Turner syndrome: Clinical manifestations and diagnosis

INTRODUCTION — 

Turner syndrome (TS) is a sex chromosome disorder that affects phenotypic females with one intact X chromosome and complete or partial absence of the second sex chromosome in association with one or more specific clinical manifestations. It is one of the more commonly occurring chromosomal aneuploidies.

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

EPIDEMIOLOGY

●Prevalence – TS occurs in approximately 1 in 2000 to 1 in 3000 live female births, based on epidemiologic and newborn genetic screening data from Europe, Japan, and the United States [1-5]. The true prevalence remains difficult to ascertain because patients with a milder phenotype may remain undiagnosed or may be diagnosed only in late adulthood [6,7]. In addition, the prevalence at birth may be declining in some countries due to prenatal diagnosis and subsequent elective termination [8,9]. Up to 42 percent of TS individuals are now being detected prenatally by first-trimester testing (mainly using noninvasive prenatal testing [NIPT]) [10]. (See 'Based on the results of prenatal testing' below.)

●Genetic epidemiology – Most individuals with TS have a karyotype consisting of only 45,X cells (monosomy X) [4,5,11]. Approximately one-half of all patients with TS have mosaic genotypes. In these cases, 45,X cells co-occur with cells containing other chromosome complements (eg, 45,X/46,XX or 45,X/47,XXX) or abnormally rearranged X chromosomes. These structural abnormalities are described using the following notation:

•Partial deletion of an X chromosome: del(p22.3)

•Ring X: r(X)

•Isochromosome X: i(X)

•Isodicentric X: idic(X)

These concepts are discussed in greater detail elsewhere. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Numerical and structural chromosome variation' and "Sex chromosome abnormalities", section on 'Isochromosome Xq'.)

The approximate frequency of karyotypes in patients with TS is as follows [5]:

•45,X – 40 to 50 percent

•45,X/46,XX – 15 to 25 percent

•45,X/46,XY – 10 to 12 percent

•46,XX, del(p22.3) – 10 to 12 percent

•46,X,r(X)/46,XX – 10 to 12 percent

•46,X i(Xq)/46,X,idic(Xp) – 10 percent

•45,X/47,XXX; 45,X/46,XX/47,XXX – 3 percent

Specific clinical manifestations associated with these karyotypes are discussed below. (See 'Features associated with selected karyotypes' below.)

PATHOGENESIS

●Causes of chromosome loss/rearrangement – All alterations in sex chromosome number and structure result from nondisjunction errors during gametogenesis or errors in cell division after egg fertilization. Mosaicism occurs due to sex chromosome nondisjunction during postzygotic cell division [12,13]. The intact X chromosome is maternally derived in two-thirds of patients [14]. This implies that the lost or truncated second sex chromosome is most often paternal in origin. Although there is evidence that the origin of the intact chromosome affects clinical manifestations [15,16], this is not routinely assessed as part of the diagnostic evaluation for TS.

●Causes of TS phenotype – The phenotypic manifestations of TS result in part from the loss of specific genes on the absent or structurally altered sex chromosome [17,18]. Although 45,X karyotypes are associated with a larger number of comorbid diagnoses than mosaic karyotypes [19], two individuals with the same karyotype may have divergent clinical presentations. This is because of differences in tissue-level gene expression. Mechanisms such as imprinting seem to play a role in the clinical findings associated with TS [18,20,21], but the factors contributing to the wide variability typically seen in TS are incompletely understood. (See 'Features associated with selected karyotypes' below and "Principles of epigenetics".)

CLINICAL MANIFESTATIONS — 

Although it is difficult to predict the clinical manifestations of TS in any individual based on karyotype alone, some general associations between genotype and TS phenotype can be described. For example, individuals with a nonmosaic 45,X genotype generally present with more TS-associated comorbidities and higher mortality risk than those who have mosaic chromosome complements [19]. (See 'Features associated with selected karyotypes' below.)

An understanding of the range of clinical findings associated with TS (even those with the same chromosomal karyotype) will allow clinicians to diagnose TS in patients who do not present with classic features.

Most common features — Short stature and gonadal insufficiency are the most common clinical features across all karyotypes in individuals with TS (table 1).

Short stature — Short stature occurs in more than 95 percent of patients (table 1). On average, infants with TS have a slightly lower birth length and weight (about 1 standard deviation [SD] below the mean). Many children experience a rapid decline in growth percentiles in the first years of life [22]. Short stature with an increased upper-to-lower segment ratio (disproportionate short stature) is often evident by age three years and is then compounded by the absence of a pubertal growth spurt [22,23]. Without growth hormone (GH) treatment, average adult height in cohorts of individuals with TS ranges from 138 to 147 cm, which is approximately 20 cm or 3 SDs below the mean for United States and European populations [22,24]. However, with GH therapy, most individuals with TS can now attain a height within the normal range. Outcomes of GH treatment in TS are discussed in detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Management of short stature'.)

Height in individuals with TS is partially determined by the specific genes lost. The homeobox gene, SHOX (short stature homeobox-containing gene on the X chromosome), is a positive regulator for growth in humans. SHOX normally escapes X inactivation (the process that silences some genes on one X chromosome). Because of this, two copies of SHOX are needed for normal growth, and short stature in TS results from haploinsufficiency of the SHOX gene [25]. Patients with mosaic karyotypes in which both copies of SHOX are preserved in some cells often have less severe short stature than those with nonmosaic 45 X karyotype [26,27]. (See "Causes of short stature", section on 'SHOX gene variants'.)

The evaluation of short stature is discussed in greater detail elsewhere. (See "Diagnostic approach to children and adolescents with short stature", section on 'Evaluation of growth'.)

Skeletal features — In addition to short stature, other skeletal findings (which may be subtle) include [28-33]:

●Short metacarpal and metatarsal bones

●Short neck (hypoplasia of the neck vertebrae)

●Madelung deformity (bayonet deformity of the wrist) (picture 1 and image 1)

●Cubitus valgus (increased carrying angle of the elbow); present in approximately 50 percent of individuals with TS (figure 1)

●Genu valgum (knock-knees) or varum (bow-legs); may become evident later in childhood

●Scoliosis and hyperkyphosis; develop in 10 to 20 percent and 40 percent of patients with TS, respectively [32]

A detailed discussion of the management of these diagnoses is found elsewhere. (See "Approach to the child with knock-knees" and "Approach to the child with bow-legs" and "Adolescent idiopathic scoliosis: Management and prognosis" and "Skeletal dysplasias: Specific disorders".)

