Presented by Rebecca Singleton Turner Syndrome Overview

Presented by Rebecca Singleton

Turner Syndrome Turner Syndrome Overview; Overview; What Is It?What Is It?

Birth defect, only seen in women Congenital absence of X-

chromosome– If all cells affected

X-monosomy (true 45 X genotype) Most severe kind Affects 60% of cases

– Or if some cells affected Mosaicism Varying severity

Or X-chromosome defects– 1 normal X-chromosome– 1 fragmented or structurally

abnormal X-chromosome

Turner Syndrome Turner Syndrome OverviewOverview

1 in 2000-2500 live female births

Not a hereditary disease, except in rare instances

Leads to sexual immaturity and generally infertility

Turner Syndrome Genotype: Turner Syndrome Genotype: 45 X; 45 X; What Does It Look Like?What Does It Look Like?

Normal Gametogenesis: Normal Gametogenesis: How How Does It Happen?Does It Happen?

Spermatocytes are formed from sperm cell precursors

Contain 1 copy of each of 22 autosomes

Contain either an X or a Y– In oogenesis, both

ova would contain an X

Abnormal Gametogenesis Abnormal Gametogenesis Leading to Turner Syndrome: Leading to Turner Syndrome:

How Does It Happen?How Does It Happen?

X or Y chromosome gets lost

Cell still has 22 normal autosomes

At least 1 X required for life– Daughter receiving 1

X from mom and no X from dad can survive

– Son receiving 1 Y from dad, no X from mom will not survive

Mosaics: Mosaics: How Do They Happen?How Do They Happen?

Normal, fertilized egg

Normal Mitosis

X chromosome lost from developing embryo

Resulting in 25% Turner Mosaic

Turner Syndrome Phenotype: Turner Syndrome Phenotype: What Is theWhat Is theDistribution?Distribution?

Note: 98% infertile and 95% have ovarian failure

Turner Syndrome Phenotype: Turner Syndrome Phenotype: What Is Affected?What Is Affected?

Affected Body Systems– Lymphatics– Heart– Kidneys– Eyes– Ears– Skin– Bones– Reproductive

Turner Syndrome PhenotypeTurner Syndrome Phenotype

Lymphatic Defects– Contribute to

Nail defects Low hairline Ear deformities Webbed neck Shield chest

Nail DeformityNail Deformity

Affects 70% of patients

Caused by peripheral lymphedema

Small, narrow, hyperconvex nails that are deeply inserted at an acute angle

Webbed NeckWebbed Neck Affects 25% of patients Jugular lymph sacs fail to

drain properly Enlarge and form a sac,

called cystic hygroma early in fetal development

Late in gestation, lymph problems are corrected, but loose folds of extra skin remain

Cystic HygromaCystic Hygroma

Most concepti with 45 X spontaneously abort

15% of spontaneous abortions have a genotype of 45 X

Other Lymphatic DefectsOther Lymphatic Defects

Cystic hygroma also causes– Low hairline– Low set ears

Lymphedema also causes– Shield shaped chest– Due to thoracic cage being stretched due to

fetal edema

Cardiovascular DefectsCardiovascular Defects

May result from defective lymphatics as well

Present in 1/3 of casesHighest cause of deathLeft side defects most common

– Coarctation of aorta– Bicuspid aortic valve– Aortic atresia

Renal DefectsRenal Defects

Usually benign Most common

horseshoe kidney – 10%– Greatest risk is UTI

risk from blocked ureters

Generally have normal renal function

Eyes, Ears and SkinEyes, Ears and Skin

Eyes– Strabismus– Ptosis

Ears– Acute, recurrent otitis media in infancy and

childhood– Hearing disorders

Skin– Multiple nevi

Orthopedic DisordersOrthopedic Disorders

Growth problems– Delayed growth– Not uniform

Small bones– 35% have short 4th and 5th metacarpals

Lack of knuckles

Decreased bone mineral density

Orthopedic DisordersOrthopedic Disorders

Scoliosis in 12% of patients Genus Valgus (knock knees) in 60% Cubitis Valgus in 45% Micrognathia (small chin) in 60% High arched palate in 34% Average adult height (not treated with GH) is

