Clinical Review & Education

JAMA | Special Communication

Medical Care of Adults With Down Syndrome

A Clinical Guideline
Amy Y. Tsou, MD, MSc; Peter Bulova, MD; George Capone, MD; Brian Chicoine, MD; Bryn Gelaro, MA, LSW;
Terry Odell Harville, MD, PhD, D(ABMLI), D(ABHI); Barry A. Martin, MD; Dennis E. McGuire, PhD, LCSW;
Kent D. McKelvey, MD; Moya Peterson, PhD, APRN, FNP-BC; Carl Tyler, MD, MSc; Michael Wells, BS; Michelle Sie Whitten, MA;
for the Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup

Editorial page 1509

IMPORTANCE Down syndrome is the most common chromosomal condition, and average life Supplemental content
expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite
the unique clinical comorbidities among adults with Down syndrome, there are no clinical CME Quiz at
jamacmelookup.com
guidelines for the care of these patients.

OBJECTIVE To develop an evidence-based clinical practice guideline for adults with

Down syndrome.

EVIDENCE REVIEW The Global Down Syndrome Foundation Medical Care Guidelines for Adults
with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/
Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple
clinical areas including mental health (2 questions), dementia, screening or treatment of
diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid
disease, and celiac disease. These questions guided the literature search in MEDLINE,
EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from
January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020.
Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation)
methodology and the Evidence-to-Decision framework, in January 2019, the 13-member
Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives,
and a methodologist developed clinical recommendations. A statement of good practice was
made when there was a high level of certainty that the recommendation would do more good
than harm, but there was little direct evidence.

FINDINGS From 11 295 literature citations associated with 10 PICO questions, 20 relevant
studies were identified. An updated search identified 2 additional studies, for a total of 22
included studies (3 systematic reviews, 19 primary studies), which were reviewed and
synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice
were developed. Overall, the evidence base was limited. Only 1 strong recommendation was
formulated: screening for Alzheimer-type dementia starting at age 40 years. Four
recommendations (managing risk factors for cardiovascular disease and stroke prevention,
screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with
existing guidance for individuals without Down syndrome. Two recommendations for
diabetes screening recommend earlier initiation of screening and at shorter intervals given
the high prevalence and earlier onset in adults with Down syndrome.

CONCLUSIONS AND RELEVANCE These evidence-based clinical guidelines provide

recommendations to support primary care of adults with Down syndrome. The lack of
high-quality evidence limits the strength of the recommendations and highlights the need for Author Affiliations: Author
affiliations are listed at the end of this
additional research. article.
Group Information: A complete list
of the members of the Global Down
Syndrome Foundation Medical Care
Guidelines for Adults with Down
Syndrome Workgroup appears at the
end of this article.
Corresponding Author: Amy Y.
Tsou, MD, MSc, Evidence-Based
Practice Center, Center for Clinical
Excellence and Guidelines, ECRI,
5200 Butler Pike, Plymouth Meeting,
JAMA. 2020;324(15):1543-1556. doi:10.1001/jama.2020.17024 PA 19462 ([email protected]).

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

D
own syndrome is the most common chromosomal
condition1 and in 2010-2014 occurred in 1 of every 700 live Box 1. Population/Intervention/Comparator/Outcome (PICO)
births in the US.1 Individuals with Down syndrome have a Questionsa
significantly lower risk for some conditions, including solid malig-
Behavioral Health (PICO 1 and PICO 2)
nancies, but a higher risk for other conditions, including congenital
PICO 1: In adults with Down syndrome, do clinical symptoms of
cardiac conditions, autoimmune diseases, and Alzheimer disease.
depression, OCD, mood disorder, catatonia, GAD, and regression/
Average life expectancy for people with Down syndrome has sub- disintegrative disorder differ from the general population?
stantially increased, from 25 years in 19832 to 60 years in 2020.3
PICO 2: In adults with Down syndrome, does performing a psychosocial
According to one estimate, the number of people with Down syn- assessment (by clinical assessment or by caregiver or patient
drome living in the US was approximately 206 000 in 2010,4 al- questionnaire)toscreenformentalhealthdisorders(suchasdepression,
though exact and current prevalence is unknown because of lack of anxiety, OCD, psychosis/regression/disintegrative disorder) improve
data, changing survival rates across decades, and trends in live births recognition and diagnosis of medical conditions or health outcomes?
vs termination rates.
Dementia (PICO 3)
Because individuals with Down syndrome are living longer, guid- What is the prevalence of dementia in adults with Down syndrome
ance is needed to support high-quality care. Although guidelines by decade?
based on expert opinion exist,5,6 evidence-based clinical practice
Diabetes (PICO 4)
guidelines (CPGs) for adults with Down syndrome have not been de-
A. What is the prevalence of diabetes (type 1 or 2) in adults with Down
veloped. This Special Communication presents a clinical guideline syndrome compared with the general population (by decade)?
with recommendations to support high-quality primary care for B. Does screening asymptomatic adults with Down syndrome for
adults with Down syndrome. diabetes improve cardiovascular outcomes, diabetic comorbidi-
ties, and functional outcomes?
C. Does screening adults with Down syndrome and obesity (BMI
ⱖ30) more often improve outcomes (cardiovascular, diabetic
Methods comorbidities, and functional outcomes?

The Global Down Syndrome Foundation (GLOBAL), a nonprofit in Cardiovascular Disease (PICO 5)
the US dedicated to improving the lives of people with Down syn- A. What is the prevalence of coronary artery disease and stroke
drome through research, medical care, education and advocacy, re- secondary to atherosclerosis in adults with Down syndrome
(compared with the general population)?
cruited expert Down syndrome clinicians, many of whom are mem-
B. In adults with Down syndrome and hyperlipidemia, does treat-
bers of the Down Syndrome Medical Interest Group–USA, and the
ment of total cholesterol, LDL-C, or triglycerides improve clini-
ECRI (originally the Emergency Care Research Institute) Evidence- cal outcomes?
based Practice Center to form the Global Medical Care Guidelines
for Adults with Down Syndrome Workgroup (Workgroup) and cre- Obesity (PICO 6)
A. Are treatments for obesity safe and effective for reducing com-
ate an evidence-based CPG for clinicians, adults with Down syn-
plications of obesity (obstructive sleep apnea, joint pain, heart
drome, and families/caregivers. disease, diabetes, mental health problems) or improving quality
In 2017, the 13-member Workgroup (11 Down syndrome of life in adults with Down syndrome?
exper ts, 1 ECRI guideline methodologist , and 1 parent B. What target BMI is optimal for reducing comorbidities of obe-
representative/advocacy leader and expert from GLOBAL) con- sity in adults with Down syndrome?
vened a 29-member committee, including all 13 members of the
Atlantoaxial Instability (PICO 7)
Workgroup plus 16 volunteers (listed at the end of this article). A. What is the prevalence of atlantoaxial instability in asymptom-
There was consensus among Workgroup members that these atic adults with Down syndrome (compared with the general
guidelines should provide guidance to support primary care clini- population)?
cians in caring for adults with Down syndrome. The 29 experts B. Does screening with imaging (radiography, CT, MRI) asymptom-
were assigned to 9 committees representing the 9 topic areas pri- atic (ie, no symptoms or examination findings) adults with
Down syndrome for atlantoaxial instability improve outcomes?
oritized for inclusion in these guidelines: behavior, dementia, dia-
betes, cardiac disease, obesity, atlantoaxial instability, osteoporo- Osteoporosis (PICO 8)
sis, thyroid disease, and celiac disease. Workgroup members A. What is the prevalence of osteopenia, osteoporosis, spinal com-
prioritized clinical topics for consideration and developed 10 pression, hip or femur fractures in Down syndrome (by decade
questions using the standardized Population/Intervention/ of life) compared to general population?
B. What is the clinical utility of screening asymptomatic adult pa-
Comparator/Outcome (PICO) format (summaries of the full-
tients with Down syndrome with DEXA (to detect osteopenia
length PICO questions are reported in Box 1). or osteoporosis)?
Clinicians caring for adults with Down syndrome must often C. In adults with Down syndrome and no known history of low
decide in what situations “standard” guidelines for adults with- bone density, do lifestyle factors or serum markers (vitamin D,
out Down syndrome (such as US Preventive Services Task Force calcium, PTH, or thyrotropin) predict diagnosis of osteopenia,
[USPSTF]recommendations) should be followed. For most of osteoporosis or fracture?
the key questions, the Workgroup anticipated that limited D. What pharmacological treatments are effective for prevention
of osteoporotic fractures in adults with Down syndrome?
published research would include adults with Down syndrome.
Thus, several PICO questions sought to identify differences in dis- (continued)
ease prevalence between adults with Down syndrome and the