Gonadal insufficiency — Primary gonadal insufficiency (also referred to as premature ovarian insufficiency [POI]) results in delayed, stalled, or absent puberty and infertility in many individuals with TS. Genes implicated in gonadal insufficiency include BMP15 on the short arm of the X chromosome (Xp) as well as (FMR1), a gene encoding fragile X messenger ribonucleoprotein (FMRP) on the long arm (Xq) [34]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'X chromosome disorders'.)

Delayed, stalled, or absent puberty — Although most individuals with TS do not enter puberty spontaneously, approximately 15 to 30 percent have either initial breast development followed by pubertal arrest or secondary amenorrhea. A small number of adolescents with TS, predominantly those with a 45,X/46,XX mosaic genotype, have normal pubertal development and spontaneous menstruation. As an example, in a retrospective study of 522 patients with TS over the age of 12 years, 84 (16 percent) had spontaneous menarche at an average age of 13.2 years; 30 individuals still had regular menses nine years after menarche, and three became pregnant without medical assistance [35].

Because follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are basic markers in the assessment of ovarian function, individuals with TS and ovarian insufficiency have an elevated FSH/LH with low estradiol. Elevated FSH may be identified as part of the diagnostic evaluation for delayed puberty, primary amenorrhea, or infertility before the TS diagnosis is made. However, a normal FSH does not necessarily exclude the possibility of having TS. A low anti-müllerian hormone (AMH), indicative of ovarian insufficiency, is also common in TS [5,36]. Predicting gonadal function for any individual with TS is challenging. Assessment of gonadal function and management of delayed puberty are discussed in detail elsewhere. (See "Management of Turner syndrome in adults", section on 'Preconception counseling and evaluation' and "Management of Turner syndrome in children and adolescents", section on 'Management of delayed or absent puberty' and "Female infertility: Evaluation", section on 'Anti-müllerian hormone'.)

Infertility — Most individuals with TS experience infertility. However, spontaneous pregnancy has been reported in approximately 10 percent of TS cohorts [37]. Although the majority of spontaneous pregnancies occur in individuals with mosaic karyotypes, a small number have been described in adults with 45,X karyotypes. In a retrospective study of 276 adults with TS, five individuals had spontaneous pregnancies despite high-grade monosomy (45,X in ≥90 percent of cells in a 50-cell karyotype) [38]. Counseling about options for family building during adolescence has been identified as a priority by TS patient groups and is recommended by professional clinical practice guidelines [5,39]. Assistive reproductive technologies offer expanded opportunities for fertility preservation in adolescents and young adults with TS. This is discussed in detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Oocyte cryopreservation' and "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)

Hearing and ear abnormalities — Individuals with TS have high rates of hearing loss and should be monitored with routine audiometric testing in childhood and adulthood. (See "Management of Turner syndrome in children and adolescents", section on 'Tympanometry and audiology' and "Management of Turner syndrome in adults", section on 'Audiology testing'.)

Hearing loss has several causes [40]:

●Conductive – Children with TS have a high risk for recurrent otitis media and middle ear effusions, with associated conductive hearing problems. The incidence for any hearing diagnosis is about 35-fold higher in all TS karyotypes combined when compared with the general population [41]. This is related to abnormalities of the Eustachian tubes and craniofacial development [42].

TS is also associated with an increased risk for cholesteatoma, which can lead to conductive hearing loss and destruction of the middle ear if not diagnosed and treated in a timely manner [43,44]. (See "Cholesteatoma in children", section on 'Natural history and complications'.)

●Sensorineural – Progressive sensorineural hearing loss develops by adulthood in more than 30 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 individuals who have a 45,X or 45,X/46,i(Xq) karyotype and tends to worsen with age [45,46].

Cardiovascular abnormalities — Cardiovascular disease is the most serious health problem for individuals with TS and is the primary reason for increased mortality rates. In particular, the increased prevalence of congenital cardiovascular malformations, compounded by kidney abnormalities and hypertension, leads to increased risk for aortic dilatation and dissection [47,48].

Congenital abnormalities of the heart and vasculature — In epidemiologic studies, 23 to 50 percent of patients with TS have congenital heart defects [49,50]. However, the prevalence of these cardiac abnormalities varies depending on referral patterns, the imaging modality used (echocardiogram versus cardiac magnetic resonance imaging [MRI]), and the purpose of the imaging (eg, diagnostic versus screening) [51,52].

Cardiac malformations encountered in the TS population and compared with the general population include [5,49]:

●Aortic valve abnormalities (primarily bicuspid aortic valve) – 15 to 30 percent. Bicuspid aortic valve is associated with the occurrence of additional cardiovascular abnormalities, such as aortic arch defects [48,53]. (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults" and "Bicuspid aortic valve: General management in adults".)

●Elongated transverse aortic arch – 40 to 50 percent

●Other aortic arch abnormalities (primarily aortic coarctation) – 4 to 18 percent [48,53-56]. Critical coarctation presents in the newborn period and, if not identified immediately, may result in heart failure and death. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Management of coarctation of the aorta" and "Management of coarctation of the aorta", section on 'Neonates with critical coarctation'.)

●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 congenital heart disease is higher in individuals with a 45,X karyotype than in individuals with mosaic karyotypes or X structural defects [54]. Neck webbing and an increased anterior-posterior thoracic diameter are strong predictors of arterial and venous anomalies in TS [57].

Other abnormalities of the heart and vasculature

●Aortic dilatation and dissection – Aortic dilatation occurs with increased frequency in patients with TS [5]. In one retrospective study of 268 adults with TS, aortic dilatation was present in 22 percent [56]. Several approaches are used to define the size of the ascending aorta while adjusting for short stature in patients with TS. These include:

•Calculation of the aortic width Z-score, or

•The aortic height index (correction by height), or

•The aortic size index (correction by body surface area)

It may be helpful to compare more than one of these indexing methods when diagnosing aortic dilatation [56]. To minimize the risk of dissection, all patients should have regular cardiovascular monitoring, with especially close follow-up and treatment 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'.)

