Overview

Turner syndrome (TS) is a chromosomal disorder that affects females and is caused by a complete or partial loss of the second sex-determining chromosome. The syndrome is typically characterized by short stature, ovarian insufficiency, and malformations in organ systems that could include cardiac defects (particularly coarctation of the aorta and bicuspid aortic valve), lymphedema (especially nuchal and over the dorsum of the hands and feet), short 4th metacarpals, and genitourinary malformations (such as horseshoe kidney). Some affected individuals are phenotypically normal females with only short stature. Others can have life-threatening cardiovascular, hormonal, and lymphatic anomalies or manifestations, such as short stature, pubertal delay, and sterility, which impart significant psycho-emotional burden and a higher risk for co-morbidities.

Bonnevie-Ullrich-Turner syndrome
Gonadal dysgenesis
Ovarian dysgenesis
Turner's syndrome
Ullrich-Turner syndrome
XO syndrome, monosomy X

ICD-10 coding

Q96, Turner syndrome

ICD-10 for Turner Syndrome provides further coding details for variants of the syndrome.

Prevalence

TS is present in approximately 1 in 2000 to 2500 live female births worldwide. [Donaldson: 2006] [Stochholm: 2006] Prevalence is greater if pregnancies that do not survive to term are taken into account; one study showed that 66% of pregnancies affected by TS resulted in spontaneous miscarriage. [Iyer: 2012]

Genetics

About half of women with TS are completely missing the second sex chromosome; in the other half, it may be partially missing or rearranged. Mosaic TS occurs when only some of the individual’s cells lack the second normal sex chromosome. The severity of the phenotype is related to the absence or presence of a second sex chromosome. Full monosomy (45,X or 45,XO) typically is the most severe form and mosaic TS is typically the mildest form.

Prognosis

Congenital and atherosclerotic heart disease increases risk of mortality. Health complications include type 2 diabetes and osteoporosis. Girls and women with TS have a small risk for fatal aortic dissection, which is greater in the presence of abnormalities of the aorta or aortic valve and hypertension. Girls with TS may have normal intelligence, but they are at risk for social immaturity, attention-deficit disorder, and learning disabilities. [Ostberg: 2003]

Practice Guidelines

Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Söderström-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF.
Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.
Eur J Endocrinol. 2017;177(3):G1-G70. PubMed abstract

Roles of the Medical Home

A child with TS needs a medical home for well-child and chronic-care visits and to facilitate and coordinate access to subspecialists (most often including cardiologists and endocrinologists) for monitoring and early intervention when applicable. The medical home may also help to reduce duplication of services and unnecessary medical appointments (which place unnecessary emotional and financial burden upon families).

Overview

Facial features of a girl with Turner syndrome

Turner syndrome (TS) may be diagnosed across the lifespan. The broad clinical spectrum of TS ranges from a classic appearance with many different physical features to no apparent or minimal observable features. Growth failure is a problem for virtually all. TS patients need ongoing health surveillance for co-morbidities throughout their life. Ideally, a multidisciplinary clinic or team of specialists with expertise in TS would coordinate and manage care.

Pearls & Alerts for Assessment

High false positive prenatal results

As many as 30% of fetuses suspected of having TS based on cytogenetic studies alone may ultimately have normal karyotypes and normal physical exam findings. Prenatal diagnosis of TS should always be accompanied by fetal ultrasonography; the likelihood of TS is reduced if sonographic results are normal (e.g., no cystic hygroma, renal, or cardiac malformations). [Gravholt: 1996] [Huang: 2002]

Risk of gonadoblastoma

Any patient with TS who has marker chromosome elements (sex chromosome material of uncertain origin) detected on the karyotype or who develops virilization should be screened for Y chromosome mosaicism. The presence of a Y chromosome can be detected by standard karyotype or PCR (polymerase chain reaction). When Y-chromosome material is present (incidence of 5–12%), prophylactic gonadectomy is recommended due to an increased risk (~10%) of gonadoblastoma. [Binder: 1995] [Gravholt: 2017]

Short stature and Turner syndrome

While individuals with TS may exhibit a constellation of unusual features and organ malformations, short stature and growth failure are the only findings that are present in virtually 100% of patients. [Palmer: 1976]

Aortic dissection and rupture risk

The incidence of acute aortic dissection in young and middle-aged women with TS is more than 100 times that of the general population, and the mean age of onset in those with TS is 30 years (range 4-64) compared to 71 years. [Bondy: 2008] [Carlson: 2007] Risk factors for dissection include systemic hypertension, aortic dilatation, and aortic valve abnormalities, though only rarely is a predisposing factor identified. Presenting complaints may be vague or minor in nature, such as abdominal pain, "heartburn," back or shoulder pain, or a change in voice (related to traction on the recurrent laryngeal nerve). If persistent, these symptoms should be given serious investigation, including trans-esophageal echocardiography,chest CT, or cardiac MRI.

For the Condition

Although screening for TS in newborn infants is not recommended, prenatal cytogenetic screening for aneuploidy is increasingly performed for mothers of advanced maternal age, and cytogenetic evidence of TS can be an incidental finding. Ultrasonography can play an important role in diagnosing TS in utero. Increased nuchal translucency is common in TS fetuses, but it is also seen in the autosomal trisomy syndromes. The presence of a frank cystic hygroma, however, makes TS diagnosis more likely.

Other ultrasound findings such as coarctation of aorta or cardiac defects, intrauterine growth restriction, renal anomalies, brachycephaly, poly or oligohydramnios are further suggestive of TS. If the results of fetal ultrasonography are normal, fetal cytogenetic studies have a relatively high false positive rate and non-invasive prenatal testing (NIPT) yields 2.5 as many false positives for TS as it does true positives. [Yu: 2017] These results should be considered with caution when counseling a family about the risk of TS. Regardless of the test procedure or results, genetic counseling should be provided before and after any prenatal diagnostic procedure. Ultrasound and maternal serum screening are not diagnostic, and karyotype conﬁrmation of TS is absolutely needed. Advanced maternal age is not a risk factor for TS.

Of Family Members

The risk of the same parents having a second child with TS is no greater than that of the general population - no screening is recommended.

For Complications

Turner Syndrome Health Maintenance Checklist ( PDF Document

80 KB)
Click image for full-size pdf.

Numerous specific screens are recommended; they are summarized below and detailed in a checklist format for use in practice (left).

Annual physical exam, including height, weight, blood pressure, and skin exam
Comprehensive ophthalmologic exam starting at 12-18 months or at diagnosis
Audiometric evaluation every 3 years starting at 9-12 months of age
Scoliosis/orthopedic evaluation annually
Renal ultrasound at diagnosis

Cardiovascular:

Resting EKG and QTc measurement at diagnosis
Transthoracic echocardiogram (TTE) at diagnosis
Cardiac MRI (CMR) as soon as feasible without need for general anesthesia

TTE or CMR (click on charts below for details)

In the absence of aortic abnormalities, every 5 years
If hypertension (HTN), bicuspid aortic valve (BAV), coarctation of the aorta (CoV), or TS-specific aortic size Z-score (TSZ) >3, yearly

After 16 years, frequency determined by risk


Cardiac screening in TS, infant - 16 yrs. (from [Gravholt: 2017]) Click image for full-size version.	Cardiac screening in TS, above 16 yrs. (from [Gravholt: 2017]) Click image for full-size version.

Thyroid function tests annually starting at age 4
Liver function tests annually starting at age 10
Annual HbA1c, glucose starting at age 10
Neuropsych evaluation at preschool and school transitions (to high school and higher education)
Pediatric dental specialist by age 2, orthodontic evaluation no later than age 7
Dermatology follow up for nevi
Nutritional evaluation, including celiac screening every 2 years, starting at age 2
25-OH vit D level between 9-11 years and every 2-3 years thereafter

Presentations

Missed and delayed diagnosis of TS remain a problem. [Gravholt: 2017] Regardless of other findings, TS should be considered in any female with unexplained growth failure or delayed puberty.

