Clinical manifestations and diagnosis of Turner syndrome

INTRODUCTION — Turner syndrome is one of the more common chromosome anomalies in humans and represents an important cause of short stature and ovarian insufficiency in females.

The clinical manifestations and diagnosis of Turner syndrome will be reviewed below. Management of Turner syndrome is discussed separately. (See "Management of Turner syndrome in children and adolescents" and "Management of Turner syndrome in adults".)

INCIDENCE AND PREVALENCE — Turner syndrome was first reported as a clinical syndrome (prior to the availability of karyotyping) in seven women with short stature, sexual immaturity, neck webbing, and cubitus valgus in a paper published in 1938 by Henri Turner, an Oklahoma physician [1]. However, Otto Ulrich had already described an eight-year-old girl with a similar phenotype several years earlier [2].

Turner syndrome is the most common sex chromosome abnormality in females and occurs in approximately 1 in 2000 to 1 in 3000 live female births, based on epidemiological and newborn genetic screening data from Europe, Japan, and the United States [3-6]. The true prevalence of Turner syndrome remains difficult to ascertain because patients with a milder phenotype may remain undiagnosed. Some individuals are not diagnosed until late adulthood if their phenotype is mild [7].

Turner syndrome occurs with more or less the same prevalence in all ethnic groups and in different countries. However, the prevalence at birth may be declining in some countries. This is related to the increased use of ultrasonographic screening prenatally and the fact that some mothers carrying fetuses with Turner syndrome choose to terminate the pregnancy [8,9]. On the other hand, most gestations (likely more than 99 percent) affected by X chromosome monosomy (45,X) do not survive to birth. The 45,X genotype is found in at least 10 percent of all spontaneous abortions [10-14].

PATHOGENESIS — Turner syndrome is a sex chromosome disorder caused by loss of part or all of an X chromosome. Genotypes associated with Turner syndrome are (table 1):

●45,X – 45,X haploinsufficiency (monosomy X) is found in approximately 45 percent of live births with Turner syndrome [15]. The X chromosome is derived from the mother in two-thirds of patients and from the father in the remaining one-third [16].

●45,X with mosaicism – Approximately one-half of all patients with Turner syndrome have a mosaic chromosomal complement (eg, 45,X/46,XX or 45,X/47,XXX, or 45,X mosaics with the X chromosome anomalies listed below); cell line mosaicism results from sex chromosome nondisjunction occurring during postzygotic cell division [17,18]. Presence and degree of mosaicism may differ among different tissues. Absence of mosaicism in a karyotype from a peripheral blood sample does not universally preclude mosaicism in other tissues. Mosaicism with a normal cell line in the fetal membranes may protect placental function and enhance fetal survival [19]. In addition, the clinical phenotype of girls with mosaicism for a normal cell line is often milder compared with that seen in 45,X patients, although this depends on which tissues are affected by the mosaicism and on the developmental timing of the mosaicism. Low degrees of mosaicism can be found in phenotypically normal females.

●X chromosome anomalies – Several types of anomalies in the X chromosome can cause Turner syndrome, with or without mosaicism:

•Isochromosome Xq (46,X,i(X)q) – This is a structurally abnormal X chromosome, consisting of two copies of the long arm of the X chromosome connected head-to-head, with some intervening centromeric (or short arm) chromosome material [15]. Patients with 46,X,i(X)q) are, by definition, monosomic for the short arm of the X chromosome. They are also believed to be at a higher risk for autoimmune disorders such as thyroiditis.

•Ring chromosome X (rX) – A ring chromosome X (rX) may form if part of the end of both the short and long arms of the X chromosome are missing; this anomaly is functionally similar to a deletion of the distal part of the short arm (Xp deletion) [20]. If the X-inactivation site XIST is also missing (usually with small rings), the risk for significant developmental delay is substantially increased and the patient may also have physical features that are not typical for Turner syndrome per se (early and more severe growth failure, atypical facial dysmorphisms, and syndactyly) [21,22]. (See 'Psychologic and educational issues' below.)

•Xp or Xq deletion – Some patients have a deletion of a portion of the short arm of the X chromosome [del(X)p], while others have 45,X/46,X,del(X)q mosaicism. If a patient only has cells with a terminal Xq deletion, she may only have ovarian insufficiency but no other features of Turner syndrome [23]. Such a patient, in principle, does not really have Turner syndrome.

●Turner syndrome with Y-chromosome mosaicism – Approximately 10 to 12 percent of all individuals with Turner syndrome have mosaicism involving a cell line containing Y chromosome material [24]. These patients may be identified if marker chromosomes (sex chromosome material of uncertain origin) are detected on the karyotype or if they present with virilization. In such patients, it is important to perform further testing to determine whether Y chromosome material is present because of the increased risk of gonadoblastoma. A 45,X/46,XY karyotype has been associated with a variety of phenotypes, ranging from the typical phenotype of Turner syndrome, to an ovotesticular disorder of sex development with genital ambiguity, to a normal male phenotype with infertility [25]. The latter individuals are not considered to have Turner syndrome. (See 'Y chromosome mosaicism' below.)

The tips of the short arms of the X and Y chromosomes are logical sites for Turner syndrome-related genes as sex chromosomes undergo meiotic recombination within the pseudo-autosomal region and normally escape X inactivation. Some of the phenotypic characteristics of Turner syndrome have been localized to specific genes:

●The homeobox gene, SHOX (short stature homeobox-containing gene on the X chromosome), is associated with short stature in Turner syndrome and in Leri-Weill dyschondrosteosis, but also in up to 15 percent of cases of idiopathic short stature, depending on the patient cohorts studied [26-30]. Short stature is the only clinical finding invariably associated with the 45,X karyotype and SHOX deficiency; it also is the only phenotypic abnormality present in virtually 100 percent of patients with Turner syndrome.

●For gonadal insufficiency, a gene for bone morphogenetic protein 15 (BMP15) on the short arm of the X chromosome (Xp), as well as two genes encoding fragile X messenger ribonucleoprotein or FMRP (FMR1 and FMR2), on the long arm (Xq) have been implicated [31] (see "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)"). Accordingly, deletions of the long arm of the X chromosome have been reported in otherwise normal women (ie, normal stature) with either primary or secondary amenorrhea [32].

