creation date: 2025-07-31 02:15
tags: Pathologies
Down Syndrome
Background
Definitions
Down syndrome refers to the syndrome that occurs when all (trisomy) or part of a third copy of chromosome 21 is present.
This syndrome was first described by John Langdon Down in 1866.
Etiology and Pathogenesis
In the majority of cases, patient’s have an extra copy of chromosome 21. There are a number of hypotheses for the genetic basis of Down syndrome.
One hypothesis is the gene dosage imbalance theory, which suggests that the increased number/dosage of genes that originate from chromosome 21. Other theories suggest that the increased number of trisomic genes results in dysfunction of the expression and regulation of genes.
The incidence of Down syndrome increases with maternal age, ranging from 1 in 319-1000 live births. It should be noted that the incidence at conception is higher but 50-75% of these fetuses are lost before term.
Other forms of autosomal trisomy are more common but the postnatal survival of trisomy 21 is much higher owing to the relatively lower gene density of chromosome 21.
The variations of Down syndrome occur due to the route of pathogenesis.
Nondisjunction is the most common cause, accounting for 95% of cases. This occurs when chromosome 21 fails to separate in meiosis I or II of gametogenesis. The sperm or egg with two copies then combine with the opposing gamete to form a zygote with three copies.
Translocation, which accounts for 3% of cases, causes a part or entire chromosome 21 to attach to another chromosome (usually chromosome 14).
Mosaicism, which accounts for 2% of cases, occurs when some cells contain the usual 46 chromosomes and others contain 47. This means that the error occurs during cell division (mitosis) following fertilization which results in different populations of cells. Presentation may be milder as a result compared to other forms of down syndrome.
Clinical Presentation
Signs & Symptoms
Dysmorphic features
Head and neck
- Upslanting palpebral fissures (near universal feature)
- Epicanthic folds (near universal feature)
- Flat facial profile/flat nasal bridge
- Folded or dysplastic ears
- Low-set, small ears
- Brachycephaly (near universal feature)
- Brushfield spots
- Open mouth
- Protruding tongue
- Furrowed tongue
- Short neck
- Excessive skin at nape of the neck
- Narrow palate
- Abnormal teeth
Extremeties
- Short, broad hands
- Incurved fifth finger with hypoplastic middle phalanx
- Transverse palmar crease
- Space between the first and second toes (sandal gap)
- Hyperflexibility of joints
Neonatal features
- Flat facial profile
- Slanted palpebral fissures
- Anomalous ears
- Hypotonia
- Poor Moro reflex
- Dysplasia of middle phalanx of fifth finger
- Transverse palmar (Simian) crease
- Excessive skin at nape of the neck
- Hyperflexibility of joints
- Dysplasia of pelvis
Neuropsychiatric/cognitive disorders
Cognitive and developmental impairment
- Mild intellectual impairment (IQ 50-70) to severe (IQ 20-35)
- IQ typically declines in first 10 years of life and plateauing in adolescence
- Developmental milestones occur at slower rate
Behavioural and psychiatric disorders
- Disruptive behavioural disorders (eg. ADHD, conduct/oppositional disorder, aggressive behaviour)
- Major depressive illness
- Autism spectrum disorder
- Insomnia
- Dementia/Alzheimer (by 6th decade of life)
Growth
Early childhood
Growth impairments to birth weight, length, and head circumference are noted compared to other infants. Weight gain in the first three years of life has improved in the last few decades but growth parameters still remained lower until puberty and growth spurts occurring earlier and blunted.
Obesity
The prevalence of obesity is great in patients with down syndrome than the general population. In infancy, weight is generally less than expected for length but increases disproportionally in childhood so majority of children are obese by age 3-4.
Other associated disorders
Cardiovascular disease
Approximately half of patients with down syndrome have congenital heart disease:
- Complete atrioventricular septal defect
- Ventricular septal defect
- Atrial septal defect
- Partial atrioventricular septal defect
- Tetralogy of Fallot
- Faten ductus arteriosis
Other patients develop valve abnormalities and/or pulmonary hypotension.
Gastrointestinal abnormalities
Patients are at greater risk for:
- Duodenal atresia/stenosis (sometimes with annular pancreas)
- Imperforate anus
- Esophageal atresia with tracheoesophageal fistula
- Hirschsprung disease
- Celiac disease
Ophthalmologic disorders
The majority of children with down syndrome require monitoring and intervention for these disorders. Common ones include:
- Refractive errors (myopia, hyperopia, astigmatism)
- Strabismus
- Nystagmus
In some children, cataracts and/or glaucoma may develop.