Presentations of TS may include:

Unexplained growth failure
Low-set ears
Micrognathia
Epicanthal folds
Nuchal redundancy, cystic hygroma
Widely spaced nipples, perhaps with shield chest and pectus excavatum
Lymphedema sequence (edema of hands or feet, webbed neck, low hairline, hyperconvex and hypoplastic nails)
Cardiac anomalies, such as bicuspid aortic valve, coarctation of aorta
Cubitus valgus
Multiple pigmented nevi
Short fourth metacarpal bones
Madelung deformity
Hearing loss
Elevated FSH

Epicanthal Folds

Cystic Hygroma

In childhood and adolescence

Short stature (in nearly 100%)
Chronic otitis media
Scoliosis
Hyperconvex, narrow fingernails; thin,
mildly dysplastic toenails
Pubertal delay
Ovarian deficiency

Scoliosis

Diagnostic Criteria

The diagnosis of TS requires the presence of characteristic features in phenotypic females and full or partial sex chromosome monosomy, with or without cell line mosaicism, demonstrated on a standard 20-cell karyotype.

Additional metaphases may be counted or FISH studies performed if there is suspicion of undetected mosaicism. Although a peripheral blood karyotype is usually adequate, a second tissue, such as skin fibroblasts, buccal mucosa cells, or possibly bladder epithelial cells from the urine, may be examined if there is a strong suspicion of TS and the karyotype is normal. Any patient with TS who has marker chromosome elements (sex chromosome material of uncertain origin) detected on the karyotype or who develops virilization should be screened for Y chromosome mosaicism. The presence of a Y chromosome can be detected by standard karyotype or FISH (fluorescent in situ hybridization) or PCR (polymerase chain reaction). PCR techniques are more sensitive than FISH in detecting cryptic Y-material. When Y-chromosome material is present (incidence of 5–12%), prophylactic gonadectomy is recommended due to an increased risk (around 10%) of gonadoblastoma. [Binder: 1995] [Gravholt: 2017]

Clinical Classification

Types of chromosomal anomalies associated with TS: [Davenport: 2010] [Shankar: 2018]

45, X (monosomy X) is found in approximately 45% of live births with TS; these patients should be evaluated for presence of Y chromosome material.
45, X mosaicism is a mosaic chromosomal complement (e.g., 45,X/46,XX) detectable in 20-30% of all patients with TS.
X chromosome anomalies:
- Xp or Xq deletion: Some patients have a deletion of the short arm of the X chromosome with or without 45,X cell line mosaicism. Patients with terminal Xq deletion, may not have any other features of TS besides ovarian insufficiency.
- Ring chromosome X
- Isochromosome Xq (46,X,i(X)q): Patients with a structurally abnormal X chromosome consisting of 2 copies of the long arm with some intervening short arm or centromeric material are at higher risk for autoimmune disorders.

Patients with mosaic 46,XX karyotype or isochromosome Xq have a milder phenotype, while patients with mosaicism for 46,XY cell line or structural rearrangement of the Y chromosome mostly have masculinized external genitalia and are at increased risk for having gonadoblastoma and other gonadal tumors.

Differential Diagnosis

Noonan syndrome (NS) is an autosomal dominant condition affecting boys and girls in equal proportions. It is most commonly associated with pathogenic variants in the PTPN11, SOS1, RAF1 or RIT1 genes (Noonan syndrome next-generation sequencing (NGS) panel testing is clinically available). As in TS, girls with NS typically have short stature, lymphedema of the extremities, and can have neck webbing, cardiac defects, ptosis, inner epicanthal folds, high-arched palate, and musculoskeletal differences (pectus deformities, cubitus valgus). However, the cardiac anomalies most commonly seen in NS are right sided (pulmonary valve stenosis in 50% of those with cardiac anomalies; septal defects and cardiomyopathy may also occur); the cardiac anomalies most commonly seen in TS are usually left sided. Individuals with NS are more likely to have gross motor or global developmental delays than those with TS. Despite these differences, considerable variability of presentations exists for both syndromes and a karyotype with complete or partial absence of the second sex-determining chromosome is often the only way to distinguish between the 2 disorders in females. [Cassidy: 2005]

Comorbid & Secondary Conditions

Co-morbidities in TS are often undiagnosed and include: [Freriks: 2011]

Aorto-cardiac anomalies
Dyslipidemia
Renal anomalies
Hypertension
Osteopenia
Hearing loss
Primary ovarian insufficiency
Infertility
Celiac disease
Hypothyroidism
Hepatic fibrosis

TS should be considered in any girl with a webbed neck, lymphedema, or coarctation of aorta during infancy. Previous guidelines suggested that a peripheral blood karyotype be considered in girls with unexplained short stature, delayed puberty, or the constellation of characteristic dysmorphic features [Bondy: 2007], but new guidelines propose that karyotyping be performed: [Gravholt: 2017] [Shankar: 2018]

In the presence of a single clinical feature such as fetal hydrops or cystic hygroma, unexplained short stature, obstructive left-sided cardiac abnormality (such as a bicuspid aortic valve, coarctation, aortic stenosis, hypoplastic left heart syndrome, or mitral valve abnormalities), delayed puberty, characteristic facial features (such as short broad neck with webbing, micrognathia, low set ears and down-slanted palpebral fissures with epicanthal folds), or infertility
If 2 or more features commonly associated with TS such as renal anomaly (hypoplasia, aplasia or horseshoe kidney), other cardiac anomalies (e.g., partial anomalous pulmonary venous return, atrial or ventricular septal defects), hearing loss, Madelung deformity, dysplastic nails, multiple nevi, and neuropsychological issues associated with short stature are seen in a girl

Current & Past Medical History

Girls with TS often come to medical attention during infancy because of the presence of distal lymphedema, nuchal redundancy, and/or murmurs associated with characteristic left-sided cardiac malformations, such as coarctation of the aorta and bicuspid aortic valve. Older girls may present with unexplained short stature. Because of abnormalities in craniofacial development, these individuals may have a history of chronic middle ear effusions. Adolescent females with TS may present with primary amenorrhea.

Inquire about the following:

Exercise intolerance, chest, or back pain, which may be a symptom of aortic dilatation or impending rupture
Acute and chronic otitis media, persistent middle ear effusion, and associated hearing loss
Problems with vision
Dental and orthodontic care, tooth abnormalities, dental pain, and difficulty chewing
Symptoms of hyper- or hypothyroidism, which may indicate the onset of autoimmune thyroiditis
Intercurrent UTIs, urinary frequency, and urgency (urinary tract infections may increase the risk for chronic renal disease and hypertension)
Abdominal pain, bloating, flatulence, chronic constipation, or diarrhea, and poor weight gain, which may reflect celiac disease (prevalence of 4-6% in TS)
Chronic abdominal pain, diarrhea, and/or constipation, which may indicate inflammatory bowel disease
Melena (dark, tarry stools) or blood in the stool, which may indicate the presence of an intestinal vascular malformation

Pregnancy/Perinatal History

Fetal ultrasonography may reveal increased nuchal translucency, cystic hygroma (the result of jugular lymphatic obstruction or malformation), left-sided cardiac defects, renal malformation, brachycephaly, poly- or oligohydramnios. Maternal quadruple screen may be abnormal. Maternal quadruple serum screening may also be abnormal but, because of a high rate of false-positives, confirmatory testing with amniocentesis or chorionic villous sampling is necessary to entertain the diagnosis of TS prenatally. Karyotype should be repeated postnatally in all individuals who were previously diagnosed prenatally. [Shankar: 2018]

Developmental & Educational Progress

Ask about school progress and relationships with family and peers. Preventive pediatric health care should include annual developmental and behavioral screenings. Conduct a neuropsychological evaluation during early life (preschool), school entry, transition to high school and higher education, or any time that difficulties arise. [Gravholt: 2017]

Maturational Progress

Girls with TS may present with pubertal delay or primary amenorrhea due to ovarian insufficiency. A degree of normal pubertal development may be seen prior to ovarian failure. Some girls with TS may achieve spontaneous menarche.

Ask about pubertal changes and menstruation in adolescents. While most girls with TS do not go through puberty, up to 30% will have some spontaneous pubertal development and 2-5% may become pregnant spontaneously. For those who do experience endogenous ovarian function, discuss birth control, prevention of sexually transmitted disease, and the pregnancy-associated risks of aortic dissection.

Social & Family Functioning

Inquire about family support as well as the child's involvement in age-appropriate sports and activities.

