Down Syndrome

Author(s): Mi Ran Shin, MD , Melissa Trovato, MD

Originally published:08/07/2012

Last updated:08/25/2016



Down Syndrome (DS), also known as Trisomy 21, is the most common inherited 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.


  Cause % Relation to maternal age Misc
Trisomy 21  Nondisjunction during meiosis produces extra chromosome in gamete 95% May be present All cells in the body are affected.
Mosaicism Two different cell lines are derived from a single zygote 1% May be present Cognitive impairments are variable due to variable presentation.
Translocation Transfer of chromosomal material from one chromosome to another is seen 4% Usually not seen Carriers are phenotypically normal but have increased risk of having chromosomally abnormal offsprings and miscarriages.

Epidemiology including risk factors and primary prevention

DS occurs once in 691 live births in the United States. There are approximately 400,000 people living with Down syndrome in United States. It is the commonest 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.


Down syndrome may be understood best as a syndrome complex of genetic and epigenetic origin with several characteristic neurodevelopmental manifestations. DS is a chromosomal disorder. Majority of cases results from complete trisomy of chromosome 21 due to 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 95% of cases of trisomy 21, the nondisjunction is of maternal origin; which occurs “randomly” during meiosis. Rarely, in about 1% of cases, nondisjunction may occur after fertilization is complete, resulting in two different cell lines, and this is referred to as mosaicism. Approximately 4% of the time, DS results from complete or partial translocation of chromosome 21 to another chromosome. This so called Robertsonian translocations occurs when the long arms of two acrocentric chromosomes fuse at the centromere. The two short arms get lost as a result. Although vary rare, 1 in 14000 new births may have unbalanced Robertsonian translocation with trisomies of the long arms. There is ongoing research on how different areas of chromosome 21 influence the phenotypic manifestation of DS. Persons with mosaicism may be more mildly affected than complete trisomy 21 or with translocation but may have indistinguishable medical complications.

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. Intelligence quotient varies, from mild (50-70), moderate (35-50), to severe (20-35). Common causes of death include leukemia, respiratory illnesses, congenital circulatory defects, diseases of digestive system, Alzheimer’s disease and epilepsy. Cognitive impairment is a good predictor of ability to live independently. There is increased risk of early onset dementia.

Specific secondary or associated conditions and complications

System Abnormalities
Cardiac Endocardial cushion defect, ventricular septal defect, atrial septal defect, aberrant subclavian artery, mitral valve prolapse, tricuspid valve prolapse, aortic regurgitation.
Endocrine Hypothyroidism, hypogonadism, small penis, diabetes, infertility, Obesity


Acute lymphoblastic leukemia, antiphospholipid antibodies, deep vein thrombosis (DVT), duodenal atresia, annular pancreas, Hirshprung disease, Celic disease


Scoliosis, joint laxity, pes planus, patellofemoral instability, simian crease, enlarged space between first and second toes, short 5th digit with clinodactyly. Atlantoaxial instability, AVN, recurrent joint dislocation


Refractive errors, cataracts, strabismus, seizures, hearing loss, myopia, depression, autism spectrum disorders




Maternal How 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?
Newborn Did the child cry at birth? Was the child blue? Did the child need to be intubated and placed on a ventilator? 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/ Adolescent Has the muscle tone changed from low to normal to high? Is there a change in gait pattern? Is there a history of new onset Torticollis? Is there change in bowel and bladder function?
Adults/ Older How is your memory? Do you have problems remembering things of late? Have you had any vision problems? How do you get around?

Physical examination

System Physical features
HEENT Brachycephaly, midface hypoplasia, flattened nasal bridge, hypoplastic frontal sinuses, brushfield spots in iris, lens opacities, refractive errors, nystagmus, strabismus, cataracts, blocked tear ducts, short neck, small mouth, oral hypotonia, hearing loss, delayed eruption, small and missing teeth.
Cardiac/Lungs/Gastrointestinal Endocardial cushion defects, imperforate anus, pulmonary hypoplasia, duodenal atresia, obstructive sleep apnea
Skin Epicanthal folds, single palmar crease, cutis marmorata, hyperkeratosis.
Growth/Development Poor moro reflex, smaller in size when compared to normal, adults have shorter height when compared to age peers; risk of obesity later in life. Overall delay in gross motor and fine motor skills, and in language development. IQ-25-50
Neurologic/Orthopedic Hip dysplasia, hypotonia, osteoporosis, behavioral problems: impulsivity, poor judgment, short attention span, slow learning, poor coordination.
Cutaneous Hyperkeratosis, Seborrhea, Xerosis, Perigenital folliculitis

