Author(s): Kavita Nadendla, MD, Melissa K. Trovato, MD
Originally published: August 7, 2012 Last updated: April 20, 2023
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Disease/ Disorder

Definition

Down Syndrome (DS), also known as Trisomy 21, is the most common chromosomal genetic syndrome and the most common pattern of human malformation and cause of moderate intellectual disability. It is named after John Langdon Down, who described the syndrome in 1866. Down syndrome is characterized by a variety of dysmorphic features, congenital malformations and systemic complications but not all of them are present in each affected individual.1

Etiology2

 Cause%Relation to maternal ageMisc
Trisomy 21Nondisjunction during meiosis produces extra chromosome in gamete95%May be presentAll cells in the body are affected.
TranslocationTransfer of chromosomal material from one chromosome to another3%Usually not seenCarriers are phenotypically normal but have increased risk of having chromosomally abnormal offspring and miscarriages.
MosaicismTwo different cell lines are derived from a single zygote2%May be presentCognitive impairments are variable due to variable presentation.

Epidemiology including risk factors and primary prevention

DS occurs approximately once in 700 live births in the United States. Compared to national prevalence estimates for many birth defects, prevalence of DS has increased across a 15-year period from 1999 to 2010.3 DS is the most common cause of miscarriage and is found in all ethnic groups and economic classes. Advanced maternal age exponentially increases the chances of having a child with DS: 0.1% in a 20-year-old woman, 1% in a 40-year-old, and >3.5% in a 45-year-old woman. Other risk factors include having a previous child with DS (1%) or another chromosomal abnormality, parental balanced translocation, and parents with chromosomal disorders. There is no evidence identifying hormones, toxins, drugs, viruses, or vitamin deficiencies as causes of DS.

Patho-anatomy/physiology1

DS may be understood best as a syndrome complex of genetic and epigenetic origin with several characteristic neurodevelopmental manifestations. Majority of cases result from complete trisomy of chromosome 21 due to random nondisjunction during meiosis. A region on chromosome 21 proximal to 21q22.3, known as down syndrome critical region, is considered responsible for pathogenesis of DS. In approximately 87% of cases of trisomy 21, the nondisjunction is of maternal origin. Rarely, in about 2% of cases, nondisjunction may occur after fertilization is complete, resulting in two different cell lines referred to as mosaicism. Persons with mosaicism may be more mildly affected than complete trisomy 21 or with translocation but may have indistinguishable medical complications. Approximately 3% of the time, DS results from complete or partial translocation of chromosome 21 to another chromosome. This so called Robertsonian translocation occurs when the long arms of two acrocentric chromosomes fuse at the centromere, resulting in the loss of the two short arms. There is ongoing research on how different areas of chromosome 21 influence the phenotypic manifestation of DS.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

DS is usually detected by prenatal screening, hypotonia at birth, and clinical features. Global developmental delay is the usual presentation. Initial hypotonia improves to close to normal tone. Life expectancy has improved from 25 in 1983 to 60 years, due to a decline in infant and child mortality and improved cardiovascular care. Intellectual quotient (IQ) ranges from 30 to 70; majority of individuals with DS having mild to moderate intellectual disability. There is increased risk of early onset dementia. Common causes of death include leukemia, respiratory illnesses, congenital circulatory defects, diseases of digestive system, Alzheimer’s disease, and epilepsy. Severity of cognitive impairment is a good predictor of ability to live independently.

Specific secondary or associated conditions and complications4

SystemAbnormalities
CardiacSeptal defects (atrioventricular > ventricular > atrial), patent ductus arteriosus, tetralogy of Fallot, pulmonary hypertension, aberrant subclavian artery, mitral valve prolapse, tricuspid valve prolapse, aortic regurgitation.
PulmonaryRecurrent lower respiratory tract infection, tracheomalacia, chronic rhinitis, pulmonary aspiration, sleep disordered breathing.
EndocrineHypothyroidism, short stature, obesity, type I diabetes, hypogonadism, infertility.
Hematological  Acute lymphoblastic leukemia, acute myeloid leukemia, antiphospholipid antibodies, deep vein thrombosis (DVT).
GastrointestinalDuodenal atresia, esophageal atresia, annular pancreas, Hirschsprung’s disease, celiac disease, constipation, gastroesophageal reflux.
Orthopedic/ MusculoskeletalScoliosis, pes planus, patellofemoral instability, simian crease, enlarged space between first and second toes, short 5th digit with clinodactyly; atlantoaxial instability, recurrent joint dislocation, arthropathy of Down syndrome, joint hypermobility, slipped capital femoral epiphysis.
NeurologicSeizures, hearing loss, developmental delay, Moya Moya disease.
OphthalmologicRefractive errors, cataracts, strabismus, myopia.
PsychiatricDepression, autism spectrum disorders, attention deficit hyperactivity disorder, intellectual disability.
ImmunologicInnate and adaptive abnormality, increased risk of infection, high mortality from sepsis.