Physical Exam

Vital Signs

Resting tachycardia may be present. Hypertension often complicates TS in older girls and adolescents, even those without left-sided cardiac abnormalities. Blood pressure should be measured at least annually and charted on height-specific growth charts. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents from the National Heart, Lung, and Blood Institute has blood pressure tables (on pages 10-11) for children and adolescents. Due to the risk of aortic dilation and dissection, hypertension should be managed aggressively.

Growth Parameters

Height should be plotted on a Turner Syndrome Growth Chart 2-19 Years ( PDF Document

1.2 MB) beginning at 2 years of age. Growth charts for girls younger than 2 with TS have not been developed; in girls younger than 2, height velocity should be monitored on a standard growth chart. Weight and body-mass index (BMI) should be plotted on a standardized BMI chart such as BMI Females 2-20 Years (CDC) ( PDF Document

68 KB), since no BMI charts for TS have been developed.

Skin

Dermatologic evaluation may reveal multiple hyperpigmented nevi throughout the body, which are not thought to be at increased risk for melanoma or other skin neoplasms. In older adolescents and adults, examine the intertriginous areas for acanthosis nigricans, a sign of insulin resistance.

HEENT/Oral

Examine for:

Bitemporal narrowing
Epicanthal folds and ptosis
Strabismus
Low-set, posteriorly rotated, prominent auricles or attached earlobes
Chronic middle-ear effusion
Micrognathia (small mandible)
High, arched palate due to narrow maxilla
Low posterior hairline
Pterygium coli (webbed posterior neck)
Broad, short appearing neck

Ocular abnormalities are common and include near-sightedness, far-sightedness, strabismus, ptosis, epicanthal folds, and hypertelorism. Girls with TS are at increased risk for recurrent ear infections, persistent middle ear effusions, and conductive or sensorineural hearing loss. Inspect tympanic membrane with pneumatic otoscopy to monitor for middle ear fluid. Assess for tooth abnormalities and malocclusion.

Chest

Visual inspection may reveal a “shield-shaped” chest with pectus excavatum and widely spaced nipples. Nipples may be hypoplastic and/or inverted.

Heart

A systolic murmur may indicate a left-sided cardiac malformation such as bicuspid aortic valve or aortic coarctation, which may be best heard over the left scapula or in the axilla. Some individuals with these lesions have no auscultatory findings; echocardiography is recommended in all cases of known or suspected TS. Absent or weak lower extremity peripheral pulses may indicate aortic coarctation, and an experienced examiner may be able to perceive brachiofemoral delay of the pulses.

Abdomen

Palpate the abdomen for a mass that may signify a renal abnormality such as collecting system malformation with obstruction or horseshoe kidney. Gastrointestinal vascular malformations may present with rectal bleeding and have been reported in individuals 4 months old to 57 years old.

Genitalia

Follow Tanner stage and consider referral for pubertal induction if no pubertal development has occurred by 12 years of age.

Extremities/Musculoskeletal

Examine for cubitus valgus, short 4th metacarpal bones, Madelung deformity of the wrist, scoliosis/kyphosis, and genu valgum or genu varum. Developmental dislocation of the hip can occur. Radiography may reveal a coarse trabecular pattern, particular at the metaphyses of long bones. Congenital lymphedema may result in residual puffiness of the dorsae of the hands and feet. Fingernails and toenails may be narrow, hyperconvex, and/or deep-set.

Sensory Testing

An audiologist should perform a hearing evaluation at diagnosis and every 3-5 years thereafter. If there is a history of otitis media or hearing loss, evaluations are usually performed annually.

TS is associated with red-green color blindness (10%), hyperopia (35%), and strabismus (25%) with risk of amblyopia. Girls with TS should be evaluated by a pediatric ophthalmologist by 12-18 months of age or earlier if clinically indicated. If initial evaluation is normal, the medical home provider should conduct annual routine vision screening.

Laboratory Testing

Routine laboratory studies to monitor for comorbid conditions should begin in early childhood or at the time of diagnosis.

If initial diagnosis occurs before 10 years of age:

Assess thyroid function with a TSH and T4.
Screen for celiac disease starting at age 2 with a tissue transglutaminase IgA (TTG) and total serum IgA.

If initial diagnosis occurs at 10 years of age or later:

Assess thyroid function with a TSH and T4.
Screen for celiac disease with a tissue transglutaminase IgA (TTG) and total serum IgA.
Perform hepatic function panel, GGT, HbA1c with or without fasting plasma glucose, fasting lipid panel.
25-hydroxyvitamin D

Ongoing assessment during childhood:

Hepatic function panel annually
Thyroid screening annually with a thyroid-stimulating hormone (TSH) and thyroid hormone (T4)
Celiac screen every 2 years with a tissue-transglutaminase IgA (TTG-IgA) and a total IgA
25-hydroxyvitamin D every 2-3 years

Ongoing assessment for adults:

Fasting lipid panel and HbA1c with or without fasting plasma glucose annually
Hepatic function panel annually
Thyroid screen with TSH and T4 annually
Celiac screen with TTG-IgA and total IgA with suggestive symptoms
25-Hydroxyvitamin D every 3-5 years

See Laboratory Guidelines for Turner Syndrome (ACMG).

Imaging

Echocardiography and cardiac MRI should be performed on all individuals with TS (50% of girls with TS have congenital heart malformations). [Lin: 2008] Prenatal detection of TS should prompt a fetal echocardiogram and referral to pediatric cardiology. Surveillance for aortic root dilation, treatment for hypertension, prophylactic medical therapy, and surgical consultation when appropriate are essential to reduce the incidence of aortic dissection. [Gravholt: 2006] Cardiac imaging may be performed with 2-dimensional and color Doppler echocardiography if performed along with a baseline electrocardiogram with QTc measurement and evaluation from a pediatric cardiologist. Echocardiography is generally sufficient in infants and young children, but thoracic abnormalities and obesity may limit its use in older individuals. [Bondy: 2007]

If echocardiography is inadequate, computed tomography or cardiac magnetic resonance imaging should be performed at a center with expertise. Whichever imaging modality is used, it is imperative that the aortic valve leaflets be adequately visualized, along with the aortic arch and descending aorta.

Depending on the cardiac malformation present, periodic echocardiography or cardiac MRI should be performed by a pediatric cardiologist. All individuals with TS should undergo cardiac MRI when they are old enough to tolerate the procedure without sedation. Sedation may be required in younger children in whom cardiac MRI is clinically indicated.

In the absence of a bicuspid aortic valve or other significant disease at the initial screening, TTE or cardiac MRI surveillance studies should be performed every 5 years in children, every 10 years in adults, or prior to anticipated pregnancy. The latest consensus guidelines assign girls less than 16 years old with TS into low-, moderate-, and high-risk categories based on a TS-specific Z-score of the aorta and recommend TTE and pediatric cardiology follow-up every 5 years, 1–2 years, and 6 months-1 year respectively. [Gravholt: 2017]

Renal ultrasound should be performed at the time of diagnosis to identify any presence of urologic abnormalities.

DEXA scan should be done to monitor bone health after adult hormone replacement has been initiated, every 5 years thereafter, and at the discontinuation of estrogen therapy at menopause.

Genetic Testing

All individuals with suspected TS should have a standard 30-cell karyotype performed as recommended by the American College of Medical Genetics. This identifies up to 10% mosaicism with 95% confidence. [Bondy: 2007] Additional metaphases may be counted or fluorescence in-situ hybridization studies (FISH) may be performed if there is a strong suspicion of undetected mosaicism. In this case, a cytogeneticist should be consulted. A second tissue source, such as skin fibroblasts, buccal mucosa cell, or bladder epithelial cells may be tested if clinical suspicion for mosaicism persists despite a normal karyotype. [Wiktor: 2005]

Other Testing

Neuropsychological testing should be performed to identify and accommodate learning disabilities in early life (preschool), at school entry, at transition to high school and higher education, or at any time that difficulties arise.

Specialty Collaborations & Other Services

Pediatric Genetics (see RI providers [5])

A team of geneticists and genetic counselors should be involved in the initial diagnosis and may help guide testing, particularly if a karyotype is normal and a suspicion for mosaicism exists. The genetics team may also coordinate initial testing for associated conditions and counsel regarding risk for long-term complications.

