Down Syndrome

Aka: Down Syndrome, Mongolism, Trisomy 21

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II. Epidemiology

  1. Most common chromosomal abnormality
  2. Down Syndrome births: 6000 to 10,000 per year in U.S. (1 in 640 live births)
  3. Prevalence: 10.3 per 10,000

III. Risk Factors

  1. Advanced Maternal Age over 34
    1. Risk increases with age, but births to young mothers still account for 50-80% of cases
    2. Mother age 35 years old: One in 400 births have Down Syndrome
    3. Mother age 40 years old: One in 105 births have Down Syndrome
    4. Mother age 45 years old: One in 12 births have Down Syndrome
  2. Prior child with Trisomy 21 (1% recurrence risk)
  3. Carriers of a balanced translocation of Chromosome 21

IV. Pathophysiology

  1. Trisomy of Chromosome 21 (Segment 21q22, long arm)
  2. Karyotypes
    1. Trisomy of entire Chromosome with 47 Chromosomes, nonfamilial (95 to 97% of cases)
    2. Unbalanced translocation (4%)
      1. Chromosome with extra or missing genetic material
    3. Genetic mosaicism (2%)
      1. At least 2 cell populations with different Genotypes in the same person

V. Signs

  1. Head and Facies
    1. Brachycephaly (100%)
    2. Small anteroposterior cranial dimension
    3. Posterior third Fontanel
    4. Small, low set, folded ears
    5. Persistent Inner Epicanthal Folds (90%)
    6. Mongoloid, upper slanted eyes (90%)
    7. Esotropia (50%)
    8. Brushfield's Spots (Speckled, hypopigmented) of iris (50%)
    9. Short flat nose
    10. Macroglossia (75%)
    11. Small chin
    12. Arched Palate
  2. Body Habitus
    1. Broad short neck with excessive skin
    2. Protuberant Abdomen
    3. Hyperflexibility
  3. Neurologic
    1. Moderate to severe Mental Retardation
    2. Muscular hypotonicity
  4. Hands
    1. Short, broad fingers and hand
    2. Curved fifth finger (clinodactyly)
    3. Single Simian crease with loss of palmar crease
  5. Foot
    1. Absence of whorl on ball of foot
      1. Presence of whorl suggests a child without Down Syndrome
    2. Sandal gap
      1. Widened gap between first and second toes
  6. Cardiopulmonary
    1. Cardiac murmur (50%)

VI. Labs: Diagnosis

  1. Fluorescent in situ hybridization
    1. Confirms Down Syndrome
  2. Complete genetic karyotype analysis
    1. Most common: 47 Chromosomes with Trisomy 21
    2. Karyotype used to guide future pregnancy plans

