Klinefelter’s Syndrome (KS) describes a group of conditions characterized aneuploidy due to possession of an extra X chromosome. Individuals with KS exhibit phenotypic manifestations related to the lack of masculine secondary sexual characteristics.
History
The symptoms of Klinefelter’s syndrome were first explored in 1942. Dr. Harry Klinefelter and some of his colleagues in the Massachusetts General Hospital in Boston observed that some me visiting the health facility had feminine or hampered masculine. This included little or the lack of facial hair, inability to produce sperms or low counts if sperms were produced, small testes enlarged breasts, and a high-pitched voice. Also, some of the male patients demonstrated feminine behavior. These observations led to the publication of a report by Dr. Klinefelter and his colleagues. As an endocrinologist, Dr. Klinefelter believed that the symptoms were due to an endocrine disorder. It was postulated that the syndrome was as a result of the actions of testicular hormones. These hormones have, however, never been isolated. As a result of his discovery, the condition was named Klinefelter’s Syndrome (KS).
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Further research followed the publication of Dr. Klinefelter et al. Towards the late 1950 s, research linked Klinefelter’s Syndrome to a genetic disorder on the sex chromosome. It was found that the men who demonstrated the KS symptoms had an extra X chromosome on their sex chromosome, thus an XXY chromosome arrangement. This discovery necessitated the quest to find out the prevalence of this genetic trait among the world’s population. The research was conducted in the 1970 s , during which over 70,000 newborn males were screened. The findings were unexpected. It was discovered that the extra X chromosome occurred in approximately 80% of the screened newborn males. 1 in 500 to 1 in 1000 male births had the XXY chromosome arrangement. However, a follow-up research of the research subjects revealed that the extra X chromosome was not manifested later in life. It was thus concluded that the extra X chromosome was latent in most of the male individuals, as most of them would not manifest the signs of Klinefelter’s Syndrome.
Epigenetic Causes
Klinefelter’s Syndrome occurs as a result of aneuploidy in the sex chromosomes in males. KS is reported to be the most common sex-chromosome aneuploidy in humans, as it affects about 1 in every 600 newborn males. Individuals males possess an extra X-chromosome. Various variants of the aneuploidy have been identified, which are karyotype 47,XXY, 48,XXYY, 48,XXXY and 49,XXXXY. The most predominant variant is 47,XXY. The mechanism by which the aneuploidy leads to the phenotypic manifestations of KS is not clearly defined. However, research has postulated that skewed X-chromosome inactivation (XCI), the source of the extra X-chromosome, and the dysregulation of gene dosage are all responsible for the phenotypic and physiological presentations of KS. These postulates point out that KS is greatly influenced by the epigenetic changes.
DNA hypomethylation across the genome has been associated with the increased chromosomal number. In a mammalian genome, DNA methylation is the formation of a 5-methylcytosine by transfer of a methyl group onto the C5 position. DNA methylation occurring in a gene promoter represses gene transcription, thereby altering the activity of the DNA segment without changing the sequence. On the contrary, DNA hypomethylation results in a loss or insufficient transfer of the methyl group on the DNA genome. Aberrant alterations in the DNA methylation i.e. demethylation and hypomethylation can lead to changes in chromatin structure and consequently changes in gene expression. The supernumerary X-chromosomes in KS individuals may act as a methylation sink. This causes interference with the establishment and maintenance of the normal methylation characteristics in the human DNA genome. As it has been earlier noted that DNA methylation is responsible for gene expression and transcription, aberrant DNA methylation interferes with the gene expression, resulting in the phenotypic features manifested in individuals with KS.
Skewed X-chromosome inactivation (XCI) has also been implicated in phenotypic manifestation of KS characteristics. XCI is the process through which the protein characteristics transcribed from the X-linked genes are equal in both males (XY) and females (XX). This specially is attained through the silencing of one of the two female X chromosomes. Supernumerary X chromosomes in KS individuals could result from the failure to suppress the extra X chromosome. This leads to the transcription and expression of the proteins on the extra X chromosome, imparting the phenotypic features to the KS individuals.
