Are You Confident of the Diagnosis?

What you should be alert for in the history

The diagnosis of Turner syndrome (TS) requires the clinical presence of phenotypic features in a female patient, with partial or complete loss of the X chromosome in some or all cells. TS is classically characterized by short stature, impaired sexual development, and infertility; however, a variety of tissue and organ systems may be affected, and thus a thorough history and physical examination may provide additional clues in diagnosing this condition (Figure 1).

Figure 1.

9-year-old girl with Turner syndrome with shield chest, widely spaced nipples and webbed neck.

Characteristic findings on physical examination

Short stature is the most common clinical feature of TS, affecting approximately 95% of patients. Growth is delayed during infancy and childhood, and the pubertal growth spurt is blunted or absent. Consequently, the final adult height is usually between 122 and 152cm (approximately 4-5 feet), or about 20cm below average, when compared with the corresponding ethnic group.

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Any female patients with short stature less than the third percentile or below two standard deviations on the female growth curve should be referred for karyotyping if additional features of TS are present.

Impaired sexual development and infertility are also common clinical features. Pubertal growth arrest results in absence of breast development and primary or secondary amenorrhea with high levels of follicle-stimulating hormone (FSH). Importantly, up to 30% of patients may nevertheless undergo some degree of pubertal growth and 2%-5% will have menses without medical intervention, although in 90% of patients gonadal failure eventually follows.

Congenital lymphedema is a common initial presentation of TS and its recognition may allow early diagnosis.

Cystic hygromas may be detected by prenatal ultrasound, and resolution of the cystic hygroma by birth leads to a characteristic webbed neck appearance (pterygium colli) or redundant neck folds resembling cutis laxa.

Acral lymphedema is another important diagnostic clue and usually resolves by age 2 but may recur unilaterally or bilaterally in the legs at a later age. Additional sequelae of congenital lymphedema include a low posterior hairline and altered nail anatomy, including hypoplastic convex nails and uplited nailplates.

Sensorineural hearing loss affects 50%-90% of patients. In addition, recurrent and severe bouts of otitis media are common and may progress to mastoiditis, cholesteatoma formation, and permanent hearing loss.

Scoliosis and excessive kyphosis are found in 10% and 40% of patients, respectively. X-ray imaging may further reveal vertebral body wedging, cervical vertebrae hypoplasia, and coalition of vertebrae and hemivertebrae.

Estrogen deficiency secondary to gonadal dysgenesis predisposes patients to early-onset osteoporosis. In addition, developmental anomalies of other bones result in a variety of other recognizable features.

Cubitus valgus, a deformity of the elbow in which the forearm deviates from the midline when extended, is an important clue to TS, especially when noted at birth. Madelung’s deformity, a malformation of the wrist, is reported to occur. The neck, as well as the fourth metacarpal or metatarsal, can be shortened. Infants with TS are also at higher risk for congenital hip dislocation.

In addition to the aforementioned physical exam findings, Turner syndrome is associated with other dermatologic stigmata. Benign melanocytic nevi are found in increased numbers, although dysplastic nevi and melanomas do not seem to be more common (Figure 2).

Figure 2.

Multiple melanocytic nevi on the face and scalp of a girl with Turner syndrome.

Altered dermatoglyphics occur in 40% of patients, likely secondary to fetal acral edema. Other associations have been reported but are of questionable increased frequency. These include alopecia areata, cafe au lait macules, keloids, persistent lymphedema, premature skin aging, psoriasis, and vitiligo.

A square-shaped chest with widely shaped nipples (“shield chest”) is frequently observed. Body proportions are abnormal, with reduced height-to-width ratio, resulting in a stocky build and relatively large hands and feet. Low-set ears, high arched palate, micrognathia, midfacial hypoplasia, and downward displacement of the outer corner of the eyes and epicanthic folds create a characteristic facies.