Functional assessment

Functional assessment includes a detailed history and physical examination aimed at evaluating phenotypic characteristics, muscle tone, and developmental milestones: delayed sitting, standing and walking, speech delay, fine motor skills, and activities of daily living (ADL). Language assessment and cognitive evaluation reveal dysphonia and articulation problems, and intellectual delay which can affect social skills and school placement.

Laboratory studies

  1. Prenatal screening: all women should be offered in their 2nd trimester by Quad screen (alpha serum fetal protein, estriol, human chorionic gonadotropin, and inhibin Alpha).
  2. Diagnostic testing: Chorionic villus sampling and amniocentesis.
  3. Chromosomal karyotype with microarray and possible fluorescent insitu hybridisation (FISH).
  4. Cell free fetal DNA in materal plasma.
  5. Thyroid function tests to monitor for hypothyroidism annually.
  6. Complete blood count (CBC): to monitor for leukemia and iron deficiency anemia at birth and annually12


  1. Flexion/extension cervical spine x-rays at age 3-5 years or when planning to participate in contact sports and then as indicated by history and exam to evaluate for atlantoaxial instability.
  2. Doppler ultrasound to evaluate for DVT.
  3. X-rays of abdomen and lungs as needed for obstruction (double bubble sign) or to evaluate for pneumonias.
  4. Magnetic Resonance Imaging (MRI) of cervical spine.
  5. Echocardiogram prior to discharge from the hospital at birth, and as young adult for acquired valve disease.

Supplemental assessment tools

  1. Screening antibodies to evaluate for celiac disease at 2 years of age or with symptoms for IgA tissue transglutaminase and total IgA.
  2. Audiologic testing at birth or by 3-months with auditory brainstem response or optoacoustic emission testing: may need to repeat every 6 month up to 3 years, than annually.
  3. Sleep study to evaluate for obstructive sleep apnea at 4 years.
  4. Ophthalmological examination at birth or by 6 months and annual vision check.
  5. Psychiatric monitoring to address depression, autism, anxiety, attention deficit hyperactivity disorder (ADHD).
  6. Referral to a dentist.
  7. Recurrence risk counseling for families.

Early predictions of outcomes

Mosaicism is associated with a better functional outcome. High-functioning adults may be able to live with minimal assistance in the community. Presence of lower IQ may be associated with being placed in sheltered workshops. Depending on cognitive ability, some may find suitable paid employment, or become volunteers.


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 dislocation places these children at risk and should be identified prior to allowing participation in recreational activities. Families and siblings should be provided information regarding local support groups.

Professional Issues

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


Available or current treatment guidelines

All treatments focus 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.

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 life styles, poor opportunities for recreational activities, poor coordination and motivation.

At different disease stages

Age Intervention
Infancy Refer 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 should be included in therapies.
Early/Late childhood Refer to outpatient therapies, including physical, occupational and speech therapies. Joint laxity with Pes planus may benefit from supramalleolar orthoses or foot orthotics to help improve cadence and step length. 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.
Adolescence Obesity monitoring: assess family lifestyle, eating habits, increased 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/ Aging Evaluate onset of Alzheimer’s and appropriate interventions and family support systems. Mobility systems should be assessed.

Coordination of care

Multidisciplinary care with various specialists, including cardiologist, neurologist/neurosurgeon, orthopedist, pulmonologist, hematologist and physiatrist, 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 geneticists to follow through with counselling the families. A carrier of Robertsonian translocation will also need education about having a child with DS. It should be explained that 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 Down syndrome. Possibility of maltreatment, including physical and sexual abuse, should be addressed with individuals with disabilities and their families. Families need to be educated regarding educational options at school, including mainstreaming, and individual educational programs (IEPs). Families also need to be educated regarding guardianship, financial planning, behavioral problems, school placement, vocational training, ADLs and places to stay once they became adults.