Genetic Testing and Counseling (see RI providers [2])

Genetic counselors work closely with geneticists and can provide counseling regarding recurrence risk and risk for comorbid conditions.

Pediatric Cardiology (see RI providers [17])

Every child with TS should be evaluated by a pediatric cardiologist who will guide the choice of imaging study to evaluate for cardiac abnormalities and give counsel regarding the increased risk of atherosclerotic heart disease, aortic dilation, and aortic dissection later in life.

Pediatric Ophthalmology (see RI providers [8])

Girls should be evaluated for red-green colorblindness, strabismus, near-sightedness, far-sightedness, and hyperopia with the risk of amblyopia by 12-18 months of age or at diagnosis in older girls with TS and then annually thereafter.

Pediatric Otolaryngology (see RI providers [6])

Girls who have middle ear effusions persisting for more than 3 months should be referred for consideration of pressure equalization tubes.

Pediatric Dentistry (see RI providers [27])

Referral to special centers may be necessary if a child requires sedation for dental treatment.

Developmental - Behavioral Pediatrics (see RI providers [14])

Referral may be helpful in ensuring optimal health monitoring, identifying comorbid conditions, assessing developmental progress, ensuring optical intervention services, and managing behavioral concerns such as attention-deficit disorder.

Audiology (see RI providers [22])

Refer for hearing screening every 5 years starting at 9-12 months of age.

Pediatric Orthopedics (see RI providers [12])

Refer if scoliosis is suspected.

Pediatric Gastroenterology (see RI providers [20])

Refer for diagnosis and management of celiac disease, inflammatory bowel disease, and intestinal vascular malformations.

Developmental Assessment (see RI providers [29])

A team (including a developmental pediatrician, psychologist, neurologist, speech, and occupational therapist) will conduct an interdisciplinary assessment of developmental and functional abilities for girls with persistent challenges in learning, attention, or behavior.

Neuropsychiatry/Neuropsychology (see RI providers [6])

Testing should be considered at major transitional stages (preschool, entry to elementary, and high school).

Overview

Managing Turner syndrome (TS) can be challenging because of the constellation of potential abnormalities. Patients with TS should ideally be managed in centers with pediatric sub-specialists.

Pearls & Alerts for Treatment & Management

Pregnancy is possible and may come with high risks

Pregnancy in individuals with TS is associated with rare, but potentially fatal, aortic dissection and rupture. While gonadal failure with pubertal delay is common, up to 30% of young women with TS will experience some spontaneous pubertal development and 2-5% of women will experience spontaneous pregnancy. When appropriate, prevention of unwanted pregnancy and potential cardiovascular complications of pregnancy should be discussed. Women with Turner syndrome and aortic valve/aortic anomalies should be counseled about the dangers associated with pregnancy and should consult with cardiology so that they can make an informed decision. See the Maturation/Sexual/Reproductive system below for more detail.

Endocrine consult

An endocrine consult should be considered in girls with Turner who have not achieved puberty by 12 years of age.

Estrogen replacement

TS is usually accompanied by hypergonadotropic hypogonadism and primary or secondary amenorrhea. Most individuals with TS will therefore need hormonal replacement therapy initially for induction of puberty and later for maintaining secondary sexual characteristics, attaining optimal bone mass, normalizing uterine growth (for possible pregnancy later). [Gravholt: 2017]

Growth or Weight Gain

Height should be monitored on a TS-specific growth chart (see Resources/Clinical Tools/Growth/BMI Charts, below).

Development (Cognitive, Motor, Language, Social-Emotional)

Developmental and behavioral issues are common; see Clinical Assessment/Testing, above, for details about evaluation.

Prescription Medications

A variety of electrocardiographic and repolarization abnormalities, such as resting tachycardia, right axis deviation, T wave abnormalities, accelerated AV conduction, and QT interval prolongation, have been described in TS. It is hypothesized that impaired sympathovagal tone plays a role. Though the clinical significance of these observations is unclear, it is recommended that individuals with QT prolongation avoid medications that could further prolong the QT interval. [Bondy: 2007]

Systems

Endocrine/Metabolism

Short stature
Short stature is the most common finding and is nearly always present, even in patients who do not display other phenotypic characteristics. The etiology of growth failure is poorly understood, but it is thought to involve skeletal dysplasia and poor responsiveness to growth hormone related to haplo-insufficiency for the short stature homeobox-containing (SHOX) gene on the X-chromosome. Growth hormone studies in these patients are typically normal. During infancy and childhood, growth rates are approximately 2 standard deviations below mean growth rates. The adult height of girls not treated with growth hormone is 56 to 57 inches (about 8 inches below the average adult woman's height). Growth hormone secretion pattern is usually normal. Recombinant growth hormone (GH) therapy has been shown to improve adult height in patients with TS by 5–8 cm in several studies, but the efficacy is variable and depends on multiple factors including age at initiation, baseline heights, genetic potential, and dose and duration of therapy.

Growth hormone (GH) therapy
Initial consultation with a pediatric endocrinologist should determine the appropriate timing for beginning therapy. The recent guidelines recommend initiating GH treatment early (around 4–6 years of age and preferably before 12–13 years) in the following circumstances:

The child already has evidence of growth failure (e.g., below 50th percentile height velocity observed over 6 months in the absence of other treatable causes of poor growth).
The child is already short or has a strong likelihood of short stature (e.g., short parents and short predicted adult height or already pubertal at the time of diagnosis).

The recommended GH dose per the recent guidelines is 45–50µg/kg/day in most instances, increasing to 68µg/kg/day (2.0mg/m2/day) if initial response is suboptimal. Height should be monitored every 4-6 months during the first year of treatment and every 6 months thereafter. Therapy with GH is generally well tolerated, although there is a slightly higher risk of serious adverse effects such as intracranial hypertension and slipped capital femoral epiphysis. [Bolar: 2008] Although human growth hormone (hGH) does not appear to increase the risk of cancer, it is not recommended for children with active neoplastic processes. hGH should be used with caution after renal transplant and should not be used in individuals with closed epiphyses. [Cave: 2003] See Clinical Practice Guidelines for Growth Hormone Use in Adults and Children (AACE) ( PDF Document

44 KB). IGF-1 levels should be monitored at least yearly to monitor safety of GH therapy. The measured IGF-1 should ideally be no greater than 2SDs above the mean for age. If the IGF-1 is above +3SDs, a GH dose decrease is warranted.

Oxandrolone
In girls with TS older than 10 years of age with poor projected adult height on GH alone, the addition of oxandrolone, an androgen and anabolic steroid, at 0.03-0.05 mg/kg/day may be considered. [Perry: 2014] [Gravholt: 2017] Oxandrolone may improve adult height by 2-5 cm when used with GH. [Menke: 2010] Potential side effects are less of a concern at the low dosages above, but they may include acne and clitoromegaly. [Perry: 2014]

Autoimmune dysfunction
Autoimmune thyroiditis is common and may be seen as young as 4 years of age. One longitudinal study found that 24% of children over 8 years old with TS developed hypothyroidism and 2.5% developed hyperthyroidism. [Livadas: 2005] Because clinical symptoms of thyroid dysfunction rarely manifest, annual screening with FT4 and TSH is recommended starting in early childhood and annually throughout the lifespan. Thyroid replacement should be prescribed in those with hypothyroidism.

Diabetes
The risk of both type 1 and type 2 diabetes mellitus is about a 10-fold and 4-fold increase in patients with TS across all ages in epidemiological studies. Obesity, insulin resistance, and impaired glucose tolerance are also common.

Lifelong annual measurement of HbA1c, with or without fasting plasma glucose, is recommended starting at age 10 years. If testing meets criteria for diabetes, the patient should be assessed for antibodies related to type 1 diabetes and be seen by a diabetes specialist.

