Down Syndrome — Trisomy 21

• Gene dosage imbalance and protein overexpression: The third copy of chromosome 21 results in approximately 150% expression of ~300 genes encoded on this chromosome. This altered stoichiometry disrupts finely-tuned protein interactions and metabolic pathways. Critical genes include APP (amyloid precursor protein), DSCR1 (Down syndrome critical region protein 1), and OLIG1/2 (oligodendrocyte lineage genes). The triplication of these genes leads to altered neuronal development, synaptogenesis impairment, and abnormal myelin formation, directly contributing to the intellectual disability phenotype. Additionally, overexpression of antioxidant enzymes (SOD1, peroxiredoxin) creates an imbalance in cellular redox state, generating oxidative stress paradoxically despite enzyme overexpression.

• Impaired neuronal development and migration: Trisomy 21 disrupts multiple signaling pathways crucial for cortical development. DSCR1 overexpression inhibits calcineurin signaling, which impairs dendritic spine maturation and synaptic plasticity. Altered expression of genes regulating neuronal migration, axonal guidance, and neurotransmitter metabolism results in reduced dendritic arborization, decreased spine density, and altered synaptic transmission. These developmental abnormalities occur during critical periods of neurogenesis (weeks 8-16 gestation), resulting in permanent structural deficits. Neuroimaging reveals reduced brain volume, hypoplasia of the cerebellum, and simplified cortical architecture, with more severe effects in the prefrontal cortex and hippocampus—regions crucial for cognition and memory.

• Cardiac developmental anomalies: Gene dosage imbalance during cardiac development (weeks 4-8 gestation) results in congenital heart defects in approximately 45% of Down syndrome patients. Trisomy 21 is strongly associated with endocardial cushion defects (atrioventricular septal defects), complete atrioventricular canal defects, and secundum atrial septal defects. These arise from impaired neural crest cell migration and differentiation—processes normally regulated by genes on chromosome 21 including RUNX1 and other transcription factors. The mechanical consequence is inadequate formation of the lower atrial septum, upper ventricular septum, and mitral and tricuspid valve leaflets, creating left-to-right shunting and subsequent volume overload of the right heart.

• Gastrointestinal and esophageal anomalies: Approximately 12% of patients have duodenal atresia or stenosis due to impaired embryologic recanalization (weeks 8-10 gestation), often presenting with polyhydramnios and the classic "double bubble" sign on prenatal ultrasound. Imperforate anus, Hirschsprung disease, and esophageal atresia occur with increased frequency. Additionally, increased rates of celiac disease (5-15%) and gastroesophageal reflux disease suggest altered innervation and motility patterns, likely reflecting abnormalities in enteric nervous system development.

• Hematologic manifestations: Transient myeloproliferative disorder (TMD), also termed transient abnormal myelopoiesis, occurs in 10% of Down syndrome newborns due to clonal proliferation of megakaryoblasts in the setting of trisomy 21. This self-limited condition typically resolves within weeks to months but carries risk of progression to acute megakaryoblastic leukemia (AMKL) within the first 5 years of life. The mechanism involves GATA1 mutations affecting megakaryocyte differentiation, with trisomy 21 providing a permissive background. Additionally, increased rates of ALL (10-15 fold higher) and AML reflect altered cell cycle regulation and apoptosis in the setting of trisomy 21.

• Endocrine dysfunction: Down syndrome is associated with elevated rates of hypothyroidism (10-15% prevalence) due to increased autoimmune thyroiditis and primary thyroid dysfunction. Type 2 diabetes mellitus occurs prematurely (2-5% in childhood, up to 50% in adulthood) stemming from insulin resistance and obesity compounded by reduced physical activity capacity. Hypogonadism and delayed sexual maturation are common, with mechanisms involving altered GnRH secretion and gonadal dysgenesis.

• Immune dysfunction: Triplication of genes regulating T-cell development and immune tolerance (including genes affecting thymic architecture) results in thymic hypoplasia, reduced T-cell counts, and impaired cell-mediated immunity. This contributes to increased susceptibility to respiratory infections, particularly in the first years of life, and increased rates of autoimmune conditions. Abnormal B-cell function also occurs, though mechanisms are less well characterized.