●For certain cardiac defects, correlations with specific karyotypic abnormalities suggest loci on the short arm of the X chromosome, but these phenotypes have not yet been linked to specific genes [33,34]. However, one study suggests that there may be a synergistic interaction between loss of the X chromosome gene, TIMP1, and a deleterious variation in TIMP3 that increases the risk of bicuspid aortic valve and thoracic aortic aneurysms [35].

Other mechanisms also play a role in the development of Turner syndrome phenotypes. The phenomenon of imprinting may play an important role, as suggested by the differences that exist between individuals with maternally derived X chromosome material compared with those with paternally derived X chromosome material [36]. For example, a study using magnetic resonance imaging (MRI) detected that prepubertal brain volume is correlated with the dose of maternal X chromosome [37]. Imprinting may explain some of the differences between 45,X females and 46,XX females. Using a mouse model of Turner syndrome, there is preliminary evidence for an association between aortopathy and an X-linked parent-of-origin effect on aortic valve malformation [38]. A mechanical effect from fetal lymphedema during organ development is thought to contribute to development of the webbing of the neck, shield chest, and probably the ear malformations, renal anomalies, and certain cardiac defects, but the specific genetic mechanism for the development of severe lymphedema remains to be elucidated [39-42].

CLINICAL MANIFESTATIONS

Typical features — The most consistent characteristic of girls and women with Turner syndrome is their short stature (table 2 and picture 1). Other anomalies include a "shield" chest with the appearance of widely spaced nipples, a short and webbed neck, cubitus valgus, and Madelung deformity of the forearm and wrist (picture 2 and image 1). The shield chest and short stature sometimes give a disproportionately broad or stocky appearance. Neonates may have congenital lymphedema of the hands and feet, webbed neck, nail dysplasia, narrow and high-arched palate, and short fourth metacarpals and/or metatarsals [43].

Hearing loss, hypothyroidism, and liver function abnormalities often occur as the girls get older [44,45]. Liver enzymes are mildly elevated in approximately 35 to 45 percent of adult patients [46,47] and often improve with estrogen/progestin hormone therapy [46]. Intelligence is usually within the normal range, but patients may have specific neurocognitive deficits, eg, problems with visuospatial organization or a nonverbal learning disorder. (See 'Psychologic and educational issues' below.)

Other manifestations include increased risk of autoimmune diseases (including autoimmune thyroiditis) [48] and specific morphologic defects of facial development and cardiovascular, urologic, and bone structure, as detailed in the following sections [44,49,50].

Short stature and skeletal anomalies — Short stature combined with a stocky appearance is the most common clinical feature of Turner syndrome. Recombinant human growth hormone therapy is recommended to optimize adult height, and prompt recognition and diagnosis of Turner syndrome is important to provide optimal benefits from growth hormone treatment. For monitoring growth, the height of patients with Turner syndrome should be plotted on growth curves specific for this disorder (figure 1) [51,52]. (See "Management of Turner syndrome in children and adolescents".)

If left untreated, the adult height in Turner syndrome is approximately 20 cm below that of the general female population [52]. Adult height is correlated with parental stature, as in the general population, but the height is significantly less than would be predicted for a girl without Turner syndrome. The short stature is secondary to abnormal growth patterns throughout life. The stocky appearance is a consequence of relatively greater reduction in body height than width and because many girls are overweight. Girls with Turner syndrome are often born with a mild degree of growth retardation (mean birth length is approximately -1 standard deviation [SD]). Linear growth remains slow during infancy and throughout childhood. The growth failure is further compounded by delayed puberty, with lack of a pubertal growth spurt. Unfortunately, many girls, in spite of their short stature, are not diagnosed until approximately age 8 to 10 years (or later), which is too late to derive full benefit from treatment with growth hormone. For individuals with Turner syndrome who are not diagnosed during infancy, the average delay of diagnosis in the United States is approximately five years after the patient falls below the fifth percentile for height. When assessing the growth of any girl with short stature, the provider should compare that girl's height percentile not only with the general female population, but also with the expected target height percentile based on the parental heights. (See "Diagnostic approach to children and adolescents with short stature", section on 'Evaluation of growth'.)

Scoliosis and/or kyphosis develops in approximately 20 percent of patients [53,54]. A number of developmental abnormalities of the skeleton result in additional findings that are characteristic of Turner syndrome, including short neck (hypoplasia of the neck vertebrae), Madelung deformity (bayonet deformity of the wrist) (picture 2 and image 1), cubitus valgus (increased carrying angle of the elbow; present in approximately 50 percent of individuals with Turner syndrome) (figure 2), genu valgum (knock-knee) or varum (bow-leggedness), and short fourth metacarpal (small knuckle) and/or metatarsal bones.

Ovarian failure — Primary hypogonadism is one of the most common features of Turner syndrome, and Turner syndrome is one of the most common causes of premature ovarian failure. Most affected women have no breast development and have primary amenorrhea. Approximately 15 to 30 percent of women with Turner syndrome either have initial breast development followed by pubertal arrest, or complete puberty but then develop secondary amenorrhea. A small percentage of women have normal pubertal development and regular menstruation. These milder phenotypes of ovarian failure are more common in girls with mosaicism (predominantly 45,X/46,XX) compared with those with 45,X monosomy.

Although the onset of adrenarche is normal in many girls with Turner syndrome, an earlier onset of adrenarche, but followed by delayed pubarche, can be observed in those girls who have already developed primary ovarian failure in late childhood. This may be an indication that the timing of adrenarche and pubarche in girls is dependent on normally functioning ovaries [55]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

Because of the ovarian failure, many girls with Turner syndrome have elevated serum concentrations of follicle-stimulating hormone (FSH). In some cases, the elevated FSH is discovered before the diagnosis of Turner syndrome is made (see "Evaluation and management of primary amenorrhea"). However, it is important to note that a normal FSH does not exclude the possibility of Turner syndrome. Measurement of anti-müllerian hormone (AMH) may be more sensitive as a marker of pending ovarian failure than FSH [56]. (See "Management of Turner syndrome in children and adolescents", section on 'Induction of puberty'.)

