What are the diagnostic criteria for Down syndrome?

Down Syndrome Diagnostic Criteria

The definitive diagnosis of Down syndrome requires chromosomal verification through karyotyping of fetal cells obtained via chorionic villus sampling (CVS) or amniocentesis, demonstrating the presence of an extra copy of chromosome 21 as either a free chromosome, Robertsonian translocation, or reciprocal translocation. 1

Distinction Between Screening and Diagnosis

It is critical to understand that screening tests are not diagnostic—they only identify pregnancies at sufficient risk to warrant genetic counseling and offer of definitive diagnostic testing. 1

• Screening methods include maternal serum markers, ultrasound measurements (such as nuchal translucency), and maternal age assessment, which provide risk estimates but cannot definitively diagnose Down syndrome 1
• Diagnostic testing requires invasive procedures (CVS at 10-14 weeks or amniocentesis at ≥15 weeks) with subsequent karyotyping to visualize the chromosomal abnormality 1
• Newer diagnostic technologies using fluorescence in situ hybridization (FISH) or quantitative fluorescent polymerase chain reaction may also be employed 1

Chromosomal Basis for Diagnosis

Down syndrome is definitively diagnosed by demonstrating trisomy 21 through one of three chromosomal patterns: 1

• Free trisomy 21 (approximately 95% of cases): Complete extra copy of chromosome 21 resulting from sporadic nondisjunction during parental meiosis, with 95% being maternal in origin and 77% occurring during Meiosis I 1
• Robertsonian translocation: Chromosome 21 material attached to another chromosome, which may be inherited when a parent carries the translocation 1
• Reciprocal translocation: Involving chromosome 21 material exchanged with another chromosome 1

Clinical Features Supporting Diagnosis

While not diagnostic criteria per se, virtually all individuals with Down syndrome present with characteristic clinical features that support the diagnosis: 1

• Universal findings: Hypotonia and minor dysmorphic features including upslanting palpebral fissures, epicanthal folds, flat nasal bridge, Brushfield spots of the iris, shortened incurving fifth finger, and transverse palmar crease 1
• Associated conditions: Congenital heart disease (40% of cases), gastrointestinal anomalies such as duodenal atresia or Hirschsprung disease (5%), and 20-fold increased incidence of childhood leukemia 1
• Long-term manifestations: Adults experience neuronal degeneration identical to Alzheimer disease 1

Screening Performance Context

Understanding screening test performance helps contextualize when diagnostic testing should be pursued: 2, 3

• Combined first-trimester screening (NT, PAPP-A, free βhCG, and maternal age) detects approximately 87% of Down syndrome pregnancies at a 5% false positive rate 2
• Integrated screening combining first and second trimester markers with ultrasound achieves approximately 90% detection at 5% false positive rate 3
• High-risk populations (maternal age ≥35 years or family history suggesting familial translocation) should proceed directly to diagnostic testing rather than relying on screening alone 4

Critical Pitfalls to Avoid

• Do not confuse screening results with diagnosis—even highly abnormal screening results require chromosomal verification for definitive diagnosis 1
• Recognize that delivery of an unaffected infant is the most common outcome even with screen-positive results, but this does not negate the need for diagnostic testing in high-risk scenarios 1, 4
• Family history of multiple Down syndrome cases may indicate familial translocation requiring urgent genetic counseling, as recurrence risk differs substantially from sporadic cases 4
• No screening test predicts severity of intellectual disability or associated medical problems in affected individuals 2, 3