Medical care of adults with down syndrome: a clinical guideline

Importance: Down syndrome is the most common chromosomal condition, and average life 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 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 additional research

Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment.

Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients' age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population

Efficacy of intermittent PTH in WT vs. Ts65Dn mice.

<p>Male mice (N = 6–8 per group) were given daily injections of vehicle or 30 or 80 ug/kg PTH(1–34) for 4 weeks. (<b>A</b>) BMD was measured at the beginning and end of the experiment. (open squares, WT; closed circles, Ts65Dn). Dotted lines show BMD of vehicle treated animals, dashed lines, 30 ug/kg PTH; solid lines, 80 ug/kg PTH (<b>B</b>) % bone volume/tissue volume (BV/TV), trabecular number (Tb.N.) and trabecular thickness (Tb.Th.) were determined in the tibia (open bars WT; solid bars Ts65Dn). Representative superior view of a transverse micro-CT images of the trabecular bone from the proximal tibia of representative animals in each group are shown. (<b>C</b>) Micro CT measurements of the effects of PTH treatment on cortical thickness, periosteal perimeter and endocortical perimeter in the distal tibia were performed (open bars WT; solid bars Ts65Dn). *, p<0.05 vs. respective vehicle control; #, p<0.05 vs. WT vehicle.</p

Histomorphometric measurement of bone formation and bone resorption following intermittent PTH in WT and Ts65Dn mice.

<p>Male mice (N = 6–8 per group) were given daily injections of vehicle or 30 or 80 ug/kg PTH(1–34) for 4 weeks. (<b>A</b>) Mineral apposition rate (MAR) (um³/um²/day), (<b>B</b>) Bone formation rate/bone surface (BFR/BS) (um³/um²/day), (<b>C</b>) Number of osteoblasts/bone perimeter (N.Ob./B.Pm), (<b>D</b>) Number of osteoclasts/bone perimeter (N.Oc./B.Pm.) were measured in WT and Ts65Dn mice vehicle or PTH treated (30 or 80 ug/kg/day) (open bars, WT; closed bars, Ts65Dn). *, p<0.05 vs. respective vehicle control; #, p<0.05 vs. WT vehicle.</p

Osteoclast and osteoblast formation is significantly decreased in 3 month old Ts65Dn Mice.

<p>(<b>A</b>) <i>Ex vivo</i> recruitment into the osteoblast lineage was measured at culture day 10 by staining for alkaline phosphatase (AP) and counting the number of AP+ colony forming units (CFU-F) per well. (<b>B</b>) <i>Ex vivo</i> osteoblast differentiation was assessed at culture day 28 by staining mineralized bone nodules containing differentiated colonies of osteoblasts (CFU-OB) with Alizarin Red and the number of CFU-OB per well enumerated. (<b>C</b>) <i>Ex Vivo</i> osteoclast differentiation was assessed by staining on day 14 for tartrate resistant acid phosphatase (TRAP) and the number of TRAP+-multinucleated cells per well counted. *, p<0.05 vs. WT vehicle control.</p