Down Syndrome

DISEASE/DISORDER:

Definition

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. 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

Etiology¹

	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	3%	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 were approximately 250,7000 people living with Down syndrome in United States in 2008.¹ 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.

Patho-anatomy/physiology²

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 result  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.  Intellectual quotient 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. Cognitive impairment is a good predictor of ability to live independently.

Specific secondary or associated conditions and complications³

System	Abnormalities
Cardiac	Endocardial cushion defect, ventricular septal defect, atrial septal defect, aberrant subclavian artery, mitral valve prolapse, tricuspid valve prolapse, aortic regurgitation.
Pulmonary	Recurrent lower respiratory tract infection, chronic rhinitis, pulmonary aspiration, sleep disordered breathing.
Endocrine	Hypothyroidism, hypogonadism, small penis, diabetes, infertility, obesity.
Hematological	Acute lymphoblastic leukemia, acute myeloid leukemia, antiphospholipid antibodies, deep vein thrombosis (DVT).
Gastrointestinal	Duodenal atresia, esophageal atresia, annular pancreas, Hirshprung disease, celiac disease, constipation, gastroesophageal reflux.
Orthopedic/ Musculoskeletal	Scoliosis, 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.
Neurologic	Seizures, hearing loss, developmental delay, Moya Moya disease.
Ophthalmologic	Refractive errors, cataracts, strabismus, myopia.
Psychiatric	Depression, autism spectrum disorders, attention deficit hyperactivity disorder, intellectual disability.
Immunologic	Innate and adaptive abnormality, increased risk of infection, high mortality from sepsis.

ESSENTIALS OF ASSESSMENT

History

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 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/ Older	How 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

1. First-trimester screening: Measurement of nuchal translucency (NT) through ultrasound, Pregnancy-associated plasma protein A (PAPP-A), free or total beta human chorionic gonadotrophin (hCG).
2. Second trimester: Triple screening (maternal serum alpha-fetoprotein, hCG, unconjugated estriol), Quadruple screening (add Inhibin A to the triple screening).
3. First and second trimester: Integrated (NT, PAPP-A, quadruple screen), serum integrated (PAPP-A, quadruple screen).
4. Cell free fetal DNA in maternal plasma. Ultrasound can also evaluate for potential markers for DS including nonvisualized nasal bone, tricuspid regurgitation, crown-rump length, femur and humeral length.

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, macroglossia, fissured tongue, geographical tongue, hearing loss, delayed eruption, small and missing teeth, low set ears, otitis media
Cardiac /Respiratory	Endocardial cushion defects with murmur, signs of pneumonia
Gastrointestinal/  Genitourinary	Imperforate anus, duodenal atresia, hypospadias, cryptorchidism
Growth/Development	Overall delay in gross motor and fine motor skills, and in language development, short stature, obesity
Neurologic	Hypotonia, poor moro reflex
Orthopedic	Short broad hands, incurved fifth finger with hypoplastic mid phalanx, transverse palmar crease, space between the first and second toes, hyperflexible joints
Psychiatric	Behavioral problems: impulsivity, poor judgment, short attention span, slow learning, poor coordination.
Cutaneous	Hyperkeratosis, 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 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. Some of the scales that can be used for this population include Alberta Infant Motor Scale, Test of Infant Motor Performance, Bayley, Peabody Gross Motor Scale, and Pediatric Evaluation of Disability Inventory.⁴

Laboratory studies⁶

Diagnostic testing to confirm diagnosis for the patient is through genetic testing such as chromosomal karyotyping.

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

1. Thyroid function tests to monitor for hypothyroidism annually.
2. Complete blood count (CBC): to monitor for leukemia and iron deficiency anemia at birth and annually ⁶

Imaging⁶

1. If myelopathic signs such as any significant neck pain, radicular pain, weakness, spasticity or change in one, hyperreflexia, change in bowel and bladder is present; obtain radiographs of the cervical spine in neutral position. If there are any abnormalities in a neutral cervical spine radiography, the patient should be referred to a pediatric neurosurgeon or an orthopedic surgeon promptly. If x-ray in neutral position is normal, may obtain flexion and extension radiographs of the cervical spine before considering referring 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 in increased risk of spinal cord injury should be done. Special Olympics has specific screening requirements for participation in some sports.
2. Echocardiogram prior to discharge from the hospital at birth or before 1 month.
3. Swallow study if marked hypotonia, slow feeding, failure to thrive, any signs of difficulty swallowing by first year.

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. Audiology screening at new born and audiology evaluation at 6 months. If normal hearing established, behavioral audiogram and tympanometry until bilateral ear specific testing possible. 
3. Sleep study to evaluate for obstructive sleep apnea by 4 years.
4. 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.
5. Psychiatric monitoring and education 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. Infants with very low birth weight and DS, African-American infants with DS and infants with congenital heart defect in their first life have higher rates of mortality than those without.¹

Environmental⁶

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 quandaries. 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.

REHABILITATION MANAGEMENT AND TREATMENTS

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. ⁶  

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, and 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 could 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 orthoses to help improve cadence and step length. 7 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, 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/ 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, 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 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 mainstream, 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 become adults.

Emerging/unique Interventions

A pilot study exploring the benefit of participation in social skills therapy (SST) and memory in children with Down syndrome had positive results.⁸

Various pharmacologic treatments to minimize respiratory complications in DS are being explored.^9,10

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

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. Research is ongoing to find out whether there are relationships between specific genetic changes and clinical outcomes.¹¹

Genetic modification and nanotechnology are being explored to treat trisomy 21.¹²

Early mobilization, early physical and occupational therapy to minimize motor delay in children with Down syndrome are being explored.¹³ Also optimal rehabilitation pathway to recommend home therapy, school based therapy and other means of therapy are being tested.^14,15

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. 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.¹⁶

REFERENCES

1. Centers for Disease Control and Prevention. Data and statistics on down syndrome. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/data.html. Updated 2019. Accessed Mar 24, 2020.
2. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: From genomics to pathophysiology. Nat Rev Genet. 2004;5(10):725-738. doi: nrg1448 [pii].
3. 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.
4. 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.
5. ACOG Committee on Practice Bulletins. ACOG practice bulletin no. 77: Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217-227. doi: 109/1/217 [pii].
6. Bull MJ, Committee on Genetics. Health supervision for children with down syndrome. Pediatrics. 2011;128(2):393-406. doi: 10.1542/peds.2011-1605 [doi].
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. 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 [doi].
9. Valentini D, Di Camillo C, Mirante N, Marcellini V, Carsetti R, Villani A. Effects of pidotimod on recurrent respiratory infections in children with down syndrome: A retrospective Italian study. Ital J Pediatr. 2020;46(1):31-5. doi: 10.1186/s13052-020-0797-5 [doi].
10. Kimura T, Takeuchi M, Kawakami K. Utilization and efficacy of palivizumab for children with down syndrome. Pediatr Int. 2020. doi: 10.1111/ped.14157 [doi].
11. 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 [pii].
12. 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.
13. 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 [pii].
14. 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 [doi].
15. 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 [doi].
16. 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 [pii].

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

Author Disclosure

Mi Ran Shin, MD
Nothing to Disclose

Courtney Sagar, MD
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Olga Morozova, MD
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