• Turner syndrome = primary hypogonadism in a phenotypic female caused by partial or complete loss of the short arm of an X chromosome.
• Main karyotypes:
  • 57% → 45,X → one entire X chromosome missing
  • 14% → structural abnormalities of X
  • 29% → mosaicism
• Important structural abnormalities:
  • 46,X,i(X)(q10) → isochromosome of Xq → loss of short arm
  • 46,X,r(X) → ring X chromosome
  • 46,X,del(Xp) or 46,X,del(Xq) → deletion of part of X chromosome
• Mosaic forms contain 45,X cells plus another cell population, such as:
  • 45,X/46,XX
  • 45,X/46,XY
  • 45,X/47,XXX
  • 45,X/46,X,i(X)(q10)
• About 5%–10% of mosaic patients contain Y-chromosome material.
• Y material → increased risk of gonadoblastoma.

Clinical Features

• Typical features include:
  • short stature
  • neck swelling in infancy → later webbed neck
  • low posterior hairline
  • cubitus valgus
  • shield-like chest with widely spaced nipples
  • high-arched palate
  • lymphedema of hands and feet
• Important congenital abnormalities (Fig. 4.20):
  • horseshoe kidney
  • bicuspid aortic valve
  • coarctation of aorta
• Cardiovascular abnormalities are an important cause of childhood death.
• At puberty:
  • poor development of secondary sexual characteristics
  • minimal breast development
  • infantile genitalia
  • little pubic hair
  • primary amenorrhea
• Ovaries become streak ovaries:
  loss of follicles → fibrous ovarian tissue → ovarian failure.
• Intelligence is usually normal, although mild visual-spatial difficulties may occur.
• Autoimmune hypothyroidism is relatively common.
• In an adult female: short stature + primary amenorrhea → strongly suspect Turner syndrome
• Mosaic or deletion variants may have much milder features and may present only with primary amenorrhea.
• Diagnosis → karyotyping.

Pathogenesis

• Normally, both X chromosomes are active during oogenesis and are needed for normal ovarian development.
• Normal fetal ovaries contain millions of oocytes, which progressively decrease with age.
• In Turner syndrome: missing second X → accelerated oocyte loss → nearly complete by about 2 years → streak ovaries
• Therefore: oocyte depletion → ovarian failure → ↓ sex hormones → failure of normal puberty + primary amenorrhea
• Conceptually: “Menopause occurs before menarche.”
• Turner syndrome also affects growth and other tissues, showing that important somatic-development genes are present on the X chromosome.
• An important gene is SHOX (short stature homeobox) at Xp22.33.
• SHOX normally:
  • escapes X inactivation
  • remains active on both X chromosomes
  • has an active equivalent on the short arm of the Y chromosome
• Therefore, normal males and females both have two active SHOX copies.
• In Turner syndrome: loss of one SHOX copy → reduced SHOX dosage → short stature
• SHOX deletions are also found in about 2%–5% of otherwise unaffected children with short stature.
• However, SHOX loss explains mainly the short stature, not:
  • cardiac abnormalities
  • endocrine abnormalities
• Therefore, other X-chromosome genes also contribute to the Turner phenotype.

KEY CONCEPT

• Turner syndrome = phenotypic female + partial/complete X monosomy, classically 45,X.
• Missing X → rapid loss of oocytes → streak ovaries → primary hypogonadism + primary amenorrhea.
• Loss of SHOX → short stature.
• Major findings:
  short stature + webbed neck + streak ovaries + amenorrhea + congenital heart disease.
• Mosaic forms are usually milder.
• Y-chromosome material → increased gonadoblastoma risk.

CONCEPTUAL EXAMPLES

• 45,X → accelerated oocyte loss → streak ovaries → ↓ estrogen → absent normal puberty.
• Loss of one SHOX gene → impaired skeletal growth → short stature.
• 45,X/46,XX mosaic → some normal cells remain → milder phenotype.
• Turner syndrome with Y material → increased risk of gonadal tumor.