Dyslipidemia
Dyslipidemia has been reported as young as 11 years and is independent of BMI. Nutrition and exercise counseling are an important component of ongoing care. Regular moderate exercise should be encouraged. Hypercholesterolemia has been reported in 37–50% of women with TS. [Garden: 1996]

According to the American Academy of Pediatrics and American Heart Association guidelines, non-fasting, non-HDL cholesterol (calculated by subtracting HDL cholesterol from total cholesterol) should be measured on 2 occasions: once between 9 and 11 years old and again between 17 and 21 years prior to transition to adult care. If non-HDL cholesterol is ≥145mg/ dL (≥3.7mmol/L), then a full fasting lipid profile should be obtained. A lipid profile should be performed in individuals who have at least 1 risk factor for cardiovascular disease starting at age 18 years. [Gravholt: 2017]

Specialty Collaborations & Other Services

Pediatric Endocrinology (see RI providers [14])

An endocrinologist will monitor growth velocity, guide the decision to initiate growth hormone therapy, monitor for associated adverse effects, guide the timing and medical management of pubertal induction, and assist in the diagnosis and treatment of TS-associated hypothyroidism, obesity, and insulin resistance.

Maturation/Sexual/Reproductive

Pubertal induction
Ovarian insufficiency is a hallmark feature of TS. While up to 30% of girls with TS have some spontaneous pubertal development, gonadal failure is more common. In many individuals, pubertal delay plays a large role in self-esteem, anxiety, and social isolation. In the past, pubertal induction was delayed until 15 years of age to maximize height potential. Age-appropriate pubertal induction is now recommended to avoid the potential long-lasting psychosocial effects of delayed pubertal development. Pubertal induction should be performed in consultation with an endocrinologist. Serum gonadotropins (especially FSH) should be assessed annually starting at about 11 years, prior to pubertal induction, to exclude the possibility of impending delayed spontaneous puberty. Low levels of anti-Müllerian hormone (AMH) and inhibin B measurements have also been shown to predict ovarian insufficiency, and AMH is perhaps the best indicator of ovarian reserve. If gonadotropins are normal for age, observation for spontaneous puberty is appropriate with future replacement therapy if gonadal failure occurs.

Transdermal 17-β estradiol (TDE) is now the preferred treatment starting around age 11–12 years. It is a more physiologic mode of delivery than oral estrogen and has better bioavailability. Replacement is usually initiated at one-tenth to one-eighth of the adult replacement dose and gradually increased over 2-4 years. Progestin supplementation should be started once withdrawal bleeding is noted or after about 2 years of estrogen therapy to minimize the risk of endometrial cancer due to unopposed estrogen effect. The use of oral contraceptive pills to induce puberty is not recommended because the synthetic estrogen doses are higher than the desired physiologic doses and synthetic progestin may interfere with optimal breast and uterine development. Routine supplementation of very low-dose estrogen in childhood to improve growth or bone mass is currently not recommended. [Shankar: 2018]

Pregnancy
As the patient with TS matures, it is important to engage her in discussions about how TS and its treatment affect sexual development, function, and reproductive potential. While most women are infertile, 2-5% may become pregnant. Others may achieve pregnancy through various reproductive assistance techniques. Young mosaic TS women with persistent ovarian function should be counseled that oocyte cryopreservation after controlled ovarian hyperstimulation is a possible fertility preservation option.

Pregnancy in TS is associated with the rare but potentially fatal complication of aortic dissection and rupture. Any woman with TS considering pregnancy should have a cardiac evaluation. Other TS-related pregnancy complications include hypertension, gestational diabetes, and need for caesarian section due to small maternal size. When appropriate, prevention of sexually transmitted disease and unwanted pregnancy should be addressed. [Bondy: 2007] Women with abnormalities of the aortic valve or aorta should be should be counseled about the dangers associated with pregnancy and should consult with cardiology so that they can make an informed decision. Pregnancy is considered high risk in women with TS who have an ascending ASI >2–2.5 cm/m2 due to risk of aortic dissection; assisted reproductive techniques are contraindicated. If pregnancy occurs, it should be managed with strict treatment of pregnancy-associated hypertension, frequent cardiac imaging, and consideration of prophylactic surgery if rapid aortic enlargement is seen. [Shankar: 2018]

Neoplasms
The presence of Y-chromosome material is associated with an approximately 10% risk of gonadoblastoma. [Mazzanti: 2005] [Cools: 2006] Prophylactic removal of gonadal streaks in these individuals is recommended.

Specialty Collaborations & Other Services

Obstetrics & Gynecology (see RI providers [0])

A delivery plan should be made by a multidisciplinary team consisting of at least an obstetrician, cardiologist, and anesthesiologist that all have expertise in pregnancy in the context of maternal heart disease and/or aortopathy.

Cardiology

Cardiovascular malformation
The most serious conditions associated with TS involve the cardiovascular system. Congenital heart disease occurs in approximately 22-70% of women with TS. [Mortensen: 2012] While left-sided cardiac anomalies are most common, the wider range of malformations includes aortic coarctation (11%), bicuspid aortic valve (15%), partial anomalous pulmonary connection (13%), persistent left superior vena cava (13%), mitral valve abnormalities (<5%), and rarely hypoplastic left heart syndrome. Coarctation may not be detected on echocardiography during infancy but found with the first cardiac MRI. Generalized dilation of major vessels has been described, although the clinical significance of this is unclear. [Lin: 2008]

Individuals with TS are at risk for rare but potentially fatal aortic dilation, dissection, and rupture, even in relatively young individuals. The risk for dissecting aortic aneurysm is greater in those with aortic valve abnormalities, coarctation/dilation of the aorta, and systemic hypertension. Counsel at-risk patients and their families about the need for medical monitoring and treatment and the potential symptoms of aortic dissection (chest or back pain). They should also be encouraged to carry medical information at all times to alert medical personnel to the presence of aortic disease. The risk of aortic dissection with pregnancy should be discussed at length with those who have endogenous ovarian function and are considering assisted pregnancy.

Those with CHD diagnosed in childhood may be at risk for postoperative valve re-stenosis, aortic re-coarctation, or residual septal defect shunts and should be monitored closely for the development of new or changing cardiac murmurs. There is a strong association between neck webbing and the presence of a congenital heart defect. Resting tachycardia and a variety of electrocardiographic and repolarization abnormalities have been recognized in TS, including prolongation of the QT interval.

The latest consensus guidelines assign girls with TS aged <16 years into low-, moderate-, and high-risk categories based on a TS-specific Z-score of the aorta and recommend transthoracic echocardiogram (TTE) and pediatric cardiology follow-up every 5 years, 1–2 years, and 6 months-1 year, respectively. In individuals with TS over the age of 16 years, the ascending aortic size index (ASI), defined as the aortic diameter in cm corrected for body surface area, is a useful prognostic indicator and, has been used to categorize risk (2–2.3 cm/m2 is moderate risk and >2.3 cm/m2 is high risk) and suggest therapy in the latest guidelines. [Gravholt: 2017] [Shankar: 2018]

Eligibility for competitive sports for individuals with TS should be determined by a cardiologist after a comprehensive evaluation. Participation in sports is restricted to low and moderate static and dynamic activities in the moderate risk category while girls in the high-risk category should avoid competitive sports and intense weight training. [Płytycz: 1986]

For patients with no cardiovascular malformation, routine pediatric care should include annual measurement of blood pressure. In the absence of a bicuspid aortic valve or other significant diseases at the initial screening, TTE or cardiac magnetic resonance (CMR) surveillance studies should be performed every 5 years in children, every 5-10 years in adults, or prior to anticipated pregnancy. [Gravholt: 2017] [Bondy: 2007]

The importance of regular moderate exercise should be stressed. Intense or contact activities, as well as isometric exercises, may unnecessarily stress the cardiovascular system.

Hypertension
Half of women with TS have hypertension. Although the exact etiology remains unclear, it is possibly due to small-vessel renovascular disease. [Ostberg: 2003] One case series identified coarctation or renal disease as primary causes of hypertension in only 20% of hypertensive TS women. [Elsheikh: 2002] Hypertension should be treated aggressively. In individuals without structural heart disease, annual assessment of blood pressure should be performed and medical treatment should be considered if hypertension is present. Medical treatment would include a beta-blocker, an angiotensin receptor blocker, or both to reduce the risk for aortic dissection in women with TS who are ≥16 years of age for whom their ascending ASI is ≥2.3cm/m2. [Gravholt: 2017]

Electrocardiographic abnormalities
Every individual with TS should receive a resting electrocardiogram (ECG) with QTc measurement at diagnosis. Electrocardiographic and repolarization abnormalities, such as resting tachycardia, right axis deviation, T-wave abnormalities, accelerated AV conduction, and QT-interval prolongation have been described in TS. Some changes such as those in P-wave and QTc-dispersion and heart-rate variability in women with TS can be attributed to the underlying characteristic autonomic dysfunction. The clinical significance of these observations is unclear. It is recommended, however, that individuals with QT prolongation avoid medications that could further prolong the QT interval. [Bondy: 2007] If they are deemed necessary, ECG should be performed 1–2 weeks after initiation of QT-prolonging drugs.

