Turner syndrome causes

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Females normally have two of the same sex chromosomes, written as XX. Males have an X and a Y chromosome (written as XY).

In Turner syndrome, cells are missing all or part of an X chromosome. The condition only occurs in females. Most commonly, the female patient has only one X chromosome. Others may have two X chromosomes, but one of them is incomplete. Sometimes, a female has some cells with two X chromosomes, but other cells have only one.

Turner syndrome results from the following mechanisms.

Nondisjunction

• During meiosis in either parent, a nondisjunction event can occur that leaves the gamete, either oocyte or spermatocyte, with neither X nor Y chromosome.
• When this gamete combines with a gamete from the other parent (with a normal X chromosome), the embryo lacks the normal two chromosomes.
• This leaves the embryo with 45 chromosomes and a single X chromosome, denoted 45,X (or, sometimes 45,XO, where the “O” is used as a placeholder). This is found in 50% of individuals with Turner syndrome.

Chromosomal structure

• An X chromosome can form a ring chromosome for example by losing a portion of the smaller arm, enabling the end of the long arm to wrap around. This is detrimental for the X chromosome in two ways. **Either the lost portion itself makes the chromosome less functional.
  • Or it causes nondisjunction, as described above. Thus, the causes listed here are partly overlapping.
• When such a ring chromosome combines with another ring chromosome in fertilization, the pair is denoted as 46, XrXp-, where rXp- means a ring chromosome missing the small (p) arm of the chromosome.
• Another variant of abnormal chromosomal structure is chromosomes with two long arms of the X chromosomes attached, and are called isochromosomes.
• Variants of chromosomal structure occur in 30% of individuals with Turner syndrome.

Nonfunctional Y

• Very rarely, the embryo has a normal X chromosome and a portion of the Y chromosome.
• In these cases, the Y chromosome does not have a functional SRY (and so develops as a female), the diagnosis is XY gonadal dysgenesis.[1]
• It is possible that some Turner syndrome diagnosis is due to gonadal dysgenesis, particularly when it is caused by a large deletion of the Y chromosome.

Mosaicism

• Each of the causes mentioned above can occur as a mosaicism, that is, some of the cells carry the mutation and some don’t. That is, two cell lines of different genetic make ups exist.
• This happens if the error takes place in one cell after the very first divisions of the early embryo after fertilization.
• The exact mixture of the two different cell types depends on when the nondisjunction occurred. *However, if the nondisjunction occurs after enough divisions, the fraction of abnormal cells is probably not large enough to show any significant effects.
• For instance, such a 45,X/46,XY individual will develop as a male, without Turner syndrome.
  • It is hypothesized that lower the percentage of mosaicism, the lesser is the phenotype expression.
• Mosaicism is found in about 20% of individuals with Turner syndrome.

No single Y

• There is no equivalent syndrome which results in a Y chromosome with no X, as such a condition is fatal in utero.

Lyonization

• In a normal 46 XX female, a process called lyonization inactivates one of the X chromosomes to equalize the number of expressible genes in males and females.
• Some genes escape this inactivation and contribute to the pathophysiology in Turner Syndrome.
• Turner syndrome might be due to the partial or complete absence of these inactivated genes and the presence of functional homologues of the Y chromosome. ^[1]

Imprinting

• Imprinting is an alteration in the expression of a gene, depending on whether it has been inherited from the mother or father.
• In the case of imprinting, it is not known whether there is a specific correlation between retention of the maternal or paternal chromosome and expression of particular phenotype.

• Short Stature is said to be due to the haploinsufficiency of the short stature homeobox (SHOX gene) which is located on the pseudoautosomal region of the X chromosome.
  • The SHOX gene is also responsible for skeletal abnormalities such as high arched palate, abnormal auricular development, cubitus valgus, genu valgum, Madelung deformity and short metacarpals.

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