Emerging/unique Interventions

Regular neurologic examination provides a good screen for atlantoaxial instability.

Prenatal screening provides information regarding the diagnosis so families are prepared for the event.

Assisted cycling therapy (ACT), a novel exercise intervention, may improve cognitive planning ability and reaction times as well as improve cognitive planning in young adults and adolescents with DS.

Pre- and early treatment with direct pharmacologic therapies and indirect intervention strategies to improve neurodevelopmental impairments are being researched including maternal choline supplements.

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

Suspicion should be high for complications like atlantoaxial instability and should be closely monitored. Spasticity in the mileu of hypotonia may present as normal tone, a red flag in an otherwise floppy child.

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 developmental of hematological malignancies should be monitored closely.

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


Cutting edge concepts and practice

Current treatment concepts focus on managing the associated comorbidities and complications that occur as a result of the condition. Proper genetic screening and testing help in the decision-making process, and noninvasive diagnosis are being developed. Nutritional supplements, use of antioxidants, facial plastic therapy, and cognitive enhancement products should be discussed with the parents, cautioning the use, as there is no research evidence to support this. Prenatal noninvasive diagnosis for DS as well as prenatal therapies including genetic treatment is being investigated for application. Early infant treadmill training may hasten motor development.


Gaps in the evidence-based knowledge

Despite the screening/testing and management of associated conditions, no definite curative treatment is currently available. 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. There is also a gap in evidence for management of OSA without tonsillar hypertrophy in DS. Prenatal therapies to improve neurodevelopment including antioxidants and supplements are ongoing areas of research.


  1. Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics 2011 Aug;128(2):393-406.
  2. Davidson MA. Primary care for children and adolescents with Down syndrome. Pediatr Clin North Am 2008 Oct;55(5):1099-111, xi.
  3. Hornyak JE. Down Syndrome: rehabilitation quick reference–pediatrics. NY: Demos Medical: 2011.
  4. Smith’s Recognizable Patterns of Human Malformations – Sixth edition. Philadelphia, PA: Elsevier;2006.
  5. National Down Syndrome Congress. 2016; Available at: Accessed 07/10, 2016.
  6. Licciardone JC, Stoll ST, Fulda KG, Russo DP, Siu J, Winn W, et al. Osteopathic manipulative treatment for chronic low back pain: a randomized controlled trial. Spine (Phila Pa 1976) 2003 Jul 1;28(13):1355-1362.
  7. Bauer A, Speers D, Wening J. Effects of SMOs on gait of children with excessive pronation associated with benign hypotonia. Journal of Proceedings, 2009, American Academy of Orthotists and Prosthetists, Atlanta, GA.
  8. Ringenbach SD, Holzapfel SD, Mulvey GM, Jimenez A, Benson A, Richter M. The effects of assisted cycling therapy (ACT) and voluntary cycling on reaction time and measures of executive function in adolescents with Down syndrome. J Intellect Disabil Res 2016 Mar 28.
  9. Health Care Information for Families of Children with Down Syndrome. 2016; Available at: Accessed 5/7, 2016.
  10. Polisenska, K., & Kapalkova, S. (2014). Language profiles in children with Down syndrome and children with language impairment: implications for early intervention. Res Dev Disabil, 35(2), 373-382. doi: 10.1016/j.ridd.2013.11.022
  11. Strupp BJ, Powers BE, Velazquez R, Ash JA, Kelley CM, Alldred MJ, et al. Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease. Curr Alzheimer Res 2016;13(1):97-106
  12. Davidson MA. Primary care for children and adolescents with Down syndrome. Pediatr Clin North Am 2008 Oct;55(5):1099-111, xi.
  13. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 2004 Oct;5(10):725-738.
  14. Capone GT. Down syndrome: advances in molecular biology and the neurosciences. J Dev Behav Pediatr 2001 Feb;22(1):40-59.

Original Version of the Topic:

Rajashree Srinivasan, MD. Down Syndrome. Publication Date:2012/08/07.

Author Disclosure

Mi Ran Shin, MD
Nothing to Disclose

Melissa Trovato, MD
Nothing to Disclose

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