What is the cause and etiology of Monosomy X (Turner syndrome)?

Monosomy X: Causes and Etiology

Chromosomal Mechanism

Monosomy X (Turner syndrome) is caused by the complete or partial absence of the second sex chromosome, resulting from instability and loss of the paternal sex chromosome during meiosis in approximately 80% of cases. 1

The fundamental etiology involves:

• Loss of the paternal X or Y chromosome during parental gametogenesis, accounting for three-quarters of cases where the paternal X chromosome is absent 2
• Meiotic instability of the Y chromosome leading to its loss is the primary mechanism generating the 45,X karyotype 1
• The maternal X chromosome remains in 80% of patients, indicating the paternal contribution is lost 1

Karyotype Distribution

The chromosomal abnormalities in Turner syndrome follow a specific distribution pattern:

• Classic monosomy X (45,X): 40-50% of cases 2
• Monosomy X with mosaicism: 3-25% of cases 2
• Isochromosome Xq: 10-18% of cases 2
• Ring X chromosome: 10-16% of cases 2
• Mosaicism with Y chromosome material (45,X/46,XY): 6-12% of cases 2
• Deletion of Xp: <5% of cases 2
• Unbalanced X-autosome translocation: <2% of cases 2

Genetic Pathophysiology

The phenotypic manifestations result from specific genetic mechanisms:

• Haploinsufficiency of multiple genes on the X chromosome short arm (Xp) is sufficient to produce the Turner syndrome phenotype 1
• SHOX gene haploinsufficiency on the short arm of the X chromosome causes the universal finding of short stature 3
• Deletion of the short arm of the X chromosome produces the characteristic features, implicating multiple genes beyond SHOX 1

Parental and Recurrence Factors

Important etiologic considerations for counseling:

• Parental age does not affect the occurrence of complete loss of one X chromosome 2
• Recurrence risk is low for phenotypically normal parents who have a child with Turner syndrome 2
• The parental origin of the remaining X chromosome has no clinical utility in routine Turner syndrome management 2

Prenatal vs. Postnatal Presentation

The timing of diagnosis reflects different survival patterns:

• Nearly all first-trimester fetuses with Turner syndrome have pure 45,X karyotype 1
• Approximately 99% of Turner syndrome conceptions result in pregnancy loss 2
• Most living patients are mosaics rather than pure 45,X, suggesting mosaic forms have better survival 1
• Prenatal ultrasound findings include cystic hygroma and hydrops fetalis 2

Clinical Implications of Karyotype Variability

The chromosomal complement influences but does not reliably predict clinical presentation:

• Pure 45,X karyotype presents with delayed puberty more frequently than mosaic forms (46,XX or 47,XXX cell lines) 1
• Phenotypic features vary significantly depending on mode of ascertainment, with postnatal diagnosis typically indicating more severe phenotype than prenatal detection 1
• Y chromosome material presence (in 10% of cases) increases risk for gonadoblastoma and requires bilateral prophylactic gonadectomy 4, 5

Associated Cardiovascular Etiology

Turner syndrome includes specific cardiovascular developmental abnormalities:

• Altered connective tissue composition due to X chromosome haploinsufficiency leads to aortic dilatation, bicuspid aortic valve, and coarctation 5
• Cardiovascular defects occur in approximately 50% of patients, including bicuspid aortic valve (15-30%), aortic coarctation (7-18%), and ascending aortic dilation (33%) 6