Gender and TS

8/17/2019 Gender and TS

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G EN D ER M E D I C I N E / V O L . 3 , N o . 1 2 0 0 6

SD G r a n d R o u n d s

Turner s Synd rome and X Chromosome-Based Differences

in Disease Susceptibility

C a r o l y n A . B o n d y M D

Dr. Carolyn Bondy earned her MD degree magna cure laude ftom Boston University School

of Medicine after obtaining her MS from the Massach usetts In stitute o f Technology and her

BA f tom the University of Massachusetts, also mag na cure taude. After an internship and

residency in inter nal medic ine at Boston University, she becam e an Endocrine Fellow in the

Develop mental Endocrinology Branch of the Nationa l Institutes of Health. S he rose through

the ranks ftom Senior Stafi~Fellow to Head o f the Growth and Meta bolism Section, and since

1995 has been C hie f of the Developmen tal Endocrinology Branch. Dr. Bond y has served on

several editorial boards, including

Endocrinology, Molecular Endocrinology,

and the

Journal of Endocrine Genetics.

She has received numerous awards for her work, including

the Curtis Award in Medicine, the Matamud Prize in Psychiatry, the Glasgow Award of the

Ame rican Medical Wo men s Association, and the US Public Health Service Special Recog-

nition Award. Ha ving publish ed m ore than 170 papers, she is internationally recognized for

her research on Turner s syndrome , ~ rom psych iatric illness to cardiovascular abno rma lities

to diabetes.

This article reviews the chromosomal etiology of Turner s syndrome (TS) and describes changing pat-

terns of ascertainment of the syndrome that influence commonly seen phenotypes. What has been

learned about the s pectrum of phenot ypic features and their prevalence from the o ngoi ng study since

2001 of >200 patients at the Nat ional Instit utes of Health (NIH) is discussed, as well as impo rt ant new

findings emerging from the study that pertain to t he care of girls and wo men with TS. The potential

role of the X chr omo som e as an agent of sex-based disparity in disease susceptibility and a ging is also

examined.

hromosomal Origins

The most co mm on genetic disorder aff ecting wom en, TS occurs in -1 of 2500 live female births, 1

more freq uently tha n Down syndrome. Short stature and/or ovarian failure are the most c om mon

clinical presentations in a phen otyp ic female. TS is caused by a sex chromo somal abnorm alit y involv-

ing the presence of 1 normal X chromosome and the complete or partial absence of a second sex

chromosome. The m o s t co mm on karyoty pe is 45,X (historically also not ed as 45,X0). Sex -chromosome

nondisjunction (failure of chromosomes to correctly separate during meiosis) that results in a 45,X

female can occur during either the first or second division of meiosis in spermatogenesis or oogene-

sis, or during mitotic cell divisions early in embryonic development. TS may also occur if a second

Based on a presentation to the Georgetown University Center for the Study of Sex Differences in Health, Aging and Disease

CSD), September 15, 2005.

Accepted for publication October 28 2005.

Ger~d Med . 2006;3:18-30.

1550-8579/06/ 19,00

] ~ Copyright © 2006 ExcerptaMedica, Inc.


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C.A. Bondy

sex chromoso me, usually the X chromoso me, is

present but has a structural abnormality. These

structural abnormalities include a partial dele-

tio n of the X chr omo som e [del(X)], result ing in

a 46,X, del(X) karyotype, or an iso chromo some (i)

in which the short arm is lost while the long

arm (q) is duplicated, resulting in a 46,X,i(Xq)

karyotype. Alternatively, a ring chromosome (r)

may occur in which a single chromosome suf-

fers 2 breaks and the broken ends are joined

together, thereby forming a ring and a 46,X,r(X)

karyotype.

T urner's syndrome occurs in ~1 of 2500 live

female births, more frequently than Down

syndrome, and is the most common genetic dis-

order affecting women.

T

umer's Syndrome Karyotypes

° Complete X deletion: 45,X

° Partial X deletion: 46,X,del(X)

° Isochromosome: 46,X,i(Xq)

° Rin g chromosome: 46,X,r(X)

TS can occur wit h mosaicism, i n whi ch >2 cell

lines demonstrate different karyotypes. Fairly

commonly, a predominant cell line carries an

abnormal X chromosome with a second, small-

er proportion of ceils missing the second X

chromosome altogether, which likely results

from the loss of the abnormal X in some cell

populations (eg, 46,X,i(Xq)/4S,X). In -15% of

cases, there is a predominant 4S,X cell line with

a minor com pon ent of normal ceils (46,XX). In

5% to 10% of cases, a normal or fragmented

Y chromosome is present in a minor cell line

(4S,X/46,XY). Because the diagn osis o f TS by

definition only includes phenotypic females,

the Y chromosome is either defective or the

dosage of the Y-containing cell line is very low

or restricted to nongonadal tissues. Hence, the

development of the default female phenotype is

permitted.