Aortic dissection or rupture is an increasingly recognized cause of death in adults with TS [58,59]. In a systematic review, aortic dissection in TS was observed in 164 per 100,000 person-years versus 6 per 100,000 person-years in the general population [60]. It most often occurs in adults with TS, but a few cases of aortic dissection have been reported in children.

Other risk factors for aortic dissection include a history of coarctation, the presence of a bicuspid aortic valve, and/or hypertension. However, not all patients with TS who develop aortic dissection have one of these risk factors, and dissection is not always preceded by progressive dilatation [61]. In individuals with TS, 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. The risk for aortic dissection or rupture is particularly high during pregnancy. (See "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy' and "Management of Turner syndrome in adults", section on 'Management' and "Clinical features and diagnosis of acute aortic dissection", section on 'Diagnosis'.)

Growth hormone (GH) therapy is not known to be associated with worsening aortic dilation [62,63]. (See "Management of Turner syndrome in children and adolescents", section on 'Cardiovascular anomalies'.)

●Vasculopathy – Individuals with TS have evidence of progressive vasculopathy, and coronary artery disease is an important contributor to their excess morbidity/mortality in adulthood [64]. Evidence of vascular changes is already present in children with TS, suggested by increased vascular resistance and stiffness in patients as young as 9 or 10 years of age [65]. Mechanisms likely include the associated cardiovascular risk factors of hypertension, dyslipidemia, and dysglycemia (see 'Comorbidities' below). Estradiol deficiency is a contributor to this risk, and estradiol therapy improves cardiovascular risk factors (lipid profile and aortic stiffness). Differences related to altered gene expression in TS may also play a role in vascular changes [66].

Data are lacking on the optimal monitoring strategy for coronary artery disease. Therefore, routine screening for coronary artery disease in otherwise asymptomatic patients with TS is not recommended [67].

●Conduction abnormalities – Individuals with TS have increased resting heart rates (possibly linked to increased sympathetic tone and dysautonomia) [68]. TS may be associated with other conduction abnormalities. In a retrospective cohort study of more than 94 patients with TS undergoing electrocardiograms (ECG), T-wave inversion was noted in two patients, and corrected QT (QTc) prolongation was noted in none. Minor abnormalities, such as sinus tachycardia and QRS axis deviation, were noted in 37 patients and were not clearly of clinical significance [69].

In contrast to findings previously reported in clinical practice guidelines, studies have shown that QTc (evaluated using the Hodges formula) prolongation is not more common in individuals with TS compared with the general population [70-72]. (See "Management of Turner syndrome in children and adolescents", section on 'Management of specific cardiovascular abnormalities' and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

Elevated blood pressure and hypertension — Hypertension is more common among individuals with TS compared with the general population. A prevalence as high as 30 percent in children and 60 percent in adults has been suggested [73-76]. In a series of 62 patients (age range 5 to 22 years) with TS, 30 percent were mildly hypertensive and 50 percent had an abnormal diurnal blood pressure profile as measured by 24-hour ambulatory blood pressure monitoring [73]. In another cohort of patients with TS compared with age-matched controls without TS, the TS group had at least one blood pressure reading above the hypertension threshold [77].

Neither the presence of kidney or cardiac abnormalities nor treatment with GH or estradiol therapy had an effect on blood pressure. In a study of 102 adults with TS (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 [78]. 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 toward the end of the study. Lifelong screening for elevated blood pressure is essential for individuals with TS. (See "Management of Turner syndrome in children and adolescents", section on 'Hypertension'.)

Oral and dental abnormalities — A variety of dental, orthodontic, and craniofacial abnormalities are associated with TS. High-arched palate and maxillary hypoplasia may be noted on newborn examination. Micrognathia and narrow mandible may contribute to feeding difficulties in infancy as well as to sleep-disordered breathing and obstructive sleep apnea in childhood and adolescence.

Smaller primary teeth, supernumerary roots, increased root resorption, increased tooth mobility, early tooth loss, smaller permanent teeth, and thinner tooth enamel may be noted on dental examination throughout the lifespan [79,80]. Routine dental examinations and early referral to an orthodontist are recommended as part of the care of patients with TS. (See "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx", section on 'Micrognathia' and "Developmental defects of the teeth" and "Developmental defects of the teeth", section on 'Enamel defects'.)

Neuropsychological concerns — Intelligence is usually normal in individuals with TS; 90 percent have overall intellectual abilities within the average range. The exception is for individuals with TS due to a small ring X chromosome with absent X-inactivation locus (XIST), which is associated with a greater risk of mild to severe intellectual disability [81,82]. (See 'Features associated with selected karyotypes' below.)

However, all individuals with TS are at increased risk of several neuropsychological deficits, including selective impairments in nonverbal skills; deficits in social cognition; difficulty with nonverbal, problem-solving tasks such as mathematics; psychomotor deficits; and problems with visual-spatial organization [83]. There is also an increased risk of attention-deficit/hyperactivity disorder (ADHD). By contrast, verbal skills are often strong. The neurodevelopmental abnormalities may result from X chromosome monosomy, sex steroid (estradiol) deficiencies due to gonadal dysgenesis, or other factors as yet unknown.

The cause of neuropsychological manifestations in TS is not fully understood. Loss of an imprinted gene in individuals with ring X chromosomes may explain aspects of the more severe developmental delays in this subgroup but does not provide an explanation for all psychological findings in TS. Such an explanation would most likely involve an interplay between many genes and interacting environmental factors [84]. (See 'Features associated with selected karyotypes' below.)

Specific strategies to detect and manage neurocognitive concerns and learning disabilities in individuals with TS, 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'.)

Additional features — Additional clinical manifestations of TS may include physical features (often present from birth) and associated comorbidities (often occurring later in childhood or adulthood).

