Turner syndrome causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

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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