T

urner's syndrome can occur with mosaicism,

in which _>2 cell lines demonstrate different

karyotypes (eg, 46,X,i(Xq)/45,X).

Monosomy X is the only chromosomal

monosomy compatible with life. Given that the

second X chromosome is inactivated in 46,XX

females forming the heterochromatic Barr

body 2 one

migh t ask, Why is there any pheno-

type from X mon oso my? In recent years, we

have learned that despite Barr body formation

of the second X chromosome, 1S% to 20% of

X-chr omosom e genes on the inacti ve X are, in

fact, transcribed. 3 Some of these X-linked genes

that escape inacti vation are termed

pseudo-

autosomat because they have Y-chromosome

homologues and are normally expressed from

both alleles. An example of this phe no me no n is

the short stature ho meob ox-c ont ain ing (SHOX)

gene, which is currently the only specific gene

know n to con tribute to the TS phenotype. 4 It

is involved in skeletogenesis, and haploinsuf-

ficiency results in short stature wi th skeletal

anomalies, such as in Madelung's deformity. All

individuals apparently need biallelic SHOX

expression to attain their full height potential.

The absence of 1 allele results in a substantial

loss in adult height, whereas an additional copy,

as found in Klinefelter's syndro me 47,XXY), is

commonly associated with taller-than-normal

height.

espite inactivation of the second X chromo-

some through Barr body formation, 15% to

20% of X-chromosome genes on the inactive X

are, in fact, transcribed.

Many nonpseudoautosomal X-chromosome

genes also escape inactivation and appear to be

expressed from 2 alleles in females but from the

sole X allele in males, s At this time, we h ave

not ascertained how these noninactivated genes

function. One possibility is that biallelic expres-

sion of unknown X-linked genes involved in

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oocyte survival is essential for normal ovarian

function and fertility, and haploinsufficiency

for _>1 of thes e X- linked genes causes o var ian

failure in TS. Another potential source of a TS

phenotype is genomic imprinting of X-linked

genes. Genomic imprinting is the differential

expression of a gene, depending on whether it

was mat ern all y (X M) or pater nall y (X I') i nher-

ited; it is associated with DNA methylation

of im pri nte d or silenced alleles. 6 Geno mic im-

printing of X-linked genes could result in differ-

ent gene expression in males and females, be-

cause 46,XX wo me n are mosa ic for X M and

X P, whereas me n are mo nos omi c for X M. Genes

imp ri nte d (silenced) on X M wou ld still be ex-

pressed in females fr om cells in wh ich the X P

is active, but would not be expressed at all

in males. Evidence for imprinting of genes in-

volved in brain development has been found in

TS 7

enomic imp rinting is the differential expres-

sion of a gene, depending on whet her it was

maternally XM) or paternally XP) inherited.

Our study at the NIH is a prospective, in-

depth characterization of the phenotypes that

are associated wit h X- chro moso me dele-

tion, using state-of-the-art imaging and dy-

namic cardiovascular and metabolic testing.

The study is particularly focused on elucidat-

ing the type and prevalence of cardiovascular

defects, and identi fying atherosclerosis risk

factors in girls and women with TS. We are

also investigating the psychological aspects

of the syndrome, and the impact that pre-

mature ovarian failure (POF) has on the self-

confidence and social functioning of indi-

viduals with TS. Our goals are to improve the

diagnosis and care of these girls and women,

and to ident ify the genes that are responsible

for the TS phenotype. Ultimately, we hope

these findings will elucidate X-chromo some

dosage effects that globally affect the differ-

ences in disease susceptibility betwe en m en and

women.

scertainment Patterns and

Phenotypic Spectrum

Patterns of TS ascertai nment are cha nging. We

recently assessed the source(s) of diagnosis for

-200 individuals participating in the NIH TS

natural history study between 2001 and 20057

In this study, -10 of the partici pants were

diagnosed prenatally, -20 at birth because

of lymphedema with or without congenital

heart defects, -40 during chil dhood because

of short stature, -20 during adolescence

because of pubertal delay and/or short stature,

and -10 after 18 years of age, usually because

of secondary arnenor rhea or infertility. A recent

study from Belgium reports that in 2005 the

current mean age of TS diagnosis occurred at

6.6 years, whereas in 1991, the mean age was

11.2 years. 9 The increase in prenatal genetic

screening and the heightened awareness in our

society of short stature, coupled with the pro-

motion of growth hormone use for increasing

height, are probably responsible for this re-

duction in age of diagnosis and also for the

increased number of girls who receive an inci-

denta l diagnosis of TS.