Sex chromosome non-disjunction is a major cause of the aneuploidy. Non-disjunction occurs during the anaphase stage of meiosis I, meiosis II or mitosis, in which the chromosomes fail to separate leading to an aberrant number of chromosomes in the cells. This could occur either during spermatogenesis or oogenesis. The rate of occurrence of meiotic non-disjunction seems to be equal in both maternal or paternal chromatid separation. Supernumerary X chromosomes occurring in oogenesis is as a result of non-disjunction in the meiosis I or II, while non-disjunction is spermatogenesis only occurs during the first meiotic division. Studies have pointed out that the origin of the of the extra X chromosome affects the phenotypic features manifested in KS patients. The evidence, however, is inconclusive. The studies have suggested that the phenotypic characteristics in individuals in which the extra X chromosome is of paternal origin have a delayed onset of puberty.
Symptoms
Individuals with KS have been shown to manifest a number of symptoms.
Sexual characteristics
Decreased androgen production results in pubertal changes with the lack of secondary sexual characteristics. The resulting phenotypic effects of this are sparse of the lack of facial, body, and sexual hair; distribution of body fat similar to that in females; and a feminine high-pitched voice. With progression into late puberty, approximately 50% of the males start manifesting symptoms of increased estradiol:testosterone ratio. These symptoms include gynecomastia. Gynecomastia predisposes the individual to 20 times higher risk of breast cancers than in normal healthy individuals. There is also the increased susceptibility to extragonadal germ cell tumors. Testicular dysgenesis may develop in postpubertal males with KS. This is characterized by small firm testis (< 10mL). Atrophy of the seminiferous tubules may lead to azoospermia and infertility. Individuals with karyotype variant 47,XXY do not commonly manifest genital abnormalities. The genital ambiguities manifested in other KS variants and mosaicism are testicular feminization, complete sex reversal, and true hermaphroditism. Ambiguous genitalia characteristics that are manifested are micropenis, female external genitalia, epispadias, and hypospadias.
Motor, Cognitive, and Behavioral Dysfunction
Early childhood can be characterized by tremors and synkinetic movements which can progress to adulthood. Adults manifest symptoms such as impaired gross and fine motor skills, poor coordination, lack of strength, and poor muscle tone. Language and executive functions are also affected. More often, individuals with KS have been seen to have affected expressive language more than comprehensive or receptive language. This primarily has been shown to be due to the levels of social engagements and skills, in which low social skills result in impaired executive functions.
Growth
Most males with KS variant karyotype 47, XXY attain taller stature than normal males. Infants and children are reported to have normal weight, height, and head circumference. Children between the ages 5 and 8 have increased height velocity. Adult males with XXY have also been found to have disproportionately long appendages.
CNS
Intellectual disability in males with KS varies among the variants, with an increase in the intellectual disability with an increase in the number of X chromosomes. Minor developmental and learning disabilities have been demonstrated in approximately 70% of the patients. Poor self-esteem among some patients has been implicated as the cause for the psychological and behavioral distress. Individuals also have a higher tendency to manifest psychiatric disorders with characteristics of neurosis, depression, anxiety, and psychosis.
Treatment
Early diagnosis and initiation of treatment and management therapies are key in mitigating the effects of Klinefelter syndrome.
Androgen Replacement Therapy
Androgens are responsible for the development of secondary sexual characteristics, especially at the pubertal age. Androgen replacement therapy is essentially helpful in maintaining the normal serum concentrations of important fertility hormones in males i.e. testosterone, follicle-stimulating hormone (FSH), estradiol, and luteinizing hormone (LH). It is recommended that initiation of the therapy should be done at the onset of puberty, i.e. at about 12 years. The therapy is continued with the progression of puberty and the concentrations of the hormones closely monitored to attain the appropriate age-appropriate concentrations. Timely-initiated and regularly administered androgen injections enhance the development of male secondary characteristics. It should, however, be noted that androgen replacement therapy does not reverse infertility of gynecomastia.
