Blythe G. Crissman

Clinical trials in children with Down syndrome: issues from a cognitive research perspective.

Clinical and translational research play a key role in the transition of basic research discoveries to effective therapies. In Down syndrome (DS), these research approaches are not well utilized or developed to test new therapies to improve cognitive and/or adaptive function in this population. This article reviews the history of clinical trial research in children with DS from a cognitive research perspective and discusses important issues relevant to the conduct of well designed clinical trials for this population. Specific issues addressed include: funding, study design, study medication, subject recruitment and retention, safety, and efficacy challenges. The Duke Down Syndrome Research Teams program of clinical research of cholinesterase inhibitors for individuals with DS serves as the model application for the identified research principles. It is hoped that this article will raise awareness of the unmet need for clinical research in the cognitive and adaptive function of individuals with DS, especially children with DS.

Safety and Efficacy of Rivastigmine in Adolescents with Down Syndrome: Long-Term Follow-Up

Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.

The accuracy of photoscreening at detecting treatable ocular conditions in children with Down syndrome

BACKGROUND Children with Down syndrome (DS) have an increased prevalence of ocular disorders, including amblyopia, strabismus, and refractive error. Health maintenance guidelines from the Down Syndrome Medical Interest Group recommend ophthalmologic examinations every 1 to 2 years for these children. Photoscreening may be a cost-effective option for subsequent screening evaluations after an initial complete examination, but no study has evaluated the accuracy of photoscreening in children with DS. The purpose of this study is to determine the sensitivity, specificity, and positive and negative predictive values of photoscreening in detecting treatable ocular conditions in children with DS. METHODS Photoscreening and complete ophthalmologic evaluations were performed in 50 consecutive 3- to 10-year-old children with DS. Sensitivity, specificity, and positive and negative predictive values were calculated with the use of ophthalmologic examination findings as the reference standard. RESULTS Most children were able to complete photoscreening (94% with Medical Technology and Innovations [MTI] and 90% with Visiscreen OSS-C [VR]). Many children had an identified diagnosis on ophthalmologic examination (n = 46, 92%). Of these, approximately one-half (n = 27, 54%) had one or more condition(s) requiring treatment. Both the MTI and VR photoscreening devices had a sensitivity of 93% (95% confidence interval 0.76-0.99) for detecting treatable ocular conditions. The specificities for the MTI and VR photoscreening were 0.35 (0.18-0.57) and 0.55 (0.34-0.74), respectively. CONCLUSIONS Photoscreening is sensitive but less specific at detecting treatable ocular conditions in children with DS. In specific instances, the use of photoscreening in the DS population has the potential to save time and expense related to routine eye examinations, particularly in children with a normal baseline comprehensive examination.

Prevalence of Iron Deficiency in Children with Down Syndrome

OBJECTIVES To determine the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) in a sample of children with Down syndrome (DS) and to evaluate the effect of macrocytosis on the diagnosis of ID/IDA in these children. STUDY DESIGN Children with DS ≥ 12 months of age who were followed at the Duke University Medical Center Comprehensive DS Clinic from December 2004 to March 2007 were screened for ID/IDA with a complete blood count, reticulocyte count, iron panel, and erythrocytic protoporphyrins. RESULTS A total of 114 children were enrolled, with a median age of 4.7 years. ID was identified in 12 subjects (10%), and IDA was identified in 3 subjects (3%). ID/IDA would not have been accurately diagnosed in 13 of 15 subjects (86%) if red blood cell (RBC) indices alone had been used for screening. Abnormal RBC indices with low transferrin saturation were 100% sensitive for ID/ IDA screening. CONCLUSIONS Prevalence of ID/IDA in children with DS was comparable with that in the general pediatric population. Macrocytosis had implications for screening of ID/IDA with only RBC indices. We suggest ID/IDA screening in DS children be done with a laboratory panel at least including complete blood count, reticulocyte count, transferrin saturation, and serum ferritin.

Hypothyroidism in Down Syndrome: Screening Guidelines and Testing Methodology

Individuals with Down syndrome (DS) are at an increased risk of developing thyroid disease, primarily autoimmune, with a lifetime prevalence ranging from 13% to 63% [Mattheis, 1997]. Fort et al. [1984] also found congenital hypothyroidism to be about 28 times more common among infants with DS than in the general population with an incidence of 1% (0.7% permanent and 0.3% transient congenital hypothyroidism) detected by newborn screening. Beyond the newborn period, the incidence of elevated TSH values in DS increases and has been reported to be as high as 85% of infants under the age of 12 months [Sharav et al., 1988]. This is a treatable cause of mental retardation, thus early detection and treatment are essential in order to maximize cognitive abilities in this already impaired population. Unfortunately, there are few studies systematically examining the frequency of thyroid disease in very young children. Current health supervision guidelines for children with DS suggest reviewing results of the newborn thyroid function screen, then repeating thyroid function tests at the age of 6 months and 12 months, and then annually [Cunniff et al., 2001].

Down Syndrome Disintegrative Disorder New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome

Over a 10-year period in a Down syndrome Clinic, 11 children and adolescents were encountered with a history of new-onset (8) or worsening (3) autistic characteristics. Ten of the 11 (91%) had cognitive decline to a dementia-like state and 9 of the 11 (82%) new-onset insomnia. The mean age at which symptoms developed was 11.4 years (standard deviation = 3.6 years; range 5-14 years), an older age than usual for autistic regression in Down syndrome. Ten of 11 cases (91%) had elevated (“positive”) thyroperoxidase antibody titers compared to only 5 of 21 (23%) age-matched control subjects with Down syndrome (P < .001). At follow-up at a mean age of 20.7 years (standard deviation = 3.9 years), 8 of the 11 (73%) were at least somewhat better. Down syndrome disintegrative disorder seems an appropriate name for this newly recognized clinical association, which may be due to autoimmunity.