Coronary artery disease
Coronary artery disease is thought to be twice as common in women with TS as in the general population. Risk factors include hypertension, insulin resistance, dyslipidemia, and estrogen deficiency. [Ostberg: 2003]

Specialty Collaborations & Other Services

Pediatric Cardiology (see RI providers [17])

A pediatric cardiologist will closely follow the child with TS, make recommendations for management of any cardiac malformations, and assist the medical home provider in managing hypertension.

Ears/Hearing

Individuals with TS often have a flattened cranial base angle resulting in an abnormal relationship between the Eustachian tube and the middle ear. This can lead to a high prevalence of otitis media, persistent middle ear effusion, and increased risk for conductive hearing loss. Those with persistent otorrhea are at risk for cholesteatoma formation. Sensorineural hearing loss is also prevalent; while the onset of this comorbidity is typically in adulthood, it has been described in patients as young as 6 years old and may necessitate the use of amplification.

Perform (at least) annual evaluations for middle ear effusions that include pneumatic otoscopy and tympanometry. Otitis media should be treated aggressively because of the significant impact that hearing loss can have on speech and language development and the risk of cholesteatoma formation in those with persistent otorrhea. Persistent middle ear effusion, particularly if associated with language delay or ongoing symptoms of illness, should prompt referral to an otolaryngologist to consider placement of pressure equalization tubes and perhaps tonsillectomy and/or adenoidectomy. Adenoidectomy may, however, exacerbate palatal dysfunction negatively impacting speech quality and should be considered with caution. See the Portal's Hearing Loss and Deafness for management information.

Specialty Collaborations & Other Services

Audiology (see RI providers [22])

Refer for diagnosis and every 1-5 years thereafter as recommended or as indicated by subjective hearing changes, persistent middle ear effusions, or recurring suppurative otitis media.

Pediatric Otolaryngology (see RI providers [6])

Referral to an otolaryngologist should be considered for persistent middle ear fluid lasting longer than 3 months or for recurrent suppurative otitis media.

Eyes/Vision

Strabismus occurs in 25% of girls with TS, hyperopia in 35%, and red-green colorblindness in 10%. Abnormalities of the external ocular adnexa, such as epicanthal folds and ptosis, are common. Cataracts and nystagmus occur more commonly in TS as well. Infants should be screened carefully for strabismus, and all should be evaluated by an ophthalmologist by 12-18 months of age or at diagnosis in older girls and annually thereafter.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see RI providers [8])

Referral should be considered at diagnosis or by 18 months of age. Follow-up will depend on whether and which abnormalities are identified.

Dental

Abnormal tooth eruption and root and crown abnormalities may occur. A flattened cranial base angle, decreased posterior cranial base length, and retrognathia may lead to dental malocclusion and bite abnormalities. Treatment with growth hormone can alter craniofacial proportions leading to further orthodontic concerns. These patients are also at risk for abnormalities in tooth development and morphology, such as early eruption of secondary teeth, simple crown morphology, thin/hypoplastic dental enamel, short dental roots, and root resorption leading to tooth loss.

Patients with cardiac abnormalities should be considered for antibiotic prophylaxis for subacute bacterial endocarditis prior to dental procedures.

Specialty Collaborations & Other Services

Orthodontics (see RI providers [1])

Girls with a narrow maxilla and a relatively wide mandible have a high prevalence of malocclusion and should see a pediatric orthodontist no later than 7 years of age and have regular orthodontic follow-up. Growth hormone therapy can alter the craniofacial proportions as well.

Pediatric Dentistry (see RI providers [27])

It is recommended that individuals with TS see a pediatric dentist by 2 years of age and have regular follow-up at intervals determined by the problems identified.

Musculoskeletal

Scoliosis and kyphosis
Monitor annually for scoliosis during routine pediatric care or every 6 months if on growth hormone therapy. Spinal curvature may progress with rapid growth. While current literature suggests that growth hormone does not cause scoliosis, it may accelerate the development of a spinal curve. Evaluation by an orthopedist is recommended in cases of significant spinal curvature or in those whose curvature is detected at a young age. Management of scoliosis (e.g., bracing or surgical intervention) does not differ from that in the general population. Other muscular complications could include pectus deformities.

Madelung deformity
Madelung deformity results from epiphyseal arrest on ulnar and volar aspects of the distal radius causing the articular surface to be directed toward the ulna and volar aspect of the wrist. This may result in wrist pain as well as limited wrist extension and supination.

Hip dislocation
Developmental dysplasia of the hip occurs with increased frequency. Conservative management with bracing (e.g., a Pavlik harness) or casting is recommended as in the general population with surgical intervention reserved for dysplasia not responsive to bracing.

Cubitus valgus
Increased cubital carrying angle may limit range of motion and interfere with function.

Chronic knee pain
An abnormal tibial plateau coupled with patellar changes may lead to chronic knee pain.

Decreased bone mineral density
Decreased bone mineral density (BMD) with increased fracture risk can occur in older individuals, particularly those not treated with estrogen. Short stature may, however, lead to an underestimation of bone-mineral density by dual-energy x-ray absorptiometry (DEXA). When adjusted for height, women with TS who receive appropriate estrogen therapy have an estrogen-independent decrease in cortical BMD with normal trabecular BMD. Causes of low BMD may include non-adherence to estrogen therapy, tobacco use, excessive alcohol use, celiac disease, and/or vitamin D deficiency. The importance of weight-bearing exercise in reaching and maintaining adequate BMD should be discussed with patients and families. Bisphosphonates are not recommended in young women because the reduced cortical BMD is not associated with an increased risk of fractures, and these medications have not been shown to increase cortical BMD. Bisphosphonate use may be considered in women with confirmed osteoporosis, those at risk for fracture, and those who have sustained a low-impact fracture. [Bondy: 2007]

Screen for vitamin D deficiency with a 25-OH vitamin D concentration between 9–11 years and every 2–3 years thereafter. DEXA scans should be obtained to monitor bone health after adult hormone replacement has been initiated, every 5 years thereafter, and at discontinuation of estrogen therapy at menopause. See Osteoporosis and Pathologic Fractures.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see RI providers [12])

Refer for diagnosis of scoliosis, hip dysplasia, and range of motion abnormalities associated with skeletal dysplasia. Orthopedics will recommend optimal management (e.g., bracing vs. surgical correction) and assist in the management of functional limitations caused by skeletal dysplasia (e.g., limited elbow extension or pain related to cubitus valgus).

Pediatric Endocrinology (see RI providers [14])

Refer for evaluation and assistance in management of osteopenia.

Renal

Malformations of the urinary system occur in 30-40% of individuals with TS. Collecting system abnormalities and abnormal positioning are seen most frequently (15-20%), followed by horseshoe kidneys (10%) and aplasia (3%). If structural renal malformations are detected on initial ultrasonography, follow-up and treatment plans will be individualized based on the condition and the recommendations of the involved subspecialists. The majority of renal malformations seen in TS do not result in renal dysfunction or disease. In some, however, complications such as hydronephrosis, reflux, and/or recurrent urinary tract infections may be severe and require treatment and ongoing monitoring. In patients with no underlying urinary tract malformation, there is no increased risk of developing renal disease. [Bondy: 2007]

Specialty Collaborations & Other Services

Pediatric Urology (see RI providers [1])

Refer for help in evaluating and managing renal or collecting system malformations and related problems.

