Summary
Turner syndrome is a genetic condition that affects individuals with a female phenotype and is caused by the complete or partial absence of one X chromosome, most commonly due to chromosomal nondisjunction. Common clinical features include short stature, characteristic physical features (e.g., webbed neck, broad chest, lymphedema), and manifestations of gonadal dysgenesis (e.g., delayed puberty, amenorrhea, infertility). Affected individuals have an increased risk of congenital malformations, particularly cardiovascular abnormalities (e.g., coarctation of the aorta, bicuspid aortic valve) and congenital anomalies of the kidney and urinary tract (CAKUT). Diagnosis is suspected based on prenatal findings and/or clinical features and confirmed by karyotype analysis, with 45,X and mosaicism being the most common findings. Management is multidisciplinary and focuses on specific manifestations. Pharmacological treatments include growth hormone therapy to optimize adult height and hormone replacement therapy (HRT) to induce puberty. Prophylactic gonadectomy may be considered for individuals with Y chromosome material due to an increased risk of gonadoblastoma. Lifelong monitoring is recommended for associated conditions and complications, which include aortic dilation and aortic dissection.
Epidemiology
- Prevalence: 1:2000–1:2500 of female individuals [1]
- Median age at diagnosis: 15 years [2]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
Turner syndrome results from the complete or partial absence of one X chromosome, most commonly due to nondisjunction.
- Meiotic nondisjunction (most often in paternal gametes) → complete sex chromosomal monosomy (45,X; no Barr body)
- Mitotic nondisjunction of an embryonic cell → sex chromosomal mosaicism (e.g., 45,X/46,XX) → phenotypic expression may be milder
Unlike sex chromosome trisomies (e.g., Klinefelter syndrome), Turner syndrome is not strongly associated with advanced maternal age. [3]
Pathophysiology
- Chromosomal nondisjunction → X chromosome monosomy or mosaicism → impaired ovarian development → malfunctioning streak gonads with connective tissue instead of normal germ cells → estrogen and progesterone deficiencies
- Presence of only one copy of the SHOX (short stature homeobox) gene; (located on the X chromosome) → short stature
Clinical features
Turner syndrome is only diagnosed in individuals with a female phenotype.
Classic Turner syndrome phenotype [1][4][5]
-
Characteristic physical features
- Short stature and/or projected adult height below the mid-parental height range [2][6]
- Down-slanted palpebral fissures with epicanthal folds
- Micrognathia and a high-arched, narrow palate [7]
- Low-set ears and a low posterior hairline
- Webbed neck: skin folds along the side of the neck between the mastoid process and the acromion [8]
- Broad chest (previously called shield chest) with widely spaced nipples [9]
- Relatively long torso
- Skeletal abnormalities: cubitus valgus, short fourth or fifth metacarpals and/or metatarsals
- Lymphedema of the hands and feet (may be present at birth and persist into adulthood)
-
Manifestations of gonadal dysgenesis
- Delayed puberty, amenorrhea (primary or secondary), infertility
- Diagnostic evaluation shows hypergonadotropic hypogonadism (↑ FSH, ↑ LH, ↓ estrogen, ↓ androgens).
Turner syndrome is only diagnosed in individuals with a female phenotype. [4]
Turner syndrome is a common cause of gonadal dysgenesis, which may manifest as streak gonads and/or primary ovarian insufficiency. [4][10]
Associated conditions [1][4][5]
-
Cardiovascular abnormalities in Turner syndrome (left-sided obstructive abnormalities) [1][4][5]
- Bicuspid aortic valve; with an increased risk of premature aortic stenosis and/or insufficiency
- Coarctation of the aorta; with brachial-femoral delay
- Aortic dilation, which can lead to aortic dissection and rupture
- Hypertension (onset may occur in childhood)
- CAKUT, e.g.:
- Prenatal lymphatic abnormalities: cystic hygroma, hydrops fetalis
- Hearing loss: conductive (e.g., from recurrent middle ear infections) and sensorineural
- Visual abnormalities: refractive errors, strabismus, ptosis
- Autoimmune diseases (e.g., Hashimoto thyroiditis, celiac disease, vitamin B12 deficiency)
- Metabolic abnormalities (e.g., overweight and obesity, diabetes mellitus)
-
Other skeletal abnormalities, e.g.:
- Structural abnormalities: scoliosis, kyphosis, genu valgum, Madelung deformity
- Impaired bone health: osteoporosis, pathological fractures
- Dermatologic findings (e.g., multiple nevi, nail dysplasia or hyperconvexity, autoimmune skin conditions)
- Gonadoblastoma (especially in individuals with Y chromosome material)
- Neurocognitive difficulties (e.g., impaired executive function skills, specific learning disorders)
For most patients with Turner syndrome, intelligence is unaffected. [4][5]
Due to the complete or partial absence of a second X chromosome, individuals with Turner syndrome may develop disorders with an X-linked recessive inheritance pattern that typically occur in male individuals. [11]
Diagnosis
Approach
Prenatal diagnosis [4][12]
-
Indications for diagnostic testing
- Prenatal ultrasound findings of Turner syndrome
- Noninvasive prenatal testing suggestive of Turner syndrome [13]
- Confirmatory invasive prenatal genetic testing (if pursued): fetal cell karyotyping
- Additional testing: detailed fetal anatomical ultrasound and fetal echocardiography
Postnatal diagnosis [4]
-
Indications for diagnostic testing
- Suspected or confirmed prenatal Turner syndrome
- Clinical features of Turner syndrome, including those identified as part of the following:
- Confirmatory testing: karyotyping of peripheral blood cells
-
Additional testing
- Additional cytogenetic testing (e.g., FISH, PCR) in selected patients
- Obtain appropriate monitoring studies for Turner syndrome to identify associated conditions.