Considering that TS affects -1 of 2500 live-

born females, we believe that at least 70,000 fe-

males have TS in the United States today; how-

ever, the estimated number of known cases is

much smaller. This discrepancy suggests that

many girls and women with TS are escaping

medical detection, most likely in many cases

because of their mild phenoty pe. An example of

the variability in TS phenotype is illustrated in

Figure 1, which depicts 2 women, both 32 years

of age with a 45,X karyotype and no evidence of

mosaicism. The woman on the left was diag-

nosed at birth because she exhibited several fea-

tures of TS, including webbing of the neck

(redundant skin folds that were residual of fetal

cystic hygroma), low-set rotated ears, micro-

gnathia (small lower jaw), and coarctation of

the aorta that was surgically corrected. Sub-

sequently, she has thrived in terms of her health,

education, and career. The woman on the right

received a diagnosis very recently because of

infertility. She has subtle signs of TS, including

a high-arched palate and low hairline. At

5'1 ,

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C.A. Bondy

• . • . . . ~

. i ~

Figure 1. Variabili ty in the Turner's syndrome phenotype. Both women have a 45,X karyotype. The woman

on the left was diagnosed at birth because of neck webbing and congenital heart disease. The

woman on the right was diagnosed recently because of secondary amenorrhea.

s h e w as n o t co n s i d e r ed t o h av e s h o r t s t a t u r e,

b u t f u r t h e r i n v e s t i g a t i o n r e v e a l e d s h e w o u l d

h a v e b e e n e x p e c t e d t o re a c h 5 ' 8 b e c a u s e b o t h

o f h e r p a r e n t s w e re q u i t e t a ll . Sh e h ad an ap p a r -

e n t l y n o r m a l p u b e r t y a n d b e g a n t a k i n g b i r t h

co n t ro l p i l l s d u r i n g co l l eg e , co n t i n u i n g t h em

u n t i l s h e mar r i ed i n h e r l a t e t w en t i e s . A f t e r s h e

s t o p p e d t a k i n g t h e p il ls , s h e n e v e r r e s u m e d h e r

men s es . T h u s , i t is i mp o r t a n t f o r a ll p h y s ic i an s ,

i n c l u d i n g f ami l y p r ac t it i o n e r s , i n t e rn is t s , an d

g y n eco l o g i s t s , a s w e l l a s p ed i a t r i d an s , t o b e

aw are o f t h e d i ag n o s i s o f T S an d t h a t t h e p h e -

n o t y p e m a y b e q u i t e m i l d .

he discrepancy between predicted and diag-

nosed numbers of patients wi th Turner's syn-

drome suggests that many girls and women are

escaping medical detection. Thus, it is extremely

important for all physicians to be aware of the

diagnosis of Turner's syndrome and that the phe-

notype may be quite mild.

l i n i c a l F e a t u r e s

T h e p r e v a l e n c e o f T S f e a tu r e s f o u n d i n t h e

N I H s t u d y b a s e d o n 1 5 0 a d u lt s is s h o w n i n t h e

t ab l e . W e ch a rac t e r i z ed ad u l t s r a t h e r t h an g i r l s

b ecau s e f ea t u r e s s u ch a s g l u co s e i n t o l e r an ce o r

t h y ro i d d i s ea s e u s u a l l y man i f e s t l a t e r i n l i f e .

Sh o r t s t a t u r e i s ex t r eme l y p r ev a l en t , b u t i t i s

i mp o r t an t t o co n s i d e r a p a t i en t ' s s t a t u r e i n l i g h t

o f h e r p r e d i c t e d a d u l t h e i g h t, b a s e d o n t h e

h e i g h t o f h e r p a r en t s . A f ew i n d i v i d u a l s w i t h a

46 ,X,de l (Xc0 k a ry o t y p e a re o f n o rm a l h e i g h t

b e c a u s e S H O X a n d m o s t o f t h e o t h e r g e n e s

i m p l i c a t e d i n T S a r e l o c a t e d o n t h e s h o r t a r m

( X p) r a th e r t h a n o n t h e d e l e t e d l o n g a r m ( Xc0.

S

ort stature is extremely prevalent in Turner's

syndrome, but it is important to consider a

patient's predicted height based on the height of

her parents.

O v a r i a n f a i l u r e i s t h e s e c o n d m o s t c o m m o n

fea t u r e o f T S. A p p ro x i ma t e l y 8 5 % o f i n d i v i d u a l s

w i t h T S w i l l ex h i b i t p r i ma ry a men o r rh ea , an d

- 1 2 % t o 1 4 % w i ll e x h ib i t s e c o n d a r y a m e n o r -

rh ea i n t h e i r t e en s o r l a te r i n l if e . A f ew w o m en

w i l l c o n t i n u e t o h a v e n o r m a l o v a r i a n f u n c t i o n

l o n g e n o u g h t o h a v e c h i l d r e n n a tu r a ll y .

varian failure is the second most common

feature of Turner's syndrome, with ~85 of

patients experiencing primary amenorrhea and

~12 to 14 of patients experiencing secondary

amenorrhea.

