Causes, Evaluation and

Management
Turner Syndrome

With Lynae Brayboy, M.D.

Learning Objectives

In this lecture we will review:

• Genetics of Turner syndrome

• Diagnosis of Turner syndrome

• Overview of Turner syndrome

• Reproductive sequelae of Turner syndrome

• Reproductive management of Turner

syndrome
Incidence of Turner Syndrome Epidemiology

Turner Syndrome affects 1 in 2.000 females.

Genetics of Turner Syndrome Etiology

The X chromosome contains near 1,000

genes, which relates to 5 % of total DNA in
cells.

© by Lecturio
Genetics of Turner Syndrome Etiology

• In 46,XX individuals, one of the

X chromosomes is randomly inactivated.

• Classic Turner 45,X0 karyotype is believed to be

one of the most common human chromosomal
abnormalities.

• It occurs in 0.8 % of ALL zygotes.

© by Lecturio
Genetics of Turner Syndrome Etiology

Fewer than 3 % of these zygotes survive to term (37

weeks) making 45,X0 a common karyotype in 37
spontaneous abortions.

© by Lecturio
Genetics of Turner Syndrome Etiology

• Absence or structural abnormality of one

copy of the X chromosome, often due to
nondisjunction

• Sporadic condition, possibly related to

advanced paternal age

• paternal sex
chromosome
Genetics of Turner Syndrome Etiology

• Half are pure monosomy 45,X0 karyotype

• Half are mosaic: phenotype may be milder in girls with 46,XX / 45, XO
mosaicism, but varies depending on the timing and tissues affected by
mosaicism.

• 46 X, del (Xp) short arm missing

Genetics of Turner Mosaics Etiology

46,XY/45,X0: found in 6 11 %

© by Lecturio
Genetics of Turner Mosaics Etiology

Variable presentation:

• Clitoromegaly vs. ambiguous genitalia vs.

descended testes

• Need to assess for gonadoblastoma

→ 12 % risk, even at a young age

Rogerio A. Lobo & David Gershenson & Gretchen M Lentz & Fidel A Valea, Comprehensive Gynecology, 7th Edition, 2017, p. 207, Fig. 11-3 & 11-4, Elsevier
The ABCs of Turner Syndrome Signs/Symptoms

Audiology

Autoimmunity

Cardiac defects Clinical pearl

Dermatologic manifestations

Failure to grow

Gastrointestinal disease

Vinay Kumar & Abul K. Abbas & Jon C. Aster, Robbins & Cotran Pathologic Basis of Disease, 9th Edition, 2015, p. 167, (Elsevier)
The ABCs of Turner Syndrome Signs/Symptoms

Genetics

Metabolic disorders

Orthopedic complications
Clinical pearl
Psychosocial manifestations

Renal abnormalities → 30 50 % with

horseshoe kidney being most common

Reproductive and pubertal disorders

X-linked disorders

Vinay Kumar & Abul K. Abbas & Jon C. Aster, Robbins & Cotran Pathologic Basis of Disease, 9th Edition, 2015, p. 167, (Elsevier)
Turner Syndrome Diagnosis

• 20 30 % diagnosis in neonatal periods

• 35 % as children with short stature

• 30 % as adolescents/adult women with

primary amenorrhea, delayed puberty

Jerome F. Strauss & Robert L. Barbieri, Yen & Jaffe's Reproductive Endocrinology, 7th Edition, 2014, p. 357, Fig. 16-5 & 16-6, Saunders (Elsevier)
Turner Syndrome Diagnosis

• 20 30 % diagnosis in neonatal periods

• 35 % as children with short stature

• 30 % as adolescents/adult women with

primary amenorrhea, delayed puberty

Jerome F. Strauss & Robert L. Barbieri, Yen & Jaffe's Reproductive Endocrinology, 7th Edition, 2014, p. 357, Fig. 16-5 & 16-6, Saunders (Elsevier)
Turner Syndrome Diagnosis

Prenatal Neonatal Adolescence

Note: The diagnosis of turner syndrome High-yield

is often delayed.
Turner Syndrome Diagnosis

Prenatal Neonatal Adolescence

Ultrasound findings include fetuses who present with:

• IUGR
High-yield
• Large septate cystic hygromas
• Nuchal thickening
• Short femur
• Total body lymphangiectasia and cardiac defects
Turner Syndrome Diagnosis

Prenatal Neonatal Adolescence

Physical findings include:

• Low birth weight
High-yield
• 30 % present with lymphedema of the lower and
upper extremities
• Webbed neck (pterygium colli)
• High arched palate
• Low set prominent ears
• Low posterior hair line
• Micrognathia
Turner Syndrome Diagnosis

Prenatal Neonatal Adolescence

The most common presentation is:

• Short stature
High-yield
• Amenorrhea
• Lack of secondary
sexual characteristics

30 % of Turner patients undergo some degree of

spontaneous puberty.
Turner Syndrome Diagnosis

• If blood tests normal, but strong clinical

suspicion → tissue sample

• Test for Y with the use of FISH/PCR for the

patient with ambiguity

• No clinical warranty for routine testing for

SRY or Y in 45,X0 without masculinization
(Turner Guidelines-2007)

Zhong and Layman, Fertility and Sterility 2012

Short Stature and Turner Syndrome

• Short stature: average of 20 cm shorter than peers

• IUGR
High-yield
• Slowed childhood growth

• Mild skeletal dysplasia upper to lower ratio

• Lack of pubertal growth spurt in Turner Syndrome

patients

Both: Jerome F. Strauss & Robert L. Barbieri, Yen & Jaffe's Reproductive Endocrinology, 7th Edition, 2014, p. 357, Fig. 16-5, Saunders
(Elsevier)
Cardiovascular Screening Management

