Down Syndrome (Trisomy 21)

Written By Danial Mirza

Definition

Down syndrome is a genetic condition defined by the presence of a full or partial third copy of chromosome 21, leading to a total of 47 chromosomes in affected cells instead of the standard 46 (1, 3). It is crucial to frame this not as an illness to be cured, but as a lifelong condition or a state of being. This distinction fundamentally shapes the clinical approach, moving it away from curative intent towards a continuous, multidisciplinary process of anticipation, surveillance, and proactive management of associated medical comorbidities (3, 7). The condition is characterized by a highly variable constellation of features, including a recognizable physical phenotype, intellectual disability of varying degrees, and a significant predisposition to specific health issues affecting multiple organ systems.

Epidemiology

In Malaysia, the incidence of Down syndrome is estimated to be between 1 in 950 and 1 in 959 live births, a figure that aligns with global statistics and underscores its status as the most common chromosomal disorder (2, 25). A key local study from Kuala Lumpur provided valuable insight into the ethnic distribution, highlighting a varied incidence of 1 in 860 for Indians, 1 in 940 for Chinese, and 1 in 981 for Malays (25). Globally, the World Health Organization estimates an incidence between 1 in 1,000 and 1 in 1,100 live births (5). Advanced maternal age is the single most significant risk factor; however, it is a clinical pearl to understand the "maternal age paradox." While the risk is highest in older women, the majority of babies with Down syndrome (up to 80%) are born to mothers under the age of 35 (30, 34). This is a simple function of demographics: younger women have far higher birth rates, so the larger absolute number of births in this group results in a greater total number of cases, despite a lower individual risk. This fact is the cornerstone of policies recommending that prenatal screening be offered to all pregnant women, regardless of age.

Pathophysiology

The clinical features of Down syndrome are a direct consequence of a "gene dosage effect," where the extra genetic material from chromosome 21 leads to a 1.5-fold overexpression of its approximately 300 genes (8). This surplus disrupts the finely balanced network of gene expression throughout the genome, altering normal embryological development and cellular function. The condition arises from one of three distinct cytogenetic mechanisms:

  • Free Trisomy 21 (Non-disjunction): This is the most common cause, accounting for about 95% of all cases (7). It is a sporadic, random error in meiosis, the process of cell division that creates eggs and sperm. During meiosis, chromosome pairs are meant to separate, but in non-disjunction, the chromosome 21 pair fails to separate, leading to a gamete with an extra copy (9). The risk of this error increases with advanced maternal age, primarily due to the aging process of the oocytes, which have been arrested in meiosis I since before birth (12).

  • Robertsonian Translocation: Responsible for 3-4% of cases, this occurs when the long arm of chromosome 21 breaks off and permanently fuses with another acrocentric chromosome, most commonly chromosome 14 (13, 14). A parent can carry this fused chromosome in a "balanced" state, being phenotypically normal but having only 45 chromosomes. The clinical significance is profound, as they can produce "unbalanced" gametes containing both the translocated chromosome and a normal chromosome 21. This form is critical to identify via karyotyping because the recurrence risk is substantially higher than the ~1% risk for non-disjunction. For a maternal carrier, the risk is 10-15%; for a paternal carrier, it is 2-5% (12).

  • Mosaicism: This is the rarest form, affecting 1-2% of individuals. The non-disjunction event occurs after fertilization during an early mitotic cell division of the embryo (18, 20). This results in the individual developing with two distinct cell lines: one with the normal 46 chromosomes and another with 47. The clinical presentation is highly variable and often, but not universally, milder. The percentage of trisomic cells in a blood sample does not reliably predict the severity of the phenotype or intellectual function, as the distribution of these cells in critical tissues like the brain cannot be easily measured (12, 21).

Key genes on chromosome 21, such as Amyloid Precursor Protein (APP) and DYRK1A, are overexpressed. The triplication of the APP gene leads to a lifelong overproduction of amyloid-beta peptide, which explains why nearly all adults with Down syndrome develop the neuropathology of Alzheimer's disease by middle age. Overexpression of the DYRK1A kinase is strongly implicated in altered brain development and intellectual disability (3, 8).

Clinical Presentation

The diagnosis is often suspected at birth based on a recognizable pattern of dysmorphic features. While no single sign is pathognomonic, the overall clinical gestalt formed by a combination of features is highly suggestive (39).