Although normal menarche is uncommon in women with Turner syndrome, the possibility of Turner syndrome should still be considered in any girl with unexplained short stature, even if she went through puberty and is having menstrual cycles. As an example, a retrospective study of 522 patients with Turner syndrome who were over the age of 12 years found that 84 (16 percent) had spontaneous menarche at an average age of 13.2 years; 30 of these women still had regular menses nine years after menarche, and three became pregnant without medical assistance [57]. In a second retrospective study of 276 adults with cytogenetically proven Turner syndrome, five women had spontaneous puberty and spontaneous pregnancies, despite high-grade monosomy (45,X in ≥90 percent of a 50-cell karyotype) [58].

The ovaries in Turner syndrome characteristically consist of small amounts of connective tissue without follicles or only a few atretic follicles ("streak gonads"). However, the degree of ovarian dysfunction is variable, ranging (at the extremes) from no ovarian function to completely normal function with normal menarche and normal reproductive function for at least a few years after menarche. Careful histologic studies of the ovaries of eight aborted 45,X fetuses are the basis of our understanding of the gonadal failure in Turner syndrome [59]. These ovaries contained apparently normal numbers of primordial germ cells for up to at least six weeks of gestation, but at later gestational ages, the numbers of germ cells were decreased and connective tissue was increased compared with age-matched normal fetuses. These findings indicate that the gonadal failure is caused by accelerated apoptosis rather than abnormal germ cell formation. The underlying mechanisms for this increased rate of loss of oocytes are yet to be determined, but haploinsufficiency of genes on the X chromosome likely leads to decreased oocyte survival (ie, two copies of these gene[s] are necessary for normal oocyte survival).

The spectrum of ovarian pathology in Turner syndrome is illustrated by a study that evaluated 104 girls aged 0.2 to 17.4 years with complete or partial X chromosome deletions using pelvic ultrasonography [60]. Approximately one-third had visible, non-streak ovaries. The girls with visible ovaries had apparently normal ovarian growth and follicular development up to the time of puberty and were more likely to have spontaneous breast development and uterine growth, indicating some ovarian function; many, but not all, of these girls had incomplete X chromosome deletions. These findings are consistent with several case reports of adult women with both 45,X and partial X chromosome deletions who conceived and bore children before developing secondary amenorrhea [61,62].

Because of the broad range of gonadal function, it is not easy to predict which girls will have absence of breast development versus those girls who will have spontaneous thelarche or even menarche. Evidence suggests that measurement of AMH is a sensitive marker of prepubertal follicular development and will be helpful in the ovarian assessment of Turner syndrome throughout childhood [56]. Specific imaging of the ovaries (eg, by ultrasound) is often not useful. (See "Management of Turner syndrome in children and adolescents", section on 'Induction of puberty'.)

Cardiovascular disease — Cardiovascular disease presents the most serious health problem for women with Turner syndrome and substantially contributes to the increased mortality rates for affected individuals. The morbidity and mortality are due to increased risk for cardiovascular malformations, compounded by renal abnormalities and hypertension [63,64], leading to increased risk for aortic dilatation and dissection. The presence of neck webbing and increased thoracic anterior-to-posterior diameters are useful predictors for cardiovascular abnormalities [39,65].

The prevalence of cardiovascular malformations in patients with Turner syndrome varies across studies. Cardiac MRI is generally more sensitive than echocardiography for detecting cardiovascular defects, especially for valvular disease, but also for systemic or pulmonary venous abnormalities, or for abnormally elongated transverse aorta [66]. Other reasons for variability among estimates across different studies include differences in the age group or the degree of mosaicism in the population examined. As an example, the prevalence of cardiovascular malformations appears to be higher in those with 45,X compared with those with a mosaic chromosomal complement (45,X/46,XX): 38 versus 11 percent [67].

Some of the more common cardiac malformations encountered in the Turner syndrome population include [68]:

●Any malformation – Up to 50 percent

●Aortic valve abnormalities (primarily bicuspid aortic valve) – 15 to 30 percent

●Elongated transverse aortic arch – 40 to 50 percent

●Other aortic arch abnormalities (primarily coarctation) – 7 to 18 percent [68,69]

●Ventricular septal defects – 1 to 4 percent

●Atrial septal defects – 1 to 2 percent

●Systemic venous abnormalities (such as persistent left superior vena cava) – 8 to 13 percent

●Pulmonary venous abnormalities – 13 to 15 percent

●Coronary artery abnormalities – Up to 2 percent

The prevalence of these cardiac abnormalities may vary depending on referral patterns, imaging study (echocardiogram versus cardiac MRI), and the focus of the examination [70].

Aortic valve disease and coarctation — Most case series report that approximately 30 percent of individuals with Turner syndrome have aortic valve abnormalities and up to 18 percent have coarctation, although the true prevalence for coarctation is likely lower [63,64,67,71-73]. A bicuspid aortic valve is particularly common, and patients with this anomaly are more likely to have additional cardiovascular abnormalities, such as aortic arch defects [64,72]. Even when initial cardiac MRI does not show aortic root dilation or coarctation, subsequent imaging may show the development of these abnormalities. Therefore, repeat scans are recommended. Despite the availability of detailed expert guidelines, the optimal frequency of repeat imaging is a subject of investigation [70,74]. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Clinical manifestations and diagnosis of bicuspid aortic valve in adults".)

Aortic dissection — Aortic dissection or rupture is an increasingly recognized cause of death in women with Turner syndrome [75,76]. The risk is predicted by a dilated ascending aorta, which is defined as an aortic size index (ASI) >2.0 cm/m² (which is >95^th percentile). To minimize the risk of dissection, all patients should have regular cardiovascular monitoring, with especially close follow-up for those with a dilated ascending aorta. (See "Management of Turner syndrome in children and adolescents", section on 'Cardiovascular anomalies' and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

Other risk factors for aortic dissection include a history of coarctation, the presence of a bicuspid aortic valve, and/or hypertension. However, not all women with Turner syndrome who develop aortic dissection have one of these risk factors, and dissection is not always preceded by progressive dilatation [77]. In individuals with Turner syndrome, aortic dissection tends to occur in the third or fourth decade of life, which is much earlier compared with aortic dissections in the general female population. A few cases of aortic dissection have been reported in children with Turner syndrome. Growth hormone therapy is not known to be associated with more dilation of the aorta or heart. (See "Management of Turner syndrome in children and adolescents", section on 'Growth hormone therapy'.)

