Clinical Research Directory

Long-term Systematic Follow-up of Patients With Klinefelter Syndrome Followed at the Department of Growth and Reproduction, Rigshospitalet

Klinefelter syndrome (KS) is the most frequent sex chromosome disorder affecting approximately 1:660 newborn boys. The prevalence of KS rises to 3-4% among infertile males and 10-15% in patients with non-obstructive azoospermia. KS is highly underdiagnosed, and diagnosis is often delayed. Phenotypic variability, and especially a presentation with mild clinical features, often leads to diagnostic delay or non-diagnosis. It has been estimated that 50-75% of males with KS never obtain a diagnosis (Berglund et al., 2019; Bojesen et al., 2003). Despite increasing interest in studying KS during recent years there remain significant gaps in our overall understanding of KS, including when and how to start testosterone replacement therapy (TRT), how to prevent co-morbidities, mechanisms of complications, success of fertility preservation and assessment of quality of life in affected individuals. This translates into differences in standards of care for these patients, with substantial variability in clinical practice. International guidelines regarding the care of patients with KS were published by the European Academy of Andrology/European Society of Endocrinology in 2021 (Zitzmann et al., 2021) to improve the clinical care of these patients. These guidelines, however, are limited by a general lack of scientific evidence due to the low number of studies in the field. This increases the need to systematically collect more information to develop individualized and optimized care for future patients. The investigators therefore aim to systematically describe the phenotype of Klinefelter syndrome throughout life by collecting clinical, biochemical, genetic, and radiological data on reproductive development, fertility, anthropometry, bone age, body composition, bone mineralization, co-morbidities, biomarkers of general health as well as psychopathology and mental health. Hypotheses: 1. Patients with KS may differ from controls in their biological health profile (hormonal, thyroid, metabolic, inflammatory, genetic, and epigenetic) which may affect their lifestyle and alter disease risk. Detailed knowledge about such alterations and at what age they appear may facilitate more individualized and optimized treatment regimens with the goal to prevent co-morbidities. 2. Hypertension, bradycardia and long QTc may be more frequently present in adults with KS. The investigators hypothesise that both blood pressure and electro cardiograph (ECG) are normal in childhood and adolescence. Knowledge about the mechanisms behind these phenomena and when they appear will help us in understanding the biological mechanism and in optimizing preventive interventions. 3. Men with KS are taller than their genetic potential. This may at least in part be attributed to an increased growth velocity through childhood before puberty. 4. Genetic and epigenetic alterations may explain the phenotypic variability and the associated co-morbidities may be caused by such alterations. 5. Virilization (penis length and width, pubic hair development, voice frequency) is impaired in adolescents and adults with KS. 6. Patients with KS face a greatly increased risk of being affected by psychopathology such as attention deficit and hyperactivity disorder (ADHD) and depression. In addition to the clinically observable lack of energy (fatigue) and social withdrawal, this may affect quality of life, and impact long-term mental health. Learning more about the factors supporting mental health in boys and men with KS will significantly advance our chances of alleviating these common complaints and preventing long-term complications. 7. Patients with KS may have distinct facial characteristics. Knowledge about such characteristics may increase the likelihood of identifying patients with KS and thereby improve the diagnostic delay. Data Collection The data base will consist of clinical and biochemical data and results obtained at the routine control visits and admittance at a hospital. Data will be collected both retrospectively (from the medical record) and prospectively. Retrospective data from the medical record will include data collected at previous visits at the Department of Growth and Reproduction (e.g. anthropometry, Dual-Energy X-ray Absorptiometry (DXA) scans, bone age (including bone health index (BHI), hormone concentrations, karyotype, biomarkers of general health, blood pressure, pulse, semen quality, results of micro testicular sperm extraction (TESE) and testicular histology as well as medical treatment in general and other diagnoses/co-morbidity).

Parent and Infant Inter(X)Action Intervention (PIXI)

The objective is to develop and test, through an iterative process, an intervention to address and support the development of infants with a confirmed diagnosis of a neurogenetic disorder with associated developmental delays or intellectual and developmental disabilities. The proposed project will capitalize and expand upon existing empirically based interventions designed to improve outcomes for infants with suspected developmental delays. Participants will be infants with a confirmed diagnosis of a neurogenetic disorder (e.g., fragile X, Angelman, Prader-Willi, Dup15q, Phelan-McDermid, Rhett, Smith Magenis, Williams, Turner, Kleinfelter, Down syndromes, Duchenne muscular dystrophy) within the first year of life and their parents/caregivers. The intervention, called the Parent and Infant Inter(X)action Intervention (PIXI) is a comprehensive program inclusive of parent education about early infant development and the neurogenetic disorder for which they were diagnosed, direct parent coaching around parent-child interaction, and family/parent well-being support. The protocol includes repeated comprehensive assessments of family and child functioning, along with an examination of feasibility and acceptability of the program.

Thyroid Function and Structure in Klinefelter Syndrome

This is a longitudinal retrospective study for the evaluation of thyroid function and structure in patients with Klinefelter syndrome compared to healthy controls and patients affected by chronic lymphocytic thyroiditis.

Klinefelter Syndrome and Testosterone Treatment in Puberty

The goal of this randomized clinical trial is to study the effect of testosterone replacement therapy during puberty in boys with Klinefelter syndrome (KS, 47,XXY). The main questions to answer are how treatment with testosterone will affect body fat mass, lipid and glucose metabolism, growth and body proportions, bone mineralization as well as effects on neurocognitive development and emotional and social difficulties. Participants will be randomized to two years treatment with testosterone or placebo.

Interrogating Fatty Acid Metabolism Impairment and Clinical Correlates in Males with Klinefelter Syndrome

This study will learn more about how the body uses energy. Usually, the body uses sugars as energy first and then fats are used when the sugar stores are gone. Some people have trouble using fats as energy. This can lead to feeling tired, difficulty exercising, and storing too much fat where it does not belong (like in the muscle). It is believed that some boys and men with Klinefelter Syndrome may not be able to use fats as energy normally, and that a medication called fenofibrate could help this.

The eXtroardinarY Babies Study: Natural History of Health and Neurodevelopment in Infants and Young Children With Sex Chromosome Trisomy

This study is designed to research the natural history of neurodevelopment, health and early hormonal function in infants with XXY/Klinefelter syndrome, XYY, XXX and other sex chromosome variations in an effort to identify early predictors of developmental and health outcomes. The Investigators will also evaluate different developmental screening tools in infants with sex chromosome variations so the investigators can develop recommendations for pediatrician caring for infants and young children with XXY/Klinefelter syndrome, XYY, XXX, and other sex chromosome variations.

Growing up With the Young Endocrine Support System (YESS!)

Transition from paediatric to adult endocrinology is a challenge for adolescents, families and doctors. Up to 25% of young adults with chronic endocrine disorders are lost to follow-up ('drop-out') once the young adult moves out of paediatric care. Non-attendance and sub-optimal medical self-management can lead to serious and expensive medical complications. In a pilot study, adolescents suggested the use of e-technology to become more involved in the transition process. The investigators have designed and developed the YESS! game, a tool to help improve medical self-management in adolescents with chronic endocrine disorders. The hypothesis is that adolescents playing the YESS! game will show a larger increase in self-management score during the first year of transition and will have a lower drop-out rate at the adult endocrine outpatient clinic (OPC), compared to adolescents who do not play the game.