The chromosomal diseases are pathologies caused by abnormalities at the chromosome level. This anomaly may be a alteration of a chromosome, which lacks a gene: we speak of structural anomaly. It can also be a altered karyotype, with an entire chromosome, absent or present several times: we speak of an anomaly in the number. Several genetic diseases, whether serious or not, caused by these abnormalities affect many people around the world. Among these, Triple X syndrome, trisomy 13, trisomy 18, Down syndrome, etc. Here we will talk about the Klinefelter syndrome, which only affects men. This syndrome is mainly manifested by infertility of the patient and delayed puberty. What are the causes and manifestations of this disease? Focus on the Klinefelter syndrome.
Definition of Klinefelter syndrome
Klinefelter syndrome, also called 47, XXY, is a genetic anomaly, more particularly, an aneuploidy characterized in the male subject, by an additional sex chromosome X. This condition only affects the male karyotype which has two X chromosomes and one Y chromosome, in other words 47 chromosomes instead of 46. The chromosomal formula of a boy with Klinefelter syndrome is therefore written in the following form “47, XXY ”. A situation which is at the origin of hypergonadotropic hypogonadism in boys.
This therefore leads to insufficient secretion of testosterone, the male sex hormone, by attacking the seminiferous tubes.
For the record, it was Klinefelter who first described the clinical picture of this condition in 1942, after he observed a puberty delay in boys with atypical morphotype. This delay was characterized at the level of the phenotype by a penis of normal size, of small testicles, gynecomastia, large size, hair and adipose tissue with female distribution (thighs, hips).
In addition to these phenotypic differences, sterility and numerous somatic complications (musculoskeletal disorders, thyroid disorders, diabetes, venous insufficiency, myotonic dystrophy). Infertility in subjects with Klinefelter syndrome is usually irreversible, since it is due to azoospermia by hyalinization of the seminiferous tubules.
Although it is a genetic pathology, the Klinefelter syndrome is not hereditary or inherited from parents. It occurs as a result of a random error during cell division of the sperm or egg cell. The latter, which is responsible for the formation of the fetus.
Different variants of Klinefelter syndrome
The Klinefelter syndrome is an abnormality that occurs in some boys, due to an extra X chromosome during the formation of a sperm or an egg cell. However, sometimes it is possible that there is more than one complementary X chromosome. All the same, these are very rare situations. The likelihood of each variant of Klinefelter syndrome occurring in newborn males is estimated as follows:
- 1 in 500 newborn males, for the variant which has an additional X chromosome (XXY);
- 1 in 50,000 newborn males, for the variant which has two additional X chromosomes (XXXY);
- 1 in 85,000-100,000 newborn males, for the variant with three additional X chromosomes (XXXXY).
These different variants of Klinefelter syndrome are very rare, as they happen due to errors that occur at random.
What are the risk factors for the disease?
The error which leads to the production of the extra X chromosome seems to be due to chance and is not hereditary. However, there are certain factors that increase the risk of this error occurring. First, boys with older mothers, may have (as with most genetic conditions) a slightly greater risk of Klinefelter syndrome compared to other newborn males who have younger mothers.
However, in almost half of the cases of Klinefelter syndrome, the cause comes from an error in the X chromosome, in the father’s sperm and is therefore not related to the age of the mother. Thus, it is possible that the advanced age of the father is also linked to an increased risk of the syndrome. There are theories that there are other risk factors associated with Klinefelter syndrome and current research is working to verify them.
A clearer and deeper understanding of Klinefelter syndrome, as well as the causes of this error, could potentially better help in its prevention.
Causes of Klinefelter syndrome
Each human being normally has 46 chromosomes, divided into pairs of two. Among these, there are two which determine the sex of the person and are thus called, the sex chromosomes. The mother is responsible for giving an X chromosome to her child and the father can donate a Y chromosome for a male descendant or also provide another X chromosome for a female descendant.
Boy with Klinefelter syndrome has extra X chromosome, which is believed to be caused by an error, due to chance. The latter usually occurs during meiosis, when the cell divides to produce sperm in the father, or the egg cell in the mother. Thus, the origins of this anomaly are found in the meiosis of the patient’s gametes, when the sex chromosomes do not distribute as they should..
Another form of the syndrome called “mosaic” has its origins during mitosis. The number of people affected by this form represents approximately 10% of cases of Klinefelter syndrome.