In a study of 166 women with Turner syndrome and 26 healthy controls, close to one-third of the patients had an ASI >2.0 cm/m² [76]. After three years of follow-up, aortic dissections occurred in three patients, all of whom had an ASI >2.5 cm/m² (>99^th percentile). This translates to an annualized rate of 618 cases/100,000 woman-years, which is approximately 100-fold higher than that seen in women of similar age without Turner syndrome. In a report of 20 women with Turner syndrome who had already experienced an aortic dissection, mean ASI was 2.7±0.6 cm/m² [77]. This study showed that individuals with a dilated ascending aorta (ASI >2.0 cm/m²) require close cardiovascular surveillance. Patients with ASI ≥2.5 cm/m² are at the highest risk for aortic dissection.

Pregnancy and cardiovascular risk — The risk for aortic dissection or rupture is particularly high during pregnancy, which is typically achieved through in vitro fertilization (IVF) with oocyte donation. The risk of death during pregnancy may be as high as 2 percent [78]. The increased risk persists into the postpartum period, owing to pregnancy-related aortic changes. Therefore, before attempting to become pregnant, women with Turner syndrome should undergo a complete medical evaluation, with particular attention to cardiovascular and renal function, as recommended by the American Society of Reproductive Medicine (ASRM) and by the Turner syndrome consensus guidelines [79]. (See "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)

Hypertension — Hypertension is more common in women with Turner syndrome compared with controls, and its prevalence increases with age [80-82]. In a series of 62 patients (age range 5 to 22 years) with Turner syndrome, 30 percent were mildly hypertensive and 50 percent had an abnormal diurnal blood pressure profile as measured by 24-hour ambulatory blood pressure monitoring [80]. Neither the presence of renal or cardiac abnormalities, nor treatment with growth hormone or estrogen therapy, had an effect on blood pressure. In a study of 102 women with Turner syndrome (age range 18 to 62 years), the onset, progression, and treatment of hypertension was studied using 24-hour ambulatory blood pressure measurements over a 12-year period [83]. The systolic and diastolic blood pressure, and pulse pressure increased significantly with age. The number of patients treated with antihypertensive medicine increased from 29 percent at baseline to 53 percent towards the end of the study.

Vasculopathy — Girls and women with Turner syndrome have evidence of progressive vasculopathy, and coronary heart disease is an important contributor to their excess mortality in adulthood [84]. Evidence of vascular changes is already present in young girls with Turner syndrome, suggested by increased vascular resistance and stiffness in patients as young as 9 or 10 years of age [85]. Mechanisms likely include the associated cardiovascular risk factors of hypertension, dyslipidemia, and dysglycemia (see 'Hypertension' above and 'Metabolic syndrome and diabetes mellitus' below). Estrogen deficiency is a contributor to this risk, and estrogen therapy improves cardiovascular risk factors (lipid profile and aortic stiffness). In a study of 93 women with Turner syndrome, 11 with 46,XX primary amenorrhea, and 25 normal controls, mean carotid intima-media thickness was increased to a similar degree in the two hypogonadal groups, suggesting a primary role for estrogen deficiency [86]. However, the patients with Turner syndrome had additional abnormalities when compared with both the 46,XX primary amenorrhea and control groups, including increased common carotid, aortic root, and brachial artery diameters, suggesting additional genetic factors that contribute to their vasculopathy. (See "Management of Turner syndrome in children and adolescents", section on 'Benefits of hormonal therapy' and "Management of Turner syndrome in children and adolescents", section on 'Mortality'.)

Conduction abnormalities — A prolonged QT interval has been reported in 20 to 40 percent of girls and women with Turner syndrome [87-90]. This occurs at any heart rate and is associated with reduced heart rate variability, resting tachycardia, and absence of the normal nocturnal dip in blood pressure, indicating autonomic dysregulation. Other conduction and repolarization anomalies include right axis deviation, P and T wave abnormalities, and accelerated atrioventricular (AV) conduction [89].

Shortening of the PR interval may be related to excessive sympathetic drive. On the other hand, it is not known if QTc prolongation is an intrinsic feature of Turner syndrome per se, and a proposed correlation with variants in the genes associated with long QT syndrome (LQTS) merits further exploration. This QTc prolongation is likely associated with an increased risk for arrhythmias, although there is no evidence for an association with sudden cardiac death [89]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Renal anomalies — Congenital malformations of the renal/urinary system are present in approximately 30 to 40 percent of patients with Turner syndrome. The more common abnormalities include collecting system malformations (20 percent) and positional abnormalities, as well as horseshoe kidneys (10 percent). The latter anomaly is more often observed in patients with the 45,X karyotype. Malrotated kidneys and other positional abnormalities have been observed in 5 percent of the Turner syndrome population in some studies [3]. Anomalies associated with obstruction of the ureteropelvic junction can produce clinically significant hydronephrosis and risks for pyelonephritis. Abnormalities involving the renovascular supply are also detected with a higher frequency than in the normal population [91].

To identify renal anomalies, patients should undergo renal ultrasonography at the time that Turner syndrome is diagnosed. (See "Management of Turner syndrome in children and adolescents", section on 'Renal anomalies and urinary tract infections'.)

Osteoporosis and bone health — The risk of low bone mineral density (BMD) and fractures is increased in girls and women with Turner syndrome. Several factors may contribute to these findings: inadequate estrogen therapy and intrinsic bone abnormalities. Comorbidities that may further increase the risk of osteoporosis include vitamin D deficiency, celiac disease, and inflammatory bowel disease (IBD).

●Suboptimal estrogen replacement – The importance of this factor is suggested by some studies that report normal bone density in children and young adults who receive physiologic replacement doses of estrogen. As an example, in a study of 70 adult women with Turner syndrome who underwent BMD testing by dual-energy x-ray absorptiometry (DXA), osteoporosis was diagnosed in seven (10 percent), six of whom were over age 45 years [92]. None of the women with osteoporosis had ever received prolonged estrogen replacement. Fracture rates in the patients who had received estrogen therapy were no different from those of age-matched controls.

