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Klinefelter syndrome - going beyond the diagnosis

Gary Butler1,2, Umasuthan Srirangalingam3, Jennie Faithfull3, Philippa Sangster4, Senthil
Senniappan5, Rod T Mitchell6
1Department of Paediatric and Adolescent Endocrinology University College London Hospital
2UCL Great Ormond Street Institute of Child Health
3Department of Endocrinology University College London Hospital
4Department of Urology and Andrology University College London Hospital
5Alder Hey Children’s Hospital, Liverpool
6MRC Centre for Reproductive Health University of Edinburgh
Abstract
Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes
being identified with speech or developmental delay or incidental antenatal diagnosis. The only
regular feature is testicular dysfunction. The postnatal gonadotropin surge (mini-puberty) may
be lower but treatment with testosterone needs prospective studies. The onset of puberty is
at the normal age and biochemical hypogonadism does not typically occur until late-puberty.
Testosterone supplementation can be considered then or earlier for clinical hypogonadism.
The size at birth is normal, but growth acceleration is more rapid in early and mid-childhood with
adult height greater than mid-parental height. Extreme tall stature is unusual. The incidence of
adolescent gynaecomastia (35.6%) is not increased compared with typically developing boys. It
can be reduced or resolved by testosterone supplementation potentially preventing the need for
surgery.
Around two-thirds require speech and language therapy or developmental support and instituting
therapy early is important. Provision of psychological support may be helpful to ameliorate these
experiences and provide opportunities to develop strategies to recognise, process and express
feelings and thoughts. KS boys are at increased risk of impairment in social cognition and less
accurate in perceptions of social emotional cues.
The concept of likely fertility problems needs introduction alongside the regular reviews of
puberty and sexual function in adolescents. Although there is now greater success in harvesting
sperm through techniques such as testicular sperm extraction, it is more successful in later
adolescence than earlier. In-vitro maturation of germ cells is still experimental.
Correspondence to: Gary Butler.

Contact author and address for correspondence: Professor Gary Butler, Department of Paediatric and Adolescent Endocrinology,
University College London Hospital, 250 Euston Road, London NW1 2PQ, gary.butler@ucl.ac.uk.
Butler et al. Page 2
Introduction
This review presents the contemporary approach to the provision of support for boys and
adolescents with Klinefelter syndrome (KS) and their parents from practitioners who have a
special interest in their clinical care and research.
Getting the diagnosis

Although KS is common, 47,XXY being present in around one in 600 males, not only
it is rarely recognised in childhood and adolescence, the majority are actually never
diagnosed. Major congenital abnormalities are unusual. Some boys are identified by
antenatal diagnosis, usually unexpectedly, but others may not present until later on account
of developmental, speech and language delay, or sometimes unusual behavioural patterns.
Much has been written about the effect on speech and development, and growth and puberty
variations from follow-up studies of newborn-identified individuals from the 1970s to 1990s
which provide an unbiased overview on account of the recruitment by population screening
[1–4]. A recent review is available with more specific information [5].
Communicating the diagnosis

On first encounter with the parents it is important to establish a rapport and set out
a balanced overview of the condition, ideally using the genetic shortcut ‘XXY’ or the
abbreviation ‘KS’ which families prefer. Use of the term ‘variant’ rather than ‘abnormality’
acknowledges that the majority of KS boys and men function pretty normally. Reassurance
that their son will not necessarily develop all the features of the syndrome is really valuable.
Many parents worry about explaining the diagnosis to the wider network of family, friends,
nursery and school, as most people have never heard of KS. Discussions of KS outwith the
immediate family are not usually necessary or helpful, unless it is relevant for medical or
educational purposes. Most KS boys grow up happily within the family environment and do
not look or behave differently. Guiding the parents that their son should be incorporated into
the family routines, doing normal things on a day to day basis without constant referring
to KS is important, and as potentially socially vulnerable individuals, encouragement, love,
care and individual attention from a supportive family are the most important elements of
their upbringing.
Infancy and early childhood

