Why does Turner syndrome occur if one of a woman's X chromosomes is normally inactivated (condensed)?

Why Turner Syndrome Exists Despite X-Chromosome Inactivation

Turner syndrome exists because, despite X-chromosome inactivation in females, both X chromosomes are required for normal development, as genes on both X chromosomes are essential for survival and proper development even when one is largely inactivated.

The Role of X Chromosomes in Development

Turner syndrome occurs when a female has complete or partial absence of one X chromosome, resulting in a 45,X karyotype (monosomy X) or other structural abnormalities of the X chromosome 1. While it's true that one X chromosome in females is normally inactivated through a process called X-chromosome inactivation (XCI), this inactivation is incomplete and critical for understanding why Turner syndrome occurs:

• Incomplete X-Inactivation: Approximately 23% of genes on the X chromosome escape inactivation 1. These genes are expressed from both X chromosomes in females.

• Pseudoautosomal Regions: Both X chromosomes contain regions that do not undergo inactivation and are essential for normal development.

• Mosaic Expression: X-inactivation occurs randomly in each cell during early development, creating a mosaic pattern where some cells express genes from one X chromosome and others express genes from the other X chromosome.

Why Both X Chromosomes Are Necessary

Despite inactivation, both X chromosomes serve critical functions:

1. Gene Dosage: Genes that escape inactivation require proper dosage from both X chromosomes for normal development.

2. Developmental Timing: Both X chromosomes are active during early embryonic development before random inactivation occurs.

3. Genetic Redundancy: Having two X chromosomes provides backup genetic material if one contains mutations.

Clinical Manifestations of Turner Syndrome

The absence of genetic material from the second X chromosome leads to various clinical manifestations:

• Cardiovascular Issues:

  • 10-25% have bicuspid aortic valve 2
  • ~8% have aortic coarctation 1
  • 33% show aortic dilatation 1
  • Significantly increased risk of aortic dissection (36:100,000 Turner syndrome years vs. 6:100,000 in general population) 1, 2

• Reproductive System:

  • Primary hypogonadism (gonadal dysgenesis) 3
  • Primary amenorrhea in 67.1% of cases 3
  • Secondary amenorrhea in 6.6% of cases 3

• Growth: Short stature is a universal finding 4, 5

• Other Features:

  • Increased risk of autoimmune disorders (thyroid disease, celiac disease) 6
  • Increased risk of metabolic disorders including diabetes 6
  • Skeletal abnormalities 7

Genetic Variants in Turner Syndrome

Turner syndrome can present with various karyotypes:

• Complete Monosomy X (45,X): 32-63.3% of cases 3, 5, 7
• Mosaicism (45,X/46,XX): 28.1-47% of cases 3, 5
• Structural X Chromosome Abnormalities: 21-28.1% of cases, including:
  • Isochromosome Xq (46,XisoXq): ~16.7% 7
  • Deletions of Xp or Xq 7
  • Ring X chromosomes 7

Clinical Implications of Different Karyotypes

The specific karyotype often correlates with clinical presentation:

• Monosomy X (45,X): Generally associated with more severe phenotypes, including short stature and primary amenorrhea 5

• Mosaicism: Often presents with milder phenotypes; patients with 45,X/46,XX mosaicism may have spontaneous puberty and even fertility in some cases 3, 5

• Structural Abnormalities: Clinical presentation depends on which genes are affected by the structural change 5

Screening and Monitoring

Due to the increased cardiovascular risks in Turner syndrome:

• Cardiovascular Screening: Baseline TTE and cardiac MRI at diagnosis to evaluate for bicuspid aortic valve, aortic dilation, and coarctation 2

• Aortic Size Index (ASI): Should be calculated for patients ≥15 years old to assess dissection risk 2

• Regular Monitoring: Ongoing cardiovascular surveillance based on risk factors 2

In conclusion, while X-inactivation does occur in females, the presence of both X chromosomes is essential for normal development due to genes that escape inactivation, pseudoautosomal regions, and the mosaic pattern of X-inactivation. The absence of one X chromosome in Turner syndrome leads to significant clinical manifestations that require lifelong monitoring and management.