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

quality studies) was selected for inclusion to avoid multiple rat-

Box 1. (continued) ings of a similar evidence base. If no relevant systematic reviews
met those criteria, relevant studies were identified with the
Thyroid (PICO 9)
highest-quality study designs (eg, randomized clinical trials for
A. What is the prevalence of hypothyroidism in adults with Down
syndrome by decade?
intervention PICOs). If no studies were identified that focused on
B. What is the diagnostic accuracy of thyrotropin, free thyroxine, a specific question, lower-quality studies (eg, observational stud-
and antithyroid antibodies for hypothyroidism in asymptomatic ies) were considered for inclusion. For example, for PICOs that
adults with Down syndrome? addressed prevalence (prevalence addressed varies by PICO
C. Does treating elevated thyrotropin levels in asymptomatic question), observational studies with 300 or more adults with
adults with Down syndrome improve clinical or functional Down syndrome were sought. However, if no studies met these
outcomes?
criteria, studies with fewer patients (eg, n ⱖ 100) were included.
D. What is the clinical utility of using antithyroid antibodies to
screen for thyroid disease in adults with Down syndrome and Data regarding study design, population characteristics,
autoimmune disease (celiac disease, rheumatoid arthritis, intervention(s), prevalence estimates, and outcome measures
lupus, alopecia areata)? were extracted from all included studies, and a narrative synthe-
sis (qualitative synthesis of evidence) was performed. Study qual-
Celiac Disease (PICO 10)
A. What is the accuracy of tTG-IgA or total IgA (compared with ity for individual studies was assessed using USPSTF methods
duodenal biopsy) for diagnosing celiac disease in adults except for prevalence studies, which were assessed using pre-
with Down syndrome? specified items (see eMethods 2 in Supplement 1). Overall quality
B. What is the clinical utility of screening asymptomatic adults of evidence for each outcome was assessed using GRADE (Grad-
with Down syndrome for celiac disease using tTG-IgA or ing of Recommendations, Assessment, Development, and Evalua-
total IgA?
tion) methodology.10
C. Does HLA antigen haplotype DQ2 or DQ8 predict risk of
developing celiac disease in adults with Down syndrome?
The 13-member Workgroup participated in a 3-day in-person
D. Does a gluten-free diet improve symptoms in adults with Down meeting from January 23 to 25, 2019. A patient advocate and
syndrome and celiac disease? families (n = 3) were also present for selected sessions. Workgroup
members reviewed evidence from the systematic review and
Abbreviations: BMI, body mass index; CT, computerized tomography;
DEXA, dual-energy x-ray absorptiometry; GAD, generalized anxiety used the GRADE Evidence-to-Decision framework to formulate
disorder; HLA, human leukocyte antigen; IgA, immunoglobulin A; recommendations.11,12 This framework uses 4 domains to deter-
LDL-C, low-density lipoprotein cholesterol; MRI, magnetic resonance mine a recommendation’s strength (strong or weak): (1) balance
imaging; OCD, obsessive-compulsive disorder; PTH, parathyroid hormone;
tTG-IgA, tissue transglutaminase IgA.
of desirable and undesirable outcomes, (2) confidence in evi-
dence quality, (3) patient values and preferences, and (4) other
a
Questions presented here are an abbreviated summary of full-length PICO
implications (including equity, feasibility, and subgroup
questions developed for the systematic review.
considerations).10 A strong recommendation indicates a high or
moderate confidence in the quality of the available evidence, a
clear difference in magnitude between the benefits and harms of
general population to inform where existing clinical recom- an intervention, and similar values and preferences, along with
mendations might warrant modification. The PICO format was consideration of other implications.
used for all questions; however, for questions focused on preva- If the Workgroup had less confidence after assessment
lence, the PICO category of “intervention” was not applicable. across these domains and determined that additional evidence
Questions targeting prevalence did include population and out- could change the recommendation, it generally assigned a weak
come, along with a comparator if the comparative prevalence recommendation. A statement of good practice (SOGP) was
was addressed. made when there was a high level of certainty, based on clinical
Using these PICO questions, ECRI performed a systematic assessment of anticipated benefits and harms, that the recom-
review. A medical librarian performed a comprehensive literature mendation would do more good than harm but there was little
search in MEDLINE, EMBASE, PubMed, PsycINFO, the Cochrane direct evidence.13 The Workgroup’s consideration of each domain
Library, and the TRIP database from January 1, 2000, to February for every recommendation included in this guideline is reported
26, 2018. Titles and abstracts were screened, followed by a full- in eTable 1 in Supplement 1.
text assessment based on predefined inclusion/exclusion criteria. After recommendations were drafted, Workgroup mem-
Detailed PICO questions, search strategies, and selection criteria bers voted with verbal assent (or dissent) to adopt (or reject) the
are reported in eMethods 1 and eMethods 2 in Supplement 1. An recommendation. If unanimous consent was not present, objec-
updated literature search was performed on August 6, 2020; 2 tions and suggested modifications to the recommendation
additional articles were identified and included. were discussed and another vote was taken. In the event unani-
To conduct the literature review, a “best evidence” approach mous consent could not be reached, a two-thirds majority of
was used, which has previously been used for systematic reviews Workgroup members was required for the recommendation to be
underpinning CPGs.7,8 For each PICO question, we identified any adopted. Disclosures and potential conflicts of interest for
relevant previously published English-language systematic all Workgroup members were obtained and updated throughout
reviews rated as good quality as per USPSTF criteria.9 If multiple the process.
relevant systematic reviews were identified, the most recent, rel- For key questions for which no direct evidence was identified
evant, and comprehensive (eg, the review with the most high- in the patient population (ie, adults with Down syndrome),