4’8” – Average normal is 5’4”– After GH treatment height can be 4’10” to 5’

Reproductive DefectsReproductive Defects

Ovarian dysgenesis – 95%– Delayed or absent sexual development

Primary amenorrhea common12% spontaneous puberty

– Often estrogen production stops– Ovarian failure later– Risk of premature menopause

Chronic ProblemsChronic Problems Thyroid problems

– Hashimoto thyroiditis (autoimmune hypothyroidism)– 35%, risk increases with age

Diabetes– Type II– 2 times the risk of normal population

High blood pressure Osteoporosis

– 10 times the risk of normal population Obesity Infertility

– Less than 5% maintain menses– Spontaneous pregnancy rare

Turner Syndrome Phenotype: Turner Syndrome Phenotype: ExampleExample

Short stature Webbed neck Shield-like chest Edema of wrists and

ankles

Turner Syndrome Phenotype: Turner Syndrome Phenotype: ExampleExample

Low hairline Broad chest Narrow hips

Turner Syndrome Phenotype:Turner Syndrome Phenotype:ExampleExample

Marked edema Many times first

indication of syndrome

Present in 1/3 of infants with Turner syndrome

Gets better with age May flare up at

puberty

Turner Syndrome Phenotype:Turner Syndrome Phenotype:ExampleExample

Generalized lymphedema

Loose skin folds at neck

Will later have webbed neck

Reproductive Anatomy of Reproductive Anatomy of Turner SyndromeTurner Syndrome

Streak ovaries present

Long, thin bands of ovarian tissue

Taken from 55 year old

No ova ever present

Anatomy of HeartAnatomy of Heart

Aortic DissectionAortic Dissection Artery lining tears or is

damaged Blood leaks into and along

artery wall Extreme medical emergency Death often occurs in

minutes May be associated with

pregnancy Can be due to collagen

disorders, (Marfan syndrome)

Hypertension and atherosclerosis also risk factors

Aortic DissectionAortic Dissection

Coarctation of the aorta is also a risk factor for aortic dissection

Coarctation of the aorta common in Turner syndrome

Aortic DissectionAortic DissectionRate

– 2 per 10,000 people– Can occur in anyone– Most often in men ages 40 to 70– Usually high blood pressure and

atherosclerosis contributing factorsSymptoms

– Usually sudden– Chest pain (similar to a heart attack)– Cognitive changes

Aortic DissectionAortic DissectionSymptoms continued

– Decreased movement or sensation– High anxiety– Pale, clammy skin– Increased heart rate– Thirst– Nausea and vomiting– Dizzy/faint– Breathing problems– Shock (may have increased or decreased

blood pressure– Murmur, abnormal heart sounds

Aortic Dissection & RuptureAortic Dissection & Rupture

Life threatening conditionLikelihood of death in untreated

individuals in the first 48 hours is 1% per hour

Curable if repaired surgically before aortic rupture

Less than half with aortic rupture survive

Aortic Dissection & RuptureAortic Dissection & Rupture

Aortic dissection can lead to– Blood loss– Thrombus– Inadequate blood supply past injury– Irreversible kidney failure– Stroke– Heart attack– Cardiac tamponade

Aortic RuptureAortic Rupture

Tear in the aorta Can lead to

exsanguination Often with

hemothorax X-ray of chest full of

blood (right side of patient)

