NICHD Klinefelter Syndrome (KS) Research Information

NICHD has a long history of supporting research to learn more about KS. Early research included a study that examined the cells of more than 40,000 infants for extra X chromosomes. NICHD-supported research has also explored topics including the roles of sex chromosomes in development; symptoms that arise in KS, such as infertility, low testosterone, and problems with language, learning, and behavior; and how best to treat males with these symptoms. Among the areas of research that hold hope for more successful intervention and prevention in Klinefelter syndrome are studies in the following areas:

• Genetics of KS. The full extent of the role of the X chromosome in development is not well understood. NICHD research into disorders of the X chromosome, such as Klinefelter, Turner, and Fragile X syndromes, will reveal more about how this chromosome functions and, ultimately, how to prevent or treat symptoms in individuals with an atypical number of X chromosomes. NICHD research also aims to improve understanding of processes that can go wrong in male germ cells before fertilization or right after it, when chromosomes conjugate and divide and can leave the resulting gamete with an unusual number of sex chromosomes.
• Pathophysiological mechanisms of KS. KS alters hormonal balance, especially reducing testosterone levels, and exactly how this leads to infertility is unclear. Researchers are studying the mechanisms behind sperm creation and how Leydig cells function, which could identify interventions that may help preserve or restore fertility in males with KS. Investigations also include those on gonadotropin-regulated genes involved in the progression of testicular gametogenesis, Leydig cell function, and other endocrine processes.
• Treatment strategies for KS. Research on early interventions has successfully limited the development and severity of symptoms in KS. NICHD is gathering evidence to identify the best interventions for learning disabilities, osteoporosis (later in life), and infertility—all symptoms of KS.

Institute Activities and Advances

KS can influence many aspects of a person’s entire life, starting very soon after conception. Therefore, many branches, sections, and laboratories at NICHD conduct research that is relevant to males with XXY or poly-KS variations.

Investigating Sex Hormones

KS arises from an unusual number of sex chromosomes, so research into sex chromosomes is important to finding ways to prevent or one day cure KS. Several components of the Division of Intramural Research are studying these types of problems. The Section on Epigenetics and Development is studying how X chromosome genes influence brain, reproductive, metabolic, and immune system development. The Section on Gamete Development is studying the fruit fly for insight into early gamete cell division and how an additional X chromosome can become included. Other scientists are examining the formation of male germ cells, which are present before and after fertilization and can contain an extra X. In the Section on Clinical Genomics, scientists apply information gained from biochemical and genomic studies to clinical investigations while also studying the biomechanical mechanisms that may contribute to genetic disorders.

Understanding KS Symptoms and Preventing or Treating Them

Infertility is a key symptom in KS and many researchers at NICHD are involved in improving understanding of how sperm production fails, starting from early in development. In the Section on Clinical Genomics, scientists developed mouse models to analyze proteins that may be key in sperm production. Other research aims to explain the network of genes involved in the renewal and differentiation of spermatogonial stem cells, meiosis, and the post-meiotic differentiation of germ cells. Researchers are also exploring mechanisms behind sperm creation and the function of Leydig cells, which produce testosterone in the presence of luteinizing hormone, and searching for new gonadotropin-regulated genes involved in testicular gametogenesis, Leydig cell function, and other endocrine processes that are disrupted in KS.

Aside from infertility, scientists are working to find ways to treat other symptoms associated with KS. The Child Development and Behavior Branch (CDBB) is examining the behavioral, neurobiological, and genetic aspects of typical development and is focusing on factors that can threaten normal development. CDBB researchers are also studying prevention steps and, where intervention is needed, the most effective conditions and timing. Their findings will have implications for boys with KS, who can have some learning difficulties, such as in processing language.

Researchers in the Pediatric Growth and Nutrition Branch focus on nutritional science, childhood antecedents of adult disease, developmental endocrinology, developmental neuroendocrinology, and physical growth and body composition. Topics relevant to KS males include bone weakness and gender identity issues.

Other Activities and Advances

The following projects also study aspects of health and infertility that might be related to KS:

• The Consortia For Infertility and Reproductive Medicine (ConFIRM) Clinical Trial Program, which replaced the Reproductive Medicine Network (RMN), addresses important questions in male and female infertility and translate new discoveries into clinical practice. The network is funded through NICHD’s Fertility and Infertility Branch (FIB) and comprises a collection of collaborative consortia, each with two or more linked clinical sites. The RMN Investigator Group still meets and publishes manuscripts and the Yale Collaborative Center for Statistics in Science still maintains the RMN Data Coordination Center and the RMN website.
• The National Centers for Translational Research in Reproduction and Infertility (NCTRI) is a national network of research-based centers, supported by FIB, that works to promote interactions between basic and clinical scientists with the goal of improving reproductive health.
• The Learning Disabilities Research Centers Consortium included four centers in Boulder, Houston, Tallahassee, and Seattle that conducted research on the causes and treatment of learning disabilities. Supported by NICHD’s CDBB, the centers emphasized, among other things, reading comprehension—how children understand what they read—which is difficult for some children with KS.
• The Biological Testing Facility, funded under contract with the Contraceptive Research Branch, has developed radioimmunoassay tests to accurately measure the impact of hormone treatment given orally, subcutaneously, or transdermally. In individuals with KS taking testosterone, accurate testing helps determine the appropriate dose.