VII. Associated Conditions

  1. Neurologic
    1. Developmental Delay
    2. Intellectual Disability
      1. Mild: IQ of 50 to 69
      2. Moderate: IQ 35 to 49 (most common)
      3. Severe: IQ 20 to 34
    3. Seizure Disorder
    4. Autism
    5. Alzheimer's Disease clinically evident
      1. Age 30-39: 0 to 10% Prevalence
      2. Age 40-49: 10 to 25% Prevalence
      3. Age 50-59: 28 to 55% Prevalence
      4. Age 60-69: 30 to 75% Prevalence
  2. Mental Illness (30%)
    1. Major Depression (treat with SSRIs)
    2. Obsessive-Compulsive Disorder
    3. Physical abuse or sexual abuse history
    4. Conduct Disorder
    5. Self-Talk (Soliloquy) is normal (esp. when stressed)
  3. Endocrine
    1. Hypogonadism (100% in males)
    2. Congenital Hypothyroidism (10 to 40%)
    3. Hashimoto's Thyroiditis (30%)
    4. Hyperthyroidism
    5. Diabetes Mellitus (RR 4 in under age 30, RR 2 in over age 30)
  4. Musculoskeletal
    1. Atlantoaxial Instability (1-2%, although up to 14% in some studies)
      1. No routine Cervical Spine imaging indicated unless symptomatic (e.g. Cervical Myelopathy)
    2. Spinal Cord Compression (with secondary Myelopathy)
      1. May present with gait disorders, bowel or Bladder changes or muscular weakness
    3. Congenital Hip Dislocation
    4. Congenital Hip Dysplasia
    5. Patella subluxation (and other ligamentous laxity)
  5. Cardiovascular
    1. Polycythemia
    2. Mitral Valve Prolapse
    3. Pulmonary Hypertension (10%)
    4. Congenital Heart Disease (50%)
      1. Ventricular Septal Defect (most common)
      2. Endocardial Cushion Defect (most specific heart defect for Down Syndrome)
        1. AV canal defect with single chamber combining atria and ventricle
  6. Gastrointestinal
    1. Duodenal Atresia (neonates)
    2. Bowel Obstruction
    3. Celiac Sprue (Gluten Sensitive Enteropathy)
    4. Constipation
    5. Hirschsprung's Disease
      1. Presents earlier in Down's Syndrome
      2. Typically fails to pass meconium
      3. May present as Constipation, painless Abdominal Distention
  7. Otolaryngology
    1. Obstructive Sleep Apnea (>50%)
    2. Conductive and Sensorineural Hearing Loss (70%)
    3. Periodontal Disease and Gingivitis
    4. Macroglossia
    5. Tracheal stenosis
    6. Recurrent Serous Otitis Media (associated Hearing Loss)
    7. Delayed dental eruption and hypodontia
    8. Tortuous small ear canals
      1. Tympanic Membranes are often difficult to visualize
  8. Ophthalmology
    1. Cataracts (13%)
    2. Refractive Error
    3. Keratoconus (15%)
    4. Strabismus
  9. Dermatology
    1. Xerosis
  10. Hematology
    1. Polycythemia (>18%)
    2. Iron Deficiency Anemia (10%)
    3. Transient myeloproliferative disorder (10%)
      1. Transient abnormal myelopoiesis (a myeloid preleukemia) is identified at birth in 10% of children
      2. Typically resolves, but up to 20 to 30% will develop Leukemia by age 5 years
  11. Malignancy
    1. Acute Myelogenous Leukemia (2 to 3% of patients)
    2. Acute Lymphocytic Leukemia
    3. Testicular Cancer

VIII. Imaging

  1. Echocardiography
    1. Typically done following delivery as newborn, and repeated as indicated
    2. Congenital cardiac defects in up to 50% of patients (some may be detected on prenatal Ultrasound)
  2. Cervical Spine XRay
    1. Not recommended for universal screening
    2. Indicated in age 3 years and older for suspicion for Atlantoaxial Instability

IX. Management: Initial Diagnosis

  1. Confirm diagnosis (see labs above)
  2. Obtain appropriate diagnostics (see approach to birth to one month below)
  3. Address consideration of Down Syndrome diagnosis with parents
    1. Unexpected Down Syndrome diagnosis will be accompanied by increased parental worry
    2. Congratulate the parents on their newborn first, then focus on the evaluation
    3. Involve consultants to help address parental questions
  4. Referrals
    1. See age specific guidelines below
    2. Early intervention program (U.S. state specific)
      1. Team of consultants (PT, OT, Speech, Vision and child psychology)
      2. Establishes medical home
      3. Investigates eligibility for services (financial, social, mental health)
      4. Creates Individual Family Services Plan (for first 3 years of life to guide care)
  5. Care Plans
    1. Individual Family Service Plan (birth to 3 years)
    2. School-focused Individualized Education Program (3 years and older)
  6. Additional resources
    1. Parent-to-parent support groups
    2. Down Syndrome organizations (see resources below)

X. Management: Adults

  1. Disposition Options for Adult Patients
    1. Independent living with supervision
    2. Group Homes
  2. Adults assumed competent to make medical decisions
    1. Address competence early if questionable
    2. Consider guardianship
    3. Evaluate Advanced Directives
    4. Consider power of attorney for finances and health
  3. Emergency department precautions
    1. Intubation precautions
      1. Macroglossia
      2. Atlantoaxial Instability (maintain c-spine precautions)
    2. Trauma precautions
      1. Low threshold for Cervical Spine imaging

XI. Prevention: Prenatal Screening

  1. Antepartum Down Syndrome Screening
    1. Offer to all pregnant patients (regardless of age, with early discussion from first Prenatal Visit)
    2. Positive screening prompts MFM consult, Level 2 Obstetric Ultrasound and Genetic Counseling
  2. Tests
    1. Placental Cell-Free DNA
    2. First Trimester Combined Screening for trisomy 18 and Trisomy 21
      1. Maternal age
      2. Free Beta Human Chorionic Gonadotropin (bHCG)
      3. Pregnancy associated plasma Protein A (PAPP-A)
      4. Fetal Ultrasound for Nuchal Translucency and absent nasal bone
    3. Second Trimester Quad Maternal Screen Panel
      1. Decreased AFP and Unconjugated Estriol (uE3)
      2. Increased hCG and Inhibin A
  3. Obstetric Ultrasound findings
    1. Thickened nuchal fold
    2. Duodenal Atresia (double-bubble sign)
    3. Shorter long bones
    4. Congenital Heart Defects