●Underestimation of bone mineral density in short subjects – A recognized limitation of DXA is that it measures areal rather than volumetric BMD, thus underestimating the BMD in smaller individuals. In a study of 40 adult women with Turner syndrome, osteoporosis was overdiagnosed in patients who were less than 150 cm tall, unless BMD measurements were adjusted for body size (and therefore bone size). After adjustment for body size, the prevalence of osteoporosis and fractures in the Turner syndrome patients who had been treated with estrogen was the same as age-matched controls without Turner syndrome [93].

●Intrinsic bony abnormalities – Bone structure abnormalities that are intrinsic to Turner syndrome are suggested by studies that control for both ovarian hormone deficiency and height. In a study comparing 41 women with Turner syndrome with a control group of 35 karyotypically normal women with premature ovarian failure, a selective reduction in cortical (forearm) BMD was seen in the Turner syndrome patients [94]. This difference persisted after adjustment for height, age of puberty, lifetime estrogen exposure, and serum 25-hydroxyvitamin D concentrations. Similarly, studies using high-resolution peripheral quantitative computed tomography (CT), which provides a more sensitive index of bone health than DXA, demonstrate that Turner syndrome patients have an abnormal trabecular microarchitecture and lower cortical bone porosity of the radius and tibia [95]. These intrinsic abnormalities of bone may be due to haploinsufficiency for bone-related X chromosome genes [96,97]. (See 'Pathogenesis' above.)

Thus, abnormal BMD appears to be intrinsic to Turner syndrome but can be minimized by optimal estrogen replacement, achieving target intakes of calcium and vitamin D, and perhaps growth hormone therapy [98]. The increased fracture risk may be explained by subtle Turner syndrome-specific bony abnormalities and, perhaps, also by coordination issues in younger patients, which may predispose them to falls.

Monitoring and management of bone health is discussed separately. (See "Management of Turner syndrome in adults", section on 'Bone health'.)

Risk of malignancy — Women with Turner syndrome whose karyotype includes a Y chromosome (as in 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma, a neoplasm that occurs in dysgenetic gonads [99]. In a population-based study, the cumulative risk for women with Turner syndrome and Y chromosome material was 7.9 percent by age 25 years [100]. If Y chromosome material is detected, prophylactic removal of the gonads is mandatory [69]. (See 'Y chromosome mosaicism' below and "Anatomy and pathology of testicular tumors", section on 'Gonadoblastoma'.)

For the general population of individuals with Turner syndrome (without Y chromosome material), risks for other cancers are probably similar to or minimally increased compared with the general population. A few studies suggest a possible increased risk for central nervous system malignancies (especially meningioma) or colon cancer [100,101]. However, other studies have reported a very low absolute risk for specific cancers [101,102]. An international consensus group suggests that screening for excess cancer is not indicated for women with Turner syndrome [69].

Although historical series indicate that the risk for breast cancer was reduced among women with Turner syndrome compared with the general population, the risk for women Turner syndrome managed in the modern era is unclear [69]. However, available data suggest that long-term estrogen use in women with Turner syndrome is not associated with an increased risk of breast cancer [103]. (See "Management of Turner syndrome in adults", section on 'Safety'.)

Ocular abnormalities — Ocular abnormalities are common among patients with Turner syndrome [104]. Nearsightedness (40 percent), farsightedness (13 percent), strabismus (15 to 30 percent), amblyopia (>15 percent), epicanthal folds (10 to 45 percent), ptosis (10 to 30 percent), hypertelorism (10 percent), and red-green color blindness (8 to 10 percent) have been noted in small case series [105-107]. Keratoconus, glaucoma, anterior lenticonus, cataracts, retinal vascular changes, and retinal detachment have been noted in case reports [104,108].

Hearing and ear abnormalities — Hearing loss associated with Turner syndrome has several mechanisms [109]:

●Conductive – Children with Turner syndrome have a high risk for recurrent otitis media and middle ear effusions, with associated conductive hearing problems. This occurs because of abnormalities of the eustachian tubes and cranial base [110].

●Sensorineural – Progressive sensorineural hearing loss develops by adulthood in more than 50 percent of patients, predominantly at a frequency of 1000 to 2000 Hz (sensorineural dip). The hearing loss is thought to be related to a defect in the outer hair cells of the lower middle coil of the cochlea. It is more common in women who have a 45,X or 45,X/46,i(Xq) karyotype and tends to worsen with age [111,112].

●Cholesteatoma – Turner syndrome is also associated with an increased risk for cholesteatoma (abnormal growth of keratinizing squamous epithelium cells in the middle ear) that can progressively enlarge leading to conductive hearing loss and destruction of the middle ear if not diagnosed and treated in a timely manner [113,114]. (See "Cholesteatoma in children".)

Patients with Turner syndrome should be monitored for these abnormalities throughout life. (See "Management of Turner syndrome in adults", section on 'Audiology testing'.)

Autoimmune disorders — Turner syndrome is associated with an increased risk of autoimmune disorders, especially autoimmune thyroid disease, celiac disease, and IBD [115]. The overall risk is approximately twice as high as in the general female population [48,116-118].

●Thyroid disease – The prevalence of autoimmune thyroid disease increases with increasing age. It is rare in the first four years of life. In a study of older children and adolescents (mean age 11.4 years), close to 16 percent had hypothyroidism, and 24 percent had positive thyroid antibodies [119]. The prevalence rises even higher during adulthood. In a prospective study that compared the frequency of autoimmune diseases in women with Turner syndrome (n = 244) with that of women with primary ovarian insufficiency (POI; ovarian failure) but normal karyotypes (46,XX) (n = 457) [48], autoimmune hypothyroidism occurred in 37 percent of women with Turner syndrome compared with 15 percent in women with POI. The prevalence in both groups was higher than that in healthy women with normal menstrual cycles (5.8 percent) based on normative data for the United States.

●Celiac disease – In the same study, the prevalence of celiac disease was significantly increased in Turner syndrome (2.7 percent) but not in POI [48]. In a separate study of 389 girls with Turner syndrome screened with immunoglobulin (Ig) A antigliadin antibodies and/or antiendomysial antibodies, 25 (6.4 percent) had celiac disease [120]. Of these, 10 had typical symptoms, eight had atypical symptoms, and seven had no symptoms. The prevalence of celiac disease in the general population of the United States and Europe ranges from 1:80 to 1:300 children (0.3 to 1.2 percent). (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Epidemiology'.)