  • Diagnostic Clues: The classic triad of significant hypotonia (low muscle tone), a flattened facial profile with a depressed nasal bridge, and upslanting palpebral fissures in a newborn should immediately raise a high index of suspicion.

  • Common Features (>50%):

    • Intellectual Impairment (~99%): This is a near-universal feature, though the severity varies widely, most commonly in the mild-to-moderate range (41).

    • Hypotonia (Low Muscle Tone) (80%): This is a cardinal sign at birth, manifesting as a "floppy" or "ragdoll" feel, poor head control, and a frog-leg posture at rest. It contributes significantly to delayed motor milestones and feeding difficulties (41).

    • Flat Facial Profile / Brachycephaly (75%): The midface is underdeveloped, contributing to a flattened appearance and a short, broad head (41).

    • Upslanting Palpebral Fissures (60%): The upward slant of the eyes, often accompanied by prominent epicanthic folds (skin folds at the inner corner of the eyes), is a well-known feature (41).

    • Increased Nuchal Skin Fold (80%): Redundant skin at the nape of the neck is a common finding in neonates (41).

    • Single Transverse Palmar Crease (53%): Also known as a simian crease, this single deep crease across the palm is present in just over half of individuals but can also be found in the general population (41).

    • Shortened Hands with Clinodactyly (57-60%): Hands are often broad and short (brachydactyly), with an inward curving of the fifth finger (clinodactyly) (41).

    • "Sandal Gap" (68%): A wide space between the first and second toes is a characteristic finding (41).

  • Less Common Features (10-50%):

    • Protruding Tongue / Macroglossia (47-75%): The tongue may appear large relative to a smaller oral cavity, often protruding (41).

    • Brushfield Spots (56%): Small, white or greyish spots on the periphery of the iris (41).

    • Congenital Heart Disease (40-60%): A major comorbidity, often silent on initial examination (11, 45).

    • Umbilical Hernia (90%): While very common, it may not be apparent until later in infancy (41).

  • ⚠️ Red Flag Signs & Symptoms:

    • Significant lethargy, poor feeding, or prolonged jaundice: These non-specific signs in a neonate with dysmorphic features are highly concerning and may be the first indication of severe congenital hypothyroidism or life-threatening congenital heart disease.

    • Bilious vomiting: In a neonate with Down syndrome, this is a surgical emergency until proven otherwise. It is the classic presentation of duodenal atresia, a strongly associated anomaly, and requires immediate surgical consultation.

    • Any new neurological signs: The onset of neck pain, a new head tilt (torticollis), changes in gait or use of arms, or new-onset incontinence at any age must be urgently investigated to rule out spinal cord compression from atlanto-axial instability.

Complications

Individuals with Down syndrome are predisposed to a well-documented range of medical conditions. Proactive screening and management are the cornerstones of care.

  • Cardiovascular: Congenital heart defects are the most common and serious complication, affecting 40-60% of newborns. Atrioventricular septal defects (AVSD), where there is a large central hole in the heart, are the most characteristic lesion. This and other defects are the leading cause of mortality in the first two years of life (45, 46).

  • Gastrointestinal: Structural anomalies occur in 6-12% of individuals. Duodenal atresia (blockage of the first part of the small intestine) is a classic association, presenting with neonatal vomiting and the "double bubble" sign on abdominal X-ray. There is also a significantly higher prevalence of Celiac disease and Hirschsprung disease (13).

  • Endocrine: Thyroid dysfunction, particularly hypothyroidism (both congenital and acquired), is extremely common and requires lifelong annual screening (8, 37). The risk of Type 1 Diabetes is also increased (13).

  • Haematological: There is a 10 to 20-fold increased risk of leukaemia, including both Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML) (12). A unique neonatal condition, Transient Abnormal Myelopoiesis (TAM), a pre-leukaemic state, can occur in up to 20% of newborns and may spontaneously resolve or evolve into leukaemia within the first few years (48).

  • Neurological: Due to the triplication of the APP gene, virtually all individuals with Down syndrome will develop the neuropathological hallmarks of Alzheimer's disease by middle age, with a high percentage developing clinical dementia, often beginning in their 50s (3, 8). Atlanto-axial instability (AAI), or excessive movement between the first two cervical vertebrae, occurs in 1-2% and carries a risk of spinal cord compression (13).

  • Sensory: Hearing loss affects over 50% of children, most commonly conductive loss due to recurrent otitis media with effusion ("glue ear") related to Eustachian tube dysfunction (11). Ophthalmologic problems affect over 60%, including refractive errors, strabismus (squint), and congenital cataracts (13).