Essentials of Assessment

History

MaternalHow old were you when you had your child? Did you have any previous miscarriages? Did any of your previous children have any genetic problems? Is there a family history of any developmental or chromosomal problems?
NewbornDid the child cry at birth? Was the child blue? Did the child need to be intubated and placed on a ventilator? Did the child pass meconium within 48 hours of birth? Were there any feeding problems? Did the child need intravenous nutrition: glucose or calcium? Was it difficult to hold the child? Did it feel like the child slipped through the parents’ fingers?
Child/ AdolescentHas the muscle tone changed from low tone to normal tone or high tone? Is there a change in gait pattern? Is there a history of new onset torticollis? Is there change in bowel and bladder function?
Adults/ OlderHow is your memory? Do you have problems remembering things of late? Have you had any vision problems? How do you get around?

Prenatal screening and diagnostic testing5

  • First-trimester (10-14 weeks of gestation): Serum analytes plus ultrasound – Measurement of nuchal translucency (NT) through ultrasound, Pregnancy-associated plasma protein A (PAPP-A), free or total beta human chorionic gonadotrophin (hCG), and alpha-fetoprotein (AFP).
  • Second trimester (15-22 weeks of gestation): Quadruple marker screening – maternal serum AFP, hCG, unconjugated estriol, and dimeric inhibin A.
  • First and second trimester: Integrated (NT, PAPP-A, quadruple screen), serum integrated (PAPP-A, quadruple screen).
  • Screening in any trimester: Analysis of cell-free fetal DNA in maternal plasma is the most sensitive and specific screening test for the common fetal aneuploidies. Cell-free DNA fragments are detectable in maternal circulation starting at 9-10 weeks of gestation until term.
  • Ultrasound can also evaluate for potential structural markers for DS including nonvisualized nasal bone, tricuspid regurgitation, crown-rump length, femur and humeral length.
  • In patients with a positive analyte or cell-free DNA screen in the setting of abnormal fetal sonographic findings, there is concern for a chromosomal abnormality. Chorionic villus sampling (CVS) or amniocentesis is recommended to confirm the diagnosis and to determine if the aneuploidy is due to a trisomy or translocation.

Physical examination6

SystemPhysical features
HEENTBrachycephaly, midface hypoplasia, flattened nasal bridge, hypoplastic frontal sinuses, hypertelorism; brushfield spots in iris, lens opacities, refractive errors, nystagmus, strabismus, cataracts, blocked tear ducts; short neck, small mouth, oral hypotonia, fissured tongue, geographic tongue, delayed dental eruption, hypodontia; low set ears, hearing loss, otitis media
Cardiac /RespiratoryEndocardial cushion defects with murmur, signs of pneumonia
Gastrointestinal/ GenitourinaryImperforate anus, duodenal atresia, hypospadias, cryptorchidism
Growth/DevelopmentOverall delay in gross motor skills, fine motor skills and in language development, short stature, obesity
NeurologicHypotonia, poor moro reflex
OrthopedicShort broad hands, incurved fifth finger with hypoplastic mid phalanx, transverse palmar crease, space between the first and second toes, hyperflexible joints
PsychiatricBehavioral problems: impulsivity, poor judgment, short attention span, slow learning, poor coordination
CutaneousHyperkeratosis, seborrhea, xerosis, perigenital folliculitis, cutis marmorata, alopecia areata

Functional assessment

Functional assessment includes a detailed history and physical examination aimed at evaluating phenotypic characteristics, muscle tone, and deficits in balance and postural control, which all have implications in achieving developmental milestones. Motor performance can be monitored in individuals with DS using the following scales – Alberta Infant Motor Scale, Test of Infant Motor Performance, Bayley, Peabody Gross Motor Scale, or Pediatric Evaluation of Disability Inventory.7 Language assessment and cognitive evaluation may reveal dysphonia and articulation problems and intellectual delay, which can affect socialization and school placement.

Laboratory studies8

If results of prenatal testing are not available, a sample of cord or peripheral blood should be obtained for postnatal karyotype to confirm the diagnosis if the clinician is concerned for DS.

