Down Syndrome

See Also

Antepartum Down Syndrome Screening

Epidemiology

Most common chromosomal abnormality
Down Syndrome births: 10,000 per year in U.S. (1 in 691 live births)
Prevalence: 10.3 per 10,000

Risk Factors

Advanced Maternal Age over 34
1. Risk increases with age, but births to young mothers still account for 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
Prior child with Trisomy 21 (1% recurrence risk)
Carriers of a balanced translocation of Chromosome 21

Pathophysiology

Trisomy of Chromosome 21 (Segment 21q22, long arm)
Karyotypes
1. Trisomy of entire Chromosome with 47 Chromosomes, unfamilial (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

Signs

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
Body Habitus
1. Broad short neck with excessive skin
2. Protuberant Abdomen
3. Hyperflexibility
Neurologic
1. Moderate to severe Mental Retardation
2. Muscular hypotonicity
Hands
1. Short, broad fingers and hand
2. Curved pinky finger (clinodactyly)
3. Single Simian crease with loss of palmar crease
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
Cardiopulmonary
1. Cardiac murmur (50%)

Labs
Diagnosis

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

Associated Conditions

Neurologic
1. Developmental Delay
2. Intellectual Disability
  1. Mild: IQ of 50 to 69
  2. Moderate: IQ 35 to 49
  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
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)
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)
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)
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
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
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
Ophthalmology
1. Cataracts (13%)
2. Refractive Error
3. Keratoconus (15%)
4. Strabismus
Dermatology
1. Xerosis
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
Malignancy
1. Acute Myelogenous Leukemia (2 to 3% of patients)
2. Acute Lymphocytic Leukemia
3. Testicular Cancer

Imaging

Echocardiography
1. Typically done following delivery as newborn, and repeated as indicated
Cervical Spine XRay
1. Not recommended for universal screening
2. Indicated in age 3 years and older for suspicion for Atlantoaxial Instability

Management
Initial Diagnosis

Confirm diagnosis (see labs above)
Obtain appropriate diagnostics (see approach to birth to one month below)
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
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)
Care Plans
1. Individual Family Service Plan (birth to 3 years)
2. School-focused Individualized Education Program (3 years and older)

Management
Adults

Disposition Options for Adult Patients
1. Independent living with supervision
2. Group Homes
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
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

Prevention
Birth to one month

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)
Screening and Immunizations
1. Standard Newborn Screen for Inborn Errors of Metabolism
2. Standard Newborn Hearing Screening
Labs and Diagnostics
1. Complete Blood Count (CBC)
2. Complete chromosomal karyotyping
3. Echocardiogram (50% have congenital cardiac defect)
4. Thyroid Stimulating Hormone (TSH)
5. Consider Swallowing study (for marked hypotonia, or feeding difficulty)
Referrals
1. Pediatric cardiology
2. Early intervention program - see below (U.S. state specific)
3. Consider audiology, endocrinology, pulmonology referrals

Prevention
Age 1 month to 1 year

Findings
1. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
2. Respiratory: Sleep Apnea
3. Eye: Congenital Cataracts (via red Reflex Exam)
Screening and Immunizations
1. Pediatric Auditory Screening at age 6 months
2. Pediatric Eye Exam
3. Standard Primary Series of Immunizations
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
Referrals
1. Ophthalmology
2. Consider otolaryngology, pediatric sleep specialist

Prevention
Age 1 to 5 years

Findings
1. HEENT: Hypodontia (or delayed Tooth Eruption), Otitis Media
2. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
3. Respiratory: Sleep Apnea
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
4. Hearing screening every 6 months until 4 years of age
5. 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)
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)
Referrals
1. Ophthalmology yearly
  1. Refractive Errors and Amblyopia risk in up to 50% of patients
2. Sleep sudy by age 4 years old
3. Consider pediatric cardiology

Prevention
Age 5 to 13 years

Findings
1. Behavioral disorders (e.g. Attention Deficit Disorder)
2. Neurologic: Myelopathy (spinal cord disorders), Seizure Disorder
3. Xerosis
Screening and Immunizations
1. Body Mass Index (BMI)
Labs and Diagnostics
1. Complete Blood Count (CBC) yearly
2. Thyroid Stimulating Hormone (TSH) yearly
3. Consider CRP and Serum Ferritin yearly
Referrals
1. Audiology yearly
2. Ophthalmology every 2 years
3. Consider pediatric cardiology, pediatric sleep specialist

Prevention
Age 13 to 21 years

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

Prevention
Adults

Standard Child and Adult Immunization Schedules
Routine cancer screening as general population
Standard Adult Health Maintenance recommendations
1. Encourage Healthy Diet, regular activity and Obesity Management
2. Address Cardiovascular Risk Factors
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
Men's Exam
1. Testicular exam yearly
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

Prevention
Counseling

Good Dental Hygiene
Diet and Exercise
Obesity
Tobacco Cessation
Alcohol use
Accident prevention
Contraception
Functional Training
1. Speech Therapy and Language Therapy
2. Vocational training or job coach
Support group for parent

Prevention
Prenatal Screening

Antepartum Down Syndrome Screening

Prognosis

Five-year survival: >90%
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

Resources

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

References

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