Trisomy 21 Down Syndrome

Slide 1 · Trisomy 21

(Down syndrome)

Chromosomal basis, developmental consequences and clinicopathologic correlations

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Interpret trisomy 21, Robertsonian translocation and mosaic cytogenetic patterns.

Connect extra chromosome 21 dosage to selected molecular and organ-system effects.

Explain major congenital, hematologic, neurologic and immune associations.

Distinguish prenatal screening from diagnostic confirmation.

Slide 3 · Down syndrome is a chromosomal disorder

The phenotype results from an extra dosage of chromosome 21 genetic material.

It as the most common chromosomal disorder and a major cause of intellectual disability.

Different cytogenetic routes converge on increased chromosome 21 dosage.

One syndrome can arise through distinct chromosomal mechanisms.

Slide 4 · Newborn frequency in the United States

United States

~1 in 700 newborns

Type of estimate

Live-birth frequency

About one affected newborn in 700 in the United States.

This is an approximate textbook incidence, not an independently verified 2026 surveillance estimate.

It expresses live-birth frequency, not the risk for a particular pregnancy.

Slide 5 · Normal human chromosome complement

Chromosome 21 in a normal diploid cell

Two homologues

Human somatic cells normally contain 46 chromosomes: 22 autosomal pairs and a sex-chromosome pair.

Karyotyping arranges metaphase chromosomes by homologous pairs.

G-banding allows recognition of whole-chromosome gains and large rearrangements.

Slide 6 · Euploidy versus aneuploidy

Term

Definition

Relevance here

Euploid

Exact multiple of the haploid set (23)

Normal diploid cells: 46

Aneuploid

Chromosome count not an exact multiple of 23

Trisomy 21: 47

Trisomy

A third copy of a particular chromosome

Extra genetic material from chromosome 21

Slide 7 · How a trisomic zygote can arise

Failure of normal meiotic separation

Gamete with two copies of 21

Fertilization with normal gamete

Zygote with three copies of 21

Nondisjunction produces gametes with an extra chromosome or with a missing chromosome.

Fertilization involving a gamete with two copies of chromosome 21 can yield three copies in the zygote.

Slide 8 · The 47-chromosome constitution

Chromosome 21 in typical free trisomy

Three separate homologues

Typical free trisomy 21 contains three separate copies of chromosome 21.

Affected individuals usually have 47 chromosomes rather than 46.

Sex chromosomes are designated separately (for example, 47,XX,+21).

Slide 9 · FISH can demonstrate three chromosome 21 signals

3 × chromosome 21 probe signals

2 × chromosome 13 probe signals

Schematic (not observed FISH)

Chromosome 21–specific probes identify its copy number in an interphase nucleus.

The source example shows three chromosome 21 signals and two chromosome 13 control signals.

Slide 10 · Three cytogenetic mechanisms underlie the phenotype

Free trisomy

95%

Robertsonian translocation

4%

Mosaicism

1%

Proportion of Down syndrome cases (%)

The source estimates approximately 95% free trisomy, 4% Robertsonian translocation and 1% mosaicism.

These are proportions among Down syndrome cases, not population prevalence.

Slide 11 · Meiotic nondisjunction is the predominant route

Failure of normal chromosomal separation occurs during gametogenesis.

The common result is a conceptus with an additional entire chromosome 21.

Parents of children with free trisomy 21 generally have normal constitutional karyotypes.

Aneuploidy in the child need not reflect an abnormal parental karyotype.

Slide 12 · Nondisjunction: The conceptual sequence

Parent with paired chromosome 21

Meiotic segregation error

Disomic gamete for 21

Trisomic embryo after fertilization

The error occurs before fertilization in the classical meiotic form.

The chromosome imbalance is then carried into subsequent embryonic cell divisions.

Slide 13 · The extra chromosome is usually maternally derived

DNA polymorphism analyses traced the extra chromosome 21 to the maternal parent in about 95% of cases.

This observation supports an important role for errors arising in the ovum.