●IBD – The prevalence of IBD in women with Turner syndrome is approximately 3 to 4 percent, which is substantially higher than in women with POI or the general population (<0.5 percent) [48,121]. (See "Genetic factors in inflammatory bowel disease", section on 'Turner syndrome'.)

Metabolic syndrome and diabetes mellitus — Patients with Turner syndrome are at risk for metabolic disorders. Insulin resistance, as measured by euglycemic clamp studies, is an early metabolic defect in girls with Turner syndrome [122]. In addition, an increased frequency of central obesity, type 2 diabetes mellitus, and dyslipidemia has been reported in adult women with Turner syndrome when compared with women without Turner syndrome [45]. The prevalence of type 2 diabetes mellitus in young adults with Turner syndrome ranges from 5 to 25 percent in different reports [45,123], which is substantially increased over the general population [124]. Patients also tend to have impaired insulin secretion [125,126]. A higher incidence for type 1 diabetes mellitus was reported based on analysis of a Danish Turner syndrome registry [63], but this has not been confirmed in other studies or in other countries [48,127].

Treatment with growth hormone reduces abdominal adiposity and improves glucose tolerance [128]. (See "Management of Turner syndrome in children and adolescents", section on 'Growth hormone therapy'.)

Abnormal liver enzymes — Increased concentrations of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transpeptidase [GGT]) occur with a higher frequency in adult women with Turner syndrome, rarely with progression to cirrhosis. The pathogenesis for these findings is still unclear, may be different in different patients, and may be multifactorial. In some patients, steatosis or non-alcoholic fatty liver disease is present; in others, an autoimmune process may play a role. The transaminitis is usually found upon routine laboratory testing and does not progress to overt liver disease. Estrogen therapy appears to be associated with improvement in the liver enzyme concentrations [46].

Skin — Girls with Turner syndrome may be more likely than others to develop pilomatrixoma, an uncommon benign skin neoplasm thought to arise from cells of the hair follicle [129-131]. In one study, these asymptomatic papules or nodules that most typically develop as single lesions on the head or neck were identified in 8 of 331 patients (2.6 percent) with Turner syndrome; there was no association between prior growth hormone therapy and the presence of skin lesions [129]. Although the prevalence of pilomatrixoma in the general population is not known, it is thought to be considerably lower than 2.6 percent. (See "Cutaneous adnexal tumors", section on 'Pilomatricoma'.)

An increased prevalence of pigmented nevi has been reported in Turner syndrome [132]. The prevalence of melanoma is probably slightly increased but less than would be expected for the excess number of pigmented nevi; routine surveillance of nevi is warranted [69]. A few studies suggest increased risk for keloid formation [133,134]. As an example, one study reported the development of hypertrophic scarring and keloid formation in 5 of 92 patients after undergoing surgery (5.4 percent) [134]. Some of the propensity for keloid formation may be because individuals with Turner syndrome tend to undergo surgery at sites that are vulnerable to keloid formation [3].

Psychologic and educational issues — Intelligence is usually normal in patients with Turner syndrome. The exception is the rare patient with a small X-ring chromosome, who may have severe intellectual disability, probably because such small X-ring chromosomes fail to undergo X-inactivation [21,135].

Although most individuals with Turner syndrome have normal intelligence, there are increased risks for selective impairment in nonverbal skills [3,136]. This may include deficits in social cognition; difficulty with nonverbal, problem-solving tasks such as mathematics; psychomotor deficits, such as clumsiness; and problems with visual-spatial organization, which may cause some issues with driving and maneuvering a car [137]. There is also an increased risk of attention deficit disorder (ADD) and problems with executive functioning. By contrast, verbal skills are often strong. The neurodevelopmental abnormalities may result from the X chromosome monosomy or from sex steroid (estrogen) deficiencies due to gonadal dysgenesis.

One report found that patients with Turner syndrome and a maternally derived X chromosome are more likely to have deficits in social and verbal function compared with those with a paternally derived X chromosome, suggesting that social functioning is influenced by an imprinted gene on the X chromosome that is switched off when this gene is inherited from the mother [138]. The existence of such a gene may partly explain the male-female differences in social cognition. It does not, however, provide an explanation for all psychological findings in Turner syndrome. Such an explanation would most likely involve an interplay between many genes and interacting environmental factors. These findings have not yet been confirmed by another study.

Specific strategies to prevent or minimize learning disabilities in individuals with Turner syndrome, including the effects of gonadal hormone replacement, are discussed separately. (See "Management of Turner syndrome in children and adolescents", section on 'Cognitive function and learning disabilities'.)

Mortality — Overall mortality rates in patients with Turner syndrome are increased approximately threefold when compared with the general population, with excess risk occurring at all ages and for most major causes of death [124,139]. This was best illustrated in a population-based study of 3439 patients with Turner syndrome in which the following results were seen (figure 3) [124]:

●Overall mortality was significantly higher than expected when compared with national mortality rates (standardized mortality rate [SMR] = 3). The relative risk of death was increased at all ages, but the absolute excess risk of death was higher in older patients.

Specific causes of excess mortality were:

•Noncongenital cardiovascular disease, most commonly coronary heart disease and stroke in older patients, which accounted for 41 percent of deaths.

•Congenital cardiovascular anomalies, which accounted for 8 percent of deaths. Aortic aneurysm was associated with the greatest increase in cardiovascular mortality rates, occurring in 17 women ages 15 to 44 years, seven of whom were under age 30 years (SMR = 280). (See "Management of Turner syndrome in children and adolescents", section on 'Cardiovascular anomalies' and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

•Pneumonia, diabetes, epilepsy, liver disease, and kidney disease, which accounted for a 3- to 11-fold increase in mortality.

●Mortality was increased for all karyotype groups but was higher among patients with nonmosaic 45,X than for patients with 46,X mosaicism (eg, 45,X/46,XX).

Estrogen deficiency throughout life may play a role in the noncongenital cardiovascular complications. In a report of 50 adult women with Turner syndrome with a mean age of 40 years, only 34 (68 percent) were still taking estrogen. Among the 16 women not taking estrogen, 11 had stopped because they were unaware of the health benefits of estrogen, and five were advised against its use by their clinicians [140]. Six of 16 women in the nonestrogen group had osteoporosis (three with vertebral compression fractures), compared with 0 of 34 in the estrogen group. (See 'Vasculopathy' above and "Management of Turner syndrome in adults", section on 'Estradiol therapy'.)

