Swier's syndrome: what is it, causes, symptoms, treatment

What is Swier Syndrome?

Swier's Syndrome - a rare disease characterized by an inability to develop the gonads (i.e. testicles or ovaries). Swier's syndrome is classified as a developmental disorder, which includes any disorder in which chromosomal, gonadal, or anatomical sexual development is abnormal. Girls with the disease have an XY chromosome composition (as in boys) instead of an XX chromosome composition (as in girls). Despite the XY chromosome composition, girls with Swier syndrome appear feminine and have functional female genitals and structures, including the vagina, uterus, and fallopian tubes.

Girls with Swier's syndrome have no sex glands (ovaries). Instead of the gonads, women develop "stripes of gonads", in which the ovaries do not develop properly (aplasia) and are replaced by functionless scar (fibrous) tissue. Due to the absence of ovaries, girls with the disease do not produce sex hormones and do not enter puberty (unless they are treated with hormone replacement therapy). Swier's syndrome is known to be caused by mutations in several different genes. This condition can occur as a result of a new gene mutation, or it can be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked pattern.

Signs and symptoms

Most people with Swier syndrome do not experience any external symptoms until adolescence, when they do not start menstruating (primary amenorrhea). At this stage, it is usually found that girls are missing ovaries and therefore lack the sex hormones (estrogen or progesterone) needed to achieve puberty. When hormone replacement therapy begins, girls have breast enlargement, axillary and pubic hair, regular menstrual cycles and other aspects of normal development during puberty.

Women with the condition can be tall and often have a small uterus and a slightly enlarged clitoris compared to most women. Because women with Swier syndrome do not have ovaries, they are infertile. However, they can get pregnant by implanting donor eggs.

The main medical problem of women with Swier's syndrome is the increased risk of developing cancer of the underdeveloped gonadal tissue. About 30 percent of women develop a tumor that arises from the cells that form the testicles or ovaries (gonadal tumor). The most common gonadal tumor in women with Swier's syndrome is gonadoblastoma, a benign (non-malignant) tumor that occurs exclusively in people with a defective development of the gonads. Gonadoblastoma usually does not become cancerous and does not metastasize. However, gonadoblastomas can be precursors to the development of a malignant (cancerous) tumor such as dysgerminoma, which is reported to be more common in women with Swier's syndrome than in general population.

Gonadal tumors can develop at any age, including childhood, even before a diagnosis of Swier's syndrome is suspected.

Causes

In most cases of Swier syndrome, the exact cause of the disorder is unknown. Researchers believe that abnormalities or changes (mutations) in a gene or genes that are involved in the normal sexual differentiation of an XY fetus cause Swier syndrome.

Genes are DNA sequences that are located in a specific place on the chromosome and are the main unit of inheritance. Genes define a particular characteristic or trait of a person. Chromosomes present in the nucleus of human cells carry genetic information for each person. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22 and are called autosomes. The sex chromosomes are designated X and Y. Men usually have one X chromosome and one Y chromosome, while women usually have two X chromosomes.

In about 15-20 percent of patients, Swier's syndrome occurs due to mutations in the Y region gene (SRY), determining sex, on the Y chromosome or deletion of the Y chromosome segment containing the gene SRY. It is believed that the gene SRY is critical for the initiation of male sex determination, causing the transformation of undifferentiated gonadal tissue into testes. The absence or mutation of this gene leads to the fact that testes are not formed.

Since only 15-20 percent of women with Swier syndrome have a gene mutation SRYThe researchers believe that defects associated with other genes can also cause the disorder. All of these genes are thought to play a role in stimulating testicular development and, ultimately, in the differentiation of an XY fetus into a male. Mutations in Map3K1 are also a common cause of Swier's syndrome.

Some women with the disease have gene mutations NROB1 on the X chromosome. Researchers have linked other cases of Swier syndrome to gene mutations DHHlocated on chromosome 12. Gene mutations DEAH37 have also been identified as a common cause. Several rare cases have been associated with mutations in the gene for steroidogenic factor 1 (SF1 or NR5A1), the Wnt-4 protein gene (WNT4) and genes CBX2, GATA4 and Wwox. The researchers believe that additional, as yet unidentified genes may also be associated with the development of Swier's syndrome.

It is believed that some cases of the disease are not inherited, but rather are the result of a new genetic mutation or abnormality that occurs for unknown reasons (spontaneously). However, in some women, due to a gene mutation SRY there were fathers (and some even brothers) who also had the SRY mutation on the Y chromosome. It is not known why in these cases the fathers and / or brothers did not develop Swier's syndrome. Researchers speculate that other genes and / or factors in combination with the gene mutation SRY may be necessary for the development of Swier's syndrome in these patients.

Cases of Swier syndrome due to gene mutation NROB1 can be inherited in an X-linked pattern. X-linked genetic disorders are disorders caused by an abnormal gene on the X chromosome. Women usually have two X chromosomes, one of the X chromosomes is "off" and all genes on that chromosome are inactivated. Women who have a gene for a disease present on one of their X chromosomes usually do not show symptoms of the disease, since the X chromosome with the abnormal gene is usually turned off. However, since women with Swier syndrome have an XY chromosome composition and do not have a second X chromosome, they will show symptoms related to a defect on one X chromosome.