It does not imply maternal causation through behavior or a controllable exposure.

Slide 14 · Maternal age strongly modifies live-birth frequency

Maternal age <20

1 in 1,550 live births

Maternal age >45

1 in 25 live births

Approximately 1 in 1,550 live births for mothers younger than 20.

For mothers older than 45, the corresponding figure is about 1 in 25.

These two reported groups are endpoints, not a continuous risk model.

Slide 15 · The age association does not fully explain nondisjunction

The maternal-age correlation indicates that meiotic chromosome segregation is age-sensitive.

Multiple hypotheses have been proposed.

The precise reason for greater susceptibility to nondisjunction is not established in the source.

Association is well established; A single definitive causal mechanism is not.

Slide 16 · Free trisomy and translocation are not synonymous

Dimension

Free trisomy 21

Robertsonian-associated Down syndrome

Chromosome complement

Usually 47

May contain 46 chromosomes

Additional material

Independent chromosome 21

Additional 21q material on a derivative chromosome

Typical mechanism

Meiotic nondisjunction

Centric fusion involving acrocentric chromosomes

Parental status

Usually normal karyotypes

Can involve a balanced carrier

Slide 17 · Robertsonian translocation joins long arms

Conceptual chromosome-arm arrangement

14q

21q

Der(14;21) containing 14q + 21q

Schematic; No physical chromosome scale implied

A Robertsonian rearrangement involves centric fusion of acrocentric chromosomes.

Chromosome 21q can be translocated to another acrocentric chromosome.

Clinical significance depends on the net dosage of chromosome 21 material.

Slide 18 · An extra 21q copy causes dosage imbalance

Two ordinary 21q copies

An additional translocated 21q

Three doses of 21q genes

Down syndrome phenotype

Two ordinary chromosome 21 copies plus a translocated 21q copy supply three doses of 21q.

The resulting gene dosage can produce the Down syndrome phenotype despite a different chromosome count.

Slide 19 · Chromosomes 14 and 22 are illustrative partners

Chromosome 21 material attached to another acrocentric chromosome, such as 14 or 22.

The rearrangement changes chromosome structure, not merely chromosome count.

Conventional karyotyping is important for classifying the rearrangement.

Slide 20 · Balanced carrier versus affected conceptus

Feature

Balanced Robertsonian carrier

Down syndrome from translocation

Genetic dosage

Essential long-arm complement remains balanced

Chromosome 21 dosage is increased

Chromosome count

Often 45

Often 46 for rob(14;21)-associated cases

Clinical phenotype

Carrier may be unaffected

Down syndrome phenotype

Reproductive relevance

Unbalanced gametes may form

May recur in a family

Slide 21 · Why carrier parents can produce unbalanced gametes

Balanced parental translocation

Complex meiotic pairing

Potentially unbalanced gamete

Child with extra 21q dosage

Rearranged and normal homologues must pair and segregate during meiosis.

This segregation can yield gametes with unbalanced chromosomal content.

Consequently, a translocation-associated case may have a familial origin.

Slide 22 · Translocation status changes genetic evaluation

About 4% of Down syndrome cases are attributed to Robertsonian translocation.

Some of these rearrangements are inherited; Others are not.

Characterizing the child’s karyotype can indicate whether parental chromosomal evaluation is relevant.

Slide 23 · Mosaicism originates after fertilization

Initially developing embryo

Early mitotic nondisjunction

Divergent cell lineages

Mosaic 46/47 cell populations

An early mitotic segregation error can create genetically distinct cell populations.

The viable mosaic typically contains both 46-chromosome and 47-chromosome cell lines.

Different tissues may contain different proportions of affected cells.

Slide 24 · Mosaic Down syndrome contains distinct cell lines

Coexisting cell lines

46: Normal

47: +21

47: +21

46: Normal

47: +21

46: Normal

Cells shown in illustrative proportions only

The classic designation uses 46- and 47-chromosome cell populations.

The textbook estimates approximately 1% of individuals with Down syndrome are mosaics.