In a national cohort study of all individuals in Denmark diagnosed with Turner syndrome between 1977 and 2014, endocrine and cardiovascular mortality and morbidity were significantly increased compared with an age-matched reference population [141]. However, there was no difference in mortality among 45,X women treated with estrogen compared with those who were not treated (hazard ratio [HR] 0.83, 95% CI 0.38-1.79).

These observations highlight the importance of preventive measures and careful monitoring for complications in both children and adults with Turner syndrome.

DIAGNOSIS — Turner syndrome is occasionally diagnosed incidentally during prenatal testing [142]. More commonly, it is suspected postnatally based upon characteristic clinical features. The diagnosis is confirmed by karyotype analysis. Prompt diagnosis is important to permit management of comorbidities, including effective treatment of short stature.

Indications for testing — A karyotype analysis for Turner syndrome should be performed in any female with characteristic features, which vary by age group (table 3) [3]:

●Prenatal – Cases of Turner syndrome are sometimes discovered incidentally during chorionic-villus sampling or amniocentesis that was performed for unrelated reasons, such as advanced maternal age. Turner syndrome also may be suspected because of certain congenital anomalies noted on fetal ultrasonography, including septated cystic hygroma, lymphangiectasia (fetal hydrops), cardiac defects, nuchal thickening, kidney anomalies, or short femur. It is mandatory to repeat the karyotype at delivery (using cord blood or the neonate's blood) to either confirm the diagnosis, or rule it out (in case of an initial false-positive result), as recommended in international clinical guidelines on Turner syndrome care [69] (see "Sonographic findings associated with fetal aneuploidy", section on 'Monosomy X (Turner syndrome)'). Positive results from noninvasive prenatal testing (NIPT) such as with cell-free DNA in maternal blood should be interpreted with great caution, especially for sex chromosome abnormalities, for which this type of testing performs worse than it does for screening for anomalies such as trisomy 21 [143,144].

●Newborn period – Turner syndrome may be apparent at birth, presenting with congenital lymphedema of the hands and feet, webbed neck, nail dysplasia, narrow and high-arched palate, and short fourth metacarpal. (See 'Typical features' above.)

●Infants and children – In infants and children, Turner syndrome should be suspected in any female with unexplained growth failure, defined as a growth velocity less than the 10^th percentile for age or stature that is substantially less than predicted from parental heights. It should also be suspected in patients with other characteristic features, including lymphedema, webbed neck, left-sided cardiac defects (eg, aortic coarctation or hypoplastic left heart syndrome), high-arched palate, short fourth metacarpal, strabismus, recurrent otitis media, nail dysplasia, learning difficulties (eg, in mathematics), and others listed in the table (table 2).

The most common reasons for screening are lymphedema during infancy and short stature during childhood and adolescence [142,145]. In addition, the combination of hearing impairment before 40 years of age and short stature or other features of Turner syndrome should prompt screening.

●Adolescence – Turner syndrome should be suspected in adolescent girls who fail to start or complete breast development, or those with secondary amenorrhea, especially if short stature and/or other features suspicious of Turner syndrome are present. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

Diagnostic tests

Standard karyotype analysis — Genetic testing should be performed to confirm the diagnosis of Turner syndrome in any patient with the characteristic clinical features listed above. The first step is a karyotype analysis, usually using peripheral blood mononuclear cells. To detect mosaicism, a minimum of 30 cells in metaphase should be scored, as recommended by the American College of Medical Genetics (ACMG). Identification of mosaicism in Turner syndrome varies with the method of ascertainment, ranging from 34 percent with conventional cytogenetic techniques, to 60 percent with fluorescence in situ hybridization (FISH) techniques, to 74 percent in a study in which reverse transcriptase polymerase-chain-reaction (PCR) assays were used [146]. The frequency of different karyotypes associated with Turner syndrome is shown in the table (table 1).

The karyotype analysis is sufficient to establish the diagnosis in most cases. However, in certain cases, the karyotype should be repeated to confirm the initial result:

●In infants who were diagnosed prenatally

●In girls initially diagnosed by karyotype on a buccal swab sample only

●If the diagnosis was based on a karyotype performed in the distant past or if no original cytogenetic report is available

If the initial karyotype is normal in a patient with a strong clinical suspicion of Turner syndrome, a second karyotype should be performed using a different tissue such as skin (fibroblasts), bladder epithelial cells from a urine sample, or buccal mucosa cells. This is because there are case reports of girls strongly suspected of having Turner syndrome on clinical grounds who have a normal peripheral blood lymphocyte karyotype (46,XX), but a 45,X karyotype on analysis of skin fibroblasts [147]. This phenomenon may be attributable to abnormal cell lines dying out with age in the bone marrow, leaving the normal cell line in the peripheral blood. Also, mosaic karyotypes may be distributed differently among tissues in the same patient.

Analysis of buccal smears for nuclear heterochromatin (Barr bodies) is an inaccurate and outmoded test and should not be used.

Newborn screening — Routine screening for Turner syndrome is not included in newborn screening programs, although the argument to implement this is strong because earlier diagnosis will allow early intervention and screening for the comorbidities.

The primary barrier to implementing a newborn screening program is development of an accurate and low-cost screening method. In addition, a reliable infrastructure is needed for follow-up of the results. Several diagnostic techniques might be applied to such a newborn screening program, but each has drawbacks:

●Karyotype analysis – This technique is well established for diagnosis of Turner syndrome but is not well suited for newborn screening, because it is costly, requires a long processing time, and requires specialized personnel.

●Real-time PCR – Polymerase chain reaction (PCR) techniques permit gene quantification and sequencing of small portions of the X chromosome, carries a sensitivity of 95 percent and could be cost effective [148].

●High-throughput pyrosequencing – This is a quantitative, pyrosequencing test based upon 18 single nucleotide polymorphisms (SNPs) from the X chromosome and one from the Y chromosome. This test appears to be both sensitive and specific for Turner syndrome [149,150]. The ultimate clinical utility and costs require further assessment.