• Advanced maternal age (most significant risk factor): Maternal age >35 years at delivery confers dramatically increased risk of trisomy 21, with incidence rising from approximately 1/1500 at age 20 to 1/30 at age 45. The etiology involves age-related deterioration of the cohesin protein complex, which holds replicated chromosome pairs together during meiosis I. This "maternal age effect" specifically increases the rate of nondisjunction (failure of proper chromosome segregation) during the first meiotic division, resulting in oocytes with 24 chromosomes. The risk curve demonstrates exponential increase particularly after age 40. For board purposes, this is the single most important modifiable risk factor recognized prenatally.

• Standard trisomy 21 (~95% of cases): Results from complete nondisjunction of chromosome 21 during meiosis (most commonly maternal meiosis I), yielding a karyotype of 47,XX,+21 or 47,XY,+21. This is the classic form and accounts for virtually all cases in the general population.

• Translocation Down syndrome (~3-4% of cases): Occurs when the long arm of chromosome 21 becomes attached (via centromeric fusion) to another acrocentric chromosome (most commonly chromosome 14, but also 13, 15, 22, or another 21). The individual may be phenotypically normal (balanced translocation carrier, 45 chromosomes with two copies of chromosome 21 material) or affected if the translocation results in three copies of chromosome 21 material. Critically for board practice, translocation Down syndrome can be inherited from a carrier parent in approximately 10-15% of cases, creating a substantial recurrence risk (10-15% if the mother is a carrier, 3% if the father is a carrier). This is distinct from standard trisomy 21, which recurs with only ~1% empiric recurrence risk (elevated above the general population risk of 1/700 but much lower than translocation inheritance).

• Mosaic Down syndrome (~1-2% of cases): Results from nondisjunction occurring during a mitotic division in early development, creating two or more distinct cell lines (some trisomic for chromosome 21, others disomic). Phenotype severity depends on the proportion and distribution of trisomic cells and the developmental timing of the event. Patients may have milder intellectual disability, fewer cardiac anomalies, and less characteristic facial features. This distinction is clinically important because prenatal testing results depend on which cell line is sampled.

• Paternal age effect (minor): While maternal age is the dominant risk factor, there is evidence for a modest independent paternal age effect, particularly for nondisjunction during spermatogenesis, though the relative contribution is much smaller than maternal age effect.

• Intellectual disability and developmental delay: The hallmark feature, present in virtually all cases of standard and translocation trisomy 21, manifests as global developmental delay evident by 6-12 months and persisting throughout life. IQ typically ranges from 25-75 (moderate to profound intellectual disability), though there is substantial individual variation (some individuals function in the mild range). Language is often disproportionately delayed relative to other domains. The mechanism involves impaired neuronal migration, reduced dendritic arborization, and decreased synaptic density in the setting of altered gene dosage during critical developmental periods.

• Characteristic craniofacial features: Brachycephaly (short, broad head), hypertelorism (widely-spaced eyes), upslanting palpebral fissures, epicanthal folds, flat nasal bridge, and open mouth posture with macroglossia (enlarged, protuberant tongue) are classic findings recognized in the delivery room. The tongue abnormality contributes to feeding difficulties, speech impediment, and increased drooling. Dental abnormalities include delayed eruption, enamel hypoplasia, and increased crowding. Low-set ears with abnormal helix folding are frequently present. These features result from altered ectodermal and neural crest cell development during weeks 6-12 gestation.

• Short stature and growth restriction: Growth velocity is slower than age-matched peers, with final adult height typically 4-6 inches below population mean. This reflects both constitutional factors and increased rates of growth hormone deficiency (5-10%). Growth charts specific to Down syndrome exist and should be used clinically rather than standard pediatric growth charts.

• Hypotonia and poor muscle tone: Generalized hypotonia (floppy infant) is typically present at birth or recognized within the first months of life, reflecting both central nervous system abnormalities and primary muscle dysfunction. Hypotonia contributes to feeding difficulties, delayed motor milestones (sitting 6-8 months, walking 18-36 months), and compensatory postural abnormalities. Persistent hypotonia throughout childhood transitions to variable tone in adulthood.