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

Workgroup members considered additional indirect evidence Evidence Summary

from other patient populations (eg, children with Down syn- No studies directly compared symptoms in adults with Down syn-
drome, people with intellectual disability) and arrived at consen- drome with the general population. However, 1 systematic review15
sus regarding whether evidence was “direct enough” to inform included 3 cross-sectional studies that described symptoms of uni-
care for adults with Down syndrome. This approach has been polar depression. Individuals with Down syndrome who met crite-
used to develop evidence-based CPGs in contexts with limited ria for major depressive episodes had common symptoms (anhe-
direct evidence.14 donia, depressed mood, and disturbed sleep) but also hallucinations,
To obtain input from patients and caregivers, a 7-day on- and a subset presented with a “deficit” syndrome (apathy, abulia,
line focus group was conducted in October 2019 and included anhedonia, and mutism) without obvious mood changes or psycho-
7 adults with Down syndrome and 27 caregivers (including sis. A case series (n = 30) reported that symptoms of patients with
parents and siblings), to solicit feedback on draft recommenda- Down syndrome with regression included changes in mood, behav-
tions, usability, importance, and areas requiring clarification. In ior, and psychotic symptoms.34 Confidence in the quality of evi-
addition, the draft guidelines were reviewed by 7 members of the dence was very low.
American Academy of Developmental Medicine and Dentistry. All
feedback was reviewed, and updates were incorporated by the Rationale for Recommendation 1
Workgroup. The full guidelines, complete methods, systematic Behavioral and mental health conditions are common in Down
review, and implementation tools are available in eAppendix 1 in syndrome and many clinicians are not familiar with distinctive
Supplement 2 or at https://www.globaldownsyndrome.org/ behaviors in this population, which differ from those in the general
global-adult-guidelines/. population. Thus, despite very low confidence in quality of evi-
Since creation of these guidelines did not involve human par- dence, the potential benefits, including identifying salient psycho-
ticipants in research, this project was determined to be exempt social issues requiring attention, avoiding misdiagnosis of adaptive
from institutional review board (IRB) approval as confirmed by behavior as a disorder, and limiting unnecessary use of psychotro-
the Colorado Multiple IRB. pic medications, warranted a weak recommendation for referral to
medical professionals familiar with the common behaviors and pre-
sentation of medical and mental health conditions in adults with
Down syndrome.
Results
Searches identified 11 295 citations, of which the systematic Rationale for the Recommendation 2
review included 20 studies (3 systematic reviews15-17and 17 pri- In the absence of tools validated specifically for Down syndrome,
mary studies, including 1 randomized clinical trial, 18 4 cohort given distinctive challenges of diagnosing mental health disorders,
studies,19-22 11 cross-sectional studies,23-33 and 1 case series).34 An clinicians should use the DSM-5 complemented by the DM-ID-2, an
updated literature search on August 6, 2020, identified 2 addi- expert consensus tool helpful in recognizing mental health disor-
tional cross-sectional studies35,36 relevant to recommendations ders in people with intellectual and developmental disabilities.
(eFigure 1 and eTable 2 in Supplement 1). No studies addressing
PICO 2 (efficacy of psychosocial assessment for recognition of Statements of Good Practice 1 and 2 and Rationale
mental or health conditions) were identified. Fourteen recom- A review of behavioral, functional, adaptive, and psychosocial fac-
mendations and 4 SOGPs were formulated (Table 1). A 1-page tors should be performed as part of an annual history that clini-
checklist tool summarizing all recommendations and SOGPs for cians obtain from all adults with Down syndrome, their families, and
families/caregivers to easily track care and support adherence caregivers (SOGP 1).
with the guideline recommendations was also created (eFigure 2 When concern for a mental health disorder in adults with Down
in Supplement 1). syndrome is present, medical professionals should evaluate pa-
tients for medical conditions that may present with psychiatric and
Diagnosis and Treatment of Behavioral Health Conditions behavioral symptoms (SOGP 2).
Recommendation 1
When concern for a mental health disorder in adults with Down Diagnosis of Dementia
syndrome is present, medical professionals should refer the patient Recommendation 3
to a clinician knowledgeable about the medical, mental health dis- Caution is needed when diagnosing age-related, Alzheimer-type de-
orders, and common behavioral characteristics of adults with mentia in adults with Down syndrome younger than 40 years be-
Down syndrome. cause of its low prevalence before this age.

Recommendation 2 Recommendation 4
When concern for a mental health disorder in adults with Down Medical professionals should assess adults with Down syndrome and
syndrome is present, medical professionals should follow guide- interview primary caregivers about changes from baseline func-
lines for diagnosis in the Diagnostic and Statistical Manual of Mental tion annually, beginning at age 40 years. Decline in 6 domains speci-
Disorders (Fifth Edition) (DSM-5). 37 The Diagnostic Manual– fied by the National Task Group–Early Detection Screen for Demen-
Intellectual Disability 2: A Textbook of Diagnosis of Mental Disorders tia (NTG-EDSD) 39 should be used to identify early-stage age-
in Persons with Intellectual Disability (DM-ID-2)38 also may be used related Alzheimer-type dementia, a potentially reversible medical
to adapt diagnostic criteria from the DSM-5. condition, or both.

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

Table 1. Recommendations and Statements of Good Practice

Confidence
Strength of in quality
Recommendation/statement of good practice recommendation of evidence
Recommendations
Behavior
Recommendation 1. When concern for a mental health disorder in adults with Down Weak Very low
syndrome is present, medical professionals should refer to a clinician knowledgeable about
the medical, mental health disorders, and common behavioral characteristics of adults with
Down syndrome
Recommendation 2. When concern for a mental health disorder in adults with Down Weak Very low
syndrome is present, medical professionals should follow guidelines for diagnosis
in the DSM-537; the DM-ID-238 also may be used to adapt diagnostic criteria from
the DSM-5
Dementia
Recommendation 3. Caution is needed when diagnosing age-related, Alzheimer-type Weak Low
dementia in adults with Down syndrome younger than 40 y because of its low prevalence
before this age
Recommendation 4. Medical professionals should assess adults with Down syndrome and Strong Moderate
interview their primary caregivers about changes from baseline function annually beginning
at age 40 y; decline in the following 6 domains as per the NTG-EDSD39 should be used to
identify early-stage age-related Alzheimer-type dementia and/or a potentially reversible
medical condition:
• Cognition, memory, and executive function
• Behavior and personality
• Communication
• Adaptive functioning
• Ambulation and motor skills
• General decline in established skills
Diabetes
Recommendation 5. For asymptomatic adults with Down syndrome, screening for type 2 Weak Moderate
diabetes using HbA1c or fasting plasma glucose should be performed every 3 y beginning
at age 30 y
Recommendation 6. For any adult with Down syndrome and comorbid obesity, screening for Weak Moderate
type 2 diabetes using HbA1c or fasting plasma glucose should be performed every 2-3 y
beginning at age 21 y
Cardiovascular disease
Atherosclerotic cardiovascular disease
Recommendation 7. For adults with Down syndrome without a history of ASCVD, the Weak Low
appropriateness of statin therapy should be assessed every 5 y starting at age 40 y
and using a 10-y risk calculator as recommended for adults without Down syndrome by
the USPSTF40
Stroke
Recommendation 8. For adults with Down syndrome, risk factors for stroke should be Weak Very low
managed as specified by the American Heart Association/American Stroke Association
guidelines for the primary prevention of stroke41
Recommendation 9. In adults with Down syndrome with a history of congenital heart Weak Very low
disease, given the elevated risk of cardioembolic stroke, a periodic cardiac evaluation
and a corresponding monitoring plan should be reviewed by a cardiologist
Obesity
Recommendation 10. Monitoring for weight change and obesity should be performed Weak Very low
annually by calculating BMI in adults with Down syndrome; the USPSTF behavioral weight
loss interventions to prevent obesity-related morbidity and mortality in adults should
be followed42
Atlantoaxial instability
Recommendation 11. In adults with Down syndrome, routine cervical spine radiographs Weak (against) Very low
should not be used to screen for risk of spinal cord injury in asymptomatic individuals;
instead, annual screening of adults with Down syndrome should include signs and symptoms
of cervical myelopathy using targeted history and physical examination
Osteoporosis
Recommendation 12. For primary prevention of osteoporotic fractures in adults with Down Neither for NA
syndrome, there is insufficient evidence to recommend for or against applying established nor against
osteoporosis screening guidelines, including fracture risk estimation; thus, good clinical
practice would support a shared decision-making approach to this issue
Recommendation 13. All adults with Down syndrome who sustain a fragility fracture should Weak Very low
be evaluated for secondary causes of osteoporosis, including screening for hyperthyroidism,
celiac disease, vitamin D deficiency, hyperparathyroidism, and medications associated with
adverse effects on bone health
Thyroid
Recommendation 14. Screening adults with Down syndrome for hypothyroidism should be Weak Moderate
performed every 1-2 y using a serum thyrotropin test beginning at age 21 y

(continued)

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

Table 1. Recommendations and Statements of Good Practice (continued)

Confidence
Strength of in quality
Recommendation/statement of good practice recommendation of evidence
Statements of good practicea
Behavior
Statement 1. A review of behavioral, functional, adaptive, and psychosocial factors
should be performed as part of an annual history that clinicians obtain from all adults
with Down syndrome, their families, and caregivers
Statement 2. When concern for a mental health disorder in adults with Down syndrome
is present, medical professionals should evaluate for medical conditions that may present
with psychiatric and behavioral symptoms
Obesity
Statement 3. Healthy diet, regular exercise, and calorie management should be
followed by all adults with Down syndrome as part of a comprehensive approach to
weight management, appetite control, and enhancement of quality of life
Celiac disease
Statement 4. Adults with Down syndrome should receive an annual assessment for
gastrointestinal and nongastrointestinal signs and symptoms of celiac disease using
targeted history, physical examination, and clinical judgment of good practice
a
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass Statements of Good Practice are made when there is a high level of certainty
index; DM-ID-2, Diagnostic Manual-Intellectual Disability 2: A Textbook of a recommendation will do more good than harm but there is little supporting
Diagnosis of Mental Disorders in Persons with Intellectual Disability; direct evidence. As per GRADE (Grading of Recommendations, Assessment,
DSM-5, Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); Development, and Evaluation) methodology, statements of good practice are
HbA1c, glycated hemoglobin; NTG-EDSD, National Task Group—Early Detection not assigned a formal strength rating.
Screen for Dementia; USPSTF, US Preventive Services Task Force.

