DOWN SYNDROME - Detailed Exam Notes

Part 1 of Many: Introduction, Etiology & Pathogenesis

SUBTOPIC 1: INTRODUCTION & EPIDEMIOLOGY

What is Down Syndrome?

• Also called: Trisomy 21 (most common form), Down syndrome, mongolism (obsolete term - never use clinically)
• Chromosome affected: Chromosome 21 (smallest autosome; gene-poor, high AT:GC ratio)
• Most common chromosomal cause of intellectual disability
• Most common autosomal trisomy compatible with survival to adulthood

Incidence & Epidemiology

Why Does Incidence Rise With Maternal Age? (Examiner Favorite)

1. Oocytes are arrested in prophase I of meiosis from fetal life onwards - they resume meiosis only at ovulation, decades later
2. This prolonged meiotic arrest makes the oocyte vulnerable to cohesin degradation over time - cohesins are the proteins that hold homologous chromosomes together; as a woman ages, cohesin levels decline, increasing the chance of premature separation
3. This leads to meiotic nondisjunction of chromosome 21
4. ~95% of extra chromosome 21s are of maternal origin (confirmed by DNA polymorphism studies)
5. Of maternal errors, ~70-80% occur in Meiosis I (the first division), which is the most vulnerable step
6. Only ~10% of nondisjunction events are of paternal origin

Exam Trap: Even though older mothers have MUCH higher risk, they contribute a MINORITY of DS births in the population - because younger mothers have far higher birth rates. More than half of all DS babies are born to mothers younger than 35. This is why screening programs target all pregnant women, not just older ones.

Comparative Risk - Autosomal Trisomies (High-Yield Table)

SUBTOPIC 2: ETIOLOGY - THE THREE KARYOTYPIC TYPES

Type 1: Free Trisomy 21 (~95% of all cases)

• Maternal Meiosis I: ~70-80% of cases (most common error)
• Maternal Meiosis II: ~20-25% of cases
• Paternal Meiosis (either division): ~10% of cases

• Trisomic egg + normal sperm = Trisomy 21 conceptus (47 chromosomes, 3 copies of chromosome 21)
• Nullisomic egg + normal sperm = Monosomy 21 (not viable, spontaneously aborted)

• Parents have completely normal karyotypes (46 chromosomes each)
• Strongly correlated with advanced maternal age
• Recurrence risk: ~1% above the age-related risk (i.e., about 1 in 100 additional risk beyond baseline)
• FISH with chromosome 21-specific probes shows 3 red signals in interphase nuclei (see image below)

FISH analysis using locus-specific probes showing 3 red signals (chromosome 21) confirming trisomy 21 - Robbins & Cotran Pathologic Basis of Disease

Type 2: Robertsonian Translocation (~4% of all cases)

1. The chromosome count is 46, not 47 - a classic trap
2. It has a familial/hereditary pattern
3. It has the highest recurrence risk
4. It is NOT related to maternal age

• Robertsonian translocation = fusion of the long arms (q arms) of two acrocentric chromosomes at their centromeres, with loss of the (genetically insignificant) short arms
• Acrocentric chromosomes: 13, 14, 15, 21, 22
• Most common partner for chromosome 21 in DS: Chromosome 14 (less commonly chromosome 22)
• The resulting translocation chromosome carries the genetic material of both 21q and 14q

• They have 46 chromosomes but are functionally trisomic for chromosome 21q
• They have: 2 normal chromosome 21s + 1 translocation chromosome (which contains another copy of 21q fused to 14q)
• Net result = triple gene dosage for chromosome 21 genes - same as free trisomy 21 in terms of phenotype

• Has only 45 chromosomes
• Karyotype: 45,XX,rob(14;21)(q10;q10) - they are phenotypically NORMAL
• Usually the mother is the carrier (more commonly maternal transmission)
• The carrier has only ONE chromosome 14 and ONE chromosome 21, replaced by the single translocation chromosome

1. Normal gamete - normal child
2. Balanced carrier gamete - phenotypically normal carrier child (like the parent)
3. Unbalanced gamete (extra chromosome 21 material) - Down syndrome child

Theoretical recurrence risk = 1 in 3 for DS offspring. However, empirical population data shows much lower rates due to selection against unbalanced gametes and embryos:

• Carrier MOTHER: ~10-15% risk for DS offspring
• Carrier FATHER: ~2-5% risk for DS offspring (lower due to selection against unbalanced sperm)

• When DS is diagnosed in a child with translocation karyotype, BOTH PARENTS MUST BE KARYOTYPED
• If a parent is a balanced carrier, siblings and other relatives should also be offered karyotyping
• This type has NO relation to maternal age

Type 3: Mosaic Down Syndrome (~1-2% of cases)

• A normal 46-chromosome zygote undergoes a faulty mitotic division
• One daughter cell gets 3 copies of chromosome 21 (47) and the other gets 1 copy (45)
• The 45-chromosome cell line (monosomy 21) is not viable and is eliminated
• The 47-chromosome line persists alongside the normal 46-chromosome line
• Result: mosaic individual with a mix of normal and trisomic cells

• Phenotype is generally MILDER than full trisomy 21
• Severity depends on proportion of trisomic cells and the tissues/organs affected
• Some mosaic individuals have near-normal intelligence
• IQ scores tend to be higher than in full trisomy 21 (range 40-75 in full trisomy vs. can be near-normal in mosaics)
• Maternal age is NOT a significant factor (this is a post-fertilization event)

Summary Table: Three Karyotypic Types (Exam Gold)

Special Sub-types Worth Knowing

• Rare, but critically important for counseling
• A carrier parent produces gametes that MUST EITHER contain a double dose of 21q OR no chromosome 21 at all
• Offspring are either Down syndrome or monosomy 21 (lethal)
• Recurrence risk = 100% - no normal children possible from a carrier of this chromosome
• Often arises de novo but when familial, requires urgent counseling

• Only a portion of 21q is present in triplicate
• Used in research to map genotype-phenotype correlations
• A region at the distal end of 21q (21q22) appears critical for the typical facial features
• A region less than 2 Mb has been identified as critical for the congenital heart defects seen in ~40% of DS patients

SUBTOPIC 3: PATHOGENESIS - HOW DOES AN EXTRA CHROMOSOME 21 CAUSE ALL THE FEATURES?