Growth
The size at birth of KS boys is not different from the population, but growth acceleration
is more rapid in early and mid-childhood resulting in upward height centile shifts and by
mid-childhood, many boys end up on a centile greater than their mid-parental height [1].
Extreme tall stature is unusual and if not present by school entry, then it is not going to
be an issue, thus parents can be reassured. Boys with other X aneuploidy variants of KS
(48,XXXY 48,XXYY) may grow even taller, but this may depend on the presence of other
congenital skeletal variations. 49,XXXXY and its variants may also be associated with
reduced height [6].
Testicular function
The hypogonadism in KS may start as early as fetal life or infancy due to the higher
prevalence of underdeveloped genitalia and cryptorchidism, reduced germ cell number in
testicular biopsies, smaller testicular size, and studies have suggested a blunted testosterone
surge during mini-puberty, the rise in gonadotropins over the first 2-3 months of infancy
[7, 8]. However, due to the lack of general understanding about mini-puberty in infants,
it is unclear if any hypogonadism in KS boys has management implications. Studies in

this area are few. Davis et al reported improved body composition in infants randomly
assigned to early testosterone treatment [9]. Another study reported higher scores on
standardized developmental assessments in multiple cognitive domains at 3 and 6 years of
age in boys who received a course of testosterone to treat a micropenis [10]. However, this
retrospective study lacked blinding and randomization thereby limiting the generalizability
of these findings. The reports of cognitive and behavioural benefits in males with KS
treated with testosterone need to be replicated with prospective studies. Hence, the current
evidence is insufficient to support the routine use of testosterone during infancy in KS [11].
Referral to a paediatric endocrinologist should be considered if micropenis is present. British
Society for Paediatric Endocrinology and Diabetes guidelines recommend three injections of
testosterone 25mg - 0.1ml at monthly intervals, or topical 1-2% testosterone cream as the
usual treatment choices [12]. If cryptorchidism or inguinal hernia is noted, the infant should
be referred to paediatric urology.
Speech and developmental delay

Around two-thirds of KS boys will require speech and language therapy or developmental
support, but it is important to be aware of their needs and institute therapy as early as
possible [1–5]. For those boys who require help, the amount of input required is entirely
dependent on the level of need, and is of the same extent as would be required for
chromosomally typical children, and thus no treatment approaches are unique to KS boys.
This is important to stress as some therapists may cite inexperience and a lack of knowledge
about specific treatments for KS.
Mid-childhood
Hypogonadism
Studies of gonadal function in mid-childhood have not shown any abnormality so there is no
clear rationale for testosterone supplementation then (Figure) [1,13–16].
Education and behaviour

Most KS boys do not fall into the category of requiring significant educational support, but
the subtleties of specific learning defects, particularly in receptive and expressive language,
may cause frustration and the inability of a boy to explain himself clearly and as quickly
as others may lead to temper tantrums and anger outbursts. Clear parenting guidelines and
professional support are valuable at this age. Social skills often take longer to develop, with
boys feeling isolated, preferring their own company. Family guidance and encouragement is
key here. Those with more severe difficulties and associated comorbidities will benefit from
multidisciplinary community paediatric services and CAMHS input.
Adolescence
Hypogonadism
The principal concerns in the second decade are around the treatment of hypogonadism,
if present, with testosterone, and the assessment of fertility prospects and possibly its
preservation.
The clinical onset of puberty is not delayed in KS boys, a frequent misunderstanding. Early
testicular enlargement occurs at the same age and to the same initial extent as typical boys.
Although the gonadotropins FSH and LH rise at the start of puberty, testosterone is usually
within the pubertal stage-related range (Figure) [1,5,13–16].
Hypogonadism can be defined biochemically or clinically (Table 1). Biochemical

hypogonadism (Table 2) does not typically occur until late puberty, at around age 14 years
and Tanner stage 5 [1]. Here the usual accelerated nocturnal rise in testosterone is blunted
(Figure). Thus assessment of hypogonadism can only be made accurately by measuring the
testosterone concentration in the morning (8 am to 9 am) when it is at its highest on account
of the significant diurnal variation in late puberty (Figure). Afternoon blood samples are not
useful diagnostically.
Clinical hypogonadism (Table 1) is also a reason to consider testosterone supplementation