Evidence Summary cantly outweighed potential harms (underdiagnosis of true

One moderate-quality Dutch study23 (n = 506 adults with Down Alzheimer-type dementia).
syndrome) found dementia prevalence of 8.9% (95% CI,
5%-12%) in 45- to 49-year-olds; prevalence increased every 5 Rationale for Recommendation 4
years to 32.1% (95% CI, 22%-42%) in 55- to 59-year-olds and Becausedementiaprevalenceincreasesafterage40years,adultswith
decreased to 25.5% (95% CI, 12%-40%) in patients 60 years or Down syndrome and primary caregivers should be interviewed an-
older. An additional study (n = 878 adults with Down syndrome)35 nually beginning at age 40 to establish a baseline and identify changes
reported increasing prevalence of dementia in adults with Down in baseline function in the adult with Down syndrome, which could
syndrome older than 45 years and 40% prevalence after age 45, suggest potential Alzheimer-type dementia. The justification was
but dementia diagnosis was based on administrative data. One based on the benefits of early identification of dementia, treatment
low-quality study from Spain and the UK36 (n = 388) also reported of potentially reversible causes of cognitive decline, or both, which
increasing prevalence rates for dementia in adults with Down syn- outweigh potential harms associated with more testing.
drome after age 40 years, with rates rising from approximately Despite absence of disease-modifying dementia treatments,
10% (for 40- to 45-year-olds) up to 90% to 100% (for 65- to most adults with Down syndrome and their families/caregivers
70-year-olds). place high value on early diagnosis, accurate diagnosis, or both
Three studies assessed prevalence in patients younger than 40 to modify existing supports and allow for additional resource
years.19,24,36 However, only 1 study36 (n = 388) used a validated mea- planning. Individuals with mild to moderate dementia will
sure for diagnosis and reported 0% prevalence in adults with Down typically have changes across multiple domains (memory and
syndrome aged 30 to 39 years. Two additional large studies executive function, behavior and personality, language and com-
(n > 5000 adults with Down syndrome)19,24 did not confirm diag- munication, gait and motor skills, activities of daily living, conti-
nosis based on validated tests but found similar low prevalence in nence, and sleep patterns) as described in the NTG-EDSD, 39
younger adults (18-39 years). Confidence in the quality of evidence which was developed for dementia diagnosis in individuals with
was low for prevalence in patients younger than 40 years but mod- intellectual disability.
erate for those older than 45 years.
Diabetes
Rationale for Recommendation 3 Recommendation 5
Because clinicians may attribute symptoms of Down syndrome to For asymptomatic adults with Down syndrome, screening for type
Alzheimer-type dementia without adequately considering alter- 2 diabetes using glycated hemoglobin or fasting plasma glucose lev-
native causes, a weak recommendation suggests that clinicians els should be performed every 3 years beginning at age 30 years.
should exercise caution when attributing symptoms to
Alzheimer-type dementia in adults with Down syndrome younger Recommendation 6
than 40 years. Benefits of considering other causes, including For any adult with Down syndrome and comorbid obesity, screen-
treatable conditions (eg, hypothyroidism, sleep apnea), signifi- ing for type 2 diabetes using glycated hemoglobin or fasting plasma

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

glucose level should be performed every 2 to 3 years beginning at of 0.8 and an overall prevalence of 1.5% for adults with Down syn-
age 21 years. drome 30 years or older.19 True incidence of ASCVD may be even lower
because the study did not distinguish between atherosclerotic ische-
Evidence Summary mia vs nonatherosclerotic ischemia due to conditions such as sleep
One population-based study in the UK19 (n = 3808) found that dia- apnea, congenital heart disease, and pulmonary hypertension, all of
betes prevalence was higher in adults with Down syndrome com- which the study found were more common in Down syndrome. Con-
pared with general population–matched controls (3.5% vs 0.7%, fidence in the quality of the evidence was low.
respectively, for ages 16 to 30 years and 5.5% vs 2.7%, respectively,
for 30 years or older). Confidence in the quality of evidence was Rationale for Recommendation 7
rated moderate. No studies evaluated if elevated lipid levels are predictive of ASCVD
for adults with Down syndrome. While limited available evidence
Rationale for Recommendations 5 and 6 suggests a reduced risk of ASCVD, given very low certainty in effect
The American Diabetes Association (ADA) recommends screening size estimates, there was insufficient justification to recommend
for abnormal blood glucose level and type 2 diabetes in all adults be- adults with Down syndrome be treated differently. Altogether,
ginning at age 45 years.43 Given risks associated with premature ag- benefits of treating potential atherosclerotic events slightly out-
ing in adults with Down syndrome (with increased risk for cataracts weighed potential harms including adverse events associated with
and kidney and peripheral nervous system damage),44-46 screen- statin therapy and polypharmacy. Thus, USPSTF guidance (using a
ing should be initiated earlier, beginning at age 30 years and to be 10-year risk calculator and personalizing lipid goals) should be fol-
repeated every 3 years if results of blood glucose screening are nor- lowed (weak recommendation).
mal (weak recommendation). The American Board of Internal Medicine Choosing Wisely cam-
The ADA recommends that individuals who are overweight or paign, in cooperation with the AMDA—The Society for Post-Acute and
obese (body mass index [BMI] ⱖ25, calculated as weight in kilo- Long-Term Care Medicine (2017), recommends against routinely pre-
grams divided by height in meters squared) and with 1 additional scribing lipid-lowering medications in individuals with limited life
risk factor begin screening for abnormal blood glucose levels expectancy.47 Weighing the ideal time to discontinue screening and
every 3 years and for type 2 diabetes after puberty.43 Because treatment for individuals with Down syndrome may also involve con-
obesity is common in Down syndrome and associated with sideration of shorter average life expectancy (60 years) for adults
increased risk for diabetes, for adults with Down syndrome and with Down syndrome.48
obesity, screening should be initiated at age 21 years and
repeated every 2 to 3 years with or without the presence of an Stroke Prevention
additional risk factor outlined by the ADA (weak recommenda- Recommendation 8
tion). Benefits of earlier identification and management of diabe- For adults with Down syndrome, risk factors for stroke should be
tes were judged to outweigh potential harms of obtaining labora- managed as specified by the American Heart Association/
tory testing and potential for overtreatment (eg, hypoglycemia). American Stroke Association’s (AHA/ASA) Guidelines for the Primary
Prevention of Stroke.41
Cardiovascular Disease Prevention
Recommendation 7 Recommendation 9
For adults with Down syndrome without a history of atheroscle- In adults with Down syndrome with a history of congenital heart dis-
rotic cardiovascular disease (ASCVD), the appropriateness of statin ease, given the elevated risk of cardioembolic stroke, a periodic car-
therapy should be assessed every 5 years starting at age 40 years diac evaluation and a corresponding monitoring plan should be re-
and using a 10-year risk calculator as recommended by the USPSTF viewed by a cardiologist.
for adults without Down syndrome.40
Evidence Summary
Evidence Summary One Australian study20 compared strokes in hospitalized adults with
No studies assessed whether treatment to reduce levels of total cho- Down syndrome (n = 1706) with those in matched controls
lesterol, low-density lipoprotein cholesterol (LDL-C), or triglycerides (n = 6828). Adults with Down syndrome had more strokes across
improve clinical outcomes. However, an Australian study20 that com- both age groups: 1.8% vs 0.5% (ages 19-50 years) and 9.8% vs 4.9%
pared hospitalized patients with Down syndrome (n = 1706) with age- (age ⱖ51 years) (P < .05 for both comparisons). On average, strokes
matched controls (n = 6828) found that in patients 50 years or occurred at a younger age in adults with Down syndrome com-
younger myocardial infarction events were similar, but in patients 51 pared with controls (mean age, 41.8 vs 57.1 years), with cardioem-
years or older (n = 1845) events were reduced in adults with Down bolic strokes being most common. Confidence in the quality of the
syndrome (8.1% for those with Down syndrome vs 13.3% for con- evidence was very low.
trols). A second UK study19 (n = 3808) also reported a mildly lower
incidence of ischemic heart disease in adults with Down syndrome Rationale for Recommendations 8 and 9
compared with controls (absolute annual incidence per 100 person- Given increased risk of cardioembolic stroke in adults with Down syn-
years for Down syndrome of all ages was 0.19 [95% CI, 0.15-0.25] with drome, the established guidelines for risk factor management for
an incidence rate ratio of 0.9 compared with matched controls). For stroke prevention should be followed as specified in the AHA/ASA
those older than 30 years (50.5% of the study population) the abso- guidelines (weak recommendation). Typical risk factors such as hy-
lute rate was 0.28 (95% CI, 0.21-0.38), with an incidence rate ratio pertension are uncommon in Down syndrome,19 while moyamoya