Aortic DilationAortic Dilation

Aneurysm Ballooning or

widening of aorta Due to weakness in

wall of aorta Increased risk of

rupture

Marfan SyndromeMarfan Syndrome Hereditary disorder

– Autosomal dominant– But 30% sporadic cases– Spontaneous new

mutation– Affects 2 per 10,000

people

Affects connective tissue– Skeletal– Cardiovascular– Eyes– Skin

Marfan SyndromeMarfan Syndrome

Features– Tall– Thin– Long limbs– Spider like fingers (Arachnodactyly)– Chest defects (pectus excavatum or pectus

carinatum)– Scoliosis


Features continued– High arched palate– Long thin face– Crowded teeth– Nearsighted– Dislocated lenses– Cardiovascular

Dilatation (enlargement) of aortic root


Cardiovascular features continued– Aortic regurgitation

Aka aortic insufficiency or aortic valve prolapse Due to weak valve Blood flows back into left ventricle

– Prolapse of mitral valve Weak valve Blood pushed back into left atrium


Cardiac features continued– At risk for dissecting aortic aneurysm– Must be monitored during pregnancy

Due to increase cardiovascular demands of pregnancy

Increased stress placed on heart and aorta

Blood Vessel LayersBlood Vessel Layers

Tunica intima– Lines lumen– Endothelial cell layer– And subendothelial cell

layer of loose connective tissue

Tunica media– Circular layers of smooth

muscle cells – Thick in arteries– Also lots of elastic fibers

Blood Vessel Layers Blood Vessel Layers ContinuedContinued

Tunica Adventitia– Loose connective

tissue Contains Fibroblasts

and collagen fibers

– Vaso vasorum Blood supply to the

blood supply

Normal Aorta Vs. Jugular VeinNormal Aorta Vs. Jugular Vein

Note Aorta’s thick, highly structured tunica media

Layers of AortaLayers of Aorta

Elastic artery Tunica media makes

up most of vessel– Many membranes of

elastic fibers in layers with circumferential smooth muscle

Intima and media boundary not well defined

Aortic Dissection ExampleAortic Dissection Example

In patient with Marfan syndrome

Just above aortic root

Extends across aorta Hemopericardium

and tamponade occurred within minutes


7 cm above aortic valve

Near the great vessels of aorta

Atherosclerosis present


Blood dissected proximally through the media

Hemopericardium resulted

Cardiac tamponade may be present due to the extreme hemorrhage


Intimal tear Created double

lumen of aorta Thrombus formation

after limited dissection

Marked atherosclerosis present


Occurred through muscular wall (tunica media)

Aortic Dissection ExampleAortic Dissection Example Right carotid

compression from dissected blood

Blood dissected upward from aortic tear– Can dissect upward

toward carotids or downward toward coronaries

– Therefore, symptoms may reflect those of a stroke or heart attack

Aortic DissectionAortic Dissection

Cross section of aorta

Thrombus of aortic lumen

From intimal tear followed by high pressure dissection of blood out through muscular wall to adventitia

Cystic Medial NecrosisCystic Medial Necrosis Mucin stain of aortic

wall Typical in Marfan

Syndrome Causes connective

tissue weakness Responsible for aortic

dissection Pink elastic fibers

should be in parallel arrays

Instead interrupted by masses of blue mucinous material

Normal PregnancyNormal Pregnancy

Normal physiological changes occur

These changes greatly affect the cardiovascular system

Cardiovascular Changes in Cardiovascular Changes in PregnancyPregnancy

Reasons– Support new and growing tissues– Hormone changes affecting fluid dynamics

(sodium and potassium metabolism) Total body water increases

– New blood vessel growth and increase in diameter of existing vessels


Blood changes– Intravascular volume increases by 25-40%

Rises quickest in weeks 6-24 Reaches max at 32 weeks and stays there Does not return to normal until 4 weeks

postpartum


Blood changes continued– Red blood cells increase

Overall increase still less than 1/3 that of total volume increase

Appears as “dilution anemia” 15% hematocrit drop Does not return to normal until 8 weeks post

partum

– Serum protein decreases– Serum lipids increase by 50%


Cardiac changes– Begin around week 13– Normal changes often look like heart

disease– Heart changes position– Heart increases in size– Biggest change is the largely increased

cardiac output


Increased cardiac output continued– Mainly due to increased stroke volume– 20-40% increase– Rises by 30% during contractions– Continues to rise during labor– Another 29% increase immediately after

delivery


Heart rate increasesBlood pressure increasesDecrease in venous returnHalf of women develop murmursExtra systoles are commonDifficulty breathing common