XII. Prevention: Birth to one month

  1. Findings
    1. Standard Newborn Examination
    2. Assess for oxygen desaturation in a Car Seat
    3. Respiratory: Apnea, Stridor, Wheezing
    4. Cardiovascular: Bradycardia
    5. Gastrointestinal: Constipation, Duodenal Atresia, GERD
    6. Eye: Congenital Cataracts (via red Reflex Exam)
  2. Screening and Immunizations
    1. Standard Newborn Screen for Inborn Errors of Metabolism
    2. Standard Newborn Hearing Screening (first 48 hours)
  3. Labs and Diagnostics
    1. Complete Blood Count (CBC)
      1. Transient abnormal myelopoiesis (previously known as transient myeloproliferative disorder)
      2. Leukemoid Reaction
      3. Polycythemia
    2. Complete chromosomal karyotyping
    3. Echocardiogram (50% have congenital cardiac defect)
    4. Thyroid Stimulating Hormone (TSH) for Congenital Hypothyroidism
    5. Consider Swallowing study (for marked hypotonia, or feeding difficulty)
  4. Referrals
    1. Pediatric cardiology
    2. Early intervention program - see below (U.S. state specific)
    3. Consider audiology, endocrinology, pulmonology referrals

XIII. Prevention: Age 1 month to 1 year

  1. Findings
    1. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
    2. Respiratory: Sleep Apnea
    3. Eye: Congenital Cataracts (via red Reflex Exam)
  2. Screening and Immunizations
    1. Pediatric Auditory Screening at age 6 months
    2. Pediatric Eye Exam
    3. Standard Primary Series of Immunizations
    4. Nirsevimab (RSV Vaccine)
    5. Monitor growth charts on Down Syndrome specific growth charts
  3. Labs and Diagnostics
    1. Complete Blood Count (CBC)
    2. Thyroid Stimulating Hormone (TSH) at ages 6 and 12 months
    3. Consider CRP and Serum Ferritin
  4. Referrals
    1. Ophthalmology
    2. Consider otolaryngology, pediatric sleep specialist
    3. Early intervention program - see below (U.S. state specific)

XIV. Prevention: Age 1 to 5 years

  1. Findings
    1. HEENT: Hypodontia (or delayed Tooth Eruption), Otitis Media
    2. Neurologic: Myelopathy (spinal cord disorders, Atlantoaxial Instability), Seizure Disorder
    3. Respiratory: Sleep Apnea
    4. Skin disorders: Xerosis, Alopecia Areata, Keratosis Pilaris
  2. Screening and Immunizations
    1. Autism screening at 18 months and 24 months
      1. Consider repeating at 3 to 5 years of age if Developmental Delay interferes with screening
    2. Influenza Vaccine
    3. Vision Screening yearly (consider annual pediatric ophthalmology)
      1. High risk of Refractive Errors (50%) and Amblyopia
    4. Hearing screening every 6 months until 4 years of age
    5. Monitor growth charts on Down Syndrome specific growth charts
    6. Review care plans (every 6 months)
      1. Individual Family Service Plan (birth to 3 years)
      2. School-focused Individualized Education Program (3 years and older)
  3. Labs and Diagnostics
    1. Complete Blood Count (CBC) yearly
    2. Thyroid Stimulating Hormone (TSH) yearly
    3. Consider CRP and Serum Ferritin yearly
    4. Consider Cervical Spine XRay
    5. Consider Celiac Disease testing (TTG)
  4. Referrals
    1. Ophthalmology yearly
      1. Refractive Errors and Amblyopia risk in up to 50% of patients
    2. Sleep Study by age 4 years old
      1. Evaluate for Obstructive Sleep Apnea
    3. Consider pediatric cardiology

XV. Prevention: Age 5 to 13 years

  1. Findings
    1. Behavioral disorders (e.g. Attention Deficit Disorder)
    2. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
    3. Xerosis
  2. Screening and Immunizations
    1. Body Mass Index (BMI)
    2. Monitor growth charts on Down Syndrome specific growth charts
    3. Testicular Cancer screening (higher risk cancer in Down Syndrome)
  3. Labs and Diagnostics
    1. Complete Blood Count (CBC) yearly
    2. Thyroid Stimulating Hormone (TSH) yearly
    3. Consider CRP and Serum Ferritin yearly
  4. Referrals
    1. Audiology yearly
    2. Ophthalmology every 2 years
    3. Consider pediatric cardiology, pediatric sleep specialist