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

disease,49 obstructive sleep apnea,50,51 and congenital heart dis- drome. Adults with Down syndrome, families, and clinicians should
ease are more common. As many as 50% of children with Down syn- support generally accepted practices for overall wellness.
drome are born with congenital heart disease, which increases the risk
of cardioembolic stroke.52,53 Thus, all patients with a history of con- Screening for Atlantoaxial Instability
genital heart disease should receive a cardiac evaluation and moni- Recommendation 11
toring plan reviewed by a cardiologist (weak recommendation). In adults with Down syndrome, routine cervical spine radiographs
should not be used to screen for risk of spinal cord injury (SCI) in
Obesity Screening and Management asymptomatic individuals. Instead, annual screening of adults
Recommendation 10 with Down syndrome should include a review of signs and symp-
Monitoring for weight change and obesity should be performed toms of cervical myelopathy, such as altered gait, new inconti-
annually by calculating BMI in adults with Down syndrome. The nence, brisk reflexes, or clonus, using targeted history and physi-
USPSTF recommendation for behavioral weight loss interventions cal examination.
to prevent obesity-related morbidity and mortality in adults should
be followed.42 Evidence Summary
No studies assessed utility of screening for atlantoaxial instability
Evidence Summary (AAI) with cervical spine radiographs. However, 2 cross-sectional
Three randomized clinical trials (RCTs) from 2 systematic studies reported prevalence of AAI. An Australian registry-based sur-
reviews16,17 assessed exercise interventions in obese adults with vey (n = 197) found that 8.1% (95% CI, 4.35%-11.9%) of adults with
Down syndrome (n = 84). Mentored physical activity had no Down syndrome younger than 30 years had AAI.25 A similar preva-
effect on weight or waist circumference at 9 weeks,16 and aerobic lence (11% [95% CI, 2.7%-19.5%]) was reported by a Spanish chart
exercise and progressive resistance exercise had no effect on review (n = 144).27 Neither study provided criteria used to estab-
weight at 9 to 12 weeks (Cohen d, 0.09; P = .37).17 Quality of evi- lish AAI or presence of signs or symptoms of myelopathy. Confi-
dence was rated very low. Studies excluded patients with ortho- dence in the quality of evidence was very low.
pedic conditions, cardiac disease, or metabolic disease, further
limiting applicability. These studies reported no adverse effects Rationale for Recommendation 11
from physical activity16 and no abnormal electrocardiogram find- Cervical spine radiographs have been used to identify individuals
ings (aerobic exercise or progressive resistance exercise). Quality with Down syndrome at risk for SCI with physical activity.
of evidence for safety outcomes was rated moderate. Although AAI prevalence is approximately 10% in adults younger
No studies assessed other interventions for obesity or the ef- than 30 years,25,27 no studies have assessed if radiographs are
fect of various BMI targets for reducing comorbidities of obesity. effective for identifying at-risk individuals or preventing SCI.
While avoiding potential SCI is important, restricting asymptom-
Rationale for Recommendation 10 atic individuals with AAI from participating in physical activities is
USPSTF guidelines recommend referring obese adults to inten- also undesirable for reasons related to physical and psychological
sive, multicomponent behavioral interventions.42 These trials in health. Additional indirect evidence has suggested that SCI from
people with Down syndrome16,17 did not provide sufficient justifi- AAI is uncommon. A 1995 review from the American Academy of
cation to warrant differing from USPSTF guidance. First, trials did Pediatrics Committee on Sports Medicine noted only 41 well-
not assess multicomponent interventions but only exercise alone documented, published cases of symptomatic AAI in adults with
(potentially limiting efficacy). Second, many factors may contrib- Down syndrome. 54 In addition, Special Olympics organizers
ute to obesity in Down syndrome, including medication adverse report no spinal cord injuries from more than 50 000 individuals
effects, conditions (hypothyroidism, obstructive sleep apnea), with Down syndrome who participated in Special Olympics activi-
poor appetite-satiety control, and lack of physical activity. ties over 20 years.55
Because obesity is common, clinicians may not consider obesity a Because the true risks of SCI are unknown, the benefits of al-
modifiable condition. However, weight loss or stabilization is pos- lowing physical activity slightly outweighed the potential harms of
sible through activity interventions such as swimming, dancing, SCI. Cervical radiographs should not be used to screen for AAI in
or working with a personal trainer and through diet management, asymptomatic individuals; instead, targeted history and physical ex-
portion control, and consistency of mealtimes. Although trials amination should be used for evaluation of signs or symptoms of my-
failed to demonstrate benefit, they reported no adverse effects. elopathy (weak recommendation).
Thus, given long-term harms of obesity, the benefits of monitor- Adults with Down syndrome, and their families/caregivers,
ing for obesity with annual BMI and adhering to USPSTF guidance may differ in preferences to avoid risk of SCI; thus, a shared
for adults outweighed potential harms. decision-making approach is endorsed that considers potential
benefits and harms of restricting participation in high-risk activi-
Statement of Good Practice 3 and Rationale ties, including but not limited to gymnastics, diving, skiing, and
Healthy diet, regular exercise, and calorie management should be horseback riding.
followed by all adults with Down syndrome as part of a comprehen-
sive approach to weight management, appetite control, and en- Screening for Osteoporosis
hancement of quality of life (SOGP 3). Recommendation 12
Although no interventions reviewed demonstrated effects on For primary prevention of osteoporotic fractures in adults with
weight, obesity is a common concern in adults with Down syn- Down syndrome, there is insufficient evidence to recommend for

