estriol (uE3)\: low in Down's syndrome
The quadruple test is less reliable than the combined test.
Non-invasive prenatal testing (NIPT)
During pregnancy, the placenta sheds cell-free DNA (cfDNA) into the mother’s bloodstream. As a result, the mother’s
blood contains a mixture of placental and maternal cfDNA. By evaluating the cfDNA in the blood and combining this
with the mother’s background chance of a trisomy (mother’s age or the combined test results), a likelihood ratio is
obtained to predict whether or not the baby is more likely to have a chromosomal condition such as Down’s,
Edward's or Patau's syndrome. It is possible from around 10 weeks gestation and has a sensitivity of around 99%.
17-20
This test is not currently part of the routine screening pathway.
Con
Karyotype analysis of fetal cells via chorionic villus sampling (9–12 weeks gestation) or amniocentesis (15–19 weeks
gestation) is the gold standard for diagnosing Down's syndrome, with equal detection rates of around 99%. There is a higher
risk of pregnancy loss with chorionic villus sampling compared to amniocentesis.
19
Post-natal investigations
Given the association of Down's syndrome with a wide range of pathologies, it is essential that comprehensive screening is
performed in the post-natal period to allow early identi
Some examples of post-natal investigations include\:
Echocardiography\: to screen for congenital cardiovascular abnormalities
Red re
TFTs\: to screen for congenital thyroid disease
FBC\: to screen for myeloproliferative disorders and polycythaemia
Hearing assessment\: to screen for congenital hearing issues
Radiographic swallowing assessment\: performed if feeding di
abnormalities (e.g. duodenal atresia)

Management

Management of Down's syndrome requires a tailored multidisciplinary approach to screen, diagnose and treat
complications. Patients with Down's syndrome often require ongoing regular review from relevant specialists.
Genetic counsellingIf a newborn is diagnosed with Down’s syndrome, parents should be referred for genetic counselling to discuss the risk of
further children having Down's syndrome.References
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