T h e f i n d i n g o f a h i g h -a r ch ed p a l a t e i s h e l p -

fu l i n p h y s i ca l d i ag n o s i s ; i n s o m e ca se s , t h e a r c~

i s p o i n t e d o r o g i v a l. Ch r o n i c o ti t is me d i a

( e ar i n f e c ti o n ) is c o m m o n i n c h i l d h o o d d u e t o

s h o r t , t o r t u o u s eu s t ach i an t u b es . Ch i l d r en may

m a n i f e s t c o n d u c t i v e h e a r i n g l o s s a s s o d a t e d

w i t h ch ro n i c o t it is , b u t t h i s l o ss o f h ea r i n g u s u -

a l ly reso lves wi th matur i ty . In con t ras t , adu l t s

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Table. Turner's syndrom e phenoty pe from the 20 05 Nat ion al Institutes of Health study (N = 150).

Short stature 98 Hype rtensio n 30

Ovarian failure 92 Impaired glucose tolerance 45

Sensorineural hearing loss 55 Neck webbing 33

Congenital heart disease

Any

Aortic coarctation

50

12

Skeletal anomalies

Renal anomalies

10

25

Elongated arch 50 Th yr oi d utoimmunity 50

Bicuspid aortic valve 23 Liver enzyme abnormalities 35

Partial anomalous pulmonary venous return 13 Obesity 36

with TS are at high risk for developing senso-

rineural hearing loss. Congenital cardiovascu-

lar defects are fou nd in -S 0% of all TS patients.

Endocrine disorders are also very common in

TS. Thyroid autoimmunity (most frequently,

Hashimoto's disease) affects -S0% of women

wit h TS by SO years of age. Im pair ed glucose tol-

erance and overt diabetes mellitus are also com-

mon and, interestingly, are associated in most

cases with preserved insulin sensitivity and

impaire d glucose-i nduced insuli n secretion. I°

Hypertension of u nkn ow n etiology affects 30%

to 40% of women with TS. Mild to moderately

abnormal liver function tests are common, but

few patients develop progressive liver disease.

Renal anomalies, mainly horseshoe kidney, are

foun d in -2 0% of patients an d are mostly clinical-

ly benign.

ndocrine Disorders in Turner's Syndrome

• Thyroid autoimmunity: ~50

° Hypertension: 30 -40

° Diabetes mellitus: 25 -30

Intelligence is typically normal, with full-

scale IQ in the normal range; however, there is

an interesting disparity in verbal versus per-

formance IQ in m any girls and wo men with TS.

The performance IQ test measures the ability

to perform mental rotations, geometry, visual-

spatial tasks, and the like. People with TS do not

score as well on these performance tests as they

do on verbal ability tests. This disparity in ver-

bal and performance scores may be associated

with having difficulty with math, but educa-

tional attainments overall have been excellent

in most of the individuals with TS who are par-

ticipating in the NIH study.

ongenital Heart Disease

Previous studies on congenital heart disease

(CI-ID) in TS have been based on retrospective

surveys of clinic records, which go back many

years and encompass patients who were stud-

ied in a limited manner. The NIH study is pro-

spective in design, and all participants are stud-

ied using state-of-the-art magnetic resonance

angiograp hy (MRA) and echocardiograms. Our

study participants are not selected for heart dis-

ease, and our st udy is not advertised as identify-

ing, treating, or curing heart disease. Most of

our patients are in good health and have not

specified concern about heart disease as a moti-

vati ng factor.

The reasons our study focuses so intently on

CHD are 2-fold. First, CHD poses the greatest

risk to life for individuals with TS. Without

expert diagnosis and treatment, a large propor-

tion of girls with TS may n ot survive childho od.

Even whe n t he mos t clinically appare nt defects

have been corrected, the risk for catastrophic

aortic dissection hangs like Damocles' sword

over the heads of otherwise relatively healthy

and high- funct ionin g girls and wo men with TS.

Aortic dissection is estimated to occur in 1% to

3% of p ati ents wi th TS, 11 and as yet ther e is no

evidence-based meth od of predicting which pa-

tients are most at risk and no well-established

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C.A. Bondy

parameters to guide intervention. Secondly,

there is at present no insight into the gene~c

basis for CHD in TS. Thus, we aim to compre-

hensively characterize the extent of CHD in as

ma ny individuals with TS as possible so tha t we

can determine the relationship between GHD

risk and kno wn X -chr omos ome aberrations as

well as abnormali~es in n ewly sequen ced candi-

date genes.

ven when the most clinically apparent defects

haw been corrected, the risk for catastrophic

aortic dissedion hangs like Darno:les' sword ov-

er the heads of otherwise relatively healthy and

high-functioning girls and women with Turners

syndrome k

lV[RA uses ga dol in iu m as a con tra st ag ent,

which enables a minimally invasive and nonra-

diating imaging modality to define cardiovascu-

lar anatomy in TS and reveal occult abnormali-

ties. Figure 2 depicts a normal aorta on the left

with a smooth candy cane shape and normal

asce ndin g vessels. On the right is an aorta from

an adult with TS who also has hypert ension.