Tissue distribution is important; One sample does not fully capture all cell lineages.

Slide 25 · Mosaic phenotype is variable

The presence and distribution of trisomic cells influence clinical expression.

Some affected individuals show milder phenotypic features.

The source notes that some mosaics can have normal or near-normal intellectual functioning.

A mosaic karyotype does not determine an individual’s phenotype with certainty.

Slide 26 · Three routes: Origin and diagnostic implications

Mechanism

When it arises

Key cytogenetic concept

Free trisomy

Usually meiotic error

Three separate chromosome 21 copies

Robertsonian translocation

Chromosomal rearrangement; Sometimes inherited

Extra chromosome 21 long-arm material

Mosaicism

Early postzygotic mitotic error

Two or more cell lines

Slide 27 · Gene dosage is the unifying pathogenic principle

Extra chromosome 21 material

Altered copy number at multiple loci

Changes in expression and cell function

Multisystem phenotype

The phenotype reflects dosage imbalance across many loci on chromosome 21.

An additional chromosome or chromosome segment can increase expression of relevant genes.

Robbins does not attribute the full syndrome to one causal gene.

Slide 28 · Most chromosome 21 protein-coding genes are overexpressed

The source describes overexpression of most protein-coding genes located on chromosome 21.

Increased gene dosage affects many pathways simultaneously.

The relationships among dosage, pathway responses and individual features remain complex.

Slide 29 · Dosage alteration differs from single-gene disease

Dimension

Trisomy 21

Simplified single-gene model

Genetic origin

Additional chromosomal material

Pathogenic change at a specific gene

Molecular consequence

Many gene products may change

A principal protein or pathway may dominate

Phenotypic explanation

Distributed dosage effects

Often focused gene–phenotype chain

Slide 30 · APP is one chromosome 21 dosage-sensitive gene

Extra APP gene dosage

Higher APP expression

Potential increased amyloid-β burden

Earlier Alzheimer-type pathology

The gene encoding amyloid-β precursor protein (APP) is on chromosome 21.

Increased APP dosage is a plausible contributor to amyloid-related neuropathology.

This as one component of a wider phenotype.

Slide 31 · Amyloid-β accumulation offers a neuropathologic link

Amyloid-β aggregation as a potential initiating event in Alzheimer disease.

Extra APP dosage in trisomy 21 may contribute to earlier amyloid pathology.

The molecular association should not be treated as an explanation for all cognitive features.

Slide 32 · Chromosome 21 dosage also affects mitochondria

Chromosome 21 gene overexpression

Perturbed mitochondrial regulation

Abnormal organelle structure/function

Cellular stress

Approximately 10% of the genes overexpressed in Down syndrome are involved directly or indirectly in mitochondrial regulation.

The source reports abnormalities in mitochondrial morphology and function.

Slide 33 · Mitochondrial cristae may be swollen or disrupted

Simplified mitochondrial ultrastructure

Illustrative intact folds

Illustrative swollen / disrupted folds

Schematic; Not an electron micrograph

Broken or swollen cristae are described in several tissues.

Altered mitochondrial structure accompanies broader functional stress.

Slide 34 · Oxidative stress may amplify cellular injury

Mitochondrial stress

Reactive oxygen species

Cellular injury signals

Apoptotic responses

Mitochondrial stress is linked in the source to generation of reactive oxygen species.

Activation of apoptosis is also reported.

These changes provide candidate mechanisms for tissue dysfunction without fully specifying organ-level causation.

Slide 35 · Noncoding RNA contributions remain uncertain

Chromosome 21 has a high density of long noncoding RNAs.

The biological functions of most of these transcripts remain unknown in the source.

Their quantitative contribution to the phenotype requires further study.

Do not assign unverified downstream effects to individual lncRNAs.

Slide 36 · Molecular disease model: Interacting contributors

Trisomy 21 gene-dosage imbalance

APP / amyloid-β

Mitochondrial function

Other coding genes

Noncoding RNAs

Gene dosage is central; APP-related amyloid biology and mitochondrial stress are examples.