Skin & Appearance

Lymphedema
Lymphedema is a major feature of TS. The etiology is uncertain, but it is thought to arise from a generalized lymphatic dysplasia. It results in ongoing puffiness of the hands and feet, as well as nuchal webbing, the classic appearance of the chest and atypical configuration of the finger and toenails. Palmar and pedal edema may be exacerbated by estrogen and growth hormone therapy. Symptomatic relief of edema with support socks, elevation, or compression dressings may be required. Chronic diuretic therapy is not recommended as it is marginally effective and may lead to fluid and electrolyte imbalances. Vascular surgery should be avoided. [Bondy: 2007] Patients and families can be directed to The National Lymphedema Network for more information about lymphedema and its management.

Melanocytic nevi
Individuals with TS have an increased number of typical melanocytic nevi. Studies conflict about whether TS is associated with increased melanoma risk. Therapy with GH may trigger melanocyte growth, but it has been shown neither to increase the number of nevi nor to trigger malignant transformation. Other skin conditions that have a greater prevalence include pilomatricomas, vitiligo, and halo nevi.

Nevi should be monitored for concerning changes in shape, color, and size. It has been suggested that girls and women with TS are at increased risk for keloid formation as well, although it is unclear whether this is due to an abnormal healing process or whether this is related to surgeries often involving the head and neck - areas more likely to exhibit keloid formation.

Specialty Collaborations & Other Services

Pediatric Dermatology (see RI providers [2])

Refer for evaluation and monitoring of nevi for atypical changes and perform removal with biopsy if indicated.

Pediatric Plastic Surgery (see RI providers [1])

Refer for surgical management of undesirable scars and nevi.

Gastro-Intestinal & Bowel Function

Gastroesophageal reflux
Feeding problems during infancy are relatively common and may include difficulties latching and sucking, gastroesophageal reflux, and failure to thrive. Anatomical differences in the oropharynx (high palate, palatal insufficiency), oral-motor immaturity, and abnormal gastrointestinal motility may contribute to these problems. Gastroesophageal reflux may safely be treated with H2 receptor blockade or proton pump inhibitors. Nasogastric tube feedings may be required if feeding difficulties are severe. Referral to a speech or occupational therapist for a feeding evaluation may be helpful. In some cases, simple interventions such as elevation of the head after feeds and use of a specialized nipple may result in improvement. [Cassidy: 2005] See the Medical Home Portal's Gastroesophageal Reflux Disease for more information.

Inflammatory bowel disease
Inflammatory bowel disease is 2-3 times more common in TS than in the general population, and it has a higher rate of complications when it occurs. Colectomy has been reported in 40% of TS-associated inflammatory bowel disease. Other potential complications include fistula formation and sepsis. [Ostberg: 2003] Treatment focuses on nutritional therapy and treatment with anti-inflammatory or immunomodulatory medications. The Portal's Inflammatory Bowel Disease provides more information.

Celiac disease
Celiac disease affects 4-6% of individuals with TS. Celiac disease refers to immune-mediated small bowel inflammation triggered by exposure to the gliadin peptide contained in gluten and found in wheat, barley, rye, and possibly oats. Treatment of celiac disease consists of complete elimination of gluten from the diet and is monitored by clinical response (including growth response), serologic marker response, and small intestinal mucosa histologic response. See the Medical Home Portal's Celiac Disease for more information.

Liver dysfunction
Asymptomatic liver test (ALT, AST, and GGT) abnormalities are a common finding with increasing prevalence with age (20–80%) and an annual incidence of 2.1–3.4%. Liver enzyme elevations tend to persist or progressively increase and rarely revert to normal.

Liver function should be assessed at age 10 and annually thereafter or as clinically indicated. If elevated hepatic enzymes persist for more than 6-12 months, liver ultrasound should be performed to evaluate for hepatic steatosis. If steatosis is not present but elevated hepatic enzymes persist, a hepatology consult should be obtained. Potentially, hepatotoxic medications such as statins and glitiazones should be prescribed with caution in patients with hepatic enzyme elevation. [Bondy: 2007] Structural changes such as fatty infiltration, fibrosis, vascular changes, and nodular hyperplasia have been reported on liver biopsy, but their relationship to liver enzyme elevation has not been defined.

The mechanism of liver disease in TS is not well understood, but it is thought to be multifactorial, with obesity and metabolic syndrome as likely contributors. Other possible risk factors include vascular anomalies, as evidenced by nodular regenerative changes, biliary lesions (e.g., primary sclerosing cholangitis) and autoimmunity (e.g., primary biliary cirrhosis). Several studies have now documented improvement or resolution of liver enzyme elevation with estrogen replacement therapy.

Intestinal telangiectasia
Patients with TS are at risk for vascular malformations throughout the gastrointestinal tract, which may present with rectal bleeding. Refer to a gastroenterologist for endoscopy and management for persistent rectal bleeding or melanotic stools.

Colonic carcinoma
A few small studies have indicated an increased relative risk of colon cancer in people with TS. Current recommendations for colon cancer screening (or treatment) in TS are no different from those in the general population.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see RI providers [20])

May assist in the interpretation of antibody tests in the diagnosis of celiac disease or perform confirmatory testing through endoscopy with biopsy. Consider consultation for persistently elevated hepatic enzymes, chronic abdominal pain, constipation, diarrhea, rectal bleeding, or melanotic stools.

Occupational Therapy, Pediatric (see RI providers [11])

Referral to speech or occupational therapy for a feeding evaluation may be helpful.

Development (general)

Ideally, a neuropsychological evaluation should be conducted during early life (preschool), school entry, transition to high school and higher education, or at any time that difficulties arise. If a neuropsychologist (or otherwise qualified psychologist) is not a member of the multidisciplinary team, then direct efforts at identifying community providers who can provide needed evaluations (e.g., school psychologists). It is also recommended that children be referred for occupational, physical, and speech therapy in early life or at school entry as warranted.

Most girls with TS will have normal motor, cognitive, and language development, although up to 10% may have developmental delay requiring early intervention or special education. [Sybert: 2004] As girls with TS reach school age, a common neurocognitive profile includes lower scores on nonverbal than verbal performance tests. This may result in difficulties with nonverbal abilities, such as math and visual-spatial skills, or difficulties with executive functioning and slower processing speed. These girls may benefit from accommodations in academic testing situations. Despite variable learning difficulties, girls and women with TS often have excellent verbal skills and many achieve college-level education.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see RI providers [14])

Referral may help with monitoring health, identifying comorbid conditions, assessing developmental progress, ensuring optical intervention services, and managing behavioral concerns such as attention-deficit disorder.

Mental Health/Behavior

Individuals with TS may have delayed emotional maturation, poor relations with peers, timidity, and negative body image. For those with difficulties in executive functioning, consider referral to a social-skills group or class. Early psychoeducational testing with appropriate classroom supports will help an affected child succeed academically, reducing the risk for psychosocial problems related to poor school performance. In older girls/adolescents, poor self-esteem may be related to delayed puberty, and pubertal induction is recommended at 12 years of age if no spontaneous pubertal development has occurred. [Loscalzo: 2008] Attention-deficit disorder is relatively common in girls with TS. [Loscalzo: 2008] Timely, comprehensive psycho-educational evaluations with re-evaluations as needed, age-appropriate pubertal induction, peer engagement, and career and vocational planning for the best long-term outcomes are recommended.

Specialty Collaborations & Other Services

General Counseling Services (see RI providers [33])

Refer children experiencing social difficulties or anxiety.

Educational Testing/Assessment (see RI providers [0])

Evaluation by a learning specialist may help identify specific learning disabilities and plan educational strategies.

Transitions

The pediatric endocrinologist (or any other care provider/coordinator) should implement a planned and staged transition process in early adolescence for their patients with TS. It is recommended that pediatric practices use TS-specific transition toolkits such as Tools for Clinicians Transitioning Women with Turner Syndrome (ACP) ( PDF Document

410 KB). TS patients will need ongoing surveillance for co-morbidities, including Type 2 diabetes mellitus, fatty liver, sensorineural hearing loss, hyperlipidemia, and hypertension. Surveillance for aortic root dilation and treatment of other cardiac abnormalities by a cardiologist familiar with the care of adults with congenital heart diseases is important. A baseline DEXA scan is recommended after adult hormone replacement has been initiated, and follow-up scans should be obtained every 5 years and at discontinuation of estrogen therapy at menopause. Estrogen supplementation should ideally be continued until menopausal age to optimize bone health and prevent osteoporosis in TS patients. [Shankar: 2018]

Specialty Collaborations & Other Services

Care for adults with TS is ideally delivered in a multidisciplinary setting with endocrinology, gynecology, cardiology, and gastroenterology as needed among other specialties. Specialized Centers of Turner Syndrome Care (TSF) lists such clinics in several states.