National Down Syndrome Patient Database: Insights From the Development of a Multi-Center Registry Study

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced‐based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co‐occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.

Current perspectives on Down syndrome: Selected medical and social issues†

Individuals with Down syndrome (DS) have multiple malformations and have cognitive impairments due to the presence of extra genetic material from chromosome 21. With medical advances, along with improvements in overall care, the median age of death of individuals with DS has increased from 25 years old in 1983 to 1949 years old in 1997 [Yang et al., 2002]. This longer life expectancy is providing clinicians with a better understanding of the natural history and the emerging needs of the individual over the lifespan. Since the last Supplement of the American Journal of Medical Genetics entitled Trisomy 21 (DS) was published in 1990, there have been many advances in the field. The sequencing of human chromosome 21 has resulted in identification of more than 400 genes on its long arm. Although the genes have been sequenced, defining their roles, functions, and interactions with other genes and the environment will increase our knowledge of the complex phenotype. Understanding the role of genes involved in biochemical/cellular pathways that are relevant to cognition in people with DS will guide future research. To put this Seminars issue in historical prospective, it is necessary to review briefly the two interwoven strands that together constitute the recent history of DS: the Civil Rights movement for people with disabilities, in which advocacy for people with DS has played an important part, and advances in medical understanding. Table I presents Legislative and Social Milestones in the Civil Rights Movement for people with DS. Throughout most of history, persons with disabilities have been largely excluded from society, usually living in isolation with their families. Beginning in the 1920s and continuing until the 1960s, parents of children with DS were strongly encouraged by physicians and by society to ‘‘place’’ their children in institutions. This drive to institutionalize people with cognitive disabilities was a part of the Eugenics Movement. The Eugenics Movement had as its main premise that the ‘‘race’’ could be ‘‘improved’’ by preventing ‘‘unfit’’ individuals from ‘‘propagating.’’ It reached its culmination in Nazi Germany, with the systematic extermination of people with disabilities, including people with DS, beginning in 1939. AfterWorldWar II, the Nuremberg Trials of Nazi war criminals established in international jurisprudence, the legal principle that everyone in a society is only as safe as the most vulnerable member of the society, providing a legal precedent for protecting people with disabilities. By the 1960s, it was recognized that institutionalization was brutalizing for many people. Stedman and Eichorn [1964] compared institutionalized and homereared children with DS and demonstrated that home-reared children developed better. In the 1960s and 1970s, the Civil Rights movement for people with disabilities began and flourished. Institutions no longer accepted as many children with disabilities and many adults were ‘‘deinstitutionalized’’ (discharged from institutions). In 1973, the National Down Syndrome Congress (NDSC) was established, and then in 1979, the National Down Syndrome Society (NDSS) was established, both providing support, information, and advocacy for individuals with DS and their families [Cooley and Graham, 1991]. Legislation (PL 94–142) began the transformation of educational services for children with disabilities by rejecting the concept of educational Assistant Guest Editor. Blythe G. Crissman,M.S., CGC is a genetic counselor in the Department of Pediatrics at Duke University Medical Center. She serves as the primary genetic counselor and clinic coordinator of the Duke Comprehensive Down syndrome clinic, and is a clinical research coordinator for the Duke Down syndrome research team. GordonWorley, M.D. is a clinical Professor of Pediatrics and the Director of the Program in Developmental Disabilities at Duke University Medical Center. He has cared for children with Down syndrome in the Duke University Comprehensive Down syndrome clinic since its inception. His research interests pertain to the medical problems of children with disabilities. Nancy Roizen, M.D. is the Chief of the Department of Developmental and Rehabilitation Pediatrics at the Cleveland Clinic Children’s Hospital for Rehabilitation. Her interests include hearing loss and autism in children with Down syndrome. Guest Editor. Priya S. Kishnani, M.D. is an associate Professor of Pediatrics and the Director of Clinical Trials in the Division of Medical Genetics at Duke University Medical Center. Her primary focus has been the translation of laboratory science into the clinic arena, to advance clinical care. She has been the coDirector of the Duke Comprehensive Down syndrome clinic with Dr. Worley since 1995. *Correspondence to: Priya S. Kishnani, M.D., Pediatrics—Division of Medical Genetics, Duke University Medical Center, 237 Bell Bldg., Trent Drive, Durham, NC 27710. E-mail: kishn001@mc.duke.edu DOI 10.1002/ajmg.c.30099

Thyroid dysfunction in patients with Down syndrome: Results from a multi-institutional registry study

The goals of this undertaking were to assess the outcomes of thyroid screening tests and adherence to thyroid screening guidelines across five Down syndrome (DS) specialty clinics in various states. Data related to thyroid screening were collected for 663 individuals across five clinics specializing in the comprehensive care of individuals with DS for a period of 1 year. Of the 663 participants, 47.7% of participants had a TSH and free T4 ordered at their DS specialty clinic visit. Approximately 19.0% (60/316) had a new thyroid disorder diagnosis made. We conclude that a sizable proportion of the patients with DS are not up‐to‐date on current guidelines when they present to a DS specialty clinic, while adherence to thyroid screening guidelines helps facilitate early diagnoses. Hypothyroidism is prevalent in the population, consistent with reported literature. DS specialty clinics can help patients stay current on screening guidelines.

Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co‐occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight‐obesity, sleep apnea, congenital heart disease, and osteopenia‐osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision‐making and management of these medically complex individuals. The development of evidence‐based clinical guidance will require an expanded clinical knowledge‐base in order to move forward.