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Review
Turners syndrome: challenges of late diagnosis
Marilyn Cheng Lee, Gerard S Conway
Girls and women with Turners syndrome who come to medical attention older than 12 years present a challenge of
medical management. Puberty is already delayed and some compromises have to be made in adjusting the timing of
articially induced puberty to optimise overall outcome with respect to stature, secondary sex characteristics, and
psychosocial endpoints. Additionally, individuals who present with primary amenorrhoea to adult services might
miss the opportunity for eective growth hormone treatment. Further, induction of puberty regimens lack an evidence
base or even clear guidelines for the timing and dose of oestrogen replacement. We have searched the scientic
literature to inform management of Turners syndrome.
Introduction
Turners syndrome is one of the most common genetic
disorders caused by partial or complete absence of one
X chromosome.
1,2
Turners syndrome aects 1 in
2500 female births and an estimated 12 500 women in the
UK. About 1000 cases are known to the Turner Syndrome
Support Society and specialist hospital clinics in the UK,
so more than 90% of cases are not under medical care
and many of these are possibly not diagnosed.
The clinical features of Turners syndrome include
short stature, ovarian failure, ear infections, and deaf-
ness, and more serious complications such as congenital
heart disease and aortic dissection.
1,3
The degree to which
each individual is aected varies widely. This variation
comes about because only part of one X chromo some
might be missing (karyotype 46,X,del[X]) rather than the
more severe form in which one entire X chromo some is
absent (karyotype 45,X).
2
Additionally, the missing X
chromosome can be present in only a proportion of the
cells of the body with the remainder being normal (45,X,
46,XX/46,XX mosaicism).
3
Part of the variation of
Turners syndrome is manifest by the age of diagnosis.
4

About a fth of all cases are diagnosed at birth with
obvious clinical features, and another fth present in
childhood with short stature
1
However, 50% of cases are
diagnosed later, typically as a teenager presenting with
primary amenorrhoea.
4
A small proportion are diagnosed
later in childhood.
The consequences of delayed presentation of Turners
syndrome have become an increasing concern.
5
When
started early enough, educational and psychological
support can help with academic achievement and social
integration. Growth hormone therapy can help achieve a
near normal female nal height and peak bone mass, and
oestrogen has benets for socialisation, sexual function,
bone integrity, and uterine hypoplasia.
3
However, in those
women who present late, these issues have to be addressed
simultaneously, and the scientic literature on which to
base management decisions is dispersed across several
subspecialties.
In this Review we have sought to bring together ideas
that have arisen from the authors experience in a large
clinic for adults with Turners syndrome over almost
20 years. For the purpose of this Review, we focus on
individuals presenting with amenorrhoea after the
median age of menarche at 13 years. The older the
presentation, the less likely that growth hormone
treatment would be relevant, with the decision based on
an assessment of bone age. Notably, although not
discussed in this Review, the diagnosis of Turners
syndrome can be as late at the 6th decade of life and
physicians need to stay aware of this possibility
throughout adult life (gure 1).
Treatment of short stature with late presentation
The height range for women with Turners syndrome
before the introduction of growth hormone therapyis
between 136 and 147 m, a decit of about 20 cm.
6

Turners syndrome is not a state of growth hormone
deciency, but of growth hormone resistance; the eective
dose of therapeutic growth hormone is twice that needed
in growth hormone-decient children to achieve a similar
increase in growth velocity.
7,8
Growth hormone treatment
has become the standard of care in girls with Turners
syndrome and it is recommended that it should be
considered as soon as reduced linear growth is reported,
9,10

and with optimum treatment, normal nal height can be
achieved.
11,12
Determinants of a good outcome for nal
height with growth hormone therapy are a young age of
initiation and the duration of treatment;
13,14
the age of
treatment initiation can be as young as 1 year.
15
Because of
the focus on achievement of near normal nal height in
young girls with Turners syndrome, the benet for older
children receiving growth hormone can be overlooked.
Although it is accepted that an increase in nal height is
of limited benet in terms of quality of life as an adult, we
believe, from experience, that maximising clinical input
addressing all features of Turners syndrome that present
in adolescence might help to mitigate against the adverse
eects of late presentation; further studies will be
required to assess this.
The eectiveness of growth hormone treatment in older
girls (>12 years) and who present late with Turners
syndrome is discussed in several reports that note
outcomes for this subgroup separately from data in
younger girls. These studies include age-stratied
treatment comparisons and registry data (table).
1620