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

or against applying established osteoporosis screening guidelines, Evidence Summary

including fracture risk estimation; thus, good clinical practice Three studies reported a similar high prevalence of hypothyroid-
would support a shared decision-making approach. ism in adults with Down syndrome. A study from the UK19 (n = 3808)
found a prevalence of 39% (95% CI, 36%-42%) in adults with Down
Recommendation 13 syndrome aged 18 to 29 years and 51% (95% CI, 49%-53%) in those
All adults with Down syndrome who sustain a fragility fracture should 30 years or older. Two additional clinic-based studies performed in
be evaluated for secondary causes of osteoporosis, including screen- Spain27 (n = 144) and the US31 (n = 141) reported similar rates: 43%
ing for hyperthyroidism, celiac disease, vitamin D deficiency, hyper- (ages 18-29 years) and 57% to 61% (age ⱖ30 years)27; 39% (ages
parathyroidism, and medications associated with adverse effects on 18-49 years) and 42% (age ⱖ50 years).31 Confidence in the quality
bone health. of evidence was moderate.
No studies assessed treating elevated thyrotropin levels in
Evidence Summary asymptomatic patients, the diagnostic accuracy of thyrotropin, free
Only 6 small, poor-quality studies (total n = 796) reported preva- thyroxine or antithyroid antibodies, or the clinical utility of anti-
lence for osteopenia, osteoporosis, or osteoporotic fracture in adults thyroid antibodies to screen for thyroid disease in adults with Down
with Down syndrome, with wide-ranging prevalence estimates for syndrome and autoimmune disease.
osteoporosis (1.4% to 45.1%).28-33
No studies assessed utility of dual-energy x-ray absorptiom- Rationale for Recommendation 14
etry (DEXA) screening or efficacy of pharmacological treatments for Symptoms of hypothyroidism are challenging to distinguish be-
osteoporotic fracture prevention. cause weight gain and constipation are common in Down syn-
drome. Furthermore, adults with Down syndrome may have diffi-
Rationale for Recommendations 12 and 13 culty communicating fatigue or cold intolerance.
Although the Fracture Risk Assessment Tool (FRAX) is typically Prevalence of hypothyroidism in adults with Down syndrome is
used to assess fracture risk,56 this model may not be applicable to substantiallyhigher(approximately50%inadultsolderthan30years19)
adults with Down syndrome because it was derived from epide- comparedwithprevalenceinUSadultswithoutDownsyndrome,61 and
miologic data from the general population. Populations with small treatment may improve cognitive function and weight management.
body size or constitutionally short stature may require volumetric Thus,adultswithDownsyndromeshouldbescreenedforhypothyroid-
bone mineral density measurement or other adjustments for bone ism every 1 to 2 years (weak recommendation).
characteristics relevant to fracture risk.57 Based on the available
evidence, standard DEXA is not helpful for assessing risk of osteo- Screening for Celiac Disease
porotic fracture in Down syndrome. Furthermore, reduced bone Statement of Good Practice 4
formation, rather than excessive bone resorption, may drive skel- Adults with Down syndrome should receive an annual assessment
etal dynamics in adults with Down syndrome,58 although this has for gastrointestinal and nongastrointestinal signs and symptoms of
not been consistently observed.59 If true, bisphosphonates, which celiac disease using targeted history, physical examination, and clini-
reduce bone resorption, may not be effective for individuals with cal judgment of good practice (SOGP 4).
Down syndrome. Given the absence of studies demonstrating ben-
efit of DEXA screening and concerns regarding applicability of Rationale for Statement of Good Practice 4
DEXA, to acknowledge the uncertainty, the recommendation is Celiac disease is more common in individuals with Down syndrome,
neither for nor against osteoporosis screening, noting that a shared with an estimated prevalence of 11% among people with Down
decision-making approach should be used to incorporate patient syndrome.27 However, diagnosis presents unique challenges be-
and family preferences. cause gastrointestinal and nongastrointestinal symptoms can be dif-
The 2016 American Association of Clinical Endocrinologists/ ficult to recognize. In addition, some gastrointestinal problems
American College of Endocrinology clinical practice guide- (eg, constipation, loose stools, and cramping) are common in Down
line 60 for postmenopausal women with osteoporosis recom- syndrome. These may also be more challenging to identify, depend-
mended evaluation for secondary causes of osteoporosis, some of ing on communication skills. No studies assessed utility of screening
which are common in Down syndrome. Given the low harms asso- asymptomatic adults with Down syndrome or efficacy of a gluten-
ciated with testing, potential benefits of avoiding fragility frac- free diet, and studies assessing diagnostic accuracy of tissue trans-
tures, and additional health benefits of treating relevant diseases, glutaminase IgA and biopsy had significant flaws.21,22
adults with Down syndrome who sustain a fragility fracture should
receive an evaluation for secondary causes of osteoporosis such as
hyperthyroidism, celiac disease, vitamin D deficiency, hyperpara-
Discussion
thyroidism, and medications with adverse effects on bone health
(weak recommendation). Providing care for the increasing number of adults with Down syn-
drome can be challenging, given their broad phenotypic variation
Screening for Thyroid Disease in health and function. As the first, to our knowledge, evidence-
Recommendation 14 based guideline for adults with Down syndrome, these recommen-
Screening adults with Down syndrome for hypothyroidism should dations provide guidance across a wide range of clinical conditions
be performed every 1 to 2 years using a serum thyrotropin test be- and support clinicians in providing high-quality medical care for adults
ginning at age 21 years. with Down syndrome.

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

Table 2. Recommendations Compared With Existing Guidance

Recommendation Existing guideline

Recommendations in Down syndrome guidelines concur with existing guidance for the general population
Recommendation 7. Statin therapy for lowering Agrees with USPSTF guidance for the general population, statin
cardiovascular risk for adults with Down syndrome use for the primary prevention of cardiovascular disease in
adults: preventive medication40
Recommendation 8. Managing risk factors for stroke Agrees with AHA/ASA guidelines for primary prevention of
prevention for adults with Down syndrome stroke41 for the general population
Recommendation 10. Obesity screening for adults with Agrees with USPSTF guidance for the general population,
Down syndrome Behavioral Weight Loss Interventions to Prevent
Obesity-Related Morbidity and Mortality in Adults42
Recommendation 13. Evaluating secondary causes of Agrees with American Association of Clinical Endocrinologists/
osteoporosis for adults with Down syndrome American College of Endocrinology (2016) guideline,60
Diagnosis and Treatment of Postmenopausal Osteoporosis for
the General Population
Recommendations in Down syndrome guidelines differ from existing guidance for the general population
Recommendation 5. Diabetes screening in asymptomatic Recommendation (screen starting at age 30 y [instead of 45]
individuals with Down syndrome every 3 y43) differs from ADA guidance for the general
population
Recommendation 6. Diabetes screening in adults with Recommendation (screen starting at age 21 y and every 2-3 y
Down syndrome and obesity [instead of every 3 y] without requiring any additional risk
factors43) differs from ADA guidance for the general population
Recommendation in Down syndrome guidelines neither for or against existing guidance for the general population
Recommendation 12. Screening for primary prevention Neither for or against osteoporosis risk prediction tools (FRAX)
of osteoporosis for adults with Down syndrome for the general population
New recommendations in Down syndrome guidelines
Recommendations 1 and 2. Diagnosis of behavioral
health conditions for adults with Down syndrome
Recommendations 3 and 4. Diagnosis and screening for
Alzheimer-type dementia for adults with Down syndrome
Recommendation 9. Refer adults with Down syndrome
and history of congenital heart disease for cardiac Abbreviations: ADA, American
evaluation and monitoring plan for adults with Down Diabetes Association;
syndrome
AHA/ASA, American Heart
Recommendation 11. Screening for atlantoaxial Association/American Stroke
instability for adults with Down syndrome
Association; FRAX, Fracture Risk
Recommendation 14. Screening for hypothyroidism for Assessment Tool; USPSTF, US
adults with Down syndrome Preventive Services Task Force.