According to the medical literature, some cases of Swier's syndrome have an autosomal dominant or recessive inheritance. Mutations genes WNT4, MAP3K1 or SF1 (NR5A1) can be inherited in an autosomal dominant manner. Gene mutation DHH can be transmitted in an autosomal recessive manner.

Dominant genetic disorders occur when only one copy of an abnormal gene is needed to cause a specific disease. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in an affected person. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for men and women. In some people, the disease occurs due to a spontaneous (new) genetic mutation that occurs in an egg or sperm cell. In such situations, the disorder is not inherited from the parents.

Recessive genetic disorders occur when a person inherits two copies of an abnormal gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, they will carry the disease but are usually asymptomatic. The risk for two carrier parents of passing on the altered gene and having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents is 25%. The risk is the same for men and women.

All humans carry 4 to 5 abnormal genes. Parents who are close relatives (blood relatives) are more likely than unrelated parents parents who have the same abnormal gene, which increases the risk of having children with a recessive genetic disease.

Patients are advised to seek genetic counseling to obtain answers to any questions regarding the complex genetic factors involved in Swier's syndrome.

Affected populations

Swier's syndrome affects girls with an XY chromosome composition, no ovaries, but functional female organs, including the uterus, fallopian tubes, and vagina. The exact frequency is unknown. One estimate is that the incidence is 1 in 80,000 births. According to another estimate, the incidence of the disease (complete dysgenesis of the gonads) and partial dysgenesis of the gonads in the aggregate is 1 case in 20,000 births. Genital abnormalities usually occur in about 1 in 4500 births.

Related disorders

Symptoms of the following disorders may be similar to those of Swier's syndrome. Comparisons can be useful for differential diagnosis.

• 46, XY violation of sexual development - a rare congenital disorder in which people have a chromosomal composition of 46, XY, external genitals that are not fully developed and / or may have signs of both sexes (ambiguous genitals), and abnormal testicular formation (partial gonadal dysgenesis) with reduced sperm production or absence. In some people, the urinary opening may be on the underside of the penis (hypospadias) with a downward curvature of the penis. Some patients may have a complete absence of Müllerian structures (vagina, uterus, and fallopian tubes) to a fully developed uterus and fallopian tubes. Individuals with 46, XY DSD are at greater risk than the general population of developing gonadal tumors such as gonadoblastoma or dysgerminoma.
• Sexual developmental disorders belong to the group of congenital diseases in which the development of an abnormal chromosomal, gonadal, or anatomical sex is atypical. Symptoms of these conditions can vary greatly, but may include ambiguous genitals, female genitalia with an enlarged clitoris, male genitalia with undescended testicles, micropenis, improper placement of the urinary opening on the underside of the penis (hypospadias), as well as a defect in the part of the embryo that develops into the lower abdominal wall (cloaca), potentially exposing the lower abdominal and nearby structures such as the urethra, bladder, and intestines (cloacal exstrophy). This group of disorders includes complete or partial insensitivity to androgens, 5-alpha reductase deficiency, congenital adrenal hyperplasia, ovotestikularny violation of sexual development (previously true hermaphroditism) and other disorders. The causes of these disorders are varied.

Diagnostics

The diagnosis of Swier's syndrome is made on the basis of a thorough clinical examination, a detailed history of the patient, identifying characteristic signs (for example, absence of menstruation, gonadal streaks) and various tests, including chromosomal analysis. For example, a special technique called fluorescence in situ hybridization (FISH) can be used to determine the karyotype of a person. A karyotype is a visual representation of a person's chromosomal composition (i.e. 46 chromosomes in a cell). These 46 chromosomes are split into 22 matched pairs (in each pair, one chromosome comes from the father and the other from the mother). The sex chromosomes are considered a separate pair, XX or XY. The diagnosis of Swier's syndrome is usually made when young people are tested for delayed puberty.

Molecular genetic testing can determine if one of the specific gene mutations associated with Swier's syndrome is present in an affected person.

Examination of the victim's immediate family can help determine whether the disease is sporadic or inherited in that family.

Standard treatments

Treating Swier's syndrome may require a coordinated effort by a team of specialists. Pediatricians, pediatric endocrinologists, geneticists, urologists or gynecologists, psychologists or psychiatrists, social workers and other health care providers may need to systematically and comprehensively plan treatment for an affective child.

Swier syndrome is treated with hormone replacement therapy, including estrogen and progesterone replacement, which is usually started at puberty. In addition to helping with the normal development of secondary sex characteristics, hormone replacement therapy can also help prevent bone loss and thinning (osteoporosis) at a later age.

Striped gonads are usually removed with surgery because they put patients at an increased risk of developing gonadal tumors.

People with SF1 mutations may have adrenal insufficiency. This should be investigated and treated, if any.

Genetic counseling is recommended for patients and their families. Other treatments are symptomatic and supportive.

Although women with the disease are infertile, they can become pregnant and carry a baby from donated eggs.