However, in some reports, despite older age groups being
described, accurate outcome data could not be reliably
extrapolated.
21,22
Findings from some studies showed an
Lancet Diabetes Endocrinol
2014; 2: 33338
Published Online
December 6, 2013
http://dx.doi.org/10.1016/
S2213-8587(13)70153-0
Institute for Womens Health,
University College London,
London, UK (M C Lee MRCP,
G S Conway FRCP)
Correspondence to:
Dr Marilyn Lee, Institute for
Womens Health, University
College London, London
WC1E 6BT, UK
marilyn1903@gmail.com
334 www.thelancet.com/diabetes-endocrinology Vol 2 April 2014
Review
additional benet from the combination of the anabolic
androgenic steroid oxandrolone and growth hormone,
20

with the greatest benet in those in whom induction of
puberty was delayed.
18
In view of the more recent
information about early induction of puberty with
transdermal oestrogen, the role of oxandrolone in late
presentation is unclear, although it is favoured in some
clinics.
9
The studies in the table show remarkably consistent
ndings. In summary, about 6 cm (30%) of the height
defect caused by Turners syndrome can be regained by
3 years of treatment with growth hormone in girls
presenting in teenage years providing the bone age or
puberty is suitably delayed. Our conclusion from this
approximation is that all girls with Turners syndrome
with primary amenorrhoea should be considered for
growth hormone treatment irrespective of age of
presentation. Growth hormone treatment in this group
should be titrated as quickly as possible to achieve high
normal insulin-like growth factor 1 (IGF1) concentrations
of about 2 standard deviations higher than the mean, and
once optimised, monitored every 3 months until a
growth rate of less than 2 cm per year is recorded, after
which treatment can be terminated.
Induction of puberty for girls with Turners
syndrome presenting with primary amenorrhoea
80% of girls with Turners syndrome have delayed puberty.
95% of girls achieve Tanner stage 2 of breast development
(clear elevation of the breast mound and enlargement of
the areola as breast budding), which is usually 13 years of
age. Menarche will generally have occurred in 95% of girls
by age 145 years.
23,24
Therefore, girls with complete
absence of breast development should be referred for full
assessment from the age of 13, and those with primary
amenorrhoea, but normal breast development, by the age
of 15 years. Despite these guidelines, watchful waiting is
often maintained for longer than is advisable.
The overall aim of induction of puberty in girls with
hypogonadism is to achieve timely secondary sex
characteristics including breast and uterine development.
The rst oestrogen eects to show will be breast budding,
which will have occurred in 50% of girls by the age of
113 years.
25
In 50% of girls, breast development
C
a
s
e
s

(
%
)
Age of presentation (years)
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41
0
2
4
6
8
10
12
14
16
18
Figure 1: Frequency distribution of the age of presentation of 413 individuals with Turners syndrome
Individuals attended the Adult Turner Clinic at University College London Hospital, London.
n Mean age
(years)
Mean duration
of GH (years)
Height gain
(cm)
Bone age
(years)
Comment
Van den Broek et al, 1999
16
136 129 42 43 NR A study of long-term GH treatment in girls with Turners syndrome starting at relatively
late age; midpoint of height gain recorded from groups one (height velocity of 04mm
per year) and two (height velocity of 59mm per year) in table 1 of report
Reiter et al, 2001
17
86 149 20 46 116 Near nal height analysis of National Cooperative Growth Study database of 344 girls
with Turners syndrome receiving exogenous oestrogen, using data from oldest age
quartile only
Stahnke et al, 2002
18
47 117 65 65 99 Randomised trial of GH vs GH and oxandrolone in 91 girls with Turners syndrome
starting after age 10 years with data reported for 47 who were near nal height;
weighted average of entire study taken to reduce small group eect
Massa et al, 2003
19
74 143 37 63 NR Retrospective analysis of data from 186 adults with Turners syndrome who had
previously received GH; height gain estimated from last column of table 2 of report for
the two older groups (age 1214 and 1419 years); patients without signs of
spontaneous puberty and those with spontaneous onset of puberty were included;
height decit from Turners syndrome status was 9864 cm in women who received
GH, which is 63 cm less of a decit than in untreated women with Turners syndrome
Menke et al, 2010
20
25 135 33 64 121 A multicentre randomised controlled trial of oxandrolone in girls with Turners syndrome
given GH; data from the oldest age group (121599 years) from supplementary dataset
combining treatment groups; among the three age groups (group one: age 2799 years;
group two: age 81199 years; group three: age 121599 years), no signicant dierence
was recorded in the eect of oxandrolone on adult height
GH= growth hormone. NR=not reported.
Table: Studies reporting height gain in girls with Turners syndrome presenting with complete pubertal delay who started growth hormone treatment after the age of 10 years
www.thelancet.com/diabetes-endocrinology Vol 2 April 2014 335
Review
continues to breast development stage 4 (near full
development with elevated areola) by the age of
133 years. The average age of menarche is 13 years.
Therefore, most breast development happens over the
2 years before menarche. In treatment terms, this would
be the equivalent of 2 years of unopposed oestrogen.
The evidence base for the induction of female puberty
with oestrogen mainly comes from expert experience
23,2628