Expected results of diagnostic studies

If there is a suspicion of TS, a peripheral blood karyotype should be performed. Although a karyotype is currently the gold standard, new DNA-based methods with high sensitivity are being developed, including quantitative pyrosequencing tests to detect X and Y chromosome single nucleotide polymorphisms (SNPs).

Prenatal diagnosis most often occurs incidentally during chorionic villous sampling or amniocentesis. Although not sufficient for diagnosis, in-utero ultrasound findings suggestive of TS include cystic hygroma, increased nuchal translucency, left-sided heart defects, coarctation of the aorta, brachycephaly, renal malformations, and growth retardation.

Maternal triple screen may be abnormal. Alpha-fetoprotein (AFP) and unconjugated estriol are reduced, and human chorionic gonadotrophin (hCG) is increased in the presence of fetal hydrops.

Diagnosis confirmation

The most important entity to consider in the differential diagnosis of TS is Noonan syndrome. The principal features of Noonan syndrome include congenital heart defects such as pulmonary stenosis, as well as short stature, webbed neck, lymphedema, pectus excavatum, cryptorchidism, gonadal dysgenesis, mental retardation, and characteristic facies with midfacial hypoplasia and hypertelorism.

Noonan syndrome is an autosomal dominantly inherited condition most commonly caused by a mutation in the PTPN11 gene, and may affect both males and females. A karyotype is necessary to distinguish Noonan syndrome from TS. Other entities to be considered include familiar short stature, Leri-Weill syndrome (mesomelic dwarfism with Madelung’s deformity of the forearms), brachydactyly E, growth hormone deficiency, hypothyroidism, pure gonadal dysgenesis, Stein-Leventhal syndrome, and hereditary congenital lymphedema.

Who is at Risk for Developing this Disease?

Turner syndrome is a sporadic genetic disease affecting approximately 1 in 2000 live birth female newborns. Despite conflicting data, at this time most experts do not believe that it is associated with advanced maternal age. Most pregnancies with TS spontaneously abort, and an estimated 10% of spontaneously aborted fetuses have TS.

What is the Cause of the Disease?

TS is a genetically heterogeneous disease. Causative genotypic alterations include the complete or partial absence of the second X chromosome, a structurally defective X chromosome, or mosaicism of 45,X with another cell line. The most common karyotype is 45,X, which accounts for about 50% of patients. Mosaicism is found in another 30%-40% of TS patients.


The pathophysiology of TS is related to the deficient expression (haploinsufficiency) of missing or altered genes on the X chromosome. Although not fully elucidated at this time, multiple genes are believed to be involved, thus giving rise to the heterogenous clinical features seen in TS.

Deletion of the SHOX (short stature homeobox) gene on the short arm of chromosome X (Xp), thought to be a transcription factor involved in embryonic patterning, is implicated in the development of short stature and skeletal abnormalities.

In general, any combination of clinical features and severity can be seen in the various karyotypes; however, mosaics may have more mild disease, while those with loss of the short arm of the X chromosome (Xp) more frequently display typical phenotypic features.

Systemic Implications and Complications

Turner syndrome is associated with multiple systemic complications and thus a multidisciplinary approach is recommended to ensure proper diagnosis and care.


Excess morbidity is usually related to cardiovascular complications. Thirty percent of patients have a congenital heart defect, most commonly bicuspid aortic valve and aortic coarctation. Aortic root dilation is rare, but when present, it is usually associated with underlying hypertension or a structural defect such as bicuspid aortic valve or aortic coarctation. It is life-threatening if dissection or rupture occurs.

All patients with TS should be referred for cardiac evaluation, and work-up should include blood pressure measurements from all extremities, an electrocardiogram (ECG), and an echocardiogram. If negative during childhood, it is recommended that the echocardiogram be repeated during adolescence and every 5-10 years thereafter, paying special attention for evidence of aortic root dilation.

Cardiac magnetic resonance imaging (MRI) is recommended once the patient reaches an age when sedation is no longer required, as it may identify cases missed by echocardiogram. Hypertension affects more than 50% of young adults with TS and is a risk factor for aortic root dilation, dissection, and rupture. Blood pressure should be monitored and treated aggressively. Furthermore, adults are at increased risk of coronary artery disease and dyslipidemia.