in KS boys as typical full virilisation may not occur. One manifestation and reason for
intervention include increasing adiposity, the occurrence of a central deposition of fat
particularly on the hips and abdomen, often described as a ‘beer-belly’ [1]. Low muscle
tone and reduced power may be subjectively improved by testosterone substitution. It can
be difficult to determine whether symptoms of lethargy and a lack of motivation are due to
testosterone insufficiency, or just part of the syndrome. In such cases a trial of testosterone
supplementation can be considered.
Gynaecomastia
From a review by Butler of all 191 published cases, the incidence of gynaecomastia
in KS boys (35.6%) is not increased compared with typically developing boys and
enlarges to the same extent, but its persistence into adulthood may result from the
absence of the late pubertal rise of testosterone and the consequent hypogonadism [17].
Consequently, testosterone supplementation in a physiological incremental approach starting
with transdermal gel 10-20mg each morning has been shown to reduce or resolve the
development of gynaecomastia potentially preventing the need for surgical intervention later
on [17]. It is most effective when treatment is started at the first appearance of breast tissue
enlargement.
Growth spurt
The magnitude of the adolescent growth spurt in height is the same in KS boys as in
typically growing boys [1,15]. Thus it is possible to predict with confidence that the adult
height of a boy whose height is within the normal centile range at the start of puberty will
not become excessive. Those with tall parents and whose heights are above three standard
deviations in late childhood, if concerned about extreme tall stature, may benefit from
®
rapidly escalating doses of intramuscular testosterone (Sustanon or testosterone enantate)
once the clinical onset of puberty is documented, monitoring height and bone age [3].
Psychological support
The constellation of the developmental variations of KS can have implications for clinical
care. Language problems can disrupt understanding of content, meaning, and may impact on
outcomes of clinical discussions. Confusion can lead to misunderstandings of information,
increased anxiety and non-compliance with treatment. Provision of psychological support is
important as part of a multi-disciplinary approach to promoting lifespan health, wellbeing
and, importantly, supporting endocrine and fertility discussions. KS males are reported to
be increased risk to impairments in social cognition and less accurate in perceptions of
social emotional cues, whilst simultaneously experiencing increased emotional arousal in
parallel with decreased ability to identify and verbalise their emotions [18,19]. This array of
difficulties may affect managing, coping with, and verbalising feelings and concerns, with a
potential to be exacerbated by receptive and expressive language problems.
These features, often in parallel with literal interpretation of language and problems with
social communication may impede understanding and be a barrier to externalising and
discussion with family and partners. This can, in turn, contribute to feelings of panic and
misunderstandings during interactions, with significant impact on relationships and can
extend to clinical encounters.
Provision of psychological support may be helpful to ameliorate these experiences and

provide opportunities to develop strategies to recognise, process and express feelings and
thoughts [20]. This may aid understanding, beneficial in reducing stress, anxiety and
promote understanding of clinical discussions, treatment and informed decision making.
Gender incongruence
The incidence of gender incongruence and gender dysphoria is not increased in KS males
[21].
Education
KS can have a significant impact on cognitive, social and emotional development and
wellbeing. The generalised breadth and range of subjects in the curriculum up to and
including GCSE years may be particularly challenging and social communication problems
may cause upset and difficulties ‘joining in’ with peers.
Short-term working auditory memory and auditory processing difficulties have been
reported in KS and may impact significantly on accessing the curriculum, particularly with
traditional forms of teaching such as speaking, listening and writing where more time to
process and record information may be required [18]. Written support from paediatricians
and psychologists can be valuable at this point, providing anticipatory and advisory
guidance including provision of one-to-one support, small group settings and extra time
in exams. Additional guidance for educators to aid learning and memory can be valuable:
provision of tailored materials such as visuals, bullet points, shorter sentences and practical
experiences.
Post 16 education and higher education may provide opportunities to study fewer,
specialised, subjects creating perhaps increased opportunities to demonstrate niche abilities

during these later educational years. In these settings, psychological and educational
guidance for provision of reasonable adjustments, accessing appropriate assistances such
as Disabled Students Allowance and careers guidance is very valuable to aid positive
transitions between school, college and beyond into employment, protecting self-esteem and
building confidence. A choice of practical, non-academic careers can alleviate the pressure
of standard learning processes. Similarly, written support and guidance for employers may
be helpful in some workplace settings.
Fertility
Previous studies of the infant and young testis have shown normal architecture and the
presence of germ cells, although there appears to be a reduction in their number [22]. When
puberty commences most of the developing tubules are Sertoli cell only and in response
presumably to the high gonadotropins, a disordered testicular architecture develops with
hyalinisation of the seminiferous tubules. It is possible to see a significant degree of initial
testicular growth, in some KS boys up to 12 ml, but subsequent involution and reduction
in size occurs, usually measuring 3-5ml in older adolescents and adults. On account of the
normal pubertal prostatic development, ejaculation occurs but the semen is azoospermic in
over 90% [23]. For those adolescents who are sexually active, contraception should still be
advised.
It is wise to introduce the concept of likely fertility problems during the teenage years
alongside the need for regular reviews of puberty and sexual function [24]. Although there
is now much greater success in sperm harvesting through newer techniques such as testicular
sperm extraction (TESE) or microscopic testicular sperm extraction (mTESE), the optimal
timing of this process is unclear. The largest meta-analysis of sperm retrieval in KS patients
suggested a success rate of 44%, with age, testosterone, FSH and testicular volume having
no significant relationship with outcome [25]. This contrasts with the initial studies which
indicated that success was less likely in men aged over 35 years and that started an interest
in attempting sperm retrieval in younger patients [26]. However, there is increasing evidence
that fertility preservation should not be offered to adolescents younger than 16 years because
of lower retrieval rates for germ cells by mTESE compared with those for adolescents and
adults between 16 and 30 years [26,27].
Many young adult males with KS are emotionally less mature than their counterparts and
the concept of fertility estimation and the emotional consequences of knowing they are
going to be infertile needs very careful counselling and preparation. The balance of carrying
out a surgical sperm retrieval at the right time must be measured against the potential
psychological distress caused if no sperm is found. The counselling process is important as
some KS males may have a reduced capacity to understand complex explanations. Points
for discussion are best presented in a simple structured way backed up by a written version.
Once a young adult with KS is mature enough to make this decision, mTESE can be
considered if azoospermia on serial semen analysis is demonstrated.
Future experimental considerations