General health and prevention screening recommended for patients with Down syndrome includes:

  • Thyroid function tests at birth, 6 and 12 months of age, and annually thereafter to monitor for acquired thyroid disease.
  • Complete blood count (CBC) with differential: to monitor for leukemia and/or anemia at birth, annually, or any visit if concern for easy bruising or bleeding, recurrent fevers, or bone pain.
  • Ferritin, serum iron, and total iron binding capacity (TIBC): to screen for iron deficiency anemia at age 1 year and annually thereafter.

Imaging8

  • If myelopathic signs are present, such as any significant neck pain, radicular pain, weakness, spasticity, hyperreflexia, and/or change in bowel and bladder, obtain radiographs of the cervical spine in neutral position. If there are any abnormalities in a neutral cervical spine radiograph, the patient should be referred to a pediatric neurosurgeon or an orthopedic surgeon promptly. If neutral radiograph is normal, flexion and extension radiographs may be obtained before considering referral to a surgeon. Routine screening radiographs for assessment of potential atlantoaxial instability in asymptomatic children are not recommended. Education on certain sports that can place the child at increased risk of spinal cord injury should be provided to caregivers.
  • Echocardiogram prior to discharge from the hospital at birth or before 1 month.
  • Feeding assessment if marked hypotonia, slow feeding, failure to thrive, or any signs of difficulty swallowing by first year.

Supplemental assessment tools8

  • Screening antibodies of tissue transglutaminase and total IgA to evaluate for celiac disease at 2 years of age or with symptoms.
  • Audiology screening at birth and 6 months. If normal hearing established, behavioral audiogram and tympanometry until bilateral ear specific testing is possible. 
  • Sleep study to evaluate for obstructive sleep apnea by 4 years.
  • Ophthalmological referral to assess for strabismus, cataracts and nystagmus between 6 months to 1 year. Eye exam for cataracts between birth to 1 month, and 1 month to 1 year.
  • Psychiatric monitoring and education to address depression, autism, anxiety, attention deficit hyperactivity disorder (ADHD).
  • Referral to a dentist.
  • Recurrence risk counseling for families.

Early predictions of outcomes

Mosaicism is associated with a better functional outcome.1,6,8 Cognitive ability and health are likely related to an individual’s ability to live independently.1 High-functioning adults with DS may be able to live with minimal assistance in the community. Presence of lower IQ may be associated with being placed in sheltered workshops. Infants with very low birth weight and DS, African-American infants with DS, and infants with DS who also had a congenital heart defect have higher rates of mortality than those without.2

Environmental

  • Cognition should be assessed for appropriate placement in schools.
  • Familial environment should be assessed for extent of involvement and understanding of their child’s condition and capability to make available appropriate interventions.
  • School services should be assessed as well, to ensure appropriateness.

Social role and social support system

  • Success at school is dependent upon having an Individualized Educational Program (IEP) in place.
  • Atlantoaxial instability places children with DS at risk and should be identified prior to allowing participation in recreational activities. Special Olympics has screening requirements for all athletes for participation in sports.
  • Families and siblings should be provided information regarding local support groups.

Professional issues

  • Diagnostic tests are associated with risks that create moral and ethical quandaries.
  • The costs involved in the care of individuals with disabilities makes care challenging.
  • Plastic surgery to normalize appearance is a controversial topic.
  • Prenatal genetic counselling, due to recurrence risk (based on maternal age and parental translocation), provides information to families regarding future pregnancies.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Management of DS is focused on treating comorbidities and associated complications, not curative. The reader is referred to the health supervision guidelines per American Academy of Pediatrics regarding various screening and referrals as necessary.8  

Early childhood intervention programs and outpatient therapies may be necessary, depending on individual need. School-based therapies address only educationally relevant goals and are utilized to ensure community integration. Short courses of intensive outpatient therapy can be used to address specific changes in overall functional status.

A structured cardiovascular conditioning program is needed due to the associated obesity, secondary to poor eating habits, sedentary lifestyles, poor opportunities for recreational activities, and poor coordination and motivation.