XVI. Prevention: Age 13 to 21 years

  1. Findings
    1. Behavioral disorders
    2. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
    3. Cardiovascular: Mitral and aortic valve disorders
    4. Gynecologic care
    5. Testicular Cancer screening (higher risk cancer in Down Syndrome)
  2. Screening and Immunizations
    1. Body Mass Index (BMI)
    2. Review School-focused Individualized Education Program
    3. Review family support
  3. Labs and Diagnostics
    1. Complete Blood Count (CBC) yearly
    2. Thyroid Stimulating Hormone (TSH) yearly
    3. Consider Echocardiogram
  4. Referrals
    1. Audiology yearly
    2. Ophthalmology every 3 years
    3. Consider pediatric cardiology, pediatric sleep specialist

XVII. Prevention: Adults

  1. Standard Child and Adult Immunization Schedules
  2. Routine cancer screening as general population
  3. Standard Adult Health Maintenance recommendations and counseling
    1. Encourage Healthy Diet, regular Exercise and Obesity Management
    2. Address Cardiovascular Risk Factors
    3. Good Dental Hygiene
    4. Tobacco Cessation
    5. Alcohol use counseling
    6. Accident prevention
    7. Contraception
    8. Functional Training
      1. Speech Therapy and Language Therapy
      2. Vocational training or job coach
  4. Specific Disease Screening
    1. Complete Blood Count (CBC) yearly
    2. Thyroid Stimulating Hormone (TSH) every 1 to 2 years starting at age 21 years
    3. Diabetes Mellitus Screening
      1. Hemoglobin A1C every 3 years starting at age 30 years (age 21 years if obese or other risk factors)
    4. Auditory screening every 2 years
    5. Ophthalmology exam every 2 years
    6. Dental exam every 6 months
    7. Major Depression
    8. Alzheimer's Disease (age 40 years and older)
      1. Early Detection and Screen for Dementia (NTG-EDSD)
        1. https://www.the-ntg.org/ntg-edsd
    9. Mitral Valve Prolapse and valvular regurgitation
      1. Screening with careful auscultation sufficient
      2. SBE Prophylaxis if valve disease suspected
      3. Echocardiogram for confirmation
    10. Obstructive Sleep Apnea symptoms and signs
    11. Atlantoaxial Instability
      1. Ask family about Atlantoaxial Instability symptoms
      2. Annual Neurologic Exam of upper extremities
    12. Celiac Disease
      1. Ask about gastrointestinal symptoms, and if persistent, consider Celiac Disease screening
  5. Men's Exam
    1. Testicular exam yearly
  6. Women's Exam
    1. Consider modified Pap Smear
      1. Localize cervical os on bimanual exam
      2. Guide cytology brush into cervical os
    2. Consider pelvic Ultrasound instead of bimanual exam
    3. Consider sedation with anesthesiology support
      1. Consider combining with other procedures if sedated
      2. Sedation medications
        1. Midazolam (Versed) PO or IV
        2. Ketamine

XVIII. Prognosis

  1. One-year survival: 93%
  2. Five-year survival: >90%
  3. Life Expectancy: Age >60 years
    1. Increased from Life Expectancy of 25 years as of 1983
    2. Early interventions and ongoing medical management have significantly improved morbidity and mortality

XIX. Resources

  1. Down Syndrome Health Issues by Dr. Leshin
    1. http://www.ds-health.com
  2. Denison Down Syndrome Quarterly
    1. http://www.denison.edu/dsq
  3. National Down Syndrome Congress
    1. http://www.ndsccenter.org/
  4. National Down Syndrome Society
    1. http://www.ndss.org

XX. References

  1. Cohen (1999) Down Syndrome Quarterly 4:1-15
  2. Bunt (2014) Am Fam Physician 90(12): 851-8 [PubMed]
  3. Bunt (2025) Am Fam Physician 111(3): 236-44 [PubMed]
  4. Smith (2001) Am Fam Physician 64(6):1031-40 [PubMed]
  5. Tsou (2020) JAMA 324(15):1543-56 +PMID: 33079159 [PubMed]

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