Klinefelter syndrome is a genetic disease that affects only males. What characterizes this disease is the presence of an extra X chromosome. This chromosome does not allow the normal development of purely male sexual characteristics during puberty.
Figure: shows a summary of the main clinical manifestations of Klinefelter syndrome. From hypogonadism to typically feminine physical characteristics (wide hips, gynecomastia and narrow shoulders), from mental retardation to diabetes mellitus.
Unfortunately, there is no specific cure. However, some therapeutic treatments reduce the most severe symptoms and consequently improve patients' quality of life.Human chromosomes
Every cell of a healthy human being contains 23 pairs of chromosomes. A pair of these chromosomes is sexual, that is, it determines the sex of the individual; the remaining 22 pairs, instead, are composed of autosomal chromosomes. In all, therefore, the human genome has 46 chromosomes.
THE GENES ALTERATIONS
Each pair of chromosomes contains certain genes .
When a mutation occurs in a chromosome, a gene can be defective. This defective gene consequently expresses a defective protein.
When, on the contrary, the number of chromosomes varies, we speak of aneuploidy . In this case, instead of two, the chromosomes can be three (trisomy) or only one (monosomy).
THE SEXUAL CHROMOSOMES
Sexual chromosomes are essential in determining a person's gender, male or female. The woman has, in the cells of her body, two copies of the so-called X chromosome ; the man, on the contrary, has an X chromosome and a Y chromosome . As for the autosomal chromosomes, also the sexual ones are inherited from the parents: a copy is given by the father, another by the mother.
There are several genetic pathologies due to sexual chromosomes. They present either alterations in the chromosomal structure, or changes in the number of chromosomes. Among the latter, in addition to that of Klinefelter, we mention the turner syndrome, the trisomy X syndrome and the double Y syndrome.
What is Klinefelter syndrome
Klinefelter syndrome is a genetic disease of the male sex, characterized by the presence of a third sex chromosome (trisomy). This chromosome is of the X type. The cells of patients with Klinefelter syndrome therefore possess a chromosomal kit 47, XXY.
Men with an extra X chromosome have:
- Testicular anomalies (male gonads), also called testicular dysgenesis .
- Little developed secondary sexual characters.
- Female somatic characters.
Epidemiology
Klinefelter syndrome affects one male for every 500 new births. The data is, however, uncertain. In fact, other estimates speak of one case per 1, 000 new births. This uncertainty is due to the fact that some mild forms of the disease go unnoticed, as they determine almost imperceptible signs and symptoms.
Furthermore, every 100 non-fertile males, 3 have Klinefelter syndrome.
Causes
The abnormal presence of an extra type X sex chromosome determines Klinefelter syndrome in males. It should be noted that this is a non-hereditary genetic anomaly. Therefore, parents are healthy.
So why are some sons born with an extra X chromosome?
Pathogenesis
The answer, from a genetic-biological point of view, is very complex. It seems that the genetic error begins during meiosis or during the mitosis of the fertilized egg, that is the embryo.
Meiosis is the process by which some cells of the body with 46 chromosomes divide into 4 sex cells with 23 chromosomes each. These cells are the spermatozoon, for man, and the egg cell ( oocyte ), for the woman. The union of an egg cell with a sperm cell gives rise to the fertilized egg, with 46 chromosomes (23 + 23).
Figure: shows the process of non-disjunction, during meiosis. One of the four nascent cells carries both chromosomes with it. If this cell is the one that fertilizes the egg (or is the egg itself), then there will be a genetic anomaly.
Mitosis is the division of a mother cell into two identical daughter cells, with a complete chromosome set.
The genetic error consists in the non-separation (or non-disjunction ) of one of the chromatids, ie the chromosomes in the duplicated form. Therefore, when the cells divide:
- In meiosis, a sex cell will have a chromosome number of 24 chromosomes.
- In mitosis, a daughter cell will have a chromosome number of 47 chromosomes.
In the case of Klinefelter syndrome, this additional chromosome is precisely the X chromosome.
GENETICS: XY / XXY MOSAICISM
Some patients with Klinefelter syndrome possess a genome completely 47, XXY. Other patients, on the other hand, have a mixed genome: 47, XXY and 46, XY. In this case we speak of genetic mosaicism .
What is the explanation of all this?