Indeed, so-called “mosaic” patients do not have all the cells affected by the chromosomal abnormality and are therefore for some of them able to have children.
Frequency of Klinefelter syndrome
It is important to note that many people carry the abnormal karyotype of Klinefelter syndrome, without being really affected by the pathology (apart from their infertility). Klinefelter syndrome is thought to affect one in every 500 to 1,000 male births. Karyotype 47, XXY accounts for 80% of Klinefelter cases, while karyotypes 48, XXXY, 48, XXYY and 49, XXXXY and other mosaics constitute 20% of cases.
Patients diagnosed before adulthood do not affect 10% of people with the syndrome and it is moreover very likely that only a quarter of cases are actually detected in the world.
Symptoms of Klinefelter syndrome
Klinefelter syndrome is a genetic pathology, which includes all or some of all of the following symptoms:
- A size generally larger than the siblings;
- A possibility of the onset of language or reading learning disabilities during childhood;
- The possibility of puberty delay ;
- Testicles that are smaller in size from puberty;
In addition, it is possible if there is a lack of testosterone in adolescence, which we notice:
- A development of the mammary glands or gynecomastia;
- a lack of muscle tone ;
- Osteoporosis in adulthood;
- A fragile tooth enamel.
In addition, you may notice mental retardation, usually moderate in the patient. It is also possible that the patient has seizures. Also, many studies have cited psychiatric disorders as Klinefelter syndrome and categorized it along with other symptoms.
Complications related to Klinefelter syndrome
The first and main complication of Klinefelter syndrome is the onset of infertility. Also remember that the risk of dying is not negligible. Indeed, for cardiovascular, neurological or pulmonary reasons, subjects can lose their lives.
The risk of developing breast cancer or of having a thromboembolic disease, diabetes or osteoporosis, increases greatly in these patients.
Diagnosis of Klinefelter’s syndrome
Diagnosing Klinefelter syndrome is sometimes difficult and comes late. However, it is possible to place a prenatal diagnosis of this pathology. The doctor does this when a karyotype analysis is done for other reasons, such as advanced maternal age.
As for the postnatal diagnosis, it begins first with a blood test, which allows the number of chromosomes on blood cells to be analyzed and confirmed. The doctor then offers a medical genetic consultation to the family. He will then do a full physical examination and sometimes blood tests. They are necessary and help in finding other associated disorders.
As soon as the male reaches puberty, it is essential that there is a close connection between the endocrinologist and the fertility specialist. This diagnosis is made using the karyotype, but it is much more delicate when faced with a case of mosaics.
The choice to make the diagnostic of Klinefelter’s syndrome, is decided at the clinical examination of a teenager with small testicles and gynecomastia. Many adult males are diagnosed during an infertility workup.
Treatment of Klinefelter syndrome
As is the case with most chromosomal pathologies, there is no treatment that can definitively treat the manifestations of this syndrome. However, if necessary, applying hormone replacement therapy for testosterone can boost puberty by increasing hair growth, as well as a deep voice.
It should also be remembered that hormonal treatment with testosterone, from puberty, certainly improves symptoms, but does not solve the problem of infertility. This treatment can also prevent some late complications, such as osteoporosis.
Regarding children with learning difficulties, it is possible to set up early and traditional care in speech therapy and occupational therapy, which could help them.
It is possible for cases of significant and disabling gynecomastia, to resort to a plastic surgery. In addition, one can also perform an excision of the small testicles, for subjects who cannot stand this state. It will therefore be a question of placing testicular prostheses.
With regard to the main problem posed by this syndrome, in particular infertility, the management is provided by the teams of medically assisted procreation (AMP). These determine the degree of infertility as well as the various possibilities that result from it. It may be the in vitro fertilization and intracytoplasmic sperm injection; adoption or evenartificial insemination with donor. At puberty, specialists must give boys with this pathology advice on preserving fertility.
Klinefelter syndrome is a common chromosomal abnormality, which affects only men. This syndrome is not hereditary, it is due to a completely hazardous error, which occurs during the separation of sex chromosomes during meiosis. Its symptoms are mainly delayed puberty, mental retardation, language and learning difficulties. Although there is not yet a specific treatment to remedy it, there are different ways to correct certain symptoms. The most famous is a testosterone supplementation.