Screening: All patients at time of diagnosis

• Evaluation by cardiologist with expertise in congenital heart disease

• Comprehensive exam including blood pressure in all extremities

• All require clear imaging of heart, aortic valve, aortic arch and
pulmonary veins
• Echocardiography usually adequate for infants and young girls
• MRI and echo for older girls and adults

• EKG

JCEM Clinical Guideline 2007

Cardiovascular Monitoring Management

Monitoring: Follow-up depends on clinical situation

• For patients with apparently normal cardiovascular system and age-

appropriate blood pressure

• Reevaluation with imaging at timely occasions, e.g. at transition to

adult clinic, before attempting pregnancy, or with appearance of
hypertension

• Otherwise, imaging about every 5 10 yr

• For patients with cardiovascular pathology, treatment and

monitoring determinded by cardiologist

JCEM Clinical Guideline 2007

Growth Hormone Management

• GH FDA approved for Turner Syndrome in

1996

• Standard of care to consider growth

hormone as soon as evidence of
decreased linear growth velocity

• Best outcomes with younger age of

initiation, higher dosing, longer duration of
therapy

• Height gain: 7 18 cm

Canadian Growth Hormone Advisory Committee, JCEM 2005, Davenport, JCEM 2010
Hormone Replacement Management

• Initiation of estrogen will mimic normal physiology.

• Once patient fully develops normal conture breasts and breakthrough bleeding, then
initiate progestins.

• It is done in context of their growth hormone administration.

JCEM Clinical Guideline 2007

Hormone Replacement Management

Age (yr) Age-specific suggestions Comments

10 11 Monitor for spontaneous puberty by Low-dose estrogen treatment may not

Tanner stagging and FSH level inhibit GH-enhanced growth in stature
12 13 If no spontaneous development and FSH Equivalent initial E2 doses: depot (im )
elevated, begin low dose E2 E2, 0.2 0.4 mg/month; trandermal E2,
6.25 dailyα ; micronized E2, 0.25 mg
daily by mouth
12.5 15 Gradually increases E2 dose over about Usual adult daily dose: 100 200
2 yr (e.g. 14, 25, 37, 50, 75, 100, 200 transdermal E2, 2 4 mg micronized E2,
daily via patch) to adult dose 20 EE2, 1.25 2.5 mg CEE
14 16 Begin cyclic progesterone treatment Oral micronized progesterone best
after 2 yr of estrogen or when option at present; usual adult dose is
breakthrough bleeding occurs 200 mg/d on d 20 30 of monthly cycle
or d 100 120 of 3-month cycle
JCEM Clinical Guideline 2007
Hormone Replacement Management

Age (yr) Age-specific suggestions Comments

14 30 Continue full doses at least until age 30 Some women may prefer using oral or
because normally estrogen levels are transdermal contraceptive for HRT;
highest between age 15 and 30 yr monitor endometrial thickness
30 50 The lowest estrogen dose providing full Monitor osteoporosis risk factors, diet,
protection vs. osteoporosis is 0.625 CEE excercise; obtain BMD and begin
or equivalent regular screening mammography by
age 45 yr
> 50 Decision on estrogen use based on New HRT options are appearing and
same consideration as for other the recommendations may need
postmenopausal women updating in near future
CEE, conjugated equine estrogens; E2, estradiol; EE2, ethinyl estradiol; HRT, hormone replacement treatment.
αThe lowest-dose commercially available E2 transdermal patches deliver 14 and 25 g daily; it is not established whether various means of

dose fractionation (e.g. administering a quarter patch overnight or daily administering whole patches for 7 10 d per month) are equivalent.

JCEM Clinical Guideline 2007

Pregnancy and Turner Syndrome Complications

2 5%
• Spontaneous pregnancy can occur in
2 5 % of Turner syndrome patients.

• Pregnancy-risk for dissection 2 in 100 High-yield

pregnancies with TS

• In 7 cases of aortic dissection reported

after assisted reproductive technologies
(ART) → 6 patients died

Turtle EJ, et al, Arch Dis Child 2015

Pregnancy and Turner Syndrome Complications

Practice Committee of ASRM

Pregnancy and Turner Syndrome Complications

Half of the aortic dissections can occur in

pregnancy or post-partum due to vascular
remodeling.
Summary

Check a karyotype on any girl with pubertal delay or

unexplained growth failure!

Women with Turner syndrome are at risk of aortic

dissection/premature death even after pregnancy.

Hormone replacement therapy protects Turner

syndrome patients from osteoporosis.

Remember the ABCs of Turner Syndrome!

Egg Donation vs. Embryo Donation: Case Study

36-year-old G0 with Turner syndrome presents to your clinic to discuss

egg donation vs. embryo donation.

What are the risks involved? How would you counsel her? What tests
would you order? How should her pregnancy be managed?

• Turner Syndrome patients who become pregnant → risk for aortic

dissection (often HTN, careful monitoring necessary)

• = constitute a high-risk pregnancy → should be seen by MFM

Keith L. Moore & T.V.N. Persaud & Mark G. Torchia, The Developing Human, 10th Edition, 2016, p. 48, Elsevier
Learning Outcomes

In this lecture we reviewed:

✓ Genetics of Turner syndrome

✓ Diagnosis of Turner syndrome

✓ Overview of Turner syndrome

✓ Reproductive sequelae of Turner syndrome

✓ Reproductive management of Turner

syndrome