This is an occult coarctation with prestenotic

dilatation of the left subclavian artery and aorta,

as well as poststenotic dilatation. Our studies

show that -5 00 of asymptomatic patients with-

out known cardiac disease have an abnormal,

elongated, squared-off, kinked aorta that we

have termed an e longated transverse aorta 12 The

clinical significance of such a natomical findings

remains to be determined, but it seems likely

that ectasia of the aorta may indicate a risk for

Figure 2. Magnet ic resonance a ngiography using gadolinium reveals details of cardiovascular anatomy. The

image on the left shows a normal aortic arch and great vessels; the image on the right shows nar-

rowing and coarctation o f the aorta just below the origin of the left subclavian artery.

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GENDER MEDICINE

aneu rysm or dissection, and we advise that blood

ical investigation of the cardiovascular

syst m

pressure be aggressively control led in these in all indivi duals wit h TS because of the excep-

patients, along wit h con ti nue d vigilant surveil- tional utility of cardiovascular MRA for detect-

lance of aortic dimensions. Twenty-three per-

ing u nsusp ecte d majo r vessel anomalies. 13

cent of TS patie nts had a bicuspid or fused tri- In addi tio n to anat omi cal defects of the car-

cuspid aortic valve. Aortic coarctation, incl udin g diovascular system, the NIH stu dy has identi-

new cases, was fou nd in -12 of the patients.

fied significant electrocar diograph (ECG) abnor-

Furthermore, we identified 2 major venous

malit ies in ind ividual s w it h TS. 14 Girls an d

anomalies: persistent left superior vena cava and wo me n wit h TS are more likely to have right-

a partial anomalo us pulmonar y venous return axis deviation, accelerated atrioventricular con-

(PAPVR). Each ano ma ly was identi fied in 12 to ducti on, and T-wave abnormali ties. The PR in-

13 of the pati ent p opu lat ion . 12 PAPVR ma y be

terval (time elapsing between the beginning of

clinically significan t wh en the s hun t is severe, the P wave and the beg inn ing of the QRS com-

and could result in right heart overload and pul- plex in an ECG) is signi fican tly shorter and the

rnonary hypertension.

rate-corrected QT interval (QTc) is significantly

In summary, -10 to 20 of patients with TS longer in TS 14 The spectrum of QTc intervals in

have clinically severe CHD requiring surgical our TS popula tion compar ed with age-matched

treatment for aortic coarctation, septal defects,

female controls is shown in Figure 3. QTc pro-

and/or anomalous pulmonary venous return.

longat ion is associated with the risk of arrhyth-

The most severe defects are usually detected and

mia and increased morbidity and mortality in

treated in infancy, but a surprising number of

other patient populations. Is Interestingly, the

occult defects emerge with decompensation

electrophysiological abnormality in TS is appar-

duri ng later life. As ma ny as 20 to 25 of pa- ent ly in dep end ent from anat omic al CHD in TS.

tients have bicuspid or fused tricuspid aortic Thus, cardiac conduction and repolarization

valves tha t require regular lifetime surveillance abnorm alit ies are likely to be intri nsic features

to detect functional impairment or dilatation of TS, suggesting that deletion of the second X

of the aortic root. Moreover, these individuals chro moso me has more prof ound effects on the

need to take antibiotics for prophylaxis to pre-

vent infecti on of the abnor mal valve. The pres-

ence of aortic ectasia may suggest an increased

risk for aortic dilatation and possibly dissection,

alt hough prospective data are not yet available.

The risk factors for aneurysm and dissection are

thought to be the same as found in non-

syndromic cases: hypertension, bicuspid aortic

valve, and aortic dilatation. Therefore, individ-

uals with any of these risk factors must be close-

ly monitored. We strongly recommend that

MRA be used in conjunction with echocardio-

grams, at least on a one-time basis, for the clin-

pproxim ately 1 0 to 20 of pat ients with

rner's syndrome have clinically severe

congenital heart disease requiring surgical

treatment for aortic coarctation, septal defects,

an d/o r anomalous pu lmon ary venous re turn .

5

450

400 -

350

Control Turner s

Syndrome

Figure 3. Differences in the rate-corrected QT inter-

val (QTc] in wom en with Turner s syn-

drome and age-matched female controls.

The QTc wa s o bta ined using Bazett s cor-

rection and shows that QTc is longer in

women with Turner s com pared with con-

trols (P< 0.001).

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C.A. Bondy

cardiovascular system than previously recog-

nized and that ECG analysis should be included

in evaluating and monitoring patients with TS.