Noncoding RNA biology remains a potential additional layer.

The magnitude of each pathway’s contribution differs across features and is incompletely resolved.

Slide 37 · The clinical phenotype can be recognized at birth

The source highlights a recognizable constellation of facial features.

Clinical examination may prompt cytogenetic assessment.

No single physical feature is sufficient to establish a chromosomal diagnosis.

Slide 38 · Characteristic facial findings

Finding

Description

Diagnostic interpretation

Flat facial profile

Reduced prominence of the midface/profile

Recognizable component of the pattern

Oblique palpebral fissures

Slanting ocular openings

One feature among several

Epicanthic folds

Skin folds near the medial canthi

Supportive, not diagnostic alone

Slide 39 · Intellectual disability is a central association

Down syndrome is a major cause of intellectual disability.

Neurodevelopmental outcomes span a spectrum of functional abilities.

Mosaic individuals may show particularly variable outcomes.

Slide 40 · The syndrome affects multiple organ systems

Trisomy 21 gene-dosage imbalance

Congenital heart

Gastrointestinal tract

Hematopoietic system

Brain / immunity

Congenital cardiac and gastrointestinal anomalies.

Leukemia risk, neurodegenerative pathology and immune dysregulation are important associations.

Clinical manifestations arise from the same chromosomal diagnosis but differ by system.

Slide 41 · Congenital heart disease affects many patients

Congenital heart disease

~40%

Without reported congenital heart disease

~60%

Approximately 40% of individuals with Down syndrome have congenital heart disease in the source.

Cardiac abnormalities are a major determinant of infant and early-childhood morbidity.

Slide 42 · Atrioventricular septal defects predominate

The source describes atrioventricular septal defects as the most frequent congenital cardiac lesion.

They account for 43% of the listed congenital heart defects among affected patients.

The name identifies abnormal septation involving the atrioventricular junction.

Slide 43 · Ventricular septal defects are also common

Ventricular septal defects account for 32% of the cardiac defects tabulated.

They represent a communication across the interventricular septum.

This category should be distinguished from complete atrioventricular septal defects.

Slide 44 · Atrial septal defects form another major category

Atrial septal defects account for 19% of the listed lesions.

They involve abnormal communication across the interatrial septum.

Defect classification informs the anatomical interpretation of congenital heart disease.

Slide 45 · Tetralogy of Fallot is less frequent

Tetralogy of Fallot in 6% of its congenital cardiac breakdown.

Its presence is an important reminder that the cardiac phenotype is not limited to septal defects.

The cited percentages apply to the specified cardiac-defect distribution.

Slide 46 · Congenital heart defect distribution

Atrioventricular septal

43%

Ventricular septal

32%

Atrial septal

19%

Tetralogy of Fallot

6%

Share of reported congenital heart defects (%)

Percentages are categories of congenital heart disease reported in the source.

They must not be interpreted as percentages among all individuals with Down syndrome.

Slide 47 · Congenital heart disease drives early mortality

Cardiac problems are described as responsible for most deaths during infancy and early childhood.

This association provides the clinical rationale for early attention to congenital heart disease.

It is a historical/source statement, not a current age-specific mortality estimate.

Anatomic diagnosis matters because cardiac lesions contribute materially to prognosis.

Slide 48 · Gastrointestinal atresias are additional malformations

Esophageal and small-bowel atresias among associated congenital anomalies.

Atresia denotes interruption or absence of a normal luminal passage.

These are developmental structural abnormalities, not consequences of leukemia or later dementia.

Slide 49 · Cardiac versus gastrointestinal malformations

System

Examples in the source

Pathologic category

Cardiovascular

AVSD, VSD, ASD, tetralogy of Fallot

Congenital defects of cardiac structure

Gastrointestinal

Esophageal atresia; Small-bowel atresia

Congenital interruption of a hollow viscus

Slide 50 · Hematopoietic malignancy risk is elevated

Children with trisomy 21 have an increased likelihood of developing leukemia.