Anatomical findings

●Lymphedema – Infants with TS may have congenital edema of the hands and feet due to lymphatic hypoplasia. Lymphedema is described in 12 to 37 percent of all patients with TS [85-87]. A mechanical effect from fetal lymphedema during organ development is thought to contribute to several aspects of the TS phenotype, including webbing of the neck, shield chest, external ear malformations, kidney anomalies, and certain cardiac defects [87]. Although nonmosaic 45,X karyotype is more associated with lymphedema, the specific genetic mechanism for the development of this finding remains unknown [29,85]. Lymphedema usually resolves by two to three years of age but may persist in a subset of patients. Anecdotal reports describe worsening of some of the edema coinciding with the institution of either GH or estradiol treatment, though this is not common. Management is discussed in greater detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Edema'.)

●Ophthalmologic concerns – Abnormalities of the eye and eyelid are common among patients with TS but do not seem to be associated with karyotype [88,89]. In a case series, the most common ocular concerns included nearsightedness (40 percent), strabismus (25 percent), amblyopia (>15 percent), farsightedness (13 percent), ptosis (10 to 25 percent), and hypertelorism (10 percent). Color blindness is more common than in the general population [88,89]. Keratoconus, glaucoma, anterior lenticonus, cataracts, retinal vascular changes, and retinal detachment have been noted in case reports [90,91]. (See "Management of Turner syndrome in children and adolescents", section on 'Ophthalmologic concerns'.)

●Abnormal morphology of the kidney and urinary tract – Congenital malformations of the kidney/urinary system are present in approximately 18 to 60 percent of patients with TS [92-94]. The more common abnormalities include collecting system malformations (15 to 20 percent) and positional abnormalities as well as horseshoe kidneys (15 to 20 percent). Malrotated kidneys and other positional abnormalities have been observed in 5 percent of the TS population in some studies [1]. Anomalies associated with obstruction of the ureteropelvic junction can produce clinically significant hydronephrosis and an increased risk for pyelonephritis. Abnormalities involving the renovascular supply are also detected with a higher frequency than in the normal population [1]. Anomalies associated with obstruction of the ureteropelvic junction can produce clinically significant hydronephrosis and an increased risk for pyelonephritis. Abnormalities involving the renovascular supply are also detected with a higher frequency than in the normal population [95].

In children and young adults with TS, kidney function (using estimated glomerular filtration rate) appears normal over time. However, creatinine may be a less accurate measure of kidney function in individuals with TS as short stature is associated with decreased muscle mass. (See "Assessment of kidney function", section on 'Limitations of creatinine-based eGFR'.)

Patients should undergo kidney ultrasonography at the time of TS diagnosis to identify anatomical malformations. (See "Management of Turner syndrome in children and adolescents", section on 'Kidney anomalies and urinary tract infections'.)

Comorbidities — Several medical conditions occur more commonly in patients with TS.

●Autoimmune disorders – TS is associated with an increased risk of autoimmune disorders, especially autoimmune thyroid disease, celiac disease, and inflammatory bowel disease (IBD) [96]. Overall, there is a 61 percent lifetime prevalence of autoimmune disease. Prevalence increases with increasing age [97-101].

•Autoimmune 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 antithyroid antibodies [102]. The prevalence is higher during adulthood. In a prospective study that compared the frequency of autoimmune diseases in 244 adults with TS with that of adults with POI (ovarian failure) and 46,XX karyotype (n = 457) [97], autoimmune hypothyroidism occurred in 37 percent of adults with TS compared with 15 percent of those with POI. The prevalence in both groups was higher than in the general population of adult females in the United States.

•Celiac disease – In the same study, the prevalence of celiac disease was significantly increased in TS (2.7 percent) but not in POI [97]. In a separate study of 389 children and adolescents with TS screened with immunoglobulin (Ig) A antigliadin antibodies and/or antiendomysial antibodies, 25 (6.4 percent) had celiac disease [103]. Of these, 10 had typical symptoms, eight had atypical symptoms, and seven had no symptoms. A meta-analysis showed that approximately 1 in 22 individuals with TS may have celiac disease [104]. The prevalence of celiac disease also increases with age and is higher in individuals with a 45,X, 45,X/46,X,i(Xq), or ring X chromosome karyotypes [19]. (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 TS is approximately 1 to 4 percent, which is substantially higher than in cohorts with POI or the general population (<0.5 percent) [97,105,106]. Moreover, IBD may present earlier in TS [107]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

●Anemia – A case series of patients with TS provides evidence for an elevated risk of iron deficiency anemia in this population. This may be due in part to the increased prevalence of autoimmune diseases (eg, celiac disease), gastrointestinal bleeding (eg, IBD), coagulopathy, or a combination of these conditions [108].

●Overweight/obesity – Individuals with TS are at greater risk for elevated body mass index (BMI) compared with the general population. Incidence of weight abnormalities increases with age. By age 30, approximately 60 percent of individuals with TS are overweight or obese [92]. Central or visceral adiposity, in particular, is increased in children and adolescents with TS, as evidenced by higher waist circumference. The increase in total fat mass is further correlated with an increased risk of cardiometabolic disease. Routine weight monitoring and management of obesity are discussed in detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Monitoring growth'.)

●Diabetes mellitus – TS is characterized by multiple alterations in glycemia. The lifetime risk of type 2 diabetes mellitus (T2DM) diagnosis is higher in patients with TS than in the general population. However, diabetes pathophysiology in TS appears to result from both insulin resistance and beta cell dysfunction, which may represent a diabetes phenotype distinct from T2DM and type 1 diabetes mellitus (T1DM) [109-113].

•T2DM – Insulin resistance occurs early in children with TS and contributes to an increased lifetime risk of diagnosis of T2DM compared with the general population [7,114]. The prevalence of T2DM in young adults with TS ranges from 5 to 25 percent in different reports [7,115] compared with an estimated T2DM prevalence of 3.8 percent globally among adults 20 to 39 years [116]. In a prospective cohort study of 106 adults with TS aged 18 to 70 years, impaired glucose tolerance or diabetes was identified in 27.3 percent of patients, with an average age of 36 years at diabetes diagnosis [113].