By mid-puberty most of the testicular damage has already occurred and germ cells are
reduced or totally absent [28]. This is believed to be due to a massive loss of spermatogonial
stem cells in the early pubertal period. However, the lack of longitudinal data make it
impossible to determine the trajectory of germ cell loss in individual patients. Whilst
cryopreservation of prepubertal testicular tissue to preserve spermatogonial stem cells is
becoming more common (e.g. those facing cancer treatment), this is not a straightforward
option for boys with KS [29]. This is due to the uncertainties whether germ cells are present
within the tissue and their potential to undergo spermatogenesis. Whilst they may be present
in tissues obtained from prepubertal patients, the majority of these germ cells are likely
to be aneuploid (XXY) and unlikely to be viable for subsequent use in transplantation
or in-vitro spermatogenesis. In addition, the potential for XX or XY spermatogonia to
spontaneously lose the extra X chromosome resulting in focal spermatogenesis at puberty is
unknown and removing testicular tissue in prepuberty may negatively impact on this [30].
As a result, current guidelines produced by European Academy of Andrology recommend
against performing a testicular biopsy in prepuberty, instead focusing on maximising the
potential for obtaining viable sperm by performing mTESE in young adulthood [24]. This
situation may change in the future should effective methods for in-vitro spermatogenesis be
developed that could be applied to germ cells obtained from KS patients. At the time of
writing, there is only experimental evidence in mouse models of chromosome loss [31].
Into adult life

We know from population mortality and morbidity studies that there is no significant
lowering of life expectancy in KS males, however higher risk areas include osteoporosis,
cardiovascular disease and breast cancer [32,33]. Lifelong follow-up is important not only
from the endocrine and metabolic perspective but also for emotional, psychological and
fertility support. Only recently have specialist services for KS adults been established, such
as our UCLH KF-Xtra clinic, a multi-disciplinary team transitioning KS boys seamlessly
from childhood and adolescence to adult services to provide lifelong care. This approach can
produce benefits both for quality of life, physical well-being and also research.
Testosterone treatment and metabolic care

Testosterone therapy is the mainstay of treatment for KS men with benefits including
reduced fat mass, improved muscle strength, bone density, libido and mood [34,35].
Current formulations of testosterone include testosterone gels (topical daily application),
weekly to monthly mixed testosterone esters given either by subcutaneous or intramuscular
injections and three monthly testosterone undecanoate (Table 3). No data exist to guide
optimal formulation and dosing in KS adults. Testosterone gels, in metered pumps, allow
self-administration, easy dose titration, minimising fluctuation in testosterone levels and
can be a helpful when introducing therapy. Intramuscular treatment requires administration
by healthcare staff so patients often find the long-acting formulation convenient, and can
be useful where compliance is an issue. Three-four weekly injections lead to greater
fluctuations in testosterone levels which can be problematic, in particular on mood variation
and energy. More frequent, lower dose self-administered subcutaneous injections can be
considered as well [36]. Monitoring of therapy includes an assessment of the testosterone
concentration, full blood count, haematocrit and prostate specific antigen (PSA) in relevant
subjects. Polycythaemia is the most frequent side-effect encountered, particularly with long-
acting testosterone [35].
KS is associated with an increased risk of the metabolic syndrome, insulin resistance