In particular, QTc should clearly be mo nit ore d

when considering the use of medications that

are known to prolong the QT interval and in-

crease the risk of cardiac arrhythmias, such as

some antibiotics and psychotropics commonly

used to treat children.

p

atients with Turner s syndrome are more likely

to have electrocardiograph abnormalities in-

cluding right-axis deviation, accelerated atrio-

ventricular conduction, prolonged rate-corrected

QT interval (QTc), and T-wave abnormaliti es.

s s u e s i n

Reproduction

Approximately 30 of girls with TS exhibi t spon-

taneous puberty at least partially, and a few are

able to maintain regular menstrual periods and

are even fertile. The literature reports roughly 2

to 3 of TS wom en have spon tane ous pregnan-

cies, though some case reports suggest these

pregnancies are associated with a high rate of

miscarriage and mater nal complications. 16 Most

girls with TS, however, either do not develop an y

signs

of puberty or have very limited develop-

ment. These girls require estrogen treatment to

undergo feminization. In our experience at the

NIH with 150 adults with TS, only 2 women

(4S,X) had spontaneous pregnancies. These were

without complications, aside from delivery

by cesarean section, and both women delivered

healt hy children.

Natural pregnancy is not an option for most

women with TS who have clear POE For many,

the experience of infertility is one of the worst

aspects of TS, if not th worst. 17 Hence, th ey have

great interest in the possibility of assisted repro-

duction with donated oocytes. The first articles

from abroad reported generally poor results with

in vitro fertilization in TS 16 but those were pub-

lished in the 1980s and early 1990s when the

techniques were new and few practitioners had

experience treating women with nonfunct ioning

ovaries. The most recent reports, however, fo und

that women with TS become pregnant just as

easily as women with other types of infertility

and carry their pregnancies to term without an

increased miscarriage ratelS; however, they do

have an increased rate of maternal complica-

tions. 19 Because of thei r small size, most wo me n

with TS need to deliver by cesarean section.

Women with TS are also prone to hypertension,

which often worsens during pregnancy. Most

critically, the risk for dilata tion a nd dissection of

the aorta appears to increase dur ing p regnanc y. 19

Because of these concerns, the American Society

for Reproductive Medicine recently published a

practice guideline suggesting that TS is a contra-

indic ation to assisted pregnancy. 2° Man y clini-

cians may not agree with a general proscription,

but it is critically important to perform a careful

cardiovascular evaluation before pregnancy,

which may be contraindicated in women with

aortic dilatation, aneurysm, or other cardiovas-

cular abnormalities.

or manywomen, the experience of infertility is

one of the worst aspects of Turner s syndrome,

if not th worst.

I

t is critically important to perform a careful car-

diovascular evaluation before pregnancy, which

may be contraindicated in women with Turner s

syndrome who have aortic dilatation, aneurysm,

or other cardiovascular abnormalities.

Psychological ssues

Shyness and social anxiety appear to be com-

mo n psych olog ical features of TS. 21 The etio log y

of this emotional phenotype is unknown, but

potential contr ibutors i nclude the physical stig-

mata of the syndrome such as short stature and

neck webbing, chro moso mall y based deficits in

social cognition, and POE

Based on conversations with our st udy partic-

ipants and their comments to counselors, we

considered the likelihood that ovarian failure

and infer tility could factor promi nent ly in psy-

2S


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GENDER MEDI INE

chosocial dysfunction in T8.17 22 To investigate

the role of POF and infertility in this em otio n-

al phenotype, we compared measures of psy-

chosocial function in women with TS with

wom en with spontan eous karyotypically nor-

mal POF and with hea lth y controls. 23 Wo men

with TS and wom en with POF had nearly iden-

tical scores on all 4 scales of psychosocial func-

tion. Both groups reported higher levels of shy-

ness, social anxiety, and depression, and lower

self-esteem compar ed with hea lth y controls. 23

This study highlights the impact of POF on a

woman s confidence and social fu nctioning.

Ovarian horm one deficiency does not explain

this shared emotional phenotype, because both

groups were taking hormone replacement ther-

apy (HRT) and the d urat ion of ovarian failure

did not influence scale scores. It is regrettable

that in our society today, these women appear

to feel stigmatized and inadequate because the y

do not have ovarian function. It is clear that

clinicians need to attend to the psychosocial

aspects of the diagnosis of POF as well as to the

medical ramifications.

oung women who lack normal ovarian func-

tion, because of Turner s syndrome o r prema-

ture ovarian failure, exhibit increased shyness,

social anxiety, and depression, and decreased

self-esteem compared with women with normal

ovarian function. Thus, clinicians need to attend

to these psychosocial aspects in addition to the

medical issues.