Everything depends on the moment in which the non-disjunction occurs .
If it occurs during meiosis, the genome is totally 47, XXY. In fact, the egg cell, or the spermatozoon, presents immediately an altered number of chromosomes.
The genome, on the other hand, is mixed, when the non-disjunction occurs during the mitosis of the fertilized egg. In this case, spermatozoon and egg cell, at the moment of fertilization, possess a normal number of chromosomes. The non-separation error occurs during the division of the embryo cells. Result: at the end of embryonic development, some cells will present 46 chromosomes, others 47.
Subjects with an XY / XXY genome usually have attenuated symptoms compared to those with the genome totally 47, XXY.
GENETICS: OTHER VARIANTS
Although rarely, patients have been observed with a chromosomal kit composed of more than 2 X chromosomes. For example:
- 48, XXXY
- 49, XXXXY
- 48, XXYY
- 49, XXXYY
The presence of these genomes is very rare and often coincides with severe forms of intellectual deficit and multiple physical malformations.
Symptoms
To learn more: Symptoms of Klinefelter syndrome
The first symptoms of Klinefelter syndrome appear during puberty, influencing normal evolution. The puberty process, in fact, suffers a slowdown and an early conclusion . The main clinical manifestations are hypogonadism (ie small testicles) and an altered sperm maturation process ( spermatogenesis ).
In the pre-pubertal age (infancy and pre-adolescence), only some patients show indications that lead to suspect Klinefelter syndrome. These are rather vague manifestations, because they are common to other pathological circumstances or because they are not so obvious as to attract the attention of family members.
POSSIBLE SIGNALS OF THE AGE? prepubertal
The deficits encountered in this growth phase can be:
| Deficit | Description |
| Slight learning difficulties and attention problems | Mental delay |
| Reduced muscle strength | Muscles are weaker than peers |
| Verbal and motor dysprassia | Speech difficulty and speech Delay in taking the first steps Lack of coordination |
| Dyslexia | Reading difficulties |
| Behavioral problems | Patients tend to be introverted and unsure of themselves. They appear immature, compared to peers |
AFTER THE PUBLIC?
At this time in life, the symptomatology of Klinefelter Syndrome becomes evident. The main clinical symptoms are:
| Symptom / sign | Description | Frequency |
| Small testicles | It is the so-called hypogonadism | > 90% |
| Sterility | Due to:
| > 90% |
| Increased gonadotropins in the blood and urine | Gonadotropins do not stimulate, as they should:
| > 80% |
| Reduction of testosterone in the blood | Consequence of the lack of action of gonadotropins on testicular cells, which produce testosterone. | > 80% |
| Reduction of hair growth | At the level of:
| 80% 30% > 45% |
| Gynecomastia | It is the bilateral development of the breasts | 50% |
| Erection problems | They are accompanied by lack of libido | > 60% |
| Reduction of penis development | > 20% | |
| Intellectual deficit | 10-20% |
Moreover, even the physical aspect assumes specific characteristics:
- Obesity
- High stature
- The upper and lower limbs are elongated and not proportionate to the rest of the body
- Physiognomy of the body similar to that of a woman (narrow shoulders and wide hips)
PSYCHOLOGICAL ISSUES, PSYCHOLOGICAL PROBLEMS
The psychological aspect deserves a separate chapter. Patients with Klinefelter syndrome suffer from depression . In fact, they perceive differences from healthy peers and respond, consequently, with attitudes characterized by:
- Introversion
- subjection
- Anxiety
Hypogonadism, lack of libido and gynecomastia are the main influences on the psyche of Klinefelter syndrome patients.
COMPLICATIONS
They are mainly due to hormonal disorders, which affect testosterone. In fact, the lack of testosterone synthesis increases cholesterol levels circulating in the blood and promotes osteoporosis . Furthermore, males with Klinefelter syndrome are more affected than breast males by breast cancer .
Finally, the association with diabetes mellitus is very common.
| Complication | deepening |
| Cardiovascular diseases | Due to hypercholesterolemia Testosterone treatment reduces cholesterol levels |
| Osteoporosis | Due to low testosterone levels |
| Breast cancer | Due to gynecomastia. The risk is much higher than in healthy males |
| Diabetes mellitus | Very common |
| Thrombus-embolism | Due to the formation of blood clots in the blood vessels |
| Autoimmune diseases |
|
Diagnosis
To trace the presence of an extra X chromosome, a genetic test known as karyotype is used .