The process for developing these guidelines adhered to stan- drome differ from those in the general population, it is possible bis-
dards for trustworthy guidelines established by the Institute of phosphonates may not be effective. Thus, these concerns were high-
Medicine62 and used the Evidence-to-Decision framework12 (eTable 1 lighted by making a recommendation neither for nor against current
in Supplement 1) to formulate 14 clinical recommendations along with osteoporosis risk prediction tools.
4 SOGPs. As anticipated, evidence was limited for many PICO ques- Remaining recommendations addressed evaluation for mental
tions. To address this challenge, a pragmatic approach was utilized, health disorders (recommendations 1 and 2), screening and diagnosis
using evidence of differences in prevalence and age of onset in adults of Alzheimer-type dementia (recommendations 3 and 4), cardiology
with Down syndrome to consider if changes to existing guidance for referralsforadultswithhistoryofcongenitalheartdisease(recommen-
the general population were justified. dation 9), screening for AAI (recommendation 11), and screening for
Half of the recommendations (n = 7) pertained to guidance for hypothyroidism (recommendation 14). Because rates of dementia in-
the general population from existing CPGs (Table 2). Four recommen- crease after age 40 years from approximately 10% to 20% (ages 45-
dations(managingcardiovascularrisk[recommendation7],strokepre- 50 years)23,36 to as high as 50% (ages 55-59 years),36 a strong recom-
vention [recommendation 8], screening for obesity [recommenda- mendation to initiate screening for behavioral changes at age 40 years
tion 10], and evaluation for secondary causes of osteoporosis was made (recommendation 4). In these guidelines, age 40 years was
[recommendation 13]) agreed with existing guidance. Conversely, for chosen because dementia prevalence is low (<1%) in patients younger
diabetes screening (recommendations 5 and 6), earlier and more fre- than 40 years,19,24,36 and initiating screening at this age allows a base-
quent screening was recommended based on studies demonstrat- line to be established. Since dementia is rare in patients younger than
ing high prevalence and earlier onset in adults with Down syndrome. 40 years, caution is required in making a dementia diagnosis in this age
Regarding optimal screening for osteoporosis, based on clini- group, a recommendation intended to prevent inaccurate attribution
cal experience, the existing tools (FRAX) for predicting fracture risk of cognitive symptoms to dementia. The high prevalence of hypothy-
are likely poor predictors in adults with Down syndrome. There is roidism in adults with Down syndrome (50% in adults aged ⱖ30
concern that patients estimated to be at increased risk for fracture years)19 was also the basis for recommending screening for hypothy-
based on FRAX, perceived to have osteoporosis on the basis of DEXA roidism every 1 to 2 years.
measurement, or both, often receive bisphosphonates, which have Adults with Down syndrome benefit from receiving care from
potential adverse effects. If causes of osteoporosis in Down syn- clinicians familiar with common behaviors, which might otherwise

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

Box 2. Future Research Priorities (Abbreviated)a Box 2. (continued)

Osteoporosis
Behavior
Create a standardized assessment tool specific to people with Describe the unique epidemiology of skeletal fracture in people
Down syndrome to help further evaluate co-occurring medical with Down syndrome and determine optimal prevention,
conditions associated with psychiatric and behavioral issues screening, and treatment strategies

Review if existing tools validated in and treatments effective for Review the comparative effectiveness of medications and other
people with IDD are useful in people with Down syndrome interventions for prevention and treatment of osteoporotic
fracture in adults with Down syndrome
Identify potential mental health risk factors, protective factors,
or both in adults with Down syndrome Create a screening tool or test for assessing risk for skeletal
fracture in people with Down syndrome
Dementia
Thyroid Disease
Research prevalence and clinical emergence of age-related
dementia symptoms in adults with Down syndrome Determine the precise thyrotropin level at which problems
manifest and over what time frame these can be corrected
Expand and validate the use of available biomarkers into clinical with treatment
practice to help inform diagnosis and decision-making
Research the clinical application of predictive biologic markers
Further validate and refine existing dementia screening tools for (antithyroid antibodies) and the discovery of new markers
adults with IDD, including expanding their repertoire of application (proteomic and molecular DNA) that predate disease in people
and usefulness in different settings with Down syndrome
Diabetes Explore the role of autoimmune thyroid disease and the clustering
Research whether early treatment of type 2 diabetes reduces the effect of autoimmune conditions seen in people without Down
extent of tissue and end-organ damage to reduce or prevent syndrome to determine if hypothyroidism in Down syndrome
long-term complications in Down syndrome could potentially indicate a higher risk of other autoimmune
Determine the prevalence of type 1 and type 2 diabetes in adults conditions more common in this population
with Down syndrome Celiac Disease
Identify genetic and/or immunological risk factors for diabetes in Describe specific HLA antigen types and risks for developing auto-
Down syndrome immune disorders in adults with Down syndrome

Cardiovascular Disease Correlate HLA antigen type with tTG-IgA levels and small-bowel
Evaluate modifiable risk factors for atherosclerotic disease in biopsy results in adults with Down syndrome
adults with Down syndrome and better understand which risk Compare magnitudes of tTG-IgA values to help define cutoffs
factors identified are relevant for this population regarding disease more appropriate for adults with Down syndrome. Formalize a
prevention diagnostic protocol for celiac disease in Down syndrome
Identify strategies to prevent stroke in adults with congenital heart Abbreviations: AAI, atlantoaxial instability; HLA, human leukocyte antigen;
disease and the potential impact of lowering lipid levels for stroke IDD, intellectual and developmental disability; tTG-IgA, tissue
prevention transglutaminase IgA.
Determine the prevalence of atherosclerotic cardiovascular disease a
For a complete list of all future research priorities, see eTable 3 in
and myocardial infarctions in people with Down syndrome Supplement 1.

Obesity
Study impact of leptin and ghrelin hormonal circuitries, whose
dysregulation could affect appetite control in Down syndrome
be mistaken as indicative of pathology. Recommendations 1 and 2
highlight the importance of referral to an experienced clinician and
Determine what weight loss strategies (including medications) are
effective in people with Down syndrome, including what
use of tools designed for individuals with intellectual and develop-
modifications or adaptations to existing fitness strategies better mental disabilities if concerns for mental health disorders such as
manage weight and appetite regulation depression, anxiety, or regression arise.
Identify the effects of obesity in people with Down syndrome and Although prevalence of AAI was found to be approximately 10%,
the potential health benefits of weight no studies assessed whether screening using cervical radiographs
allows identification of otherwise asymptomatic individuals at risk
Atlantoaxial Instability
Research the symptomatic true incidence of AAI in adults with
for SCI. Participation in physical activities offers highly desirable, po-
Down syndrome, what factors are predictive of the future tential physical and psychological benefits. In the absence of other
development of symptoms, and what interventions are best at evidence, reports from Special Olympics organizers of no SCI over
preventing spinal cord injury the past 20 years was considered. After considering the potential
Determine the comparative impact on morbidity and mortality of benefits and harms (including SCI), a weak recommendation was
conservative (watchful waiting) vs surgical intervention of AAI made against cervical spine radiography for screening asymptom-
Study compliance of medical professionals to universal precaution atic individuals, reasoning that no evidence suggests that cervical
of proper neck positioning for people with Down syndrome during spine radiographs are helpful, whereas restricting patients from
medical procedure, treatment, or recovery physical activity has known harms.
(continued) In some cases for which no evidence was identified, aspects of
care many would consider standard were highlighted. To accom-
plish this, 4 SOGPs were formulated pertaining to mental health

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 Clinical Review & Education Special Communication Medical Care of Adults With Down Syndrome—A Clinical Guideline

disorders (SOGP 1 and SOGP 2), healthy practices for obesity PICO questions were formulated to identify whether sufficient evi-
(SOGP 3), and assessment for signs/symptoms of celiac disease at dence justified alterations to existing guidance for the general popu-
annual examinations (SOGP 4) (Table 1). Based on identified evi- lation (eg, initiating screening earlier based on higher prevalence at
dence gaps, key priorities for future research across each clinical do- earlier age). Although the Evidence-to-Decision framework is typi-
main were identified (Box 2; eTable 3 in Supplement 1). cally used for interventions, using this framework provided a trans-
parent, systematic process for considering benefits, harms, and other
Limitations important factors in drafting clinical guidance.
The guideline development process had several limitations. First, lim-
ited evidence meant recommendations were often based on little,
indirect, or low-quality evidence. However, it is important to pro-
Conclusions
vide guidance where possible, despite very low-quality evidence, as
others have affirmed.63 Second, recommendations for screening in- These evidence-based practice guidelines provide recommenda-
terventions would ideally be based on clinical trials that demon- tions to support primary care of adults with Down syndrome. The
strated that screening resulted in better clinical outcomes. How- lack of high-quality evidence limits the strength of the recommen-
ever, because it was anticipated that the evidence would be limited, dations and highlights the need for additional research.