At different disease stages

AgeIntervention
InfancyRefer to early childhood intervention to focus on developmental therapies. Audiological and ophthalmological/neuro-optometric evaluation. Swallow evaluation. Monitor growth parameters (failure to thrive). Sensory integration and vestibular stimulation could be included in therapies.
Early/Late childhoodRefer to outpatient therapies, including physical, occupational and speech therapies. Joint laxity with pes planus may benefit from supramalleolar orthoses or foot orthoses to help improve cadence and step length. 9 Knee-ankle-foot orthosis for patellofemoral instability may be helpful. Orthoses do not cure joint laxity or promote early ambulation. C-spine instability evaluation/monitoring. Sleep study for evaluation and monitoring of obstructive sleep apnea. Referral to support systems is important at every stage.
AdolescenceObesity monitoring: assess family lifestyle, eating habits, level of physical activity. Establish optimal dietary and physical exercise regimen. Monitoring of sleep apnea and its treatment. Gynecological care should be set up in prepubescent females. May need wheelchair assessment. Vocational rehabilitation evaluation is important.
Adults/AgingEvaluate for onset of Alzheimer’s disease and appropriate interventions and family support systems.10 Mobility systems should be assessed.

Coordination of care

Multidisciplinary care with various specialists, including cardiologist, neurologist/neurosurgeon, orthopedist, pulmonologist, hematologist, physiatrist and developmental pediatrician, has the advantage of addressing all aspects of care. In the event that multidisciplinary clinics are unavailable, either the physiatrist or pediatrician would take the lead in coordinating care.

Patient & family education

Diagnosis of DS needs a referral to genetics to follow through with family counselling. A carrier of Robertsonian translocation will also need education about having a child with DS. The risk of recurrence is 10–15% if the mother is the translocation carrier and about 2.5% if the father is the carrier. If a parent carries the rare 21:21 translocation, all the offspring will have DS.8 Possibility of maltreatment, including physical and sexual abuse, should be addressed with individuals with disabilities and their families. Families need to be informed of educational options, including mainstream schooling and IEPs. Families also need to be educated regarding guardianship, financial planning, behavioral problems, school placement, vocational training, ADLs and residential facilities as children with DS age.

Emerging/unique interventions

Virtual reality training, either alone or in combination with motor training, may lead to improvements in sensory-motor functions.11

A study examining a 12-week group exercise intervention demonstrated a positive effect on improved memory performance in individuals with DS.12

A pilot study exploring the benefit of participation in social skills therapy (SST) and memory in children with Down syndrome had positive results.13

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Change in hypotonia to normal tone or hypertonia could be a subtle sign of cervical myelopathy as a result of atlantoaxial instability and should be closely monitored.

Developmental delay may be worsened by hypothyroidism.

Sleep apnea affects behavior and development.

It is important to remember that early poor and slow growth during infancy gives way to obesity approaching adolescence.

Predilection to DVT and development of hematological malignancies should be monitored closely.

Deficiency of language production relative to other areas of development often causes substantial impairment.

Cutting Edge/ Emerging and Unique Concepts and Practice

Research is ongoing to find out whether there are relationships between specific genetic changes and DS phenotypes.14

Genetic modification and nanotechnology are being explored to treat trisomy 21.15

Studies in mouse models of DS carried out over the past 20 years provide proof of principle evidence that neurogenesis can be pharmacologically ameliorated in DS, offering hope for fetal therapy to improve cognitive development.16

Early mobilization and early physical and occupational therapy are being explored to minimize motor delay in children with Down syndrome.17 Also optimal rehabilitation pathway to recommend home therapy, school based therapy and other means of therapy are being tested.18,19

Gaps in the Evidence-Based Knowledge

Despite the screening/testing and management of associated conditions, no definite curative treatment is currently available for DS. Research is ongoing to focus on finding better function and quality of life. A lot of research is being done in rehabilitation therapies to improve speech, motor function, and cognitive function but currently lack randomized, well powered studies. Treatment strategies to decrease complications such as Alzheimer’s disease in individuals with DS have been investigated but there are no guidelines to prevent such complications.20

