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).