●Whole-exome sequencing – One study describes a method for diagnosing Turner syndrome using automated whole-exome sequencing [151]. The method was highly accurate in the population tested and can detect Y chromosome material, which is important to identify because it is associated with an increased risk of gonadoblastoma (see 'Risk of malignancy' above). Modeling predicted good accuracy in patients with low-level mosaicism. The technique would be practical for use in newborn screening as it could also screen for other diseases that are already included in newborn screens.

The potential burdens of newborn screening for Turner syndrome also warrant consideration. In particular, some individuals with Turner syndrome are clinically normal and experience few or no medical problems. For these individuals, detecting Turner syndrome through a newborn screening program would have little benefit and might create unwarranted concern.

ADDITIONAL TESTING

Y chromosome mosaicism — Y chromosome material, which is associated with an increased risk of gonadoblastoma, is found in approximately 10 to 12 percent of patients with Turner syndrome using standard cytogenetic techniques [15,100]. Patients with virilization or marker chromosome elements (sex chromosome material of uncertain origin) detected on the karyotype should undergo additional testing to look for occult Y chromosome mosaicism using techniques such as fluorescence in situ hybridization (FISH) with different probes specific for the X and Y chromosome [152]. The presence of an entire Y chromosome (or identifiable pericentromeric fragments of a Y chromosome) is associated with an increased risk of gonadoblastoma (germ cell tumor) (see 'Risk of malignancy' above). Routine molecular searches (on all Turner syndrome patients) for Y chromosome-derived DNA, including the SRY gene (sex-determining region of the Y chromosome), are not useful, because the gene that increases the risk of gonadoblastoma has not been identified [153].

If Y chromosome material is detected, prophylactic removal of the gonads (oophorectomy or salpingo-oophorectomy) is still indicated, due to the tumor risk [69]. (See "Management of Turner syndrome in children and adolescents", section on 'Gonadoblastoma risk'.)

Other tests — Once the diagnosis of Turner syndrome is established by karyotype analysis, management includes evaluation and monitoring for associated abnormalities, including cardiac pathology, thyroid disease, hearing and eye abnormalities, and learning disabilities. Screening for these disorders should be performed as part of the baseline evaluation of the patient after diagnosis of Turner syndrome and repeated periodically thereafter, as summarized in the tables (table 4 and table 5) and discussed in a separate topic review. (See "Management of Turner syndrome in children and adolescents", section on 'Monitoring and managing comorbidities'.)

Key screening steps at diagnosis are (see "Management of Turner syndrome in adults", section on 'Cardiovascular health'):

●Renal ultrasonography.

●Comprehensive cardiovascular evaluation by a cardiology specialist, consisting of echocardiography in infants and children and magnetic resonance imaging (MRI) in older girls and women. (See "Management of Turner syndrome in children and adolescents", section on 'Cardiovascular anomalies' and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

●Laboratory tests

•Age 4 years and older – Serum thyrotropin (thyroid-stimulating hormone [TSH]), to screen for chronic autoimmune thyroiditis, and tissue transglutaminase (tTG) with total immunoglobulin A (IgA), to screen for celiac disease.

•Age 10 years and older – Fasting blood glucose, glycated hemoglobin (A1C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serum creatinine, and urinalysis, because of the risks of diabetes mellitus, fatty liver disease, and kidney dysfunction.

FAMILY SUPPORT — Information for caregivers and patients can be obtained from:

www.turnersyndrome.org

www.turnssyndromefoundation.org

www.tss.org.uk

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Turner syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Turner syndrome (The Basics)")

SUMMARY

●Clinical manifestations

•Typical features – Turner syndrome is caused by loss of part or all of an X chromosome, and is one of the more common chromosome anomalies in humans. It is almost always associated with short stature. It is typically associated with primary amenorrhea due to early ovarian failure, but a minority of girls with Turner syndrome begin pubertal development and a few may achieve regular menses and even fertility. Other physical features are described in the table (table 2 and picture 1). (See 'Typical features' above.)

•Cardiovascular disease – Patients with Turner syndrome are at increased risk for cardiovascular morbidity, due to their predilection for cardiovascular malformations, compounded by renal abnormalities and hypertension. Cardiovascular malformations include aortic valvular disease (mainly a bicuspid aortic valve), aortic arch anomalies (primarily coarctation), pulmonary or systemic venous abnormalities, ventricular septal defects, and hypoplastic left heart syndrome. Patients are at risk for aortic dilatation and dissection, particularly during pregnancy. (See 'Cardiovascular disease' above and 'Aortic dissection' above and 'Pregnancy and cardiovascular risk' above.)

•Bone health – Osteoporosis and fractures are common in adult women with Turner syndrome, and are thought to be due to both ovarian failure resulting in estrogen deficiency, and possibly haploinsufficiency for bone-related X chromosome genes resulting in abnormal trabecular microarchitecture. Appropriate estrogen replacement therapy starting in the second decade of life, and continued until the age of menopause, can help to prevent the suboptimal bone mineralization. (See 'Osteoporosis and bone health' above.)

•Metabolic risks – Girls with Turner syndrome are more likely than girls without Turner syndrome to develop obesity, insulin resistance, and type 2 diabetes mellitus. Patients with Turner syndrome are also at increased risk for autoimmune endocrinopathies, most importantly, hypothyroidism. (See 'Metabolic syndrome and diabetes mellitus' above and 'Autoimmune disorders' above.)

•Risk of malignancy – Girls or women with Turner syndrome whose karyotype includes a Y chromosome (such as 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma, a neoplasm that occurs in dysgenetic gonads. This risk can be reduced by prophylactic gonadectomy. (See 'Risk of malignancy' above.)

•Other – Patients with Turner syndrome are at risk for many other comorbidities, including hearing and ocular abnormalities, autoimmune disorders, psychologic and educational issues, and others (table 2). (See 'Clinical manifestations' above.)

●Diagnosis – Turner syndrome may be diagnosed incidentally during prenatal testing. It should be suspected based upon characteristic clinical features, which may include webbed neck and congenital lymphedema in a neonate, short stature and reduced growth velocity in a child, and/or failure to develop breasts. (See 'Diagnosis' above.)

Indications for diagnostic testing are described in the table (table 3). (See 'Indications for testing' above.)

The diagnosis is confirmed by karyotype analysis (table 1). Prompt diagnosis is important to permit effective treatment of short stature and management of comorbidities. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.