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INTRODUCTION
S U M M A RY
In 1942, Harry F Klinefelter, Edward C Reifenstein
Klinefelter syndrome is the most common sex-chromosome disorder;
and Fuller Albright described nine patients with
it affects approximately one in every 660 men. This syndrome is
a syndrome characterized by gynecomastia,
characterized by the presence of one or more extra X chromosomes,
azoospermia, hyalinized and small testes, elevated
and the karyotype 47,XXY is the most prevalent type. The ‘prototypic’
man with Klinefelter syndrome has traditionally been described as tall,
levels of follicle-stimulating hormone (FSH), and
with narrow shoulders, broad hips, sparse body hair, gynecomastia, hypogonadism.1 The cause of this syndrome
small testicles, androgen deficiency, azoospermia and decreased verbal was unknown until 1959, when Jacobs and
intelligence. A less distinct phenotype has, however, been described. Strong demonstrated the presence of an extra X
Klinefelter syndrome is an underdiagnosed condition; only 25% of the chromosome in the karyotype of patients with
expected number of patients are diagnosed, and of these only a minority Klinefelter syndrome.2
are diagnosed before puberty. Patients with Klinefelter syndrome should Early studies on inmates in prisons and insti-
be treated with lifelong testosterone supplementation that begins at tutions for mental health problems revealed
puberty, to secure proper masculine development of sexual characteristics, disturbing findings of an increased risk of
muscle bulk and bone structure, and to prevent the long-term deleterious psychiatric disturbances, mental retarda-
consequences of hypogonadism; however, the optimal testosterone tion and criminal behavior in patients with
regimen for patients with Klinefelter syndrome remains to be established. Klinefelter syndrome. 3 These prejudicial
beliefs are still wrongly held to be true by many
KEYWORDS Klinefelter syndrome, morbidity, mortality, testosterone treatment
people. Since the 1960s, a number of studies
REVIEW CRITERIA have added to our knowledge about this
The full PubMed database was searched (without time restrictions) on 23 syndrome, especially the chromosome surveys
October 2006 using the keywords “Klinefelter”, “Klinefelter’s” and “XXY” in titles that identified unselected newborn babies
and abstracts. Papers relevant to the topic were obtained and reviewed, as well with sex-chromosome aberrations. These indi-
as older articles selected by the authors. Publications cited in this Review were
selected from those identified by the searches at the authors’ discretion. viduals were followed up throughout the 1970s
and 1980s;4–6 the published studies, however,
focused mainly on the development of affected
individuals throughout infancy, childhood and
adolescence, which left the natural history of
adults with Klinefelter syndrome comparatively
poorly described.
The ‘prototypic’ man with Klinefelter syn-
drome has traditionally been described as tall,
with narrow shoulders, broad hips, sparse body
hair, gynecomastia, small testes, androgen defici-
ency and reduced intelligence.7 An alternative
A Bojesen is Specialist Registrar in the Department of Clinical Genetics, Vejle phenotype has since