with some observational trials
2932
and very few controlled
trials with small study groups.
33,34
Randomised trials are
especially di cult in this specialty because of the
heterogeneous population, endpoints that are di cult to
quantify precisely, and the long duration that might be
needed to establish some outcomes such as bone density
and psychosocial adjustment. The paucity of controlled
trials might explain the slow uptake of new approaches.
35
The main concern with giving oestrogen to girls with
Turners syndrome is the competing eects of low-dose
oestrogen, which increases height velocity, and high-dose
oestrogen, which results in closure of the epiphyseal
growth plates. Indeed, most of the information on this
subject is derived from studies of the e cacy of growth
hormones in individuals with Turners syndrome with
oestrogen eects being a secondary outcome. Findings
of early studies in which relatively high doses of oral
conjugated equine oestrogen were used showed early
closure of ephiphyses and reduced nal height.
36
These
results led to an unfortunate practice of delaying the start
of induction of puberty to at least 14 years of age, and an
emphasis on an oestrogen-free interval of growth
hormone treatment.
17
Over the past 510 years, the
starting dose of oestrogen for the induction of puberty
has decreased, allowing early treatment in girls as young
as 8 years.
15
The once common practice of delaying
induction of puberty to allow growth hormones to act in
oestrogen-free time should now be regarded as obsolete.
This is of particular importance to girls with late
presentation who should start oestrogen and growth
hormone simultaneously (gure 2).
Another important consideration is the route of
administration of oestrogen. In all the large studies of
growth in Turners syndrome, investigators have used oral
oestrogen, and the likely benets of transdermal oestrogen
have been explored in only small observational studies.
Oral oestrogens, and especially ethinyloestradiol,
antagonise the eect of growth hormone by inhibition of
hepatic IGF1 synthesis,
37,38
and this is manifested by
diminished e cacy of growth hormone treatment in
women with a growth hormone deciency. In Turners
syndrome, transdermal oestrogen is suitable for the
induction of puberty,
32
and investigators of an observational
report of growth hormone treatment in 704 girls with
Turners syndrome in a French registry described a 21 cm
height gain for girls using transdermal compared with
oral oestrogen.
14
Oral ethinyloestradiol is inferior to
transdermal oestradiol in terms of blood pressure and
bone density, both of which are particularly relevant to
girls with Turners syndrome; oral ethinyloestradiol can
contribute to high blood pressure and transdermal
oestradiol is better for bone density.
39,40
Conversely, two
studies have failed to identify a benet in transdermal
over oral oestradiol in individuals with Turners syndrome.
Findings of a recent study
41
that compared the eects of
oral versus transdermal oestradiol, given for 12 months in
40 girls with Turners syndrome, showed no signicant
dierence in body composition, lipid oxidation, and lipid
concentrations. An older study
42
compared oral con jugated
equine oestrogen with transdermal oestradiol in 12 girls
with Turners syndrome, and recorded no overall benet
in terms of glucose homoeostasis, bone accrual, uterine
growth, or pubertal development, although transdermal
oestradiol resulted in faster bone accrual at the spine and
increased uterine growth compared with conjugated
equine oestrogen.
In summary, transdermal oestradiol may be introduced
for the induction of puberty at the time of late presentation
Chernausek et al
(2001)
Sas et al (1999) Ross et al (2011)
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60
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0
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0
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A
B
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Figure 2: A comparison of three key studies of the interaction between
oestrogen and growth hormone when used as treatment for girls with
Turners syndrome
(A) Oestrogen dose in each study, expressed as an estimated percentage of an
adult dose of oestrogen. (B) Average age of starting oestrogen in each study.
(C) The eect on nal height attributed to the addition of oestrogen ranging
from a height decit of 3 cm in Chernausek and colleagues,
36
zero eect in Sas
and coworkers,
11
and a height gain of 2 cm in Ross and colleagues.
22
In summary,
low-dose oestrogen allows an early start of induction of puberty with potential
gain in nal height.
336 www.thelancet.com/diabetes-endocrinology Vol 2 April 2014
Review
of Turners syndrome (and perhaps by the age of 10 years
for those with younger presentation) simul taneously with
the start of treatment with growth hormones. The starting
dose and timing of escalation of oestrogen with late
presentation should be individualised according to the
priorities of each individual, be they breast size, menarche,
or nal height. However, from our experience, an example
would be to start with a transdermal oestradiol patch
125 g twice per week, increasing to 25 g after
36 months, and then 50 g after another 6 months,
introducing progestogen after the rst breakthrough
bleed. This quite fast pace could be slowed if growth
proceeds well in the rst two visits, with monitoring of
height and uterine length at 3 month intervals.
Psychosocial aspects of late diagnosis
Specic psychological traits have been consistently
described in girls and women with Turners syndrome
with an emphasis on an increased risk for social isolation,
immaturity, and anxiety.
43,44
Identity development, social
relationships, interpersonal skills, independence and
interdependence, and psychological and emotional
challenges are major developmental issues that confront
adolescents with Turners syndrome.
45
Despite these
ndings, studies using quantitative measures of quality
of life have generally failed to capture these concerns.
4648