Malformations of the urinary system are present in 30%-40% of patients, and include structural defects of the collecting system, horseshoe kidney, and malrotation. These defects do not generally impact renal function, although patients are at higher risk of developing urinary tract infections. A renal ultrasound should be performed at the time of diagnosis for screening.


Thyroid disease occurs with high frequency in TS, and is reflective of an overall predisposition toward autoimmunity. Hypothyroidism and hyperthyroidism was found in one longitudinal series to affect 24% and 2.5% of patients, respectively. Thyroid dysfunction is usually detected beginning in childhood, and therefore annual screening for thyroid-stimulating hormone (TSH) and thyroxine (T4) is recommended starting from age 4.

Patients with thyroid autoantibodies have a higher risk of developing disease and may require closer monitoring of thyroid function. In addition, patients are at increased risk for diabetes, and thus monitoring of fasting blood glucose is recommended.


Patients with TS have a higher incidence of celiac disease, and therefore screening with tissue transglutaminase IgA antibodies is recommended starting at age 4 and every 2-5 years thereafter.

Liver enzymes are commonly elevated in women; however, there is usually no overt hepatic disease. If liver enzymes remain elevated for greater than 6-12 months, a liver ultrasound is recommended to rule out hepatosteatosis, and if negative, a hepatology consult should be obtained for further workup.


Although mental retardation is rarely a feature of TS, learning disabilities may occur and include impairments in visual-spatial learning, social cognition, and psychomotor skills.

Patients often have difficulty with social adjustment as a result of short stature, impaired sexual development, and other features associated with TS. The above may impact ability to develop relationships with others, attain an education, enter the workforce, and live independently. Patients should be referred for psychological care as appropriate.


Sensorineural hearing loss occurs secondary to defective outer hair cells of the cochlea and may present in childhood, necessitating a baseline hearing evaluation for all patients. If no evidence of hearing loss is found, audiologic examinations are recommended every 2-3 years.

Otitis media occurs frequently, as a result of abnormal anatomy of the ear and cranial base, with persistent otorrhea possibly eventuating in conductive hearing loss and cholesteatoma formation. Thus, clearance of middle ear effusions should be documented after an episode of otitis media. Those with persistent middle ear effusions or recurrent otitis media should be referred to an otolaryngologist for management to prevent sequelae.


Strabismus, amblyopia, and ptosis may be seen in TS, and ophthalmologic evaluation should be obtained as appropriate.


TS is associated with an increased number of melanocytic nevi, although rates of melanoma do not appear to differ from the general population. Dermatology evaluation should be obtained for mole monitoring or evaluation of suspicious lesions. A higher incidence of keloid formation is reported in patients with TS, and this should be discussed prior to undertaking any surgical procedures such as correction of neck webbing.


Estrogen deficiency places patients at risk for early-onset osteoporosis and subsequent fractures; thus, bone mineral density should be measured starting at age 18. If normal, repeat evaluation can be delayed until 40 or 50 years of age.

Treatment Options


Growth hormone (GH) is a well-established therapy for increasing growth velocity and final adult height. Optimum age of therapy initiation has not been established, although studies have shown efficacy starting as early as 9 months of age. Experts generally recommend that it be considered as soon as growth failure is observed. Below age 9, GH is usually administered as monotherapy. The addition of a nonaromatizable anabolic steroid such as oxandrolone may be considered for older girls and those with extreme short stature.


The goal of therapy is to induce puberty as well as to prevent the sequelae of low estrogen levels. Estrogen therapy is used to induce puberty in patients who show lack of spontaneous development and whose FSH levels are elevated.

Low-dose estrodiol may be considered as early as 12 years of age, although the impact on height development must be measured against the importance of sexual maturation. In order to allow breast and uterine development, progestin is usually added after 2 years of estrogen therapy or when breakthrough bleeding occurs.


