Turner syndrome pathophysiology

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. Loss the paternally or maternally derived X chromosome would lead to the class 45 XO karyotype. Sometimes, an individual may have two cells lines with different genetic makeups. The percentage of this mosaicism is said to determine the severity of the phenotype in the patient. Structural abnormalities such as the formation of a ring chromosome or an isochromosome and other mechanisms such as lyonization or imprinting also play a role in the pathophysiology of Turner Syndrome.

• The normal karyotype of a female and male is 46 XX and 46 XY respectively.
• Loss of the Y chromosome would mean an absence of the sex determining region of Y and therefore, the absence of testis determining factor (responsible for the process that converts dihydrotestosterone to testosterone and thereby the development of male genitalia).
• Karyotype abnormalities may take place during the formation of reproductive cells (45 XO) or during cell division processes responsible for fetal development (mosaicism).
• Turner syndrome is not an inherited condition.
• Therefore the physical manifestations of Turner’s syndrome are due to aneuploidy, absence of two normal sex chromosomes or haploinsufficiency (presence of 1 set of genes in the cell instead of 2 ) of genes present in the Y chromosome.
• Distal to Xq24, small deletions of the long arm of the X-chromosome are not included in the diagnosis of TS. ^[1]
• Females with short stature and deletion of the distal region of the paternal X chromosome including the SHOX gene are generally not diagnosed with Turner syndrome.
• Similarly, individuals with deletions of Xq24, with primary or secondary amenorrhea and without short stature are diagnosed as premature ovarian failure.
• Small deletions of the long arm of the X-chromosome distal to Xq24 are not included in the diagnosis of Turner syndrome.
• A study of 67 Turner syndrome in China found 50 percent of the patients with the classic 45 X karyotype followed by the mosaic pattern, a chromosomal structural abnormality (isochromosome or ring chromosome) and a Y chromosomal structural abnormality. ^[2]

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. ^[3]

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.

• Visuospatial deficits (visuo-spatial function, visuomotor learning and spatial working memory) in Turner syndrome is hypothesized to be independent of hormone deficiencies and due to abnormalities in parieto-occipital mechanisms/morphology along with volumetric differences in the superior parietal lobule and the postcentral gyrus. ^[3]
• Executive skill deficiencies are said to be due to abnormalities in the prefrontal-striatal pathways.
• Reduced white matter in the frontal parietal pathways and defects in neurodevelopment and connectivity in these regions are responsible for the inability of Turner syndrome patients to link visuo-spatial functioning with executive functioning when performing complex tasks.
  • The patient is able to compensate for this deficiency whilst performing simple tasks by recruiting fronto-parietal resources. This recruitment is not possible during complicated tasks.
• One study suggested that volumetric differences in the amygdala were responsible for poor facial recognition and judgement. Poor connectivity between the amygdala and fusiform and aberrant development in the orbitofrontal cortex and superior temporal sulcus further contribute to this.
• Premature ovarian failure is secondary to ovarian dysgenesis and early follicular apoptosis.
• Fractures are due to estrogen deficiency and X chromosomal abnormalities. ^[4]
• Increased susceptibility to gonadoblastomas are seen in those individuals with Y chromosomal abnormality karyotypes.
  • It is proposed that a gonadoblastoma susceptibility locus is located on the pericentromeric region of the Y chromosome.
• Presence of autoimmune diseases may be due to haploinsufficiency of X chromosome or due to proinflammatory cytokines such as IL-6, IL-8 and tumor necrosis factor alpha. ^[5]

• While phenotype-kartyotype correlations are unreliable in predicting clinical features in Turner syndrome, some studies have suggested the following: ^[1]
  1. Loss of short and long arm of X chromosome – decreased ovarian function, number and survival of oocytes.
  2. Loss of interstitial or terminal long arm of X chromosome – Short stature, primary or secondary ovarian failure
  3. Loss of short arm of paternally inherited X chromosome– Full phenotype
  4. Loss of a region at Xp22.3 – Neurocognitive problems
  5. Loss of a region at Xp11.4 – Critical for the development of lymphedema
  6. Presence of an isochromosome Xq – Increased risk of hypothyroidism and inflammatory bowel disease
  7. Presence of ring chromosome – Increased risk of mental retardation.
  8. Lack of the XIST locus – Phenotype with more severe mental retardation.

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