ARTICLE INFORMATION Bulova, Capone, Gelaro, Harville, Peterson, Tyler, Cincinnati Children’s Hospital Medical Center,
Accepted for Publication: September 1, 2020. Wells, Whitten. Cincinnati, Ohio); Jarrett Barnhill (University of
Supervision: Tsou, Capone, Chicoine, Gelaro, North Carolina, Chapel Hill). Dementia Committee:
Author Affiliations: Evidence-Based Practice McKelvey, Whitten. Lead authors: George Capone (Johns Hopkins
Center, ECRI Center for Clinical Excellence and School of Medicine, Baltimore, Maryland); Brian
Guidelines, Plymouth Meeting, Pennsylvania Conflict of Interest Disclosures: Dr Capone
reported receiving grants from the LuMind Chicoine (Advocate Medical Group Adult Down
(Tsou); Division of Neurology, Michael J. Crescenz Syndrome Center, Park Ridge, Illinois); Dennis E.
Veterans Affairs Medical Center, Philadelphia, Foundation and serving on the board of directors of
the Down Syndrome Medical Interest Group–USA McGuire; Coauthors: Bryn Gelaro (Global Down
Pennsylvania (Tsou); University of Pittsburgh Syndrome Foundation); Volunteers: Seth M. Keller
Medical Center, Pittsburgh, Pennsylvania (Bulova); (DSMIG-USA), the steering committee of the Down
Syndrome International Health Guideline Project, (Virtua Health, New Jersey); Ira T. Lott (University
Down Syndrome Clinic and Research Center, of California, Irvine). Diabetes Committee: Lead
Kennedy Krieger Institute, Baltimore, Maryland the clinical and scientific advisory board of the
National Down Syndrome Society, and the authors: Moya Peterson (University of Kansas
(Capone); Johns Hopkins School of Medicine, Medical Center, Kansas City); Brian Chicoine
Baltimore, Maryland (Capone); Advocate Medical executive committee of the LuMind Down
Syndrome–Clinical Trials Network. Dr Chicoine (Advocate Medical Group Adult Down Syndrome
Group Adult Down Syndrome Center, Park Ridge, Center, Park Ridge, Illinois); Volunteers: Stephanie
Illinois (Chicoine); Global Down Syndrome reported receiving personal fees from Woodbine
House Publishing, serving as the current treasurer L. Santoro (Massachusetts General Hospital,
Foundation, Denver, Colorado (Gelaro, Whitten); Boston); Mary M. Stephens (Christiana Care Health
Division of Hematology, Department of Pathology of DSMIG-USA, the clinical advisory board for the
National Down Syndrome Society, and the System, Wilmington, Delaware). Cardiovascular
and Laboratory Services, Department of Internal Committee: Lead authors: Peter Bulova (University
Medicine, University of Arkansas for Medical executive committee of the LuMind Down
Syndrome–Clinical Trials Network. Drs Bulova, of Pittsburgh Medical Center, Pittsburgh,
Sciences, Little Rock (Harville); Division of General Pennsylvania); Brian Chicoine (Advocate Medical
Internal Medicine, University of Colorado School of Capone, Chicoine, Martin, McGuire, McKelvey, and
Peterson and Mss Gelaro and Whitten are current Group Adult Down Syndrome Center, Park Ridge,
Medicine, Anschutz Medical Center, Aurora Illinois); Barry A. Martin (University of Colorado
(Martin); Private Practice, Evanston, Illinois members of the DSMIG-USA. No other authors
reported disclosures. School of Medicine, Aurora); Volunteers: Robert H.
(McGuire); University of Arkansas for Medical Eckel (University of Colorado, Anschutz Medical
Sciences, Little Rock (McKelvey); University of Funding/Support: This work was funded and Campus, Aurora); Elizabeth Yeung (University of
Kansas Medical Center Schools of Nursing and supported by the Global Down Syndrome Colorado, Anschutz Medical Center and Children’s
Medicine, Kansas City (Peterson); Developmental Foundation (GLOBAL; a 501 c3 nonprofit Hospital Colorado, Aurora). Obesity Committee:
Disabilities—Practice-Based Research Network, organization dedicated to improving the lives of Lead authors: Peter Bulova (University of
Cleveland, Ohio (Tyler, Wells); Family Medicine and people with Down syndrome through research, Pittsburgh Medical Center, Pittsburgh,
Community Health, Cleveland Clinic Lerner College medical care, education, and advocacy) and by Pennsylvania); George Capone (Johns Hopkins
of Medicine, Case Western Reserve University generous donations from the Down syndrome School of Medicine, Baltimore, Maryland); Moya
School of Medicine, Cleveland, Ohio (Tyler). community (Supplement 1). No government Peterson (University of Kansas School of Medicine,
Author Contributions: Drs Tsou and Capone had funding supported the work. Kansas City); Volunteers: Judy L. Kim (Baylor
full access to all of the data in the study and take Role of Funder/Sponsor: GLOBAL determined the College of Medicine, Houston, Texas); Joan Medlen;
responsibility for the integrity of the data and the need for updated, evidence-based guidelines, Kamala G. Cotts (University of Chicago, Chicago,
accuracy of the data analysis. contracted ECRI, recruited the Workgroup, and Illinois). Atlantoaxial Instability Committee: Lead
Concept and design: Tsou, Bulova, Capone, provided organizational, administrative, and authors: Barry A. Martin (University of Colorado
Chicoine, Gelaro, Martin, McKelvey, Peterson, Tyler, financial support including fundraising. ECRI and School of Medicine, Aurora); Moya Peterson
Wells, Whitten. the author Workgroup designed, managed, (University of Kansas Medical Center, Kansas City);
Acquisition, analysis, or interpretation of data: Tsou, analyzed the data. The author Workgroup Volunteers: James E. Hunt (University of Arkansas
Capone, Chicoine, Gelaro, Harville, Martin, McGuire, interpreted the data, prepared and approved of the for Medical Sciences and Arkansas Children’s
McKelvey, Peterson, Tyler, Wells, Whitten. manuscript, and decided to submit the manuscript Hospital, Little Rock); Paul J. Camarata (University
Drafting of the manuscript: Tsou, Bulova, Capone, for publication. of Kansas School of Medicine, Kansas City); Mary M.
Harville, Martin, McGuire, McKelvey, Peterson, Global Down Syndrome Foundation Medical Care Stephens (Christiana Care Health System,
Tyler, Wells. Guidelines for Adults With Down Syndrome Wilmington, Delaware). Osteoporosis Committee:
Critical revision of the manuscript for important Workgroup: Behavior Committee: Lead authors: Lead authors: Kent D. McKelvey (University of
intellectual content: Tsou, Bulova, Capone, George Capone (Johns Hopkins School of Medicine, Arkansas for Medical Sciences, Little Rock); Carl
Chicoine, Gelaro, Harville, Martin, McKelvey, Baltimore, Maryland); Dennis E. McGuire; Tyler (Cleveland Clinic Lerner College of Medicine
Peterson, Tyler, Wells, Whitten. Coauthors: Bryn Gelaro (Global Down Syndrome and Case Western Reserve University School of
Obtained funding: Gelaro, Whitten. Foundation); Volunteers: Anna J. Esbensen Medicine, Cleveland, Ohio); Coauthors: Michael D.
Administrative, technical, or material support: Tsou, (University of Cincinnati College of Medicine and Wells (Developmental Disabilities–Practice-Based

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 Medical Care of Adults With Down Syndrome—A Clinical Guideline Special Communication Clinical Review & Education

Research Network); Volunteers: Micol Rothman Department of Defense Guidelines for Stroke 21. Cerqueira RM, Rocha CM, Fernandes CD,
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Campus, Aurora). Thyroid Committee: Lead Manual appendix VI: criteria for assessing internal 1097/MEG.0b013e3283328341
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