•T1DM – Data are inconsistent regarding the association between TS and T1DM. A higher incidence of T1DM was reported in one analysis of a Danish TS registry but was not identified in other TS cohorts [47,97,117]. Although T1DM-associated autoantibodies (glutamic acid decarboxylase [GAD], zinc transporter 8 [ZnT8], and islet antigen-2 [IA-2]) are more commonly detected in patients with TS than in the general population [118], this finding has not been associated with a greater risk of developing T1DM. In the cohort of adults with TS ages 18 to 70 discussed previously, the prevalence of T1DM-associated autoantibodies was 8.5 times higher than in the general population but did not differ between individuals with and without diabetes [113]. (See "Management of Turner syndrome in children and adolescents", section on 'Metabolic syndrome'.)

Routine diabetes screening is recommended by professional guidelines and discussed in detail elsewhere. (See "Management of Turner syndrome in adults", section on 'Diabetes mellitus' and "Management of Turner syndrome in children and adolescents", section on 'Metabolic syndrome'.)

●Hypoglycemia – Case series have suggested an association between TS and hyperinsulinemic hypoglycemia [119,120]. In about 50 percent of cases, the clinical presentation of hypoglycemia was noted shortly after birth; in other patients, the diagnosis was made later in infancy [119]. Although the mechanism is unknown, hyperinsulinemic hypoglycemia may in part be caused by haploinsufficiency of the gene KDM6A, a gene on the X chromosome associated with hyperinsulinism in Kabuki syndrome [120,121]. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism", section on 'Syndromic hyperinsulinism'.)

Small size for gestational age, feeding difficulties, and congenital heart disease may also contribute to risk of hypoglycemia in infants with TS. Monitoring of blood glucose levels with a clinical evaluation in the neonatal period is recommended to identify the etiology if hypoglycemia persists. (See "Approach to hypoglycemia in infants and children", section on 'Evaluation for the cause of hypoglycemia' and "Management of Turner syndrome in children and adolescents", section on 'Neonates'.)

●Dyslipidemia – Patients with TS are at risk for lipid abnormalities including hypercholesterolemia, selective elevation of low-density lipoprotein (LDL) cholesterol, and hypertriglyceridemia. Increased prevalence of obesity, diabetes, and estradiol deficiency have been hypothesized to play a role in hyperlipidemia in TS, but the mechanism has not been fully elucidated [122]. Routine lipid monitoring in individuals with TS is the same as for other children and is discussed in detail elsewhere. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis".)

●Abnormal liver function – Increased concentrations of liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transpeptidase [GGT]) occur with a higher frequency (40 to 80 percent) in adults with TS. Transaminitis is usually found on routine laboratory testing and, in most cases, does not progress to overt liver disease. Although elevated liver enzymes are observed in young patients with TS, risk factors for transaminitis include older age, obesity, insulin resistance, and a karyotype with an isochromosome Xq [123,124]. Estradiol therapy appears to be associated with improvement in the liver enzyme concentrations [125].

The pathogenesis for these findings is still unclear. In some patients, steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD) is present; in others, an autoimmune process may play a role [123,124]. Routine monitoring of liver function in individuals with TS is recommended by professional guidelines and discussed in detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Liver disease' and "Management of Turner syndrome in adults", section on 'Liver disease'.)

●Skin findings – An increased prevalence of pigmented nevi has been reported in TS [126-129]. In one cohort study, self-reported history of GH use was associated with an increased number of acquired melanocytic nevi in adults with TS [130]. However, GH therapy is not the primary cause of melanocytic nevi development in TS. The prevalence of melanoma is probably slightly increased in TS, and routine surveillance of nevi is warranted [5]. (See "Acquired melanocytic nevi (moles)".)

A few studies suggest increased risk for keloid scar formation [1,131,132]. Individuals with TS may also be more likely than others to develop pilomatrixoma, an uncommon benign skin neoplasm thought to arise from cells of the hair follicle (see "Cutaneous adnexal tumors", section on 'Pilomatricoma'). Other skin problems more often observed include vitiligo, alopecia areata, and lichen sclerosis. (See "Management of Turner syndrome in adults", section on 'Skin'.)

●Low bone mineral density (BMD) – The risk of low BMD is increased (approximately 24 percent) in individuals with TS. Several factors may contribute to this, including inadequate estradiol therapy, intrinsic bone abnormalities, vitamin D deficiency, and comorbidities (eg, celiac disease, IBD). Failure to appropriately height-adjust results of dual-energy X-ray absorptiometry (DEXA) may underestimate bone density in patients with TS and short stature [133].

Studies that examine bone architecture while controlling for both ovarian hormone deficiency and height are suggestive of intrinsic bone abnormalities in TS. As an example, in a study comparing 41 adults with TS with a control group of 35 females with 46,XX karyotype and POI, there was a selective reduction in cortical (forearm) BMD in patients with TS [134]. This difference persisted after adjustment for height, age of puberty, lifetime estradiol exposure, and serum 25-hydroxyvitamin D concentrations. Studies using high-resolution peripheral quantitative computed tomography (CT) similarly demonstrate abnormal trabecular microarchitecture and lower cortical bone porosity in patients with TS compared with healthy controls [135]. These intrinsic abnormalities of bone may be due to haploinsufficiency for bone-related genes on the X chromosome (eg, SHOX) [136]. (See 'Pathogenesis' above and "Management of Turner syndrome in adults", section on 'Bone health' and "Management of Turner syndrome in children and adolescents", section on 'Vitamin D deficiency'.)

●Fracture risk – Available evidence suggests that there is not an increased risk of fracture in children and adolescents with TS [136]. However, fracture risk increases with age in patients with TS; adults with TS have an almost 25 percent increased risk of fracture compared with peers without TS [137-139]. This difference appears to primarily reflect the effects of inadequate estrogen exposure related to timing of and adherence to estradiol treatment [136]. Additional TS-associated fracture risks include abnormal bone architecture and impaired balance, which may increase fall risk [138,140-142].

●Gonadoblastoma – Patients with Y chromosome material are at increased risk for gonadoblastoma and require appropriate counseling and management. (See 'Features associated with Y chromosome mosaicism' below and "Management of Turner syndrome in children and adolescents", section on 'Gonadoblastoma risk'.)