KARYOTYPE
Figure: the chromosome set of a patient with Klinefelter syndrome, observed with the karyotype test.
It consists in the analysis of an individual's chromosome set.
The karyotype reveals whether there are variations in the normal number of chromosomes. It can be performed on a sample of amniotic fluid, for a pre-natal diagnosis of the disease, or on a blood sample, for a post-natal diagnosis.
As mentioned above, puberty is the crucial time for the onset of Klinefelter syndrome symptoms. In the previous phases (pre-natal and pre-pubertal age), the karyotype is the only diagnostic test useful to detect Klinefelter syndrome. When it is performed, very often it is for fear of other pathologies.
After pubertal development, the karyotype confirms the pre-diagnosis, based on the signs.
OTHER USEFUL EXAMINATIONS
Next to the karyotype, there are other very useful and indicative investigations of the disease. They consist of blood and urine tests, testicular biopsy and bone densitometry.
Below is a table showing the test, why it takes place and invasiveness.
| Diagnostic test | Why? | MICROdentistry |
| Blood test | To evaluate the levels of:
| No |
| Urinalysis | To evaluate the levels of:
| No |
| Testicular biopsy | To evaluate:
| Yes. Minimally invasive, it is a surgical intervention; requires local anesthesia; does not require post-operative hospitalization. |
| Bone mineral density | To evaluate:
| No |
Finally, some assessments of the physical-anatomical aspect, such as:
- The small size of the testicles (hypogonadism).
- The minor hair growth of the face, armpits and pubis.
Therapy
Being a genetic disease, there is no cure that solves the root problem. However, some therapeutic measures can be applied, useful for:
- Correct and limit hypogonadism
- Reduce the effects of gynecomastia
- Foster fertility
HORMONAL THERAPY
The main cure, for patients with Klinefelter syndrome, is testosterone- based hormone treatment. The purpose is to raise the low levels present in the blood.
Testosterone hormone therapy begins at the time of puberty and, in some cases, lasts a lifetime.
The table illustrates the main characteristics of hormonal treatment.
| Characteristics of testosterone treatment | Description |
| Why administer it? | To increase patients' low testosterone levels |
| Effects of testosterone |
|
| dosage | 250 mg every 3-4 weeks |
| No effect or minimal effect |
|
TREATMENT OF GYNECOMASTIA
Abnormal development of the breasts often creates depression and a sense of embarrassment in patients. Therefore, there is the possibility of undergoing surgery to reduce breast volume. In fact, fat and glandular tissue is eliminated. This is a rather invasive operation.
TREATMENT OF STERILITY? (Infertility?)
The patient with Klinefelter syndrome, who wishes to have children, should contact a geneticist and a male infertility specialist.
The first is asked to assess whether there is a possibility of hereditary transmission of the disease. The second has the task of investigating the spermatogenesis capacity of the patient, in order to understand if there is a concrete possibility of conception.
If even a minimal amount of spermatozoa is ripe and able to fertilize an egg (or egg), we can proceed to:
- In vitro fertilization (IVF)
- Intracytoplasmic sperm injection (ICSI) in the oocyte
PSYCHOLOGICAL TREATMENT
The psychological aspect is very important. Testosterone administration, surgical breast reduction and possible fertility improve self-esteem in patients with Klinefelter syndrome. In fact, they manage to overcome the sense of exclusion from an active social life and relationship, which is instead common to their peers.
OTHER TREATMENTS
Some patients experience symptoms before puberty. The table shows the possible countermeasures to be taken in the presence of some of these disorders.
| Countermeasure and related disturbance |
| Language therapy, to improve the difficulties in articulating a speech |
| Physiotherapy, to improve the lack of coordination |
| Specialized dyslexia treatment |
Prognosis
Hormonal care is essential to improve the quality of life of patients with Klinefelter syndrome. In fact, in addition to overcoming physical deficits due to illness, they also improve their integration into social life.
The prognosis becomes worse, however, for those who are not treated promptly or who are mentally retarded. In particular, in untreated subjects, azoospermia, sterility and small testicles are irreversible conditions.