Specically, nal height and previous use of growth
hormone does not have a signicant negative eect on
quality of life.
4851
By contrast, ndings of several studies have shown that
late diagnosis and late induction of puberty are associated
with adverse outcomes in Turners syndrome.
49,52
These
ndings raise the question of whether early induced
puberty could contribute to better wellbeing later in life
even at the expense of a decit on nal height. Success in
nding a life partner is a particular problem for women
with Turners syndrome and a major determinant of
quality of life.
45
An important nding that might be
relevant in this area is that earlier induction of puberty is
associated with less delay in sexual debut in women with
Turners syndrome.
50
In a population-based cohort study
of 566 women with Turners syndrome aged 22626
years, by the age of 25 years, roughly 57% of women with
Turners syndrome had not had a sexual debut if
oestrogen was started after the age of 14 years compared
with 42% of those who had earlier exposure to oestrogen
in a reference group without Turners syndrome, the
gure was less than 18%.
50
Another consequence of delayed diagnosis of Turners
syndrome is that behavioural traits can interfere with
education and might be compensated for by simple
measures. For instance, a decit in mathematical
processing is common, but can be overcome if extra time
is allowed for preparation.
53,54
Similarly, social skills,
which can be slow to develop in individuals with Turners
syndrome, leading to the common nding of social
isolation in adulthood, can be the focus of psychological
intervention.
55
Lastly, some of the educational problems
relating to Turners syndrome might be the result of
unrecognised deafness, and early detection would enable
simple measures to be taken, such as placement in class.
These issues underline the need for a screening method
to allow for earlier diagnosis of Turners syndrome. Still,
the overall educational attainment of women with
Turners syndrome is equal to or better than the general
population of women.
46,5658
In conclusion, previous recommendations to delay
oestrogen treatment until the age of 15 years to optimise
height potential
36
is no longer acceptable because the
psychosocial importance of age-appropriate pubertal
maturation and other aspects of health and wellbeing
might outweigh the eect of short stature.
33
Access to
clinical psychology or experienced counsellors should be
available for women with Turners syndrome to address
the issues relating to delayed diagnosis.
Future prospects for ameliorating the eects of
late presentation of Turners syndrome
Achieving an earlier diagnosis
For girls known to have Turners syndrome before
puberty, management strategies have already been
adjusted to allow for earlier induction of puberty. The
most pressing problem is to prevent the delay in
diagnosis of Turners syndrome whereby girls miss out
on the benets of timely intervention and support.
There is no one solution for this problem and strategies
might vary between countries. Where systematic height
records are taken in school, then the possibility of
karyotype screening for all girls with short stature would
be possible.
59,60
Unfortunately, such a height-screening
programme is not in place in the UK, and mass
molecular screening at birth would not be cost eective.
Another possible method of ascertaining a risk group
would be to choose an alternative common feature of
Turners syndrome such as otitis media. Once again,
there are di culties because otitis media is very
common in the general population. As health data
resources develop, cross correlating height data at birth
and the presence of otitis media might identify a group
for whom genetic screening would be a reasonable
proposition, and further research in this area is
welcome.
Controlled trial of transdermal oestrogen in puberty
An important change in the management of puberty in
girls is the move from oral to transdermal oestrogen, but
no trial data conrm the benets that have largely been
extrapolated from observation and experience. The
emphasis of most trials in Turners syndrome have been
on nal height, which is a much easier endpoint on
which to base an outcome compared with sexual
development, socialisation, and wellbeing much later in
life. Nevertheless, an achievable goal is to achieve pubertal
milestones that match reference data more accurately.
www.thelancet.com/diabetes-endocrinology Vol 2 April 2014 337
Review
Conclusions
The late age of diagnosis of many women with Turners
syndrome is a continuing problem, and new strategies
for earlier detection would result in many benets. For
now, the management of women with Turners syndrome
in whom puberty is delayed needs specialist input,
preferably with a multidisciplinary team who have
experience in balancing the requirements for optimum
outcome in an individualised holistic way.
Conicts of interest
We declare that we have no conicts of interest.
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