  • Respiratory: Obstructive Sleep Apnea (OSA) affects up to 60% of individuals. This is multifactorial, caused by a combination of central hypotonia, a relatively large tongue (macroglossia), midfacial hypoplasia, and narrowed airways, requiring a high index of suspicion and a low threshold for investigation (8).

Prognosis

With dramatic improvements in medical care, particularly early corrective cardiac surgery and proactive management of comorbidities, the life expectancy for individuals with Down syndrome has surged. While it was less than 25 years in the 1980s, many individuals now live into their 60s and beyond (7). Despite this, mortality in the first two years of life remains significant and is most commonly due to complications from severe congenital heart disease (45). The overall prognosis and, importantly, the quality of life are heavily influenced not just by the presence of major medical issues, but by the quality and intensity of supportive care, early intervention, educational opportunities, and social inclusion received throughout their lives (65).

Differential Diagnosis

While the phenotype is often recognizable, other chromosomal and genetic conditions can share features like hypotonia and dysmorphism, necessitating a definitive karyotype.

  • Trisomy 18 (Edwards Syndrome): This is a key differential for a neonate with multiple congenital anomalies. Infants with Trisomy 18 typically have a more severe presentation with features not typical of Down syndrome, such as a prominent occiput, low-set malformed ears, rocker-bottom feet, and clenched hands with overlapping fingers. The prognosis for Trisomy 18 is significantly poorer, with most infants not surviving the first year (40).

  • Trisomy 13 (Patau Syndrome): This should be considered if the infant presents with significant midline defects, such as holoprosencephaly (failure of the brain to divide), cleft lip/palate, and microphthalmia or anophthalmia (small or absent eyes). These specific midline structural anomalies are characteristic of Trisomy 13 and are not typical features of Down syndrome (40).

  • Zellweger Syndrome: This is a rare peroxisomal disorder that can present with severe hypotonia and dysmorphic features that overlap with Down syndrome, including a high forehead and flattened facies. However, the presence of significant hepatomegaly, seizures from birth, and a lack of any developmental progress points towards a severe metabolic disorder like Zellweger syndrome rather than a primary chromosomal aneuploidy (40).

  • Congenital Hypothyroidism: Severe, untreated congenital hypothyroidism can result in a clinical picture (cretinism) that mimics some features of Down syndrome, such as a large tongue, umbilical hernia, poor tone, and developmental delay. An urgent thyroid function test is essential in any suspected case, as this is a readily treatable condition and is also a very common comorbidity in Down syndrome itself, requiring exclusion in its own right (11).

Investigations

A parallel approach is crucial: while sending blood for definitive genetic confirmation, an immediate and simultaneous workup for common and life-threatening comorbidities must be initiated without delay.

Immediate & Bedside Tests

  • Full Blood Count and Peripheral Blood Film: This is an essential STAT test to identify polycythemia, a common finding that may require partial exchange transfusion to prevent thrombotic complications, and to screen for Transient Abnormal Myelopoiesis (TAM) (the action), a unique neonatal leukaemia-like state that requires urgent haematology consultation for monitoring and management (the rationale) (11).

  • Newborn Hearing Screen (OAE/ABR): This must be performed prior to hospital discharge to detect congenital hearing loss (the action), as unidentified hearing loss is a major barrier to language acquisition and cognitive development, and early intervention with hearing aids can significantly alter this trajectory (the rationale) (11).

Diagnostic Workup

  • First-Line Investigation (Confirmation): A peripheral blood karyotype is the mandatory gold standard test. It provides the definitive diagnosis by visualizing the extra chromosome 21 (e.g., 47,XX,+21) (the rationale) and, crucially, distinguishes between non-disjunction and translocation (e.g., 46,XX,t(14;21)), which is absolutely essential for providing accurate genetic counselling to the family regarding recurrence risk (the action) (37).

  • Gold Standard (Comorbidity Screening): An echocardiogram, performed by a paediatric cardiologist, is the gold standard for cardiac assessment and is mandatory for every newborn with Down syndrome, regardless of the presence of a murmur or other clinical signs. This is performed to definitively identify or exclude congenital heart defects like AVSD (the rationale), as a normal clinical exam does not rule out a significant, life-threatening lesion that requires timely surgical planning to prevent irreversible pulmonary hypertension (the action) (11, 45).

