What is Turner syndrome and what are its major health risks?

Turner Syndrome: Definition and Major Health Risks

Turner syndrome is a genetic disorder affecting approximately 1 in 2,500 liveborn girls, caused by complete or partial loss of the second X chromosome, and is associated with substantially increased cardiovascular mortality—particularly from aortic dissection—alongside short stature, ovarian failure, and multiple organ system complications. 1

Genetic Basis and Karyotype Variants

• Turner syndrome results from complete or partial absence of one X chromosome, often presenting in mosaic karyotypes rather than pure monosomy X. 1
• Common karyotypes include classic monosomy X (40-50%), monosomy X mosaicism (3-25%), isochromosome X (10-18%), ring X (10-16%), and mosaicism with Y chromosome material (6-12%). 2
• The paternal X chromosome is absent in approximately 75% of cases, though parental age does not affect occurrence and recurrence risk for phenotypically normal parents is low. 2
• Approximately 99% of Turner syndrome conceptions result in pregnancy loss; surviving fetuses may show prenatal ultrasound findings including cystic hygroma and hydrops. 2

Cardinal Clinical Features

Short stature and ovarian failure are the most prevalent manifestations, but the phenotype extends far beyond these classic findings. 1

• Short stature is nearly universal and results partly from SHOX gene deficiency on the X chromosome. 3
• Premature ovarian failure with hypergonadotropic hypogonadism leads to delayed or absent puberty and infertility in most patients. 4, 2
• Additional physical features include lymphedema, webbed neck, and characteristic skeletal abnormalities. 1, 5
• Average age at diagnosis remains approximately 15 years despite often conspicuous phenotype, representing substantial diagnostic delay. 4

Cardiovascular Risks: The Primary Mortality Driver

Cardiovascular abnormalities are the leading cause of premature death in Turner syndrome, with aortic dissection representing the most catastrophic risk. 1

Structural Cardiac Defects

• Bicuspid aortic valve occurs in 15-30% of patients and independently predicts larger ascending aortic diameters. 1, 6
• Aortic coarctation affects 7-18% of patients (with some cohorts reporting up to 21%), typically located juxtaductally distal to the left subclavian artery. 6, 7
• Ascending aortic dilation is present in approximately 33% of individuals and constitutes a major contributor to cardiovascular mortality. 1, 6
• Other congenital defects including ventricular septal defects, atrial septal defects, and additional valve abnormalities occur at lower frequencies but require screening. 6

Aortic Dissection: Quantifying the Risk

• The population-based incidence of aortic dissection is 36 per 100,000 patient-years (approximately 1.4% lifetime risk), representing a six-fold increase compared to the general population. 1
• Mean age at aortic dissection is 31 years, and survival after dissection is less than 50%. 1
• Major risk factors include bicuspid aortic valve, aortic coarctation, hypertension, and aortic dilation. 1, 6
• Pregnancy substantially elevates aortic dissection risk, especially with pre-existing cardiovascular abnormalities. 1, 6

Critical Measurement: Aortic Size Index (ASI)

For patients ≥15 years old, the American Heart Association recommends calculating ASI to assess dissection risk rather than using absolute aortic diameters, which systematically underestimate risk in short-statured patients. 1, 6

• ASI = maximal aortic diameter (cm) ÷ body surface area (m²) 1, 6
• ASI >2.0 cm/m² is abnormal 1
• ASI >2.3 cm/m² indicates increased dissection risk requiring at least annual surveillance 1, 6
• ASI ≥2.5 cm/m² with risk factors warrants consideration for prophylactic surgical replacement of the aortic root/ascending aorta 1, 6
• For children <15 years, Turner syndrome-specific z-scores should be used instead of general population references to avoid overestimating risk. 1, 7

Endocrine and Metabolic Complications

• Type 1 and type 2 diabetes mellitus occur at increased rates, requiring lifelong metabolic surveillance. 4, 3
• Thyroid disease and autoimmune disorders are more prevalent than in the general population. 4, 3, 2
• Osteoporosis risk is elevated due to estrogen deficiency and requires monitoring and treatment. 4, 3

Neurocognitive Profile

• Average intellectual performance falls within the normal range, though specific learning differences may be present. 3
• The neurocognitive phenotype does not typically include intellectual disability but may involve specific processing challenges. 3

Mandatory Surveillance Requirements

All patients with Turner syndrome require lifelong cardiovascular surveillance regardless of initial findings. 1

Initial Diagnostic Evaluation

• Both transthoracic echocardiography and cardiac MRI are required at diagnosis to evaluate for bicuspid aortic valve, aortic dilation, coarctation, and other congenital defects. 6, 7
• Cardiac MRI is essential because transthoracic echocardiography inadequately visualizes the mid-ascending aorta. 6

Ongoing Imaging Protocol

• Low-risk patients (no bicuspid aortic valve, coarctation, hypertension, or dilation): imaging every 5 years for children, every 10 years for adults 1, 6, 7
• Moderate-risk patients (ASI ≤2.3 cm/m², stable): imaging every 2-3 years 1
• High-risk patients (ASI >2.3 cm/m²): at least annual imaging, with increased frequency as ASI approaches 2.5 cm/m² 1, 6, 7
• Presence of bicuspid aortic valve, coarctation, or hypertension triggers more frequent imaging regardless of ASI. 1, 6

Hypertension: A Modifiable Risk Factor

• Hypertension is a major modifiable risk factor for aortic dissection and must be treated aggressively. 1, 6
• Beta-blockers and/or angiotensin receptor blockers should be considered to potentially inhibit aortic growth. 6

Pregnancy Considerations

• Mandatory thorough cardiovascular evaluation is required before attempting pregnancy due to substantially elevated aortic dissection risk. 1, 6
• Risk is especially elevated with pre-existing bicuspid aortic valve or aortic abnormalities. 6
• Extensive pre-conception counseling is necessary, and pregnancy may be contraindicated in high-risk patients. 6
• Egg donation and oocyte vitrification represent fertility treatment options. 8

Critical Pitfalls to Avoid

• Never rely on absolute aortic diameters without indexing to body surface area, as this systematically underestimates dissection risk in short-statured Turner syndrome patients. 6, 7
• Never use transthoracic echocardiography alone for aortic surveillance, as cardiac MRI or CT is required to adequately visualize the mid-ascending aorta. 6
• Do not use general population z-scores in children <15 years; Turner syndrome-specific references are required. 1, 7
• For short-statured but obese patients or those with low body weight relative to height, an absolute aortic diameter >4.0 cm may indicate dissection risk even when ASI appears reassuring. 1

Multidisciplinary Care Requirements

• Turner syndrome affects multiple organ systems throughout all life stages, necessitating coordinated care across cardiology, endocrinology, gynecology, and other specialties. 4, 8
• The transition period from pediatric to adult care is particularly vulnerable and requires structured protocols. 3
• Care coordination is increasingly concentrated in specialized Turner syndrome centers. 8