Medical Care

Recommendatio ns for the diagnostic evaluation

and continuing care of girls and women with

TS have b een published. 24 To summarize, newl y

diagnosed patients with TS, whatever their age,

need expert cardiac evaluation with an echocar-

diogr am an d MR imaging. It is essential to clear-

ly visualize the aortic valve to determine if it

is bicuspid or otherwise abnormal in anatomy

and/o r functio n. These patients need a baseline

ECG as well. If cardiovascular abnormalities are

found, monitoring should be performed rela-

tively frequently and patients should optimally

be under the care of a cardiologist. If the heart

appears normal, imaging should be undertaken

every 3 to S years to ascertain that the aorta is

not dilating and threatening an aneurysm or a

dissection. Both young girls and adults with TS

should have hearing and ear-nose-throat evalu-

ations, thyroid and blood pressure assessments,

fasting bloo d sugar and liver funct ion tests, an d

renal imaging.

ewly diagnosed patients with Turner s syn-

drome, no matter what their age, need expert

cardiac evaluation with echocardiogram and mag-

netic resonance imaging to clearly visualize the

aortic valve to assesswhether it is bicuspid or other-

wise abnormal in anatomy an d/or function.

As noted previously, mo st individuals wit h TS

need to take estrogen to induce and maintain

feminization. Continuing HRT (estrogen along

with a progestin to protect the uterus) is essen-

t ial throughout young adulthood to prevent

osteoporosis. Young women with TS who dis-

continue HRT for several years are very likely

to develo p severe, clinica lly significant , symp-

tom ati c ost eoporosis, 2s as depicte d in Figu re 4.

Note the extremely osteoporotic vertebral bod-

ies, which are undergoing spontaneous com-

pression fractures. Adults should continue HRT,

unless contraindic ated, until -45 years of age, at

which time a plan for decreasing and eventually

discontinuing treatment can be implemented.

W

omen with Turner s syndrome need to take

estrogen to induce and maintain feminiza-

tion. Continuing estrogen treatment, along with a

progestin to protect the uterus, is essential through-

out young adulthood to prevent the development

of severe symptomatic osteoporosis.

X Chromosome Disparity and Disease

Of the m an y sex-based differences in disease sus-

ceptibility, 2 prominent examples are autoim-

26


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C.A. Bondy

Figure 4. Severe osteoporosJs in a young woman. Bolh radiographs are from 30-year-old women w lh Turner s

syndrome. The woman on the left discontinued eslrogen when she entered college. Her vertebral bod-

ies are extremely osteoporotic and are undergoing spontaneous compression fractures. The woman

on lhe right has continuously received hormone replacement therapy since 12 years of age.

mune thyroid disease and coronary artery dis-

contributes to the increased susceptibility, then

ease CAD). Thy roi d disease is 2 to 4 times mor e

disease inciden ce should be re duced in TS 4S,X)

co mm on in wome n, whereas CAD occurs more compa red with 46,XX wom en with POE If tissue

fre quen tly and at an earlier age in men. Sex- mosaicis m contr ibut es to disease susceptibility,

based differences in disease susceptibility could then the incidence should be reduced in pure

be d ue to gonad al steroid differences, to X- 45,X nonmosaic TS patients compared with mosa-

ch rom oso me gene-d osing disparities XX vs ic TS patients.

XY), or to t he cellula r level of m osaic ism for X M

an d X p XM,X p vs XM¥ bu t n ever xPY). We plan

to test these different possibilities in our popula-

otential Causes of Sex-Based Differences in

tions of TS and women with POE For example,

Disease

if ovarian steroids increase susceptibility to

• Gonadal steroid differences

autoimmune thyroid disease, then there should

Gene-dosing disparities (XX vs XY)

be a reduced incidence in disease in women

• Cellular rnosaicisrn (XM,XP vs XMY)

with ovari an failure TS or POF) com par ed with

healthy women. If the second X chromosome

27


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GENDER MEDI INE

Women enjoy a more salutary lipid profile

than men do, which is thought to contribute to

wom en s relative prot ecti on f rom CAD. Men

have greater amoun ts of visceral fat, and higher

triglyceride and low-density lipoprotein choles-

terol levels than wo me n have, 26 and this unfa-

vorable lipid profile is thought to be a major

contri butor to men s increased risk for coronary

disease. Ma ny of the differences in body co mpo-

sition and lipid homeostasis have been attributed

to gonadal steroid effects. Although estrogens

and androgens clearly affect disease susceptibil-

ity, differences in X-chromosome gene dosage

may also contribute to these sex-based differ-

ences. For example, CAD incidence is increased

in women with TS, 27 28 suggesting that the sec-

ond X chromosome is cardioprotective in 46,XX

women.

he second X chromosome is likely to confer

cardioprotection in 46,XX women because

coronary artery disease susceptibility is in-

creased in women with Turner s syndrome com-

pared with 46,XX women with premature o varian

failure, who share similar gonadal steroid status

to women with Turner s.