Mortality — Overall mortality rates in patients with TS are increased approximately threefold when compared with the general population, with excess risk occurring at all ages and for most major causes of death [143,144]. A population-based study of 3439 patients with TS demonstrated that overall mortality in adults with TS was significantly higher than national mortality rates (standardized mortality rate [SMR] = 3), primarily due to noncongenital cardiovascular disease (41 percent of deaths) and congenital cardiovascular anomalies (8 percent of deaths) (figure 2) [144]. (See "Management of Turner syndrome in children and adolescents", section on 'Cardiovascular anomalies' and "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

In a national cohort study of all individuals in Denmark diagnosed with TS between 1977 and 2014, endocrine and cardiovascular morbidity and mortality were significantly increased compared with an age-matched reference population [145]. There was no difference in mortality between the population with TS who were treated with estrogens when 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 TS. This is discussed at length elsewhere. (See "Management of Turner syndrome in children and adolescents" and "Management of Turner syndrome in adults".)

Features associated with Y chromosome mosaicism — Approximately 10 to 12 percent of all individuals with TS have mosaicism involving a cell line containing Y chromosome material (45,X/46,XY or 45,X/46,X,marY) [146]. These patients may also be identified if marker chromosomes (Y chromosome material of uncertain origin) are detected on the karyotype. Some experts will also assess for Y chromosome material in patients with small ring chromosomes. (See 'Confirmatory diagnostic testing' below.)

●Clinical features – A mosaic karyotype containing 45,X cells and cells containing Y chromosome material may be associated with a broad range of genital phenotypes. Individuals with this karyotype may have typical female external genital structures, moderate genital virilization (genital structures neither typically male nor typically female), or typical male genital structures with infertility [147].

Genital phenotype (virilized or not virilized) does not predict likelihood of other TS-associated manifestations [148,149]. As an example, in one cohort study of 76 children with mosaic monosomy X and Y chromosome material, patients with virilized external genital structures had similar rates of congenital heart disease, autoimmune disease, and neurodevelopmental disorders to those with typical female external genital structures [148]. Therefore, we use the same monitoring approach in individuals with a karyotype containing 45,X and Y chromosome mosaicism regardless of external genital structure [5].

The clinical diagnosis of TS excludes individuals with 46,XY cell lines who do not have typical-appearing female external genital structures. In other words, an individual who has a 45,X/46,XY karyotype and typical female external genital structures will be considered to have TS, whereas an individual with 45,X/46,XY karyotype and partially or fully virilized external genital structures will not be considered to have TS [5].

The approach to evaluation and management of patients with genital variations, also called differences of sex development, is discussed elsewhere. (See "Causes of differences of sex development", section on 'Sex chromosome differences of sex development' and "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Mixed gonadal dysgenesis (45,X/46,XY mosaicism)'.)

●Gonadoblastoma risk – All patients with Y chromosome material are at increased risk of gonadoblastoma. In a population-based study, the cumulative risk for gonadoblastoma in adults with TS and Y chromosome material was 7.9 percent by age 25 years [150]. Expert opinion differs regarding the optimal approach to managing gonadoblastoma risk [5]. This is discussed in detail elsewhere. (See "Management of Turner syndrome in children and adolescents", section on 'Gonadoblastoma risk' and "Anatomy and pathology of testicular tumors", section on 'Gonadoblastoma'.)

Features associated with selected karyotypes — Several structural anomalies of the X chromosome can be causative of TS. These may occur with or without mosaicism for other cell lines but may be associated with a higher risk of certain clinical features:

●Isochromosome Xq (46,X,i(Xq)) – Isochromosomes are structurally abnormal X chromosomes consisting of two copies of either the short or long arm of the X chromosome connected head-to-head with some (but not necessarily all) intervening centromeric (or short arm) chromosome material [11]. Patients with 46,X,i(Xq) are, by definition, monosomic for the short arm of the X chromosome; they are also believed to be at a higher risk for certain autoimmune disorders [118].

●Ring chromosome X (r(X)) – A ring chromosome X (r(X)) may form if the ends of both the short and long arms of the X chromosome break and then fuse together; when it involves an X chromosome, this anomaly is functionally similar to a deletion of the distal part of the short arm (Xp deletion) [151]. If the ring lacks the X-inactivation site (XIST; usually the case with small rings), the risk for significant developmental delay is substantially increased; the patient may also have physical features that are not typical for TS per se (early and more severe growth failure, atypical facial dysmorphism, and syndactyly) [81,152]. (See 'Neuropsychological concerns' above.)

●Isolated terminal Xq deletions (not TS) – 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. Isolated terminal Xq deletions may be associated with isolated gonadal insufficiency but no other features of TS [153]. Expert clinical practice guidelines specify that the TS diagnosis does not refer to individuals with more distal X chromosome deletions. However, patients with smaller sex chromosome deletions may have clinical features that overlap with TS and therefore can sometimes benefit from the same medical surveillance recommended for patients with TS [5]. (See "Management of Turner syndrome in children and adolescents", section on 'Monitoring and managing comorbidities' and "Sex chromosome abnormalities", section on 'X-chromosome deletions'.)

DIAGNOSIS OF TURNER SYNDROME

When to suspect Turner syndrome — TS may be suspected based on abnormal prenatal testing or by the presence of characteristic clinical features in fetal life, infancy, childhood, or adulthood (table 1) [154]. TS is typically diagnosed based on blood karyotype demonstrating total or partial loss of one sex chromosome. (See 'Confirmatory diagnostic testing' below.)

In either case, the diagnosis of TS requires confirmatory testing, the most common being peripheral blood karyotype [5]. (See 'Confirmatory diagnostic testing' below.)

Based on the results of prenatal testing — Concern for monosomy X (45,X) may arise in the prenatal period in the setting of routine prenatal screening tests (eg, noninvasive prenatal screening using cell-free deoxyribonucleic acid [cfDNA] from maternal blood, ultrasound assessment of nuchal translucency), during diagnostic evaluations (eg, chorionic villus sampling [CVS], amniocentesis), or based on other characteristic anomalies identified on routine US. (See "Prenatal screening for common fetal aneuploidies: Cell-free DNA test", section on 'Sex chromosome aneuploidies'.)