Both precursor B-cell acute lymphoblastic leukemia and acute myeloid leukemia.

The reported relative-risk increases differ substantially by leukemia category.

Slide 51 · Precursor B-ALL: Approximately 20-fold relative risk

Precursor B-cell ALL

~20-fold higher risk

Metric type

Relative risk increase

An approximately 20-fold increased risk for precursor B-cell acute lymphoblastic leukemia.

A relative-risk multiplier is not an absolute probability of developing leukemia.

Disease-specific numerical claims are retained in their textbook context.

Slide 52 · Acute myeloid leukemia: Approximately 500-fold risk

Acute myeloid leukemia

~500-fold higher risk

Metric type

Relative risk increase

The source reports an approximately 500-fold increase in acute myeloid leukemias.

This is a relative-risk comparison with the general population, not lifetime incidence.

The cited statement does not subdivide AML into molecular subtypes.

Slide 53 · The two leukemia risk statements are distinct

Leukemia category

Reported increase

Interpretation

Precursor B-cell ALL

20-fold

Marked increase in relative risk

Acute myeloid leukemias

500-fold

Even larger relative increase

Both categories

No absolute rates stated

Do not infer absolute incidence from fold change

Slide 54 · Alzheimer-type neuropathology develops early

The source states that virtually all people with trisomy 21 beyond age 40 develop neuropathologic changes characteristic of Alzheimer disease.

This is a statement about neuropathologic changes, not a claim that every individual has symptomatic dementia.

The APP dosage pathway provides one mechanistic link.

Slide 55 · Distinguish Alzheimer pathology from clinical dementia

Trisomy 21 / extra APP dosage

Amyloid-related brain pathology

Alzheimer-type lesions

Variable clinical expression

The appearance of neuropathologic lesions and the manifestation of dementia are different outcomes.

The textbook’s near-universal statement concerns microscopic neuropathology over age 40.

Slide 56 · Immune disturbances increase infection susceptibility

Down syndrome is associated with abnormal immune responses.

The source identifies serious infections, especially in the lungs, as an important consequence.

It describes reported abnormalities affecting predominantly T-cell functions.

Slide 57 · Immunologic disturbance: Clinical consequences

Altered immune responses

Reported T-cell abnormalities

Increased infection susceptibility

Pulmonary infections

The precise immunologic basis is not fully defined in the source.

The relationship to respiratory infection is established clinically, though not explained by a single pathway.

Slide 58 · Thyroid autoimmunity is another immune association

The textbook specifically mentions predisposition to thyroid autoimmunity.

The immune phenotype encompasses more than susceptibility to infection.

The source does not specify the frequency or detailed autoantibody profile.

Slide 59 · Medical care has changed survival

Increased longevity to improvements in medical care.

The text provides historical median age-at-death figures (25 years in 1983 and 47 years at a later reporting point).

These figures should not be used as validated contemporary survival estimates without independent updating.

Survival statistics depend strongly on era, population and clinical care.

Slide 60 · Prenatal screening analyzes fetal-derived DNA

Maternal blood sample

Cell-free DNA mixture

Sequencing-based dosage analysis

Trisomy 21 screening result

Maternal blood contains a cell-free DNA mixture with a fetal-derived component.

The fetal-derived component as the basis of chromosome-dosage screening.

The assay assesses relative chromosome 21 representation rather than a physical karyogram.

Slide 61 · Fetal-derived cell-free DNA fraction in the source

Fetal-derived fraction

~5–10%

Specimen

Maternal blood

That approximately 5–10% of circulating cell-free DNA in maternal blood is fetal-derived.

The reported percentage is an illustrative source range rather than a universal result for every specimen.

Polymorphic markers can help distinguish fetal-derived material.

Slide 62 · Sequencing detects relative chromosome 21 dosage

The source describes next-generation sequencing analysis of chromosome-linked DNA abundance.

An excess representation of chromosome 21 sequences generates a high-risk screening signal.