Estrogen replacement, calcium/vitamin D replacement, and weight-bearing exercise are the mainstay of therapy for bone protection. For patients with osteoporosis, medical treatment as recommended for the general population is indicated.


Treatment of lymphedema includes compression stockings, leg elevation, lymphatic massage, and skin and nail care. Surgical treatment of webbing of the neck has been performed; however, these procedures can be complicated by keloid formation, limited range of motion, hairline displacement, and recurrence of webbing.


At this time, various reproductive techniques are available to assist with achieving pregnancy, and studies show that the rate of achieving term pregnancy in TS is comparable to that of women with other infertility issues.

Patients are at high risk of prenatal complications, given higher prevalence of hypertension, diabetes, and other systemic associations of TS. Additionally, the risk of aortic dilatation and dissection is shown to be increased during pregnancy.

Optimal Therapeutic Approach for this Disease

A multidisciplinary approach to the main systemic manifestations of TS (short stature, infertility, osteopenia/osteoporosis, and lymphedema) is optimal. The specific approaches to these myriad issues are given under Treatment Options.

Patient Management

The following are recommendations published by The Turner Syndrome Study Group:

At the time of diagnosis:

Cardiology referral: echocardiogram for infants and young girls, cardiac MRI once patient reaches age when sedation is no longer required, ECG

Blood pressure measurement

Endocrine referral for evaluation of growth and development

Renal ultrasound

Audiology referral for hearing test

Evaluation for kyphosis and scoliosis

Support group referral and educational/psychosocial evaluation

Evaluation for congenital hip dislocation (age 0-4 years)

Ophthalmology referral (age 1+)

Thyroid function screen—TSH, T4 (age 4+)

Celiac screen— transglutaminase antibody (TTG Ab) (age 4+)

Orthodontic referral (age 7+)

Liver function test (LFT), fasting blood glucose (FBG), lipids, complete blood count (CBC), creatinine , blood urea nitrogen (BUN) (age 10+)

Endocrine referral for evaluation of ovarian function and estrogen replacement (age 10+)

Bone mineral density (BMD) (age 18+)

Ongoing care:

Blood pressure monitoring annually

Cardiac imaging every 5-10 years. Also repeat prior to attempting pregnancy, if hypertension develops, or upon transition from pediatric to adult clinic

Hearing test and otolaryngology evaluation every 1-5 years

Thyroid screen annually (age 4+)

Celiac screen every 2-5 years (age 4+)

LFT, FBG, lipids annually (age 10+)

Educational and psychosocial evaluation annually

Unusual Clinical Scenarios to Consider in Patient Management

Any patient with virilization or presence of marker chromosome should be tested for the presence of Y chromosome using fluorescent in-situ hybridization (FISH) or DNA analysis. Approximately 5% of cases of TS may be associated with mosaicism of the Y chromosome. The presence of Y chromosomal material is associated with an approximately 12% risk of gonadoblastoma formation, and as such, prophylactic gonadectomy is currently recommended.

Patchy or streaky pigmentary skin changes (hypo- or hyperpigmented) following the lines of Blaschko are cutaneous clues to the presence of chromosomal mosaicism.

TS associated with pigmentary mosaicism (Figure 3) represents a rare situation with fewer than ten cases reported in the literature. In this scenario, it is important to refer patients for chromosomal analysis via molecular techniques such as FISH or pyrosequencing assays in order to detect low levels of mosaicism associated with the Y chromosome, which may be missed using classical cytogenetic karyotyping.

Figure 3.

Turner syndrome in an infant with linear streaks of hyperpigmentation along the lines of Blaschko on the arm (pigmentary mosaicism). This patient was diagnosed prenatally with a 45,X karyotype. (Courtesy Jeanette Jakus, MD)

Several cases of new-onset and exacerbation of psoriasis have been reported in TS patients being treated with growth hormone (GH). In a few case reports, withdrawal of GH or lowering of the dose was associated with improvement of the psoriasis, while relapses were observed with reintroduction of GH therapy.