If Turner syndrome is confirmed prenatally, postnatal karyotyping is recommended to confirm and further characterize the chromosomal abnormality (e.g., degree of mosaicism). [4]
Karyotype findings [4]
Karyotyping is the criterion standard for diagnosing Turner syndrome. Findings include:
- Monosomy X (45,X): most common [4]
- 45,X/46,XX mosaicism
- Mosaicism with Y chromosome material (e.g., 45,X/46,XY)
Screening studies for associated conditions [4]
The following monitoring studies for Turner syndrome may be obtained at diagnosis and/or as part of ongoing monitoring in asymptomatic individuals.
Laboratory studies [4]
- Thyroid screening with TSH
- Celiac disease screening with tissue transglutaminase and total IgA
- Ovarian testing to assess for primary ovarian insufficiency (↑ FSH, ↑ LH) and diminished ovarian reserve (↓ AMH)
- Vitamin D screening with 25-hydroxyvitamin D level
- Diabetes screening with HbA1c and/or fasting glucose
- Liver enzyme testing to assess for elevated liver enzymes
- Dyslipidemia screening with lipid profile
- Proteinuria screening with urinalysis in patients with congenital kidney abnormalities
- Anemia screening with CBC
Imaging [4]
- Cardiac imaging (TTE, cardiac MRI) to assess for cardiovascular abnormalities in Turner syndrome [14]
- Kidney ultrasound at diagnosis to assess for CAKUT
- DXA scan to assess bone health
Other assessments [4]
- ECG with QTc calculation at diagnosis to assess for arrhythmia and conduction abnormalities [14]
- Audiology referral for age-appropriate audiology evaluations
- Tympanometry to assess for middle ear pathology
- Ophthalmology referral for eye evaluation at age 6–12 months [4]
Additional or more frequent testing may be indicated based on symptoms, abnormal findings, or associated conditions. [4]
Management
General principles [4]
-
Prenatal management
- Consult appropriate specialists (e.g., genetics, maternal-fetal medicine).
- Recommend delivery in a facility that can provide appropriate newborn monitoring.
-
Management of children and adults
- Management is multidisciplinary.
- Monitoring for disease manifestations and complications is typically lifelong.
- Treatment is targeted at specific disease manifestations.
Routine health care [4]
As part of routine health maintenance visits, pay particular attention to the following:
- Review of pediatric growth parameters
- Infant hip examination to screen for developmental hip dysplasia
- Blood pressure screening
- Otoscopic examination to evaluate for middle ear disease (e.g., infection, effusion)
- Scoliosis screening annually from infancy until skeletal maturity is reached
- Pubertal assessment
- Education on the need for dental and orthodontic examinations [4]
- Screening and/or referral for developmental, neuropsychological, and behavioral assessments [4]
- Coordination of specialist follow-up and recommended monitoring studies for Turner syndrome
A Turner syndrome-specific growth chart for linear growth is available. [4]
Management of condition-specific manifestations [4]
In addition to a genetics referral at diagnosis, management of Turner syndrome typically includes the following specialist-directed care.
-
Cardiovascular care
- Refer to cardiology at diagnosis and before pregnancy.
- Management includes screening and treatment of congenital heart disease, aortic root dilation, and hypertension. [1][14]
-
Management of renal and urinary tract abnormalities
- Refer to nephrology for proteinuria, hypertension, or congenital renal abnormalities.
- Refer to urology for congenital urinary tract abnormalities requiring surgical evaluation.
-
Audiological care
- Refer to audiology at diagnosis and for ongoing monitoring.
- Hearing amplification devices may be indicated for sensorineural hearing loss.
- Refer to ENT for recurrent otitis media, conductive hearing loss, or structural ear abnormalities.
-
Growth and pubertal management
- Refer to endocrinology at diagnosis.
- Growth hormone therapy is recommended for most children with remaining growth potential. [4]
- HRT (estrogen and progesterone) is typically initiated at 11–12 years of age in patients with primary ovarian insufficiency. [4]
-
Reproductive health and fertility management
- Offer referral to reproductive endocrinology or a fertility specialist at diagnosis and before early adolescence.
- Counseling topics may include:
- Fertility preservation options (e.g., ovarian stimulation and cryopreservation) if residual ovarian function is present
- Assisted reproductive technologies (e.g., IVF with donor oocytes)
Spontaneous conception is possible in some individuals (e.g., those with mosaic karyotypes). [4]
Prophylactic gonadectomy or salpingo-oophorectomy may be considered in individuals with Y chromosome material due to the increased risk of neoplasms. [4]
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