Klinefelter Syndrome Vincent Ruiz, Jolyn Taylor, Erica Cannell

Transcription

1 Klinefelter Syndrome Vincent Ruiz, Jolyn Taylor, Erica Cannell Diagnostic Criteria, and Genetic Risks to Family Members/Counseling Definitive diagnosis of Klinefelter syndrome requires a cytogenic analysis of the patient in question. However, physical manifestations may play an important role in the diagnosis of an affected individual. Although physical manifestations of Klinefelter syndrome are extremely variable, there is a direct correlation between severity of physical manifestations and the amount of sex chromosomes present. 1 Thus, certain physical characteristics may aid in the differential diagnosis of an undiagnosed male, and may indicate the need for a karyotype analysis. Common physical features associated with Klinefelter include: small testes, infertility, gynecomastia, long legs and arms, developmental delay, speech and language deficits, learning disabilities, psychosocial difficulties, and behavioral issues. 1,2 Some of these physical characteristics are common for Klinefelter as well as other causes of hypogonadism, and hence other illnesses ought to be considered. 1 Diagnosis may be made prenatally or at any time after the birth of an affected male. Prenatal diagnosis may be made through cytogenetic analysis of cells obtained through such procedures as amniocentesis and chorionic villus sampling. 1 The presence of a Barr Body, and hence an extra X chromosome, in a karyotype analysis and a male phenotype is considered the major etiological factor of Klinefelter Syndrome and is indicative of the disorder. 2 If an individual is not diagnosed prenatally, then 47, XXY males may be tested and diagnosed after presenting with any of the aforementioned subtle clinical signs. As would be intuitive, these physical manifestations are age-related, and hence differ for infants, toddlers, young children, adolescents, and adults. Diagnosis of an affected individual should be considered only after a karyotype analysis of peripheral blood, as this is the gold standard. Individuals with Klinefelter will also have elevated levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol. These individuals will also commonly have a lower than normal testosterone level. Moreover, the presence of an increased level of urinary gonadotropins are increased due to abnormal testicular and consequently Leydig cell formation. Before and after an individual is tested and diagnosed, it is important that the individual receive counseling from a geneticist. The purpose of the counseling is to prepare and educate the individual on any possible outcomes that testing may have. Moreover, it is important to educate the individual on the implications that a positive test will have as well as to introduce them to treatment options. Another important part of genetic counseling is determining the risk of other family members, and explaining these risks to the proband prior to carrying out any testing. Another aspect of counseling that may come into play with Klinefelter syndrome is antenatal counseling to parents of a possibly affected male. The first important part of the counseling would be to educate the patient about the disease. In addition to providing the individual in question with the information contained within the body of this paper, such as a discussion of the genotype and phenotype of Klinefelter syndrome, it would be important to explain to the patient, or parents of a possibly affected individual (if antenatal or adolescent), that if he were to be affected there would be an increased risk of infertility. It is important to note that although most individuals affected by Klinefelter are infertile there have been reports of several patients with Klinefelter that have been able to produce offspring without assisted medical technology. 1 After thoroughly explaining the