Regardless of the type of prenatal testing pursued, a postnatal karyotype (or other confirmatory test) is recommended to confirm the diagnosis and evaluate for low levels of mosaicism. Postnatal confirmatory testing may be performed on either cord blood or venous blood. (See 'Confirmatory diagnostic testing' below.)

When available, individuals with any positive prenatal testing should have prenatal counseling, ideally from providers experienced with TS. The major challenge of prenatal counseling is the uncertainty regarding specific phenotypic manifestations of TS in any one individual. (See 'Clinical manifestations' above.)

●cfDNA testing with result indicating high risk of TS-associated chromosomal alterations – Noninvasive prenatal testing (NIPT), using fetal cfDNA from maternal blood, is widely employed to screen for detection of chromosomal anomalies in low-risk pregnancies [10]. The false-positive rate for monosomy X using cfDNA is higher than for other chromosomal aneuploidies (estimates of positive predictive value vary from 9 to 85.2 percent) [155]. A NIPT result indicating "high risk of monosomy X" warrants comprehensive genetic counseling, which should include a discussion of the major limitations of NIPT in this regard and the need for confirmatory testing to establish the diagnosis.

Evaluation of high-risk cfDNA results may include [155-158]:

•Prenatal CVS or amniocentesis, depending on gestational age. CVS is available four to six weeks before amniocentesis.

•Detailed fetal ultrasound to identify features consistent with TS.

●Routine ultrasonography with findings suggestive of TS – TS also may be suspected because of certain congenital anomalies noted on routine fetal US. Findings concerning for TS include septated cystic hygroma, cardiac defects, increased nuchal translucency, kidney anomalies, or short femur. Enlarged nuchal translucency may be caused by lymphatic dysplasia, although it is a nonspecific finding that may be associated with multiple chromosomal aneuploidies and cardiac malformations. Fetal hydrops occurs with greater frequency in TS and is associated with reduced fetal survival [159-161]. (See "Enlarged nuchal translucency and cystic hygroma" and "Nonimmune hydrops fetalis".)

If there are ultrasound findings suspicious for TS, confirmation of the diagnosis requires assessment of fetal karyotype with CVS or amniocentesis. Some patients elect to pursue karyotype testing after delivery. (See 'Confirmatory diagnostic testing' below.)

●CVS or amniocentesis with TS-associated chromosomal alterations – At times, these tests may identify monosomy X (or other karyotypes associated with TS) as part of prenatal screening for some groups (eg, advanced maternal age when cfDNA cannot be performed). In contrast to cfDNA, diagnostic tests such as CVS and amniocentesis can be considered. In such cases, a 45,X karyotype in a fetus with a large cystic hygroma or hydrops makes the diagnosis of TS highly likely [162]. No further prenatal genetic testing is needed, though a detailed ultrasound may still offer additional phenotypic information, and the diagnosis should still be confirmed postnatally. Additional information about the use of CVS and amniocentesis is discussed elsewhere. (See "Chorionic villus sampling", section on 'Indications' and "Prenatal genetic evaluation of the fetus with anomalies or soft markers" and "Diagnostic amniocentesis", section on 'Genetic tests' and "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray", section on 'Inability to detect low levels of mosaicism'.)

Based on clinical features — Typical clinical manifestations are often subtle. Therefore, it is vital to perform a comprehensive physical examination when a diagnosis of TS is being considered and to not rule out the TS diagnosis if some characteristic findings are absent. Importantly, TS-associated features vary by age. As an example, the most common reasons for testing for TS are lymphedema during infancy and short stature during childhood and adolescence [154,163].

Newborn period — TS-associated features that may be evident in the perinatal period (but can be found at any time throughout the lifespan) include [5]:

●Neck webbing

●Lymphedema of the hands and/or feet

●Short hands (metacarpals), feet (metatarsals), or limbs

●High-arched palate

●Left-sided heart disease (eg, aortic coarctation or hypoplastic left heart syndrome)

Careful examination is particularly important in the newborn period because some features may be difficult to ascertain in young infants. TS is not a part of newborn screening, though some have advocated for its inclusion. (See 'Most common features' above.)

Infancy and childhood — In addition to the characteristic features described in the newborn period, features that may become evident in childhood include [162] (table 1):

●Height below midparental height, as calculated here (calculator 1), and/or height velocity less than 10^th percentile for age

●Dental abnormalities and malocclusion

●Strabismus

●Recurrent otitis media

●Hearing loss

●Abnormally formed/rotated pinnae

●Increased carrying angle of the arms

●Kyphosis/scoliosis

●Nail dysplasia

●Learning difficulties (eg, nonverbal learning disability, specific deficits in spatial reasoning)

Adolescence — TS should be suspected in adolescent females who fail to start or complete breast development or those with primary or secondary amenorrhea, especially if short stature and/or other clinical features of TS are present. Laboratory assessment demonstrating signs of gonadal failure (low estradiol with elevated follicle-stimulating hormone [FSH]/luteinizing hormone [LH] and/or low anti-müllerian hormone [AMH]) should immediately prompt an evaluation for TS. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

Adulthood — In adults, TS should be suspected in any cases of unexplained hypogonadism (low estradiol with elevated FSH/LH and/or low AMH) and in cases of unexplained infertility. In addition, the combination of hearing loss before 40 years of age and short stature or other features of TS should prompt screening [5].

Confirmatory diagnostic testing — Genetic testing, most often with a karyotype, is performed to confirm the diagnosis of TS in any patient with abnormal prenatal screening tests and/or with characteristic clinical features (table 1). Prompt diagnosis is essential to facilitate timely counseling and management of comorbidities.

●Choice of test

•Karyotype (most common) – Karyotype remains the standard diagnostic test for TS [5]. A karyotype is a cytogenetic test in which cells are cultured to induce division and then arrested in metaphase to allow chromosomes to be readily counted. This test can be performed using blood drawn from the umbilical cord if the diagnosis is suspected at delivery or from a peripheral venous sample at any time [5]. The karyotype reflects the chromosome complement on peripheral blood mononuclear cells because these are the most abundantly available cells in venous blood. This is important because chromosome mosaicism may vary across tissues and therefore may not be identified on peripheral blood analysis [11].

