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.
Other Names & Coding
Bonnevie-Ullrich-Turner syndrome Gonadal dysgenesis Ovarian dysgenesis Turner's syndrome Ullrich-Turner syndrome XO syndrome, monosomy X
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).
Clinical Assessment
Overview
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.
Screening
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 ( 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
Epicanthal FoldsMissed 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
Cystic HygromaLymphedema sequence (edema of hands or feet, webbed neck, low
hairline, hyperconvex and hypoplastic nails)
Cardiac anomalies, such as bicuspid aortic valve,
coarctation of aorta
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]
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
History & Examination
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 ( 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) ( 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.
Testing
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
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.
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.
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.
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.
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.
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.
Testing should be considered at major transitional stages (preschool, entry to elementary, and high school).
Treatment & Management
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]
How should common problems be managed differently in children with Turner Syndrome?
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) ( 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]
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.
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]
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.
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.
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.
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.
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.
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.
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).
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]
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.
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.
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.
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.
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.
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.
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) ( 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.
Ask the Specialist
When should a child with Turner syndrome begin therapy with growth hormone?
The recent guidelines recommend initiating GH treatment early (around 4–6 years of age and preferably before 12–13 years)
if 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 cause of poor growth) or if 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).
When should an adolescent with Turner syndrome undergo induction of puberty?
In the past, medical induction of puberty with estrogen was delayed until about 15 years of age to maximize a patient's height
potential. Recent data indicates that beginning pubertal induction with estradiol at age 11-12 years allows a normal pace
of puberty without interfering with the effect of growth hormone on ultimate height. Delaying pubertal induction may have
several deleterious effects, including reduced bone mineralization as well as the negative psychosocial consequences of late
pubertal development. [Bondy: 2007] Gonadotropins (esp. FSH) should be monitored annually starting at about 11 years to confirm hypergonadotropic hypogonadism
prior to pubertal induction. Transdermal 17-beta estradiol is now the preferred treatment starting at around age 11-12 years.
[Gravholt: 2017]
Can women with Turner syndrome become pregnant?
While the majority of women with TS are infertile, spontaneous pregnancy has been
reported. Some women with TS become pregnant through assisted reproductive
technology. Reports of fatal aortic dissection during pregnancy and the
postpartum period have raised concerns about the safety of pregnancy in TS. If
pregnancy is being considered, a full, preconception cardiac evaluation,
including an MRI of the aorta, should be performed. Women who have a repaired cardiovascular defects, bicuspid aortic
valve, current aortic
dilatation, or systemic hypertension should probably not become pregnant.
[Bondy: 2007]
What is the risk of Turner Syndrome recurring in future pregnancies?
The likelihood of a woman having a second child with TS is no greater than in the general population.
Resources for Clinicians
On the Web
The following modules/pages within the Portal provide more detailed
information about conditions associated with TS:
SHOX Deficiency Disorders (GeneReviews) Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular
pathogenesis; from the University of Washington and the National Library of Medicine.
Turner Syndrome (GARD) Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations;
Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.
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
Turner Syndrome Health Maintenance Checklist ( 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 Growth Chart 2-19 Years ( 1.2 MB) Printable growth chart with curves for girls with and without Turner syndrome; percentiles derived from the National Center
for Health Statistics.
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) ( 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 (Medline Plus) Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the National Library of Medicine.
Turner Syndrome (MedlinePlus) Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the 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 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.
* number of provider listings may vary by how states categorize services, whether providers are listed by organization
or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited
to web-based services, provider locator services, and organizations that serve children from across the nation.
Authors & Reviewers
Initial publication: September 2009; last update/revision: August 2019
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