• Cardiac manifestations: Approximately 45% of Down syndrome patients have congenital heart disease, most commonly atrioventricular septal defects (AVSD) or endocardial cushion defects (40-50% of cardiac lesions). Complete AVSD presents with signs of left-to-right shunting, including tachypnea, poor feeding, failure to thrive, and cardiac murmurs. A systolic ejection murmur across the left ventricular outflow tract and a holosystolic murmur of mitral regurgitation may be heard. Some patients remain asymptomatic with cardiac disease detected only on screening echocardiography. Secondary pulmonary hypertension can develop if large left-to-right shunts persist uncorrected. Structural abnormalities also include patent foramen ovale, secundum ASD, VSD, and tetralogy of Fallot (less common, ~5%).

• Gastrointestinal symptoms: Feeding difficulties are nearly universal in the newborn period due to hypotonia, macroglossia, and poor suck-swallow coordination. This may necessitate nasogastric feeding or extended hospitalization. In infancy, duodenal atresia presents with bilious vomiting and severe abdominal distension within the first days to weeks of life (classically described as the "double bubble" sign on abdominal X-ray representing gastric and duodenal air-fluid levels). Celiac disease (5-15% prevalence) manifests with chronic diarrhea, failure to thrive, and iron deficiency anemia; serologic screening (tissue transglutaminase IgA) is recommended. Gastroesophageal reflux disease occurs in a substantial proportion of patients.

• Hearing loss: Conductive hearing loss (40-75%) results from chronic otitis media with effusion secondary to Eustachian tube dysfunction—a nearly universal finding. Sensorineural hearing loss occurs less commonly (~5-15%). Combined hearing loss occurs in some patients. Hearing impairment further impairs language development and should be screened systematically with audiology testing.

• Ophthalmologic abnormalities: Refractive errors (myopia, hyperopia, astigmatism) occur in 60% of patients. Strabismus (25-50%) and nystagmus are common. Cataracts, both congenital and acquired, occur in 15-20% of patients. Keratoconus develops in some adolescents and young adults, potentially causing progressive vision loss. Retinal abnormalities may include retinal folds at the disc margin.

• Skin and skeletal findings: Excessive skin on the posterior neck (especially prominent on prenatal ultrasound), which thickens with age. Single palmar crease (simian crease) is present in ~45% of patients and is also found in ~3-5% of unaffected individuals, making it a supportive but non-specific finding. Clinodactyly of the fifth finger (incurving) occurs frequently. Increased space between the first and second toes creates a "sandal gap" appearance. Short, broad hands with significant clinical variation.

• Atlantoaxial instability: Approximately 10-15% of Down syndrome patients have radiographic evidence of atlantoaxial subluxation (increased distance between the anterior arch of the atlas and the odontoid process of the axis), due to ligamentous laxity and os odontoideum. Most remain asymptomatic, but symptomatic atlantoaxial subluxation with myelopathy presents with progressive quadriparesis, loss of fine motor control, gait disturbance, or loss of bladder control. This serious complication requires imaging (flexion-extension cervical spine X-rays or MRI) and potential surgical fusion. Screening for atlantoaxial instability is recommended in adolescents by some experts, and activity restrictions (avoiding contact sports) are recommended for those with confirmed instability.

• Behavioral and psychiatric features: Autism spectrum disorder occurs in 5-10% of Down syndrome patients at significantly higher rates than in the general population. Attention-deficit/hyperactivity disorder is common. Behavioral problems, oppositional defiance, and mood disorders (depression, anxiety) occur at increased rates in adolescents and adults. Obstructive sleep apnea (secondary to anatomic factors: macroglossia, hypotonia, midfacial hypoplasia) occurs in 30-60% of patients, further contributing to behavioral disruption, daytime somnolence, and cognitive decline.

• Premature aging and Alzheimer disease: Individuals with Down syndrome experience accelerated aging, with cognitive decline often becoming apparent in the 4th-5th decades of life. Neuropathologic features of Alzheimer disease (amyloid-beta plaques, neurofibrillary tangles) are nearly universal by age 40 due to APP gene triplication. Clinical dementia develops in approximately 50% of individuals by age 60. This represents an important long-term complication and contributor to disability in middle-aged and older individuals with Down syndrome.

