Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology

Abstract

Although first identified over 70 years ago, Klinefelter syndrome (KS) continue to pose significant diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed.In fact, as few as 25% of KS patients are accurately diagnosed, and most of these diagnoses are not made until adulthood.Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment.However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role.For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype.KS is also associated with more general health markers, including higher morbidity and mortality rates, and lower socio-economic status (which likely affects both morbidity and mortality).In addition, hypogonadism is associated with greater risk of of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors.Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy has not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes.This review presents a comprehensive, interdisciplinary examination of recent developments in genetic, endocrine and neurocognitive science, including the study of animal models regarding KS.It also provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence. Essential points:1. Identification of KS is more difficult than previously anticipated, with only a fraction (25-40%) of cases accurately diagnosed.This has broad implications for the interpretation of research literature and the effectiveness of clinical practice.More accurate KS diagnoses are unlikely with current clinical approaches, and we suggest incorporation of KS in neonatal screening programs.2. KS is associated with a globally changed DNA methylation profile, with large areas of hypermethylation and, to a lesser degree, hypomethylation.More subtle differential RNA expression extending far beyond the supernumerary X chromosome is also present.These findings suggest the importance of linking phenotypical and genotypical components of KS. 3. Morbidity and mortality is increased from a wide variety of diagnoses, many that are not easily reconciled to the known KS phenotype or effects of hypergonadotropic hypogonadism.Poor socioeconomic status explains part of the increased morbidity and mortality.