  • Rapid Confirmation: Fluorescence In Situ Hybridization (FISH) can be used on a blood sample for a rapid (24-48 hour) preliminary result. It uses fluorescent probes that bind specifically to chromosome 21, allowing for a quick count of the chromosomes (the rationale). This allows for earlier, confident parental counselling and initiation of the management pathway while awaiting the full, detailed karyotype which can take several weeks (the action) (19).

Monitoring & Staging

  • Thyroid Function Test (TFT): A TFT (TSH and Free T4) must be checked in the neonatal period to screen for congenital hypothyroidism (the action), a common and eminently treatable cause of severe intellectual disability (the rationale). This test must then be repeated at 6 and 12 months, and annually thereafter for life, to monitor for the high risk of developing acquired autoimmune hypothyroidism (11).

  • Ophthalmology Assessment: A formal evaluation by an ophthalmologist is required within the first 6 months of life. This is to screen for congenital cataracts, which require urgent surgery to prevent blindness, as well as significant refractive errors and strabismus (the action), as uncorrected vision problems can severely hamper a child's ability to learn and interact with their environment (the rationale) (11).

Management

Management is not curative but focuses on a lifelong, multidisciplinary framework of proactive surveillance, treatment of comorbidities, and supportive care designed to maximize functional potential and enhance quality of life.

Management Principles

The management of Down syndrome is built on three core pillars: early and aggressive detection and treatment of medical comorbidities; provision of consistent developmental and educational support through early intervention programmes; and comprehensive, continuous family support (6, 62). The guiding philosophy should be a palliative and supportive one, which in this context means a holistic approach to improving quality of life starting from the moment of diagnosis, not just at the end of life.

Acute Stabilisation (The First Hour)

While most newborns are stable, a house officer may encounter an infant with a critical comorbidity. The approach follows the standard ABCDE framework.

  • Airway/Breathing: For an infant with respiratory distress, often exacerbated by hypotonia and a large tongue, ensure a patent airway with proper positioning. Administer supplemental oxygen via nasal prongs or mask to maintain SpO2 >94% (the action), which is vital to prevent hypoxia, especially in the context of a potential underlying cardiac lesion that impairs oxygen delivery (the rationale).

  • Circulation: If the infant presents with signs of shock (tachycardia, poor perfusion, hypotension, weak pulses), secure IV access immediately. Administer a fluid bolus of IV Normal Saline 10-20mL/kg over 20-30 minutes (the action) to restore circulatory volume and improve tissue perfusion (the rationale). This is a critical temporizing measure while urgently investigating for underlying sepsis or a duct-dependent cardiac lesion requiring prostaglandin infusion.

  • Disability (Hypoglycaemia): Check a bedside glucose level in any unwell or hypotonic infant. If low (<2.6 mmol/L), administer an IV Dextrose 10% bolus of 2mL/kg (the action) to rapidly correct the glucose level and prevent irreversible neurological injury from neuroglycopenia (the rationale).

Definitive Therapy

This involves targeted medical and surgical management of comorbidities by various subspecialists.

  • First-Line Treatment (Cardiac): For significant defects like a complete AVSD, the definitive therapy is corrective open-heart surgery. This is typically performed before 6 months of age to prevent the development of irreversible pulmonary vascular disease (Eisenmenger syndrome), a devastating complication that is known to develop faster and more aggressively in children with Down syndrome (11).

  • First-Line Treatment (Endocrine): For hypothyroidism, the treatment is lifelong oral levothyroxine replacement. The dose is carefully titrated based on regular TFT monitoring with the goal of maintaining a euthyroid state (normal TSH/T4 levels), which is absolutely essential for promoting normal growth, energy levels, and cognitive function (37).

  • First-Line Treatment (Developmental): The single most critical "definitive" therapy for maximizing a child's developmental outcome is early and intensive enrollment in an Early Intervention Programme (EIP). This multidisciplinary approach, involving physiotherapy to improve gross motor skills, occupational therapy for fine motor and self-care skills, and speech therapy for communication, is the most effective strategy to help a child achieve their maximum potential (62, 66).

Supportive & Symptomatic Care

  • Nutrition: Establish a comprehensive feeding plan. For infants with severe hypotonia and a weak suck, this may require input from a lactation consultant, the use of special teats, or fortifying breast milk or formula to ensure adequate caloric intake for growth. In some cases, a temporary nasogastric tube may be required to prevent failure to thrive (6, 59).