Screening is noninvasive but does not independently establish a fetal karyotype.

Slide 63 · A positive screen requires diagnostic evaluation

High-risk cfDNA screen

Counseling / diagnostic assessment

CVS or amniocentesis

Karyotypic confirmation

Cell-free DNA testing is framed as screening.

The source notes that positive screens are generally confirmed with conventional cytogenetic testing.

Chorionic-villus sampling or amniocentesis can provide fetal-derived cells for analysis.

Slide 64 · Screening versus diagnostic cytogenetics

Approach

Material/target

Question answered

Maternal cfDNA screen

Cell-free DNA in maternal plasma

Is trisomy 21 likely?

FISH

Chromosome-specific signals in cells

Are three 21-linked signals present?

Conventional karyotype

Cultured or prepared cells/chromosomes

What is the chromosomal constitution and structural pattern?

Slide 65 · Sampling route and assay should not be conflated

Chorionic-villus sampling and amniocentesis are methods of obtaining fetal-related material.

Karyotyping and FISH are laboratory methods applied to collected cells.

A sampling procedure is not itself a chromosomal result.

Slide 66 · Recognizing free trisomy, translocation and mosaicism

Cytogenetic pattern

What is seen

Interpretive caution

Free trisomy 21

Extra independent chromosome 21

Parents commonly have normal karyotypes

Translocation form

Additional 21q on a derivative chromosome

Consider balanced familial rearrangement

Mosaic form

46- and 47-chromosome lineages

Proportions differ by sampled tissue

Slide 67 · Clinical appearance is not molecular classification

Similar phenotypic features can arise from different chromosomal mechanisms.

Clinical features prompt diagnosis; Cytogenetic analysis classifies the underlying abnormality.

Translocation detection is especially important for understanding possible familial origins.

Slide 68 · Trisomy 21 versus trisomy 13/18

Dimension

Trisomy 21

Trisomy 13 or 18

Common pathway

Usually nondisjunction

Usually nondisjunction

Maternal age

Strong association

Also associated with advanced maternal age

Malformations

Multisystem abnormalities

Generally more severe and widespread

Infant survival

Substantial survival possible

Early death far more frequent

Slide 69 · Case application: Newborn with suggestive features

A newborn has a flat facial profile, oblique palpebral fissures and epicanthic folds.

Question: What type of investigation can establish the chromosomal constitution?

Answer: Cytogenetic testing, with a karyotype to classify free trisomy versus rearrangement.

Morphology supports clinical recognition; Cytogenetics defines the mechanism.

Slide 70 · Case application: Chromosome 21 material on chromosome 14

An affected child has extra 21q material attached to an acrocentric chromosome.

Question: Why might examination of parental chromosomes matter?

Answer: A balanced Robertsonian carrier parent is possible in some cases.

Familial inheritance is possible, not obligatory, in translocation-associated cases.

Slide 71 · Case application: Distinct 46- and 47-cell populations

Cytogenetic examination identifies both normal-count and trisomy 21 cell lines.

Question: Which early developmental event can account for this pattern?

Answer: Postzygotic mitotic nondisjunction during embryogenesis.

Phenotypic expression depends partly on cell-line representation and distribution.

Slide 72 · Integrated clinicopathologic synthesis

Three cytogenetic routes lead to extra chromosome 21 dosage: Free trisomy, Robertsonian translocation and mosaicism.

Effects span neurodevelopment, congenital heart disease, gastrointestinal malformations, leukemia risk, neurodegeneration and immunity.

Gene dosage is polygenic; APP and mitochondrial pathways are examples, not complete explanations.

Prenatal cfDNA is a screening modality; Cytogenetic testing defines the chromosomal pattern.

Slide 73 · Primary reference

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Chapter: Genes and Human Diseases — Chromosomal Disorders.

Teaching scope: Trisomy 21 (Down Syndrome) and directly relevant cytogenetic background.

All factual quantitative estimates in this lecture reflect the supplied textbook excerpt; they have not been independently updated.