Gastro-Intestinal & Bowel Function

Celiac Disease Testing

On the Web

The following modules/pages within the Portal provide more detailed information about conditions associated with TS:

SHOX Deficiency Disorders (GeneReviews)
Detailed review of SHOX gene deficiencies (of which Turner syndrome is the best known), diagnosis, manifestations, management, and more.

Turner Syndrome (GARD)
Symptoms, causes, management, prognosis, and resources; Genetic and Rare Diseases Information Center, National Institutes of Health.

Helpful Articles

PubMed search for articles on Turner Syndrome in children for the last 3 years.

Klein KO, Rosenfield RL, Santen RJ, Gawlik AM, Backeljauw PF, Gravholt CH, Sas TCJ, Mauras N.
Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.
J Clin Endocrinol Metab. 2018;103(5):1790-1803. PubMed abstract

Lee MC, Conway GS.
Turner's syndrome: challenges of late diagnosis.
Lancet Diabetes Endocrinol. 2014;2(4):333-8. PubMed abstract

Levitsky LL, Luria AH, Hayes FJ, Lin AE.
Turner syndrome: update on biology and management across the life span.
Curr Opin Endocrinol Diabetes Obes. 2015;22(1):65-72. PubMed abstract

Milbrandt T, Thomas E.
Turner syndrome.
Pediatr Rev. 2013;34(9):420-1. PubMed abstract

Ranke MB.
Why Treat girls with Turner Syndrome with Growth Hormone? Growth and Beyond.
Pediatr Endocrinol Rev. 2015;12(4):356-65. PubMed abstract

Shankar RK, Backeljauw PF.
Current best practice in the management of Turner syndrome.
Ther Adv Endocrinol Metab. 2018;9(1):33-40. PubMed abstract / Full Text

Care Processes & Protocols

Recommended Approach for Transitioning into Adult Practice, Turner Syndrome (ACPonline) ( PDF Document 265 KB)
A 3-page clinical guide that lists guidance for the first encounter and ongoing monitoring of the woman with TS who is transitioning to adult care; American College of Physicians.

Clinical Checklists & Visit Tools

Turner Syndrome Health Maintenance Checklist ( PDF Document 80 KB)
A checklist with age recommendations for the initial and follow-up screenings of girls (birth - 18 years) with Turner syndrome; Vana Raman, MD; based on Gravholt et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017.

Turner Syndrome Care Checklist: Childhood and Adult (TSF) ( PDF Document 78 KB)
Includes components of care and follow-up in childhood, adolescence, and adulthood; Turner Syndrome Foundation.

Growth/BMI Charts

Turner Syndrome Growth Chart 2-19 Years ( PDF Document 1.2 MB)
Printable growth chart with curves for girls with and without Turner syndrome; percentiles derived from the National Center for Health Statistics.

BMI Females 2-20 Years (CDC) ( PDF Document 68 KB)
Body mass index for age percentiles; Centers for Disease Control.

Medication Guides

Dosing Standards for Estrogen in Turner Syndrome (ACPonline) ( PDF Document 141 KB)
The overall approach and goals of dosing standards; American College of Physicians.

Questionnaires/Diaries/Data Tools

Clinical Summary & Transfer Record for Young Adults with Turner Syndrome (ACP) ( PDF Document 363 KB)
Form for sharing information about patients with Turner syndrome preparing for the transition to adult care; American College of Physicians.

Toolkits

Turner Syndrome Guidelines and Clinical Practice (ES)
Clinical tools for patient assessment, evaluation of transition readiness, dosing standards for estrogen, and clinical summary/transfers; Endocrine Society.

Turner Syndrome Health Care Guidelines and Checklists (TSSUS) ( PDF Document )
Guidelines, checklists, growth charts, patient education, and other clinical tools related to Turner syndrome; Turner Syndrome Society of the United States.

Other

Laboratory Guidelines for Turner Syndrome (ACMG)
Provides information on appropriate prenatal and postnatal diagnostic cytogenetic studies for Turner syndrome; American College of Medical Genetics and Genomics.

Patient Education & Instructions

Turner Syndrome: A Guide for Families (TSSUS) ( PDF Document 1.4 MB)
A 32-page booklet with information for parents about growth and development, health considerations, and social and emotional support; Turner Syndrome Society of the United States.

Turner Syndrome Brochure (TSSUS) ( PDF Document 125 KB)
Two-page brochure providing an overview of Turner syndrome for parents; Turner Syndrome Society of the United States.

Turner Syndrome

Information on the Web

Turner Syndrome (Medline Plus)
Brief description and links to many reliable sources of information, compiled and maintained by the National Library of Medicine.

Turner Syndrome (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; U.S. National Library of Medicine.

Turner Syndrome (The Magic Foundation)
Information, videos, and a variety of resources; from the Magic Foundation, a non-profit that provides support for families of children with problems that cause problems with growth.

Turner Syndrome Foundation
Supports research and facilitates education to enhance the care of those affected by Turner syndrome.

Turner Syndrome Society of the United States
A non-profit with chapters and resource groups located throughout the country that provides resources to patients, families, and physicians for the diagnosis and treatment of Turner syndrome.

Turner Syndrome for Teens (TeensHealth)
A short article to help teens cope with TS; from Nemours.

National & Local Support

Turner Syndrome Society - Local Resource Groups
Links to local groups of the Turner Syndrome Society of the United States in several states, along with frequently asked questions about the groups, what they offer, and how to develop one.

Turner Syndrome Foundation Resource Map
Interactive map providing information about numbers of women with Turner syndrome in each state and how to connect with resources via social media.

Studies/Registries

Turner Syndrome, Children (ClinicalTrials.gov)

Services for Patients & Families in Rhode Island (RI)

Service Categories	RI	NW		ID	MT	NM	NV
Audiology	22	2	29	51	280	7	52
Developmental - Behavioral Pediatrics	14	1	3	9	5	4	9
Developmental Assessment	29		139	11	255	3	41
Educational Testing/Assessment			113		230	9	17
General Counseling Services	33		217	150	112	151	496
Genetic Testing and Counseling	2		5	6	67	2	11
Neuropsychiatry/Neuropsychology	6		3	3		8	14
Obstetrics & Gynecology			3	11	85		74
Occupational Therapy, Pediatric	11		25	35	294	14	40
Orthodontics	1		1	51	7	5	22
Pediatric Cardiology	17	1	4	17	35	5	7
Pediatric Dentistry	27		57	50	67	26	60
Pediatric Dermatology	2	1	1	5	3	1	2
Pediatric Endocrinology	14	1	2	15	28	5	6
Pediatric Gastroenterology	20	1	3	23	6	6	4
Pediatric Genetics	5	1	4	7	3	3	6
Pediatric Ophthalmology	8	1	8	15	9	6	7
Pediatric Orthopedics	12	2	4	13	12	6	19
Pediatric Otolaryngology	6	1	4	5	1	5	10
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Authors & Reviewers

Initial publication: September 2009; last update/revision: August 2019

Current Authors and Reviewers:

Author:	Vandana Raman, MD
Reviewer:	Alan F. Rope, MD

Authoring history

2016: update: Meghan Candee, MD^R

2011: revision: Vandana Raman, MD^A

2011: update: Alan F. Rope, MD^A

2009: first version: Catherine Jolma, MD^A

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

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Overview

Other Names & Coding

Prevalence

Genetics

Prognosis

Practice Guidelines

Roles of the Medical Home

Clinical Assessment

Overview

Pearls & Alerts for Assessment

Screening

For the Condition

Of Family Members

For Complications

Presentations

Diagnostic Criteria

Clinical Classification

Differential Diagnosis

Comorbid & Secondary Conditions

History & Examination

Current & Past Medical History

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Maturational Progress

Social & Family Functioning

Physical Exam

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HEENT/Oral

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Extremities/Musculoskeletal

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Overview

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Issues Related to Turner Syndrome

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