Treatment for Infertility
Artificial reproductive technologies and microsurgical technologies are essential in the treatment of infertility in patients with KS. Intracytoplasmic sperm injection (ICSI) is also a technique that can improve the fertility and siring ability in men with azoospermia. Studies conducted have demonstrated a 72% sperm retrieval rate in 69% of the patients undergoing ICIS.
Speech and Behavioral Therapy
Speech difficulties, cognitive impairments, and academic difficulties can be assisted by using a multidisciplinary team approach. Speech and language therapy should be initiated early in children for maximum effectiveness. Prepubertal boys should be subjected to psychoeducational evaluation to determine their learning weaknesses and strengths. These evaluations are particularly important in making informed decisions and planning for the therapies.
Surgical Care
Mastectomy may be done for gynecomastia. This therapy requires adequate presurgical and postsurgical psychological treatment of the patient.
Conclusion
Klinefelter Syndrome (KS) describes a group of chromosomal disorders in which the male karyotype consists of an extra X chromosome. The condition was first described in 1942 when Dr. Harry Klinefelter and his colleagues at Massachusetts General Hospital published an article describing the feminine physical manifestations in male patients visiting the facility. Preliminary research pointed out that the conditions were entirely due to endocrinological disorders. These conclusions were supported by Dr. Klinefelter, who was an endocrinologist himself. Further research into the late 1950 s however, pointed out that the condition was of a genetic etiology. It was found out that the male individuals with KS have an extra X chromosome in their genetic make-up. The extra X chromosome is most likely due to non-disjunction of the chromatids during oogenesis and spermatogenesis. The supernumerary X chromosomes in male individuals lead to manifestation of phenotypic, cognitive, behavioral, and fertility disorder. DNA hypomethylation and the skewed X chromosome inactivation influence the phenotypic manifestations of the KS symptoms. Most KS patients exhibit lack of secondary sexual characteristics due to the high estradiol:testosterone ratio. It is important to identify the condition early so as to initiate effective treatment and management therapies. Screening of infants and prepubertal children is vital in early identification and diagnosis of the condition. The therapies have been shown to be most effective when initiated early. Androgen replacement therapy is the most preferred treatment modality of KS. Androgen replacement therapy aims at normalizing the serum androgen concentrations, thereby initiating secondary sexual characteristics among the patients. Mastectomy, fertility therapies, and cognitive and behavioral therapies are also employed in the treatment of KS patients.
References
Bonomi, M., Rochira, V., Pasquali, D., Balercia, G., Jannini, E. A., Ferlin, A., … Vicari. (2017). Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. Journal of Endocrinological Investigation , 40 (2), 123–134. http://doi.org/10.1007/s40618-016-0541-6
Kanakis, G. A., & Nieschlag, E. (2018). Klinefelter syndrome: more than hypogonadism. Metabolism
Nahata, L., Richard, N. Y., Paltiel, H. J., Chow, J. S., Logvinenko, T., Rosoklija, I., & Cohen, L. E. (2016). Sperm retrieval in adolescents and young adults with Klinefelter syndrome: a prospective, pilot study. The Journal of pediatrics , 170 , 260-265.
Paduch, D. A., & Ryan, C. T. (2015). Klinefelter Syndrome: Early Treatment of the Adolescent Is Warranted. In Biennial Review of Infertility (pp. 203-211). Springer, Cham.
Ross, J. L., Kushner, H., Kowal, K., Bardsley, M., Davis, S., Reiss, A. L., ... & Roeltgen, D. (2017). Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. The Journal of pediatrics , 185 , 193-199.
Zitzmann, M., Bongers, R., Werler, S., Bogdanova, N., Wistuba, J., Kliesch, S., ... & Tüttelmann, F. (2015). Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. The Journal of Clinical Endocrinology & Metabolism , 100 (3), E518-E523.