• Prenatal screening and diagnosis: First-trimester combined screening (11-14 weeks) incorporates maternal serum markers (beta-hCG, pregnancy-associated plasma protein A [PAPP-A]) combined with ultrasound measurement of nuchal translucency (NT). Increased NT (>3 mm at 12-13 weeks), elevated beta-hCG, and decreased PAPP-A are associated with increased trisomy 21 risk. This approach has detection rate of ~85% with ~5% false-positive rate. Second-trimester screening (15-20 weeks) includes the quadruple marker screen (elevated hCG, elevated inhibin A, decreased uE3, decreased AFP) with detection rate ~80% and false-positive rate ~5%. These are screening tests generating a calculated risk; they do not diagnose trisomy 21. Noninvasive prenatal testing (NIPT) using cell-free fetal DNA from maternal blood (implemented after 10 weeks gestation) has superior detection rate (>99% sensitivity, <0.5% false-positive rate for trisomy 21) with lower miscarriage risk than invasive procedures. NIPT is offered to all pregnant patients in current practice, particularly those with elevated screening risk or advanced maternal age. Positive NIPT results should be confirmed by invasive testing.

• Invasive prenatal diagnosis: Amniocentesis (performed after 15-16 weeks gestation) or chorionic villus sampling (CVS, 10-12 weeks) provides definitive karyotype diagnosis. Amnio

Newborn stabilization

• Airway and feeding: hypotonia, macroglossia, and midface hypoplasia cause obstruction and poor suck; support with positioning, thickened/high-calorie feeds, and NG feeding if intake is inadequate.
• Bilious emesis: presumed duodenal atresia — NPO, NG decompression, IV crystalloid, upright abdominal film, then surgical duodenoduodenostomy. This is a surgical emergency in the first days of life.
• Screening at birth: echocardiogram in every newborn regardless of exam (AAP); CBC with smear to detect transient abnormal myelopoiesis; and confirmation of the newborn state screen TSH, with repeat TSH at approximately 6 and 12 months and annually thereafter (AAP), since both congenital and acquired hypothyroidism are increased.

Congenital heart disease

• Medical bridge: loop diuretic (furosemide) ± afterload reduction with an ACE inhibitor (enalapril) and caloric augmentation for shunt-related heart failure.
• Definitive therapy: surgical repair of complete AVSD in infancy, typically within the first several months of life, before irreversible pulmonary vascular disease develops (ACC/AHA adult congenital heart disease guidance emphasizes that unrepaired large shunts progress to Eisenmenger physiology, at which point repair is contraindicated).
• RSV immunoprophylaxis: nirsevimab for eligible infants per current AAP/CDC recommendations; palivizumab remains an alternative for children with hemodynamically significant CHD or chronic lung disease when nirsevimab is not used.

Ongoing organ-specific therapy

• Hypothyroidism: levothyroxine, guided by the TSH surveillance schedule above.
• Obstructive sleep apnea: polysomnography by early childhood per AAP; adenotonsillectomy is first-line, CPAP if residual disease.
• Transient abnormal myelopoiesis: observation with serial counts, since most resolve; cytoreduction (low-dose cytarabine) is reserved for hydrops, hyperleukocytosis, or organ dysfunction. Down syndrome megakaryoblastic leukemia is highly chemosensitive with dose-reduced regimens.
• Developmental: early intervention services under IDEA Part C, speech/OT/PT, individualized education plan.

Avoid

• Megavitamin, antioxidant, or "targeted nutraceutical" regimens — AAP explicitly advises against them.
• Contact sports and unprotected neck extension (intubation, Special Olympics participation) in anyone with symptoms or confirmed atlantoaxial instability; routine screening radiographs in asymptomatic children are not recommended.
• Growth hormone outside documented deficiency.