Anatomy of HeartAnatomy of Heart

Cardiac TamponadeCardiac Tamponade

Cardiac TamponadeCardiac Tamponade Ventricles compressed Cannot fill and pump

blood adequately Affects 2 per 10,000

people Symptoms

– Chest pain; anxiety; dyspnea, tachypnea; faint; pallor; abdominal swelling; palpitations; very weak heart sounds

Have to drain pericardium

Scientific MethodScientific Method

ObservationsHypothesisVariablesExperimentResultsConclusion

ObservationsObservations

25 to 50% of Turner syndrome patients have a cardiovascular malformation

Turner syndrome patients also have an inherent risk of death from aortic rupture or dissection– 10% of these individuals with aortic dilation, rupture

or dissection had no risk factors (such as CV malformation)

– Most of the patients with rupture or dissection have the causative factor of cystic medial necrosis, which is the same defect of Marfan syndrome


The normal physiological changes of pregnancy place increased demands on the mother’s body, especially on the cardiovascular system

Marfan patients are cautioned about the increased stress that pregnancy places on the heart and aorta

Maternal death for Marfan patients without aortic defects is 5 to 15%

Death for those patients with aortic defects is 25 to 50%


The cause of death for these women is aortic dissection or rupture

50% of all aortic dissections in women of reproductive age occur in late pregnancy

Turner syndrome patients are encouraged to either adopt or seek IVF services for oocyte donation

HypothesesHypotheses

Turner syndrome patients who turn to oocyte donation to alleviate infertility problems face the risk of death, if pregnancy is achieved, through aortic dissection or rupture

Many clinicians are unaware of this risk, and fail to appropriately screen and monitor Turner syndrome patients

HypothesesHypotheses

Authors also stated that one objective of the study was to determine the pregnancy outcomes and rate of spontaneous abortion in this population

But a hypothesis regarding this objective was neither stated nor implied early in the paper

VariablesVariables

The authors of this paper failed to compare a control group to the experimental group

As Turner syndrome patients generally do not achieve pregnancy naturally, it would be implausible to compare patients undergoing oocyte donation versus those who do not utilize IVF

VariablesVariables

However, authors could have compared Turner syndrome patients who achieve and maintain pregnancy to the normal population of pregnant women (via oocyte donation) who die as a result of pregnancy and resultant aortic dissection or rupture

VariablesVariables

Authors also could have compared risk of death from aortic dissections and ruptures in non-pregnant Turner Syndrome patients of reproductive age to the patients achieving pregnancy through oocyte donation

ExperimentsExperiments

Literature searches using PubMed and MEDLINE to determine the number of US cases of deaths or cardiac events in the Turner syndrome population during pregnancy

Medical questionnaires regarding treatment and outcomes of Turner syndrome patients were faxed to medical directors of the 258 donor-egg programs listed in the 1997 National Summary and Fertility Clinic Reports


Survey ran from September 1, 2000 to July 31 2001 (10 months)

Each program was allowed to respond by fax, phone or e-mail

Each program that did not respond to the initial invitation was faxed 2 more times

If still no response, the donor-egg coordinators or medical directors were contacted by phone and asked to respond then over the phone or by fax


The questionnaire was designed to be easy to answer, consisting of 9 check-box style questions

Letters of intent, which assured anonymity to the responders, accompanied the questionnaires

Patient identifiers were neither used nor requested

ResultsResults

Literature reviews revealed 4 deaths of Turner syndrome patients during or shortly after pregnancy

2 women died in 1997– Sudden death in last trimester– From aortic dissection– Pregnant via oocyte donation

