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Prevalence is about 5/10 000 live female births. Incidence among all conceptions is higher, since aneuploidy is a common cause of spontaneous abortion.

Patients typically present with significant statural growth retardation during childhood and/or primary ovarian insufficiency, often associated with homogeneous X monosomy. However, clinical features are heterogeneous and some may be milder or even absent in front of a 45,X/46,XX mosaic karyotype. Approximately 30% of patients will undergo the first pubertal stages such as breast development, 20% will experience spontaneous menarche and 95% have primary ovarian insufficiency before the age of 40. Around 5-7% are able to have a natural pregnancy. Patients may have a low posterior hairline, webbed neck, broad chest, hypoplastic nails, skeletal anomalies, congenital cardiovascular abnormalities (bicuspid aortic valves, aortic coarctation) as well as acquired vascular features, such as hypertension (50% of adult cases). Monitoring of aortic root diameters indexed to body surface area is recommended, since aortic bicuspidy, coarctation and hypertension may lead to aortic root dilatation and ultimately to aortic dissection. Other manifestations are renal defects, congenital lymphedema, liver steatosis or other hepatic diseases, ophthalmologic problems, hypothyroidism and autoimmune disorders. Intellectual disability is rarely reported, but patients may present impaired social skills and subtle cognitive difficulties. Variable comorbidities include obesity, insulin-resistance, conductive and sensorineural hearing impairment associated with repeated otitis media during childhood, and hyperlipidemia.

X monosomy is the most common underlying etiology, while some cases have mosaicism or structural X chromosome anomalies. Clinical signs are more severe in patients with 45,X monosomy than in 45,X/46,XX or 45,X/46,XX/47,XXX mosaicism. Patients with an X isochromosome have a higher risk of liver and autoimmune diseases, while those with a ring chromosome are more prone to growth retardation and metabolic disorders. Haploinsufficiency of the SHOX gene is a well-established cause of short stature. The presence of Y material is related to the occurrence of gonadoblastoma.

Suggestive clinical findings are confirmed by lymphocytic karyotype, demonstrating a 45,X cell line or deletion of the short arm (Xp) of the X chromosome. A second cell line study, such as buccal or urinary cell FISH analysis, may also be helpful.

Differential diagnosis includes Noonan syndrome; 46,XX gonadal dysgenesis; 46,XY complete gonadal dysgenesis, SHOX-related short stature, as well as a single deletion of the long arm of the X chromosome downstream of Xq24.

Typical forms with associated malformations can be diagnosed during ultrasound examination showing fetal abnormalities including diffuse edema, increased nuchal translucency, cystic hygroma, and left-sided obstructive cardiac anomalies. Noninvasive screening of circulating cell-free fetal DNA in maternal serum, amniocentesis or chorionic villus sampling can detect X chromosome abnormalities. Karyotyping must be repeated postnatally to confirm the diagnosis.

Early diagnosis is beneficial, as it is recommended to start recombinant growth hormone therapy (GH) around 4-6 years and preferably before 12-13 years in case of growth failure (< 50th percentile) or short stature. This requires monitoring of insulin-like growth factor 1 and glycemia, due to a higher risk of glucose intolerance. A majority of patients require induction of puberty with estrogen replacement therapy at gradually increased doses, followed within 2 years by progestin supplementation to minimize endometrial hyperplasia and the long term risk of endometrial carcinoma. Hormonal replacement therapy with estrogen and progesterone/progestin is prescribed until the mean age of natural menopause (51 yrs). Lifelong follow-up is necessary, especially for the regular evaluation of aortic diameters.

Early diagnosis, timely pubertal induction, successful transition to adult care, and long-term follow-up by a multidisciplinary team are key elements in the achievement of optimal growth, psychosocial milestones and fertility.