Cardiopulmonary

• Eisenmenger syndrome: an unrepaired AVSD/VSD drives chronic pulmonary overcirculation, pulmonary arteriolar remodeling, and shunt reversal. Signaled by loss of a previously loud murmur, loud single P2, cyanosis, and clubbing. Once established, surgical closure is contraindicated — this is the reason infancy repair is non-negotiable.
• Postoperative complete heart block after AVSD repair (AV node sits near the septal suture line) — bradycardia and syncope; may require permanent pacing. Residual left AV valve (mitral) regurgitation is the other common late reoperation indication.
• Obstructive sleep apnea: anatomic crowding plus hypotonia; signals include snoring, restless sleep, daytime behavioral deterioration, and pulmonary hypertension on echo.
• Recurrent lower respiratory infection from T-cell/thymic dysfunction and impaired airway clearance.

Hematologic

• Transient abnormal myelopoiesis: circulating megakaryoblasts and hepatosplenomegaly in the newborn period; hepatic fibrosis with hydrops or liver failure is an emergency. Approximately 20–30% of survivors progress to acute megakaryoblastic leukemia within the first four years of life, which is why serial CBC follow-up is mandatory even after apparent spontaneous resolution.
• ALL and AML: markedly increased risk; unexplained cytopenias, bone pain, or persistent blasts. Methotrexate toxicity (mucositis, myelosuppression) is exaggerated in trisomy 21.

Neurologic — emergency

• Symptomatic atlantoaxial subluxation with cervical myelopathy: ligamentous laxity ± os odontoideum. Torticollis, new gait change, clumsiness, hyperreflexia, or bladder dysfunction demands urgent neck immobilization, MRI, and neurosurgical consultation for fusion.

Endocrine/GI

• Hypothyroidism: autoimmune thyroiditis; falling growth velocity, constipation, lethargy — easily mistaken for baseline phenotype.
• Celiac disease: chronic diarrhea, poor growth, iron deficiency anemia.
• Obesity and type 2 diabetes in adolescence/adulthood.

Late

• Early-onset Alzheimer dementia from APP triplication — functional regression, new seizures, or incontinence in a young adult. Depression, hypothyroidism, OSA, and hearing loss must be excluded before attributing decline to dementia.

• ***Double bubble* on abdominal radiograph with bilious emesis in a hypotonic newborn** = duodenal atresia in trisomy 21. Best next step is NG decompression and IV fluids, then surgical repair — not a contrast study first.
• Endocardial cushion defect (complete AVSD) is the signature lesion. The ECG buzzword is a superior/left-axis deviation in an infant with a left-to-right shunt. Every newborn with Down syndrome gets an echocardiogram even with a normal exam (AAP).
• Quad screen pattern in trisomy 21: ↓AFP, ↓estriol, ↑hCG, ↑inhibin A. Trisomy 18 shows ↓AFP, ↓estriol, and ↓hCG with a normal inhibin A — the low-hCG/normal-inhibin pattern is the contrast examiners test.
• NIPT (cell-free DNA) is a screen, not a diagnosis. A positive result in a vignette should be followed by CVS or amniocentesis for karyotype, per ACOG.
• If the diagnosed child has translocation Down syndrome, the single best next step is parental karyotyping — a balanced Robertsonian carrier parent carries a substantially elevated recurrence risk, versus the ~1% empiric risk after standard nondisjunction.
• Advanced maternal age is the strongest risk factor, but most affected infants are born to mothers under 35. Examiners use this to test that screening is offered to all pregnancies regardless of age.
• New clumsiness, gait change, hyperreflexia, or incontinence = atlantoaxial subluxation with myelopathy until proven otherwise: immobilize and image. Routine screening radiographs in the asymptomatic child are not recommended — a favorite trap answer.
• Blasts on a newborn smear suggest transient abnormal myelopoiesis; management is usually observation with serial counts, not immediate induction chemotherapy — but follow-up matters, since a substantial minority later develop megakaryoblastic leukemia.
• A single transverse palmar crease is supportive, not diagnostic — it occurs in a few percent of unaffected people. Karyotype confirms the diagnosis.
• Functional regression in a 40-something adult points to APP-triplication Alzheimer disease, but check thyroid, hearing, depression, and sleep apnea first.