When requesting a karyotype, a minimum of 30 cells in metaphase must be counted to detect mosaicism. Other techniques (such as exome sequencing) may have greater accuracy for identifying mosaicism [11,164]. Information about the technical aspects of karyotype testing is found elsewhere. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Chromosomal analysis'.)

Additionally, if the diagnosis of TS is not considered until adulthood, interpretation of the karyotype warrants additional considerations. Specifically, mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of females, and risk increases with age. Although mLOX may be detected on blood karyotype in adults without classic features of TS, these individuals do not have TS [165].

•Microarray – Microarray (comparative genomic hybridization [CGH] array) can be used to confirm the diagnosis of TS [166]. CGH array has advantages over conventional karyotyping in that it can detect rearrangements and deletions/duplications that are less than 1 to 2 Mb. Although the resolution of CGH array is better than conventional karyotype analysis, the detection of chromosomal mosaicism may be more difficult. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization'.)

•Exome/genome sequencing – In centers where "next generation sequencing" using exome and/or genome sequencing is reliably used for clinical diagnostics, these modalities may be used to confirm the diagnosis of TS. They have the potential to detect mosaicism as low as 5 percent and to detect small fragments of Y chromosome material but may be expensive or return unwanted findings in other genes [5,167]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Clinical use of next-generation sequencing'.)

●When additional genetic testing is needed – The karyotype analysis (or CGH array, exome/genome sequencing) is sufficient to establish the diagnosis in most cases. However, in certain cases, the confirmatory diagnostic test should be repeated:

•In infants for whom prenatal screening was "high risk" for TS-associated karyotypes or prenatal testing demonstrated a TS-associated karyotype (see 'Based on the results of prenatal testing' above)

•In any patient previously diagnosed by karyotype using 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 an unidentified or supernumerary marker chromosome (SMC) is identified on cytogenetic testing

If the karyotype report includes an unidentified chromosome fragment or SMC, it is important to perform further testing (such as fluorescence in situ hybridization [FISH], CGH array, or exome/genome sequencing) to characterize the fragment. The primary reason is to determine whether Y chromosome material is present [168]. This is because the presence of specific Y chromosome fragments confers a risk of gonadoblastoma, which is a neoplasm that occurs in dysgenetic gonads [169]. (See 'Features associated with Y chromosome mosaicism' above and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

If the initial karyotype is normal in a patient with a strong clinical suspicion of TS, some experts perform karyotypes using a different tissue such as skin (fibroblasts), bladder epithelial cells from a urine sample, or buccal mucosa cells. However, this is not routine practice in many centers. This approach is based on case reports of individuals with clinical features of TS who had a normal peripheral blood karyotype (46,XX) but a 45,X karyotype on analysis of skin fibroblasts [170].

FAMILY/CAREGIVER SUPPORT — 

Counseling and support are very important for the individual with TS as well as their family members/caregivers. Professional guidelines emphasize the need for support from medical and mental health clinicians with TS expertise beginning in the prenatal period and extending throughout the lifespan. Access to knowledgeable clinicians is particularly important at the time of diagnosis, during the sharing of information with young people who have TS, and around significant medical decisions. Support groups consisting of people with TS and caregivers/family members may offer excellent resources for support from those with lived experience [5].

Information for caregivers and patients can be obtained from:

www.turnersyndrome.org

A summary of the 2024 Turner syndrome clinical practice guidelines has been prepared for patients with TS and their families/caregivers.

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 AND RECOMMENDATIONS

●Pathogenesis and epidemiology – Turner syndrome (TS) is caused by the loss of part or all of one sex chromosome and occurs in 1 in 2000 to 1 in 3000 live female births. (See 'Pathogenesis' above and 'Epidemiology' above.)

●Most common features – Short stature and ovarian insufficiency are the most common clinical features in all individuals with TS, regardless of karyotype (table 1). (See 'Most common features' above.)

●Other important features – Patients with TS are at risk for cardiovascular, kidney, hearing, and ocular abnormalities; obesity and metabolic syndrome; autoimmune disease; and neurocognitive and educational issues (table 1). (See 'Additional features' above and 'Most common features' above.)

Predicting phenotype based solely on chromosome karyotype is challenging, although some general karyotype-phenotype associations exist (eg, nonmosaic 45,X karyotype is associated with more TS-associated clinical findings than mosaic karyotype). (See 'Features associated with Y chromosome mosaicism' above.)

●Diagnosis

•Whom to test for TS – TS may be suspected based upon abnormal prenatal screening (eg, cell-free DNA [cfDNA]), prenatal diagnostic testing (eg, amniocentesis, chorionic villus sampling [CVS]), or based on characteristic clinical features at any time in infancy, childhood, or adulthood (table 1). (See 'When to suspect Turner syndrome' above.)

•Confirmatory diagnostic testing – TS is typically diagnosed based on blood karyotype demonstrating total or partial loss of one sex chromosome. The karyotype may be determined using cord blood if the diagnosis is suspected at delivery or from a peripheral venous sample at any time. Microarray (comparative genomic hybridization [CGH] array) or exome/genome sequencing may be used to confirm the diagnosis in settings where these technologies are available and reliable.

Additional testing may be indicated for individuals with marker chromosome material detected on karyotype. (See 'Confirmatory diagnostic testing' above.)

●Counseling

•In the prenatal period – When TS is suggested by prenatal screening or diagnostic testing, we offer detailed genetic counseling to address the limitations of testing and approach to confirming the diagnosis. (See 'Based on the results of prenatal testing' above.)

•Through the lifespan – Patients with TS benefit from a multidisciplinary approach to care, ideally through a dedicated clinic or group of specialists with experience in the management of TS. When possible, we include clinicians with expertise in mental and psychological health as well as patient support organizations in the routine care of patients with TS and their families/caregivers. (See 'Family/caregiver support' above.)

ACKNOWLEDGMENT — 

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