The Core Principle: Gene Dosage Effects

Key Molecular Mechanisms

1. Gene Dosage and Overexpression

• Critical developmental thresholds are disrupted
• Cell signaling pathways are dysregulated
• Protein-protein interaction networks are disturbed by stoichiometric imbalance

2. APP Gene and Alzheimer Disease

• With 3 copies of chromosome 21, there are 3 copies of APP
• APP is the precursor to amyloid-beta (Aβ) peptides
• Overproduction of Aβ leads to its aggregation and deposition as amyloid plaques in the brain
• This is the same mechanism implicated in familial early-onset Alzheimer disease
• Result: virtually ALL individuals with DS over age 40 develop neuropathological changes of Alzheimer disease (senile plaques, neurofibrillary tangles, cortical atrophy, ventricular dilatation)
• Clinical dementia typically appears 1-2 decades earlier than in the general population

Examiner's Gem: People with DS who have only a partial trisomy 21 NOT including the APP locus do NOT develop early-onset Alzheimer disease - confirming that APP gene dosage is responsible, not the trisomy state per se.

3. Mitochondrial Dysfunction

• Mitochondria show broken or swollen cristae on electron microscopy
• Increased generation of reactive oxygen species (ROS)
• Activation of apoptotic pathways
• This contributes to intellectual disability, premature aging, and tissue damage

4. Leukemia Predisposition

• GATA1 gene on the X chromosome is a key regulator of megakaryocyte and erythroid differentiation
• In DS, the trisomic environment during fetal development promotes clonal expansion of abnormal megakaryocyte-erythroid progenitors
• Specifically, fetal DS cells with mutations in GATA1 undergo clonal expansion causing Transient Myeloproliferative Disorder (TMD) in newborns
• TMD is unique to DS and resolves spontaneously in most cases within 3 months
• However, ~20-30% of TMD cases progress to Acute Megakaryoblastic Leukemia (AMKL) within 1-3 years
• Leukemia risk overall in DS:
  • 20-fold increased risk for precursor B-cell ALL
  • 500-fold increased risk for Acute Myeloid Leukemia (specifically AMKL)

5. Cardiac Defect Pathogenesis

• The ~2 Mb critical region on 21q22 contains genes critical for cardiac morphogenesis
• DSCAM (Down Syndrome Cell Adhesion Molecule) and DYRK1A kinase are among the candidates
• These disrupt endocardial cushion development, explaining the high rate of atrioventricular septal defects

6. Noncoding RNAs

7. Down Syndrome Critical Region (DSCR)

• Located at distal 21q22
• Children with partial trisomy limited to this region show typical Down syndrome facial features
• However, the concept of a single "critical region" is now considered an oversimplification - the full phenotype requires trisomy of multiple regions
• DYRK1A (Dual-specificity Tyrosine-phosphorylation Regulated Kinase 1A) in this region:
  • Involved in neuronal development
  • Overexpression disrupts dendritic spine development and synaptic plasticity
  • Key contributor to intellectual disability

8. Immune Dysregulation

• Mainly affects T-cell functions
• Predisposes to serious infections, especially pulmonary infections (leading cause of death after the neonatal period)
• Also predisposes to thyroid autoimmunity - Hashimoto's thyroiditis is significantly more common in DS
• The molecular basis is not fully understood but relates to chromosome 21 gene effects on immune cell development

Genotype-Phenotype Correlation Summary

How Gene Imbalance Drives the Phenotype - The Big Picture

1. The same trisomy 21 karyotype can produce variable phenotypes because other genes in the rest of the genome (from both parents) modify the effects of chromosome 21 overexpression
2. This explains why some DS individuals are more severely affected than others, even with the same karyotype
3. It also explains why mosaics are variable - the proportion of trisomic cells AND which tissues carry them matters

Quick-Fire Exam Facts for This Section

• Down syndrome chromosome 21 was fully sequenced in 2000
• Chromosome 21 is gene-poor with a high AT:GC ratio
• Extra chromosome 21 is of maternal origin in 95% of cases
• Most common meiotic error is in Maternal Meiosis I
• Nondisjunction is linked to cohesin degradation in aging oocytes
• APP gene dosage explains early Alzheimer disease
• GATA1 mutation + trisomy 21 = Transient Myeloproliferative Disorder
• Chromosome 21 has the highest lncRNA density of any chromosome
• DSCR at 21q22 is critical for facial features and cardiac defects

Sources Used

• Robbins & Cotran Pathologic Basis of Disease (p. 163-165)
• Thompson & Thompson Genetics and Genomics in Medicine, 9th edition (p. 102-104)
• Emery's Elements of Medical Genetics and Genomics (p. 263)

• Subtopic 4: Clinical Features - Head to Toe (The Full Phenotype)
• Subtopic 5: Associated Conditions and Systemic Complications
• Subtopic 6: Diagnosis - Prenatal Screening and Postnatal Confirmation