  • Immunisations: Administer all vaccinations according to the Malaysian National Immunisation Programme (NIP) schedule without delay. It is crucial to provide this protection, as the inherent immune system differences in Down syndrome lead to an increased susceptibility to and severity of respiratory infections (11, 57).

  • Genetic Counselling: Arrange for a formal genetic counselling session for the parents. This should be a dedicated, unhurried consultation to explain the diagnosis, the specific genetic cause found on the karyotype, and the accurate recurrence risk for future pregnancies, allowing for informed family planning (11).

Key Nursing & Monitoring Instructions

  • Plot length, weight, and head circumference at every visit on Down syndrome-specific growth charts, as growth patterns differ from the general population.

  • Maintain a strict feeding and fluid balance chart, especially in the neonatal period, to quantify intake and output accurately.

  • Monitor closely for subtle signs of respiratory distress (tachypnoea, nasal flaring, retractions) or cardiac failure (tachycardia, hepatomegaly, oedema).

  • Educate parents on feeding techniques that account for hypotonia and potential tongue thrust, such as providing chin and jaw support.

  • Inform medical staff immediately if there is any episode of bilious vomiting, temperature instability, seizures, or any apnoeic episodes.

Long-Term Plan & Patient Education

The long-term plan involves a structured transition from paediatric to adult care services, with continued annual health checks for known comorbidities. Patient education is a continuous process focused on empowering the family. Key points include explaining the lifelong nature of health supervision, the profound benefits of early intervention, and actively connecting them with national and local support systems. A critical role for the clinician is to guide the family through the process of registering their child as Orang Kurang Upaya (OKU) with the Social Welfare Department (Jabatan Kebajikan Masyarakat, JKM). This is not just paperwork; the OKU card is the essential gateway to accessing a wide range of government health, education, and welfare benefits that are vital for the child's long-term care (62, 63).

When to Escalate

A house officer must maintain a low threshold for seeking senior help when managing a child with Down syndrome, as they can deteriorate quickly.

Call Your Senior (MO/Specialist) if:

  • A newborn with suspected Down syndrome has bilious vomiting, abdominal distension, or signs of circulatory collapse (shock).

  • An infant shows clear signs of heart failure (e.g., persistent tachycardia >160/min, tachypnoea >60/min at rest, an enlarging liver, or new-onset feeding difficulties with sweating).

  • A child of any age develops new neurological symptoms, particularly neck pain, torticollis, gait changes, or new-onset incontinence, suggesting possible spinal cord compression.

  • A full blood count result shows blasts or other features suggestive of leukaemia or Transient Abnormal Myelopoiesis (TAM).

Referral Criteria:

  • All newborns with a confirmed or suspected diagnosis must have an urgent referral to a Paediatric Cardiologist for an echocardiogram (11).

  • Upon diagnosis, refer immediately to the hospital's multidisciplinary team for enrollment in an Early Intervention Programme (Physiotherapy, Occupational Therapy, Speech Therapy) (62).

  • Refer to an Ophthalmologist within the first 6 months and an Audiologist for regular, structured screening as per guidelines (11).

  • Refer the family to a Medical Social Worker to facilitate OKU registration and to key Non-Governmental Organisations (NGOs) like the Kiwanis Down Syndrome Foundation (KDSF) for its renowned EIPs and the Persatuan Sindrom Down Malaysia (PSDM) for invaluable family and community support (66, 69).

References

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(48) Tan, P. L., et al. (2016). GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder. PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC4971451/

(57) Immunise4Life. (n.d.). The Malaysian National Immunisation Programme (NIP). Retrieved July 12, 2025, from https://immunise4life.my/the-malaysian-national-immunisation-programme-nip/

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(63) Ministry of Health Malaysia. (n.d.). Manual on the management of children with personal & social problems. Retrieved July 12, 2025, from https://hq.moh.gov.my/bpkk/images/Kesihatan_Orang_Kurang_Upaya/PDF/A_Series_Of_Six_Manuals_On_the_Management_Of_Children_With_Disabilities/6_Manual_On_Management_Of_Children_With_Personal___Social_Problems.pdf

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(66) Kiwanis Down Syndrome Foundation. (n.d.). KDSF NATIONAL CENTRE. Retrieved July 12, 2025, from https://www.kdsf.org.my/about-national-centre/

(69) Persatuan Sindrom Down Malaysia. (n.d.). Home. Retrieved July 12, 2025, from https://downsyndromemalaysia.com/

Danial Mirza
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