2 physical and psychosocial manifestations of the disease, it would be important to discuss possible treatment options that address and alleviate the aforementioned characteristics. Antenatal diagnosis of Klinefelter is sometimes difficult because fetuses with Klinefelter syndrome typically do not have abnormal ultrasound. Hence cases that are diagnosed prenatally occur fortuitously arising from cytogenetic analysis for other reasons such as advanced maternal age. 3,4 Although diagnosis is not extremely difficult it is important to note that fetal karyotype is not a good indicator of the post-natal phenotype. As mentioned prior, Klinefelter syndrome demonstrates a great phenotypic variability, and hence the clinical presentation of the child may not correlate with the prenatal findings. 5 Another important fact of which to make note is that the family of the affected individual has no increased risk of the disease above that of the general population, as there is no evidence to suggest that a chromosomal nondisjunction event will repeat within a given family. 1 Basic Genetics, Biochemistry, and Molecular Biology Klinefelter Syndrome is a chromosomal aneuploidy resulting in the genotype of 47,XXY. This anomalous extra X chromosome stems from a nondisjunction event occurring in the sex chromosomes undergoing gametogenesis during either of the two meiotic divisions. 1 Mosaicism leading to Klinefelter Syndrome, however, probably results from nondisjunction during mitotic division after conception. Though these sex chromosomal nondisjunction events could be inherited from either parent, some studies suggest that a majority of Klinefelter Syndrome chromosomal nondisjuctions are inherited from maternal sources. The observation that such events are often linked to increased maternal age further implies a maternally derived nondisjunction event. 6 In addition, analysis of the methylation-sensitive restriction site CfoI, which is located within 100bp of the repeat, allows for confirmation of X-chromosomal inheritance pattern and determination of degree of imprinting and methylation. 7 As a result of the more common maternal pattern of inheritance, genetic imprinting plays a significant part in the phenotypic presentation. Genetic imprinting of the X chromosome determines the degree of phenotypic abnormality. Based on studies examining the affects of paternal versus maternal X chromosomal inheritance in Turner Syndrome, various social interaction skills (such as verbal and higher order executive skills) were determined to be linked to the maternal pattern of imprinting. 7 Though these are the majority of the cases, there are exceptions. A rare presentation, the 47 XXY/46XX mosaic karyotype, arises following a distinct set of events: Non-disjunction occurs in the father in 26 66% of 47,XXY patients. Since it was shown by molecular analysis that the origin of the extra X chromosome is of paternal origin, we can assume that the Y was lost postzygotically in some cells of a 47,X M X P Y fetus, which resulted from fertilization of a normal ovum by an XY sperm. The fact that the 46,X M X P cell line was found in the blood and in the skin, but not in the testis, all tissues of mesodermic origin implies that the Y chromosome was lost relatively late during embryonic development. 8 The phenotype of a patient with Klinefelter Syndrome depends on the pattern of maternal imprinting as discussed as well as the number of superfluous X chromosomes and the length of the CAG repeat.

3 The greater the number of extra X chromosomes, the greater the phenotypic consequences, both gonadal and extragonadal. The effects on physical and mental development increase with the number of extra Xs, and each extra X is associated with an IQ decrease of approximately points, with language most affected, particularly expressive skills. 8 The phenotype in Klinefelter patients also appears to be modified by the length of the CAG polymorphism (repeated on average 23 times) of the androgen receptor gene which occurs in the first exon. 7 There is an inverse correlation between the CAG repeat length and the transactivational activity of the androgen receptor. This can consequently lead to a deficiency of the androgen hormone testosterone. A long bone abnormality, resulting in increased length of the legs, independent of the increased length of both the arms and legs, is believed to be caused by a testosterone deficiency. 9 Further physical manifestations of an increased CAG repeat length were found in a study of 77 newly diagnosed and untreated Klinefelter patients (48 of whom were hypogonadal), in which longer CAG repeat length was associated with taller stature, lower bone mineral density, gynecomastia, and employment not requiring a high level of education. 10 In a similar study of 35 patients with Klinefelter syndrome, longer CAG repeat length was inversely correlated with penile length. 11 Intelligence level, social and educational performance, and penis length also appear to be linked to the CAG repeat length and parental inheritance pattern. 3 Treatment and Prognosis The treatment of patients with Klinefelter syndrome varies with age of diagnosis. Because overt symptoms such as infertility or gynecomastia do not manifest themselves until adulthood, neonatal and childhood diagnosis are less common. However, when diagnosis is made in early childhood, treatment options can include physical therapy, infant stimulation programs and speech therapy. 12 Physical therapy intervention for 47, XXY children can decrease mean age of walking from 18 months to 12 months while speech therapy addresses the finding that 47, XXY children have difficulty coordinating lip and tongue movement. 13 For diagnosis in which a testosterone deficit is evidenced directly in the laboratory, treatment with exogenous testosterone is often recommended. 9 Hormone therapy counteracts many of the effects of hypogonadism including loss of bone and muscle mass. In one study that followed 12 Klinefelter patients for a mean of 3.2 years after beginning hormone replacement therapy found a significant increase in bone mineral density and a small but significant increase in paraspinal muscle area. 14 Another study showed that while adult Klinefelter patients had reduced grey matter volumes of the left temporal lobe when compared to normal control subjects, those who had been treated with testosterone replacement since puberty showed a relative preservation of gray matter compared to untreated Klinefelter patients. Testosterone replacement has also been associated with increased verbal fluency scores for Klinefelter patients. 15 Finally, treatment with hormone therapy is often accompanied by improved confidence and sense of well being for the patient. 12 As mentioned previously, assisted reproductive techniques (ART) available for 47, XXY patients. These include testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). 16 In one study, 42 Klinefelter patients underwent 54 TESE procedures. TESE involved stopping any hormonal therapy 6 months prior to extraction, regulation of serum testosterone using testolactone or anastrazole or hcg, and finally a microdissection with examination of seminiferous tubule morphology until the presence of sperm was detected and subsequently collected. Spermatozoa were then used to fertilize retrieved oocytes in ICSI and embryos were