References

  1. Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, Sherman SL, Reeves RH. Down syndrome. Nature Reviews Disease Primers. 2020;6(9). doi: 10.1038/s41572-019-0143-7.
  2. Centers for Disease Control and Prevention. Data and statistics on down syndrome. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/data.html. Updated 2022. Accessed Mar 13, 2023.
  3. Mai CT, Isenburg JL, Canfield MA, Meyer RE, Correa A, Alverson CJ, Lupo PJ, Riehle-Colarusso T, Cho SJ, Aggarwal D, Kirby RS. National population-based estimates for major birth defects, 2010-2014. Birth Defects Research. 2019; 111(18):1420-1435. doi: 10.1002/bdr2.1589.
  4. Lagan N, Huggard D, Mc Grane F, et al. Multiorgan involvement and management in children with down syndrome. Acta paediatrica (Oslo, Norway: 1992). 2020. https://www.ncbi.nlm.nih.gov/pubmed/31899550. doi: 10.1111/apa.15153.
  5. ACOG Committee on Practice Bulletins. ACOG practice bulletin no. 226: Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2020;136(4):e48-e69. doi: 10.1097/AOG.0000000000004084.
  6. Bani Bandana Ganguly (Ed.). (2022). Genetics and Neurobiology of Down Syndrome(pp. 135-180). London, UK: Associated Press.
  7. Moriyama CH, Massetti T, Crocetta TB, et al. Systematic review of the main motor scales for clinical assessment of individuals with down syndrome. Developmental Neurorehabilitation. 2020;23(1):39-49. http://www.tandfonline.com/doi/abs/10.1080/17518423.2019.1687598. doi: 10.1080/17518423.2019.1687598.
  8. Bull MJ, The Council on Genetics. Health supervision for children and adolescents with down syndrome. Pediatrics. 2022;149(5):e2022057010. doi: 10.1542/peds.2022-057010.
  9. Puszczalowska-Lizis E, Nowak K, Omorczyk J, Ambrozy T, Bujas P, Nosiadek L. Foot structure in boys with Down Syndrome. Biomed Res Int. 2017;2017:7047468. doi: 10.1155/2017/7047468.
  10. Ballard C, Mobley W, Hardy J, Williams G, Corbett A. Dementia in Down’s syndrome. Lancet Neurol. 2016;15(6):622-36. doi: 10.1016/S1474-4422(16)00063-6.
  11. Lopes J, Duarte N, Lazzari R, Oliveira C. Virtual reality in the rehabilitation process for individuals with cerebral palsy and down syndrome: a systematic review. J Bodyw Mov Ther. 2020;24(4):479-83. doi: 10.1016/j.jbmt.2018.06.006.
  12. Ptomey L, Szabo A, Willis E, Gorczyca A, Greene J, Danon J, Donnelly J. Changes in cognitive function after a 12-week exercise intervention in adults with down syndrome. 2018;11(3):486-90. doi: 10.1016/j.dhjo.2018.02.003.
  13. Milojevich HM, Slonecker EM, Lukowski AF. Participation in social skills therapy is associated with enhanced recall memory by children with down syndrome: An exploratory study. Behav Modif. 2019:145445519841051. doi: 10.1177/0145445519841051.
  14. Yu YE, Xing Z, Do C, et al. Genetic and epigenetic pathways in down syndrome: Insights to the brain and immune system from humans and mouse models. Prog Brain Res. 2020;251:1-28. doi: S0079-6123(19)30197-9.
  15. Tafazoli A, Behjati F, Farhud DD, Abbaszadegan MR. Combination of genetics and nanotechnology for down syndrome modification: A potential hypothesis and review of the literature. Iran J Public Health. 2019;48(3):371-378.
  16. Stagni F, Bartesaghi R. The challenging pathway of treatment for neurogenesis impairment in down syndrome: achievements and perspectives. Front Cell Neurosci. 2022;16:903729. doi: 10.3389/fncel.2022.903729.
  17. Okada S, Uejo T, Hirano R, et al. Assessing the efficacy of very early motor rehabilitation in children with down syndrome. J Pediatr. 2019;213:227-231.e1. doi: S0022-3476(19)30655-9.
  18. Neal GE, Effgen SK, Arnold S, Baldwin J, Jeffries LM. Description of school-based physical therapy services and outcomes for students with down syndrome. J Autism Dev Disord. 2019;49(10):4019-4029. doi: 10.1007/s10803-019-04109-7.
  19. Walker BJ, Washington L, Early D, Poskey GA. Parents’ experiences with implementing therapy home programs for children with down syndrome: A scoping review. Occup Ther Health Care. 2020;34(1):85-98. doi: 10.1080/07380577.2020.1723820.
  20. Priebe GA, Kanzawa MM. Reducing the progression of alzheimer’s disease in down syndrome patients with micro-dose lithium. Med Hypotheses. 2020;137:109573. doi: S0306-9877(19)31233-2.

Original Version of the Topic:

Rajashree Srinivasan, MD. Down Syndrome. 08/07/2012

Previous Revision(s) of the Topic

Mi Ran Shin, MD, Melissa Trovato, MD. Down Syndrome. 8/25/2016

Mi Ran Shin, MD, Courtney Sagar, MD, Olga Morozova, MD. Down Syndrome. 5/4/2020

Author Disclosure

Kavita Nadendla, MD
Nothing to Disclose

Melissa K. Trovato, MD
Nothing to Disclose