Provide a comprehensive overview of Turner syndrome, including genetics, clinical features, diagnosis, management, and follow‑up.

Turner Syndrome: Comprehensive Overview

Genetics and Epidemiology

Turner syndrome results from complete or partial loss of the second X chromosome and affects approximately 1 in 2,500 to 3,000 liveborn girls. 1, 2

• Only 40–50% of patients have classic 45,X monosomy; the remaining cases include mosaicism (3–25%), isochromosome Xq (10–18%), ring X chromosomes (10–16%), Y chromosome mosaicism (6–12%), Xp deletions (<5%), and X-autosome translocations (<2%). 3, 4
• The paternal X chromosome is absent in approximately 75% of cases. 4
• Approximately 99% of Turner syndrome conceptions result in spontaneous pregnancy loss; prenatal ultrasound findings include cystic hygroma (present in 50–80% of prenatally detected cases) and nonimmune hydrops fetalis. 5, 4
• Recurrence risk for phenotypically normal parents is low. 4

Clinical Features

Cardinal Features

• Short stature is universal in classic 45,X monosomy (100%) and present in approximately 78% of mosaic forms. 5, 6
• Ovarian dysgenesis with hypergonadotropic hypogonadism leads to primary amenorrhea in all patients with 45,X monosomy and 63% of those with other karyotypes; the remainder experience secondary amenorrhea. 5, 6

Physical Dysmorphic Features

• Webbed neck (pterygium colli) is a classic visible stigma. 5, 7
• Lymphedema of hands and feet, particularly prominent in infancy. 5, 8

Cardiovascular Abnormalities

Approximately 50% of patients have cardiovascular defects, which represent the leading cause of premature mortality. 1, 8

• Bicuspid aortic valve (BAV) occurs in 15–30% of patients. 1, 5, 9
• Aortic coarctation is present in 7–21% of patients, typically located juxtaductally distal to the left subclavian artery. 1, 5, 9
• Ascending aortic dilation affects approximately 33% of patients. 1, 5, 9
• Aortic dissection occurs at a population-based incidence of 36 per 100,000 patient-years (approximately 1.4% lifetime risk), representing a six-fold increase compared with the general population; 85% are type A (ascending) and 15% are type B (descending). 1, 8
• The mean age at aortic dissection is 31 years, with survival after dissection less than 50%. 8
• Other structural cardiac anomalies include ventricular septal defects, atrial septal defects, and additional valve abnormalities at lower frequencies. 9

Endocrine and Metabolic Disorders

• Hypothyroidism occurs with increased frequency and requires regular screening. 5
• Increased risk of type 1 and type 2 diabetes mellitus. 2, 4
• Osteoporosis develops due to estrogen deficiency. 2

Other Organ System Involvement

• Renal anomalies occur with increased frequency. 5, 6
• Autoimmune disorders are more common. 5, 2, 4
• Recurrent otitis media is frequently reported. 6

Diagnosis

Timing and Presentation

• The average age at diagnosis is approximately 15 years, representing substantial diagnostic delay despite often conspicuous phenotype. 2
• Only 36.5% of patients are diagnosed in infancy; the remainder are diagnosed during childhood or later. 6
• Karyotype variations affect phenotype but do not reliably predict clinical presentation. 6

Diagnostic Evaluation

All patients require chromosomal analysis (karyotype) for definitive diagnosis, as clinical features alone are insufficient. 4, 6

• Karyotype should be performed promptly in all suspected cases during childhood to enable early management planning. 6

Management

Initial Cardiovascular Assessment

At the time of diagnosis, perform both transthoracic echocardiography (TTE) and cardiac MRI to evaluate for BAV, aortic coarctation, aortic dilation, and other congenital cardiovascular abnormalities. 1, 5, 9

• Relying solely on TTE is inadequate because the mid-ascending aorta requires cardiac MRI or CT for proper visualization. 9

Aortic Size Index (ASI) Calculation

For patients ≥15 years old, calculate the Aortic Size Index (ASI) by dividing maximal aortic diameter (cm) by body surface area (m²) to assess dissection risk. 1, 8, 9

• ASI >2.0 cm/m² is considered abnormal. 1, 8
• ASI >2.3 cm/m² indicates increased dissection risk. 1, 9
• ASI ≥2.5 cm/m² is associated with markedly increased risk of aortic dissection. 1, 8, 9
• For children <15 years old, use Turner syndrome-specific z-scores rather than ASI to avoid overestimating risk. 1, 8

Cardiovascular Surveillance Protocol

Surveillance imaging frequency depends on ASI and presence of risk factors (BAV, coarctation, hypertension, aortic dilation): 1, 9

• Children without risk factors: TTE or MRI every 5 years. 1, 9
• Adults without risk factors: TTE or MRI every 10 years. 1, 9
• ASI >2.3 cm/m²: At least annual imaging is mandatory. 1, 5, 9
• ASI approaching 2.5 cm/m²: Increase imaging frequency beyond annual. 1, 9
• Before planned pregnancy: Mandatory comprehensive cardiovascular evaluation. 1, 9

Surgical Intervention Thresholds

In patients ≥15 years old with ASI ≥2.5 cm/m² plus risk factors (BAV, coarctation, hypertension), prophylactic replacement of the aortic root, ascending aorta, or both is reasonable (Class IIa recommendation). 1, 9

• In those without risk factors but ASI ≥2.5 cm/m², surgical intervention may be considered (Class IIb recommendation). 1, 9
• For short-statured but obese patients or those with low body weight relative to height, an absolute aortic diameter >4.0 cm may be a more accurate indicator of dissection risk than ASI alone. 8

Hypertension Management

Treat hypertension aggressively, considering beta-blockers and/or ARBs to potentially inhibit aortic growth. 9

• Hypertension is a major modifiable risk factor for aortic dissection. 1, 8, 9

Pregnancy Considerations

Pregnancy carries substantially increased cardiovascular risk, particularly for aortic dissection, and requires mandatory pre-conception cardiovascular evaluation with extensive counseling. 5, 8, 9

• Risk is especially elevated with pre-existing BAV or aortic abnormalities. 9
• Surveillance imaging should be performed before planned pregnancy. 1

Growth and Hormone Replacement Therapy

• Growth hormone therapy is used to address short stature. 2
• Hormone replacement therapy is necessary for ovarian dysgenesis and hypogonadism. 2

Multidisciplinary Care

• Lifelong multidisciplinary care is required due to involvement of multiple organ systems through all stages of life. 2, 7

Critical Pitfalls to Avoid

Using absolute aortic diameters without indexing to body size systematically underestimates dissection risk in Turner syndrome patients due to their characteristic short stature. 1, 5, 9

• Type A aortic dissection may occur at relatively small absolute aortic diameters. 1

Failure to perform baseline cardiac MRI at diagnosis misses important structural abnormalities not visible on echocardiography alone. 5, 9

Inadequate surveillance frequency for patients with ASI >2.3 cm/m² (requires at least annual imaging, not longer intervals such as 5–10 years). 5, 9