4 transferred back to a uterus. Of the 42 men, 28 had successful procedures in which sperm was retrieved and 72% of attempts to retrieve sperm were successful. However, previous publications report a sperm retrieval rate of 40-48%. 17 This suggests that sperm retrieval, while possible for Klinefelter patients, is by no means guaranteed to circumvent infertility. In fact, there are no current clinical parameters such as age, testicular volume, or testosterone and androgen sensitivity index that predict whether a particular patient will have a successful sperm retrieval procedure. 18 In the Schiff, et al experiment, once sperm were identified, 56% of ICSI attempts resulted in pregnancy. 17 Published data indicates that these babies have an increased risk of having either a sex chromosomal abnormality or an autosomal chromosomal abnormality when compared with a control group. Still, it must be noted that ICSI offspring of any parents, not just those of Klinefelter parents, have increased chromosomal abnormalities compared to spontaneous pregnancies in the general population. Unbalanced offspring of Klinefelter patients either have 47, XXX or 47, XXY karyotypes, neither of which is associated with mental retardation although 47, XXX patients show IQ scores between points below that of siblings. 16 An important point with regard to ART is that there was a 20% lower sperm retrieval rate in men who had previously undergone testosterone therapy. 17 Thus, the benefits achieved by early treatment of 47, XXY with testosterone therapy at the time of diagnosis must be weighed against the decreased ability to retrieve sperm when the patient decides to start a family. References 1. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis 2006; 1: Smyth CM, Bremmer WJ. Klinefelter Syndrome. Arch Intern Med 1998; 158: De Vigan C, Baena N, Cariati E, Clementi M, Stoll C. Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe. Ann Genet 2001; 44: Abramsky L, Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY: Estimated rates of and indication for postnatal diagnosis with implications for prenatal counseling. Prenat Diag 1997; 17: Pettenati MJ, Wheeler M, Bartlett DJ, Subrt I, Rao N, Kroovand RL, Burton BK, Kahler S, Park HK, Cosper P, et al. 45,X/47,XXY mosaicism: clinical discrepancy between prenatally and postnatally diagnosed cases. Am J Med Genet 1991; 39: Paulsen CA, Gordon DL, Carpenter RW, et al. Klinefelter's syndrome and its variants: a hormonal and chromosomal study. Recent Prog Horm Res 1968; 24: Stemkens D, Roza T, Verrij L, Swaab H, van Werkhoven MK, Alizadeh BZ, Sinke RJ, Giltay JC. Is there an influence of x-chromosomal imprinting on the phenotype in Klinefelter syndrome? A clinical and molecular genetic study of 61 cases. Clin Genet 2006; 70: Velissariou V, Christopoulou S, Karadimas C, Pihos I, Kanaka-Gantenbein C, Kapranos N, Kallipolitis G, Hatzaki A.. Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report. Eur J of Med Genet 2006; 49: Snyder, PJ. Causes of primary hypogonadism in males. UpToDate 2006; Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as

5 pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 2004; 89: Zinn AR, Ramos P, Elder FF, Kowal K, Samango-Sprouse C, Ross JL. Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J Clin Endocrinol Metab. 2005; 9: Wattendorf DJ, Muenke M. Klinefelter Syndrome. Am Fam Physician 2005; 72: Simpson, JL, de la Cruz F, Swerdloff RS, Samango-Sprouse C, Skakkebaek NE, Graham JM Jr, et al. Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med 2003; 5: Leifke E, Korner HC, Link TM, Behre HM, Peters PE, Nieschlag E. Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men. Eur J Endocrinol 1998; 138: Patwardhan AJ, Eliez S, Bender B, Linden MG, Reiss AL. Brain morphology in Klinefelter syndrome: extra X chromosome and testosterone supplementation. Neurology 2000; 54: Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril 2004; 82: Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter Syndrome. Clin Endocrinol Metab 2005; 90: Vernaeve V, Staessen C, Verheyen G, Vansteirteghem A, Devroye P, Tournaye H. Can biological or clinical parameters predict testicular sperm recovery in 47, XXY Klinefelter s syndrome patients? J Urol 2005; 173: 1280.