and Type 2 diabetes mellitus, obesity, dyslipidaemia and an approximate doubling of risk
for cardiovascular disease [37]. Whilst the exact mechanisms responsible remain to be
elucidated, data regarding a modifying influence of testosterone therapy are conflicted in
hypogonadal men [35,38]. Education regarding healthy lifestyle choices, careful surveillance
and appropriate interventions to actively manage cardiovascular risk therefore remains
essential.
Conclusions
The approach to supporting KS boys and adolescents is age dependent, and needs multi-
agency input. Provision of an accurate picture of the condition in contrast with internet
search findings is important for reassurance. The report in this journal of the outcome of
the KS boys identified in the Edinburgh newborn population screening study presents a
balanced perspective on the range of functioning and lifestyles of KS adults, and this can
help guide parents when KS is diagnosed [39]. Although the information in this review may
benefit those in whom KS is already recognised, how do we address the issue of the 75%
of KS males who remain unidentified? Discussions around population genetic screening and
prospective identification continue, but this has many ethical and financial considerations.
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Figure.
Diurnal variation profiles 09.00-21.00h of free testosterone concentrations, measured in
saliva. Unpublished data from 10 XXY boys (52 diurnal profiles) and 13 XY boys at
Tanner stage G1, 6 XXY boys (10 diurnal profiles) and 25 XY boys at Tanner stage G3,
and 11 XXY boys (20 diurnal profiles) and 13 XY boys at Tanner stage G5. XXY and
XY boys were recruited by newborn population screening [1] and the mean testosterone
concentrations in the XXY boys are compared with the 95% confidence intervals (CI)
from XY controls by pubertal stage based on data from [40]. The plasma testosterone
equivalent is approximately 10 times higher (regression equation for conversion: salivary

free testosterone (pmol/l) = 9.8 plasma testosterone (nmol/l) + 34.5 [40]).
Table 1
Classification of hypogonadism in Klinefelter syndrome
Biochemical hypogonadism
• Low testosterone
– mini puberty
– main puberty: usually not before puberty stage G5
Clinical hypogonadism
• Micropenis
• Slow virilisation ie delayed pubertal progress
• Gynaecomastia
• High BMI-obesity
• Poor muscle development/tone?
• Lethargy?
Table 2
Assessment of hypogonadism at each time point
Infancy
4-8 weeks
Testosterone, FSH, LH
Mid-puberty (age 13 yr +)
8 am Testosterone, FSH, LH
Late puberty (age 15 yr +)
8 am Testosterone, FSH, LH, inhibin
On testosterone gel
4-6 hr after application
Testosterone, FBC, FSH, LH
Sustanon/testosterone enantate injections
Pre-injection (trough) level
Testosterone, FSH, LH, FBC, LFT
Testosterone undecanoate (Nebido) injections
Peak level 4 weeks after injection AND pre-injection (trough) level
Testosterone, FSH, LH, FBC, LFT
Table 3
Types and dosages of testosterone suitable at each age
Intramuscular or subcutaneous
Infancy or toddler (for micropenis) Sustanon® or testosterone enantate 25mg (0.1ml) for 3 injections at monthly intervals. Course can be
repeated if required
Puberty Sustanon® or testosterone enantate 50mg (0.2ml) IM/SC once clinical signs of puberty evident, escalation at 6-12 monthly intervals to
full dose 250mg 3-4 weekly
Post puberty Sustanon® or testosterone enantate 250mg 3-4 weekly IM or 100mg every 7-10 days SC Testosterone undecanoate (Nebido®)
1000mg IM 10-14 weekly
Transdermal
Puberty Testosterone 2% gel (Tostran®) 10mg daily once clinical signs of puberty evident. May be more effective if administered in morning if
gynaecomastia present. Dose escalation at 6-12 monthly intervals to full dose (product dependent)
Post puberty Adult dose (Tostran® 60mg, Testavan® 69mg, Testogel® 40mg) titrated to clinical effect and to achieve 4-6 hour post
administration plasma testosterone concentration in mid-upper male range

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Europe PMC Funders Group

Klinefelter syndrome - going beyond the diagnosis

Correspondence to: Gary Butler.

Getting the diagnosis

Communicating the diagnosis

Infancy and early childhood

it is unclear if any hypogonadism in KS boys has management implications. Studies in

Speech and developmental delay

Education and behaviour

Hypogonadism can be defined biochemically or clinically (Table 1). Biochemical

Clinical hypogonadism (Table 1) is also a reason to consider testosterone supplementation

Provision of psychological support may be helpful to ameliorate these experiences and

specialised, subjects creating perhaps increased opportunities to demonstrate niche abilities

Future experimental considerations

Into adult life

Testosterone treatment and metabolic care

KS is associated with an increased risk of the metabolic syndrome, insulin resistance

Seminars in medical genetics. 2015; 169 (2) 150–157. [PubMed: 25939399]

equivalent is approximately 10 times higher (regression equation for conversion: salivary

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