To investigate the effect of X-chromosome

dosage on lipid metabolism, we assessed lipids

in women with TS. Because these women have

ovarian failure as a part of the 4S,X syndrome,

we compared th em with karyotypically normal

women with POE.29 Both groups comprised

young, healthy, age- and body mass index-

matched women who, in general, were taking

HRT but stopped treatment during this study.

We found that low-density lipoprotein and

triglyceride levels were signi ficant ly high er in

women with TS suggesting that the second X

chromosome in women with POF played an

important role in lipid homeostasis that was

dist inct fro m sex-steroid effects. 29

As previously noted, genomic i mpri ntin g could

also contribute to differential X-chromosome

gene expression in males and females. Genomic

imprinting involves the selective expression of

certain genes determined by their parental ori-

gin, and is often associated with DNA methyla-

tion of impr int ed or silenced alleles, a° Geno mic

impr inti ng of X-linked genes could result in dif-

ferent gene expression in males and females,

because heal thy w ome n are mosaic for X M and

X e, where as me n are m on os om ic for X M. Genes

imp rin ted (silenced) o n X M woul d still be ex-

pressed in females fro m cells in whi ch the X e is

active, but not expressed at all in males. To

determine whether imprinting of X-linked

genes is associated with lipid homeostasis, we

compared plasma lipids and regional fat distri-

bution in wom en with TS, who were assigned to

either of 2 groups based on an X M or X P geno-

type. 31 By com par ing pa rental and pati ent poly-

morphic X-chromosome sequences, we could

identif y the parental origin of the nom~al X

chromosome in women with TS. We found that

mo no so my for X M was associated w ith muc h

greater visceral fat accumulation and a more

atherogenic lipid profile than mo no so my for X P

(Figure S). The differences b etwe en X M and X P

wom en parallel the usual metabolic and adipos-

ity differences between h ealthy m en and wom-

en, wh o are bot h mon oso mi c for X M.

onosomy for a maternal X chromosome

(XM) was associated with much greater vis-

ceral fat accumulation and a more atherogenic

lipid profile than monosomy for a paternal X

chromosome, paral leling the usual metabolic and

adip osity differences beh, een hea lthy men and

women, who are both monosomic for XM.

Increased visceral adiposity is not likely due

to testosterone, because male hypogonadism

is associated with increased visceral fat that is

reduced with testosterone replacement. Fur-

thermore, because both nonmosaic and mosaic

TS groups had ovarian failure, sex steroids are

not likely to be major contributors to these

findings. Thus, this study suggests that differen-

tial X e and X M effects in metab olic regul atio n

could be explained by the imprinting (silenc-

ing) of maternally transmitted X-linked genes

28


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C.A. Bondy

1 5 3

20

10

-0

100

50 0

[ 1

XM XP XM XP

LDL-C Visceral Fat

Figure 5, Comparison of low-density lipoprotein cholesterol LDL-C) levels and visceral adipos ity in women

with a maternally derived XM) versus a pate rnall y derive d XP) X chrom osome , sl

t h a t n o r m a l l y p r e v e n t v i s ce r al f a t a c c u m u l a t i o n ,

o r o f p a t e r n a l l y t r a n s m i t t e d X - l i n ke d g e n e s t h a t

n o r m a l l y p r o m o t e v i s c e r a l f a t a c c u m u l a t i o n .

F u r t h e r r e s e a r c h i s n e c e s s a r y t o i d e n t i f y s u c h

g e n e ( s) a n d d e t e r m i n e i f t h e y c o n t r i b u t e t o d i f-

f e r e n c e s i n c o r o n a r y d i s e a se s u s c e p t i b i l i ty i n T S .

T h i s s t u d y i l l u s t r a t e s t h e g r e a t v a l u e t o b e

g l e a n e d f r o m s t u d ie s o f T S w o m e n i n f u r t h e r i n g

o u r u n d e r s t a n d i n g o f t h e r e l at i v e c o n t r i b u t i o n s

o f g o n a d a l s t er o id s , X - c h r o m o s o m e d o s a g e e f-

f e c t s , a n d g e n e t i c i m p r i n t i n g o n t h e m y r i a d d i s -

e a s e p r o c e s s e s t h a t e x h i b i t s e x - b a s e d d i f f e r e n c e s

i n i n c i d e n c e , a g e o f o n s e t , d i s e a s e p r o g r e s s i o n ,

d i a gn o s is , r e s p o n s e t o t r e a t m e n t , a n d o u t c o m e s .

CKNOWLEDGMENTS

D r. B o n d y w i s h e s t o t h a n k V l a d B a k al o v, M D ,

a n d E i l e e n L a n g e , R N , f o r t h e i r e x c e l l e n t c a r e o f

s t u d y p a t i e n t s , a n d V i n c e H o , M D , f o r M RA

s t u d i e s .

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Gender and TS