Recently, a 9-year-old girl with TS, who was started on GH 1 year ago, presented to our clinic with psoriasiform scalp lesions that started one month after initiation of therapy. Subsequently, she developed erythematous papules and plaques with micaceous scale on her trunk (Figure 4). She is currently being treated with mid-potency steroid ointment for the lesions on her body and a mid-potency steroid solution and tar shampoo for her scalp. The pathogenesis of GH-induced psoriasis remains unclear.

Figure 4.

New-onset psoriasis in a girl with Turner syndrome, 1 month after starting growth hormone therapy.

What is the Evidence?

Lowenstein, EJ, Kim, KH, Glick, SA. “Turner’s syndrome in dermatology”. J Am Acad Dermatol. vol. 50. 2004. pp. 767-76. (A comprehensive review on the skin manifestations of TS. This article also discusses the genetic basis and pathogenesis of this complex disorder.)

Bondy, CA. “Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 10-25. (Consensus guidelines addressing the evaluation and treatment of patients with TS from a multidisciplinary panel of experts. Recommendations focus on genetic, cardiologic, endocrinologic, gynecologic, and general medical concerns.)

Saenger, P, Wikland, KA, Conway, GS, Davenport, M, Gravholt, CH, Hintz, R. “Recommendations for the diagnosis and management of Turner syndrome”. J Clin Endocrinol Metab. vol. 86. 2001. pp. 3061-69. (Comprehensive recommendations on the diagnosis and practical guidelines for the management of TS. This interdisciplinary paper also reviews the genetic mechanism of this syndrome.)

Elder, DA, Roper, MG, Henderson, RC, Davenport, ML. “Kyphosis in a Turner syndrome population”. Pediatrics. vol. 109. 2002. pp. e93(Study examining the prevalence of vertebral abnormalities in Turner syndrome, along with a brief review of bony growth abnormalities observed in Turner Syndrome)

Hall, JG, Sybert, VP, Williamson, RA, Fisher, NL, Reed, SD. “Turner’s syndrome”. West J Med. vol. 137. 1982. pp. 32-44. (A comprehensive review of the genetic and clinical manifestations of TS)

Kajii, T, Ferrier, A, Niikawa, N, Takahara, H, Ohama, K, Avirachan, S. “Anatomic and chromosomal anomalies in 639 spontaneous abortuses”. Hum Genet. vol. 55. 1980. pp. 87-98. (In this study, 10% of spontaneous abortuses examined were found to have a 45,X karyotype.)

Livadas, S, Xekouki, P, Fouka, F, Kanaka-Gantenbein, C, Kaloumenou, I, Mavrou, A. “Prevalence of thyroid dysfunction in Turner’s syndrome: a long-term follow up study and brief literature review”. Thyroid. vol. 15. 2005. pp. 1061-6. (Study evaluating prevalence and age of onset of thyroid pathology, along with a brief review on thyroid disease in TS )

Ruiz, C, Lamm, F, Hart, FS. “Turner syndrome and multiple marker screening”. Clinical Chem. vol. 45. 1999. pp. 2259-61. (Study examining maternal triple screen abnormalities in TS )

Cools, M, Drop, SL, Wolffenbuttel, KP, Oosterhuis, JW, Looijenga, LH. “Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers”. Endoc Rev. vol. 27. 2006. pp. 468-84. (A review of the development of germ cell tumors in various disorders of sexual development, including the risk of gonadoblastoma formation in 45,X/46,XY mosaic TS )

Rivkees, S, Hager, K, Hosono, S, Wise, A, Li, P, Rinder, H, Gruen, J. “A highly sensitive, high throughput assay for the detection of Turner syndrome”. J Clin Endocrinol Metab. vol. 96. 2010. pp. 699-705. (Validation study for a novel high-throughput, pyrosequencing-based assay for the diagnosis of TS )