ResultsResults

Literature review continued– 1 of the women had essential hypertension– She had been treated since childhood– Underwent preconception screening

Revealed mildly dilated aortic root

– Second woman had no known risk factors

ResultsResults

Literature review continued– 1998 3rd woman developed aortic

dissection during pregnancy– History of hypertension– 24 weeks presented with epigastric pain– After misdiagnosis and worsening of

condition found to have aortic dissection– Surgical repair – Died 3 months later from complications of

ordeal

ResultsResultsLiterature review continued

– 4th revealed in study of pregnancy outcomes for patients with a history of aortic coarctation

– 50 women identified Some had surgical repair before or after

pregnancy or both Some had no repair 1 woman died

– Only patient with Turner syndrome– Had surgical repair at 4 years old– No known history of hypertension

ResultsResults

Literature review concluded– Screening revealed aortic dimensions

within normal limits– Died at 36 weeks gestation– Aortic dissection– Autopsy revealed aortic cystic medial

degradation– Oocyte recipient

Conceived triplets Reduced to twins at 12 weeks

Survey ResultsSurvey Results

52% of programs responded146 Turner syndrome patients reportedNone died of aortic complications

resulting from pregnancy



Survey ResultsSurvey Results146 patients seen49% (72) were screened with

echocardiogram8% (6) of these had an abnormality

– 5 out of these 6 had aortic problems 2 had unspecified aortic abnormalities 1 had coarctation 1 had bicuspid aortic valve 1 had bicuspid aortic valve with aortic

regurgitation and dilatation of ascending aorta 1 had mitral valve regurgitation


2 of the screened patients were not treated with oocyte donation– 1 with complex findings– 1 died of a dissecting aorta before

undergoing treatment


69% (101) of the 146 patients undergoing treatment became pregnant

Out of these 94 resulted in a live birth– Spontaneous abortion was only 6% or 7

cases17% (17) multiple gestations occurred100% of these resulted in at least 1 live

born baby

Communications to the Communications to the Scientific CommunityScientific Community

The authors estimate (by applying their numbers to some other assumptions) that the death rate of Turner syndrome patients who achieve pregnancy through oocyte donation to be 2%

This number is based on the 4 deaths found in the literature search out of an estimated 194 successfully treated patients (extrapolated from the fact that 101 pregnancies were achieved in 52% of the nation’s programs)

CommunicationsCommunications

Specifically, they estimate that 4 deaths occurred in 200 possible donor oocyte pregnancies

They estimated that the 48% of programs that did not respond had similar success rates (or 93 more pregnancies)

ConclusionsConclusions

Authors state that the death rate could be smaller if the programs that did not respond treated more Turner syndrome patients

However, they speculate that the death rate is actually higher– Note that no deaths were actually reported– May reflect an over tendency to

underreport events


Furthermore, they speculate that deaths may not be reported because– Doctors lost contact with the patients if

patients were seen at high-risk centers as a result of their condition

– IVF centers fear lawsuits, and are tight-lipped


Another likely possibility for higher death rates could be that only the centers treating Turner syndrome patients did respond

This would cause the death rate to be 4 per 101 patients, or about 4%

Conclusions & Further StudiesConclusions & Further Studies

The other important findings of the study were that only half of the treated patients were screened for cardiovascular defects

Guidelines for such screenings are not widely reported in reproductive literature, but are present in pediatric literature

Now reproductive specialists need to be made aware of these procedures

Conclusions & Future StudiesConclusions & Future Studies

Furthermore screening alone does not totally abolish the risk

Authors state that counseling should be made available for Turner syndrome patients

There is even debate about the screening tools used: echo or MRI?

Authors further recommend a national registry for Turner syndrome patients and ASRM guidelines for treatment

Thanks ToThanks To

Dr. Jay Ko, Univ. of Kentucky

Dr. Doris Baker, Univ. of Kentucky

The Department of Clinical Sciences, Univ. of Kentucky

Documents

Presented by Rebecca Singleton Turner Syndrome Overview