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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
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,XMXPY fetus, which resulted from fertilization of a normal ovum by an XY
sperm. The fact that the 46,XMXP 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.
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 15–16 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
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 10-15 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
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