Hearing loss
Hearing impairments affect many patients with down syndrome, often a congenital condition or caused by otitis media.
Endocrine disorders
Thyroid disease and type 1 diabetes are prevalent among patient’s with down syndrome.
Significantly decreased penile length and mean testicular volume are common and fertility is often impaired due to primary gonadal deficiency. Females with down syndrome are fertile (although with much greater risk of an offspring having down syndrome) while males with down syndrome are generally thought to be infertile.
Hematologic disorders
Abnormalities affect red blood cells, white blood cells, and platelets.
Common findings include:
- Polycythemia at birth
- Macrocytosis
- Leukopenia
- Thrombocytosis
Disorders include:
- Transient myeloproliferative disorder (generally asymptomatic with spontaneous resolution after 2-3 months)
- Acute megakaryoblastic leukemia
- Acute lymphoblastic leukemia
The lifetime risk of leukemia in down syndrome is 1-1.5%.
Immunodeficiency
Down syndrome is associated with increased susceptibility to:
- Infections
- Autoimmune disorders
- Malignancies
There may also be abnormalities with immunoglobulin levels and T and B cell systems.
Pulmonary disorders
Obstructive sleep apnea is common in children with down syndrome, including those who are not obese. Other respiratory disorders include:
- Disorders of pulmonary vasculature
- Parenchymal lung disease
- Upper and lower airway abnormalities (incl. asthma)
- Chronic aspiration
Dermatologic disorders
In most cases, skin conditions are benign. Most commonly found are:
- Eczematous dermatitis
- Folliculitis
- Alopecia areata
- Seborrheic dermatitis
- Hidradenitis suppurativa
- Palmoplantar hyperkeratosis
- Fissured or geographic tongue
- Dermatophyte infection
Urologic abnormalities
Down syndrome is associated with increased incidence of:
- Hypospadias
- Cryptorchidism
- Testicular cancer
- Kidney anomalies
Musculoskeletal disorders
Atlantoaxial instability, characterized by excessive mobility of the articulation of the atlas (C1) and axis (C2), lead to subluxation of the c-spine. This can be asymptomatic or present with signs of spinal cord compression
Arthropathy is also more prevalent in patients with down syndrome, often in the form of early-onset polyarticular disease.
History & Physical Exam
As diagnosis occurs at the latest shortly after birth, most patient encounters focus on evaluation and monitoring of the associated abnomalities, comorbidities, and disorders.
The AAP provides recommendations for health supervision based on the age of the patient. This is summarized here.
Diagnosis
Criteria
Diagnosis is typically suspected through prenatal screening and confirmed using diagnostic genetic testing.
If a prenatal diagnosis is not made, characteristic phenotypic features in the newborn should prompt genetic test. This is typically a karyotype performed on a blood sample.
Work-up
Following diagnosis, one-time assessments in initial months of life include:
- Congenital heart disease (via consultation of pediatric cardiologist)
- Newborn hearing screening with brainstem auditory evoked response or otoacoustic emission
Patients should be regularly assessed for the following:
- Growth (via down syndrome specific growth charts)
- Obesity (monitoring for purpose of prevention)
- Cardiovascular disease (mitral valve prolapse and aortic regurgitation)
- Audiology evaluation
- Otoscopic exam for otitis media
- Ophthalmologic assessment (more frequent if affected in initial evaluation)
- Thyroid function testing
- Diabetes testing
- Complete blood count with differential, ferritin/iron, and C-reactive protein (for hematologic disorders)
- Neurological screening for symptomatic atlantoaxial instability
Screening for symptoms of the following should also occur regularly:
- Skin and periodontal disease
- Celiac disease
- Sleep apnea (symptom screening and pulse oximetry during sleep)
- Neurodevelopmental and behavioural problems
- Alzheimer disease
Differential
The constellation of clinical features are generally strongly suggestive of Down syndrome and karotyping definitively confirms the diagnosis.
Another possible diagnoses include other aneuploidy (including trisomy 18).
Management
The management of Down syndrome is generally multidisciplinary, involving a number of specialists.
Parental education is the most important element of management and involves educating on:
- Associated conditions and the signs/symptoms
- Managing a balanced diet, exercise, and physical therapy to ensure the patient has optimum growth
As Down syndrome is non-curative, treatment is based on symptoms and management revolves around monitoring and screening as described above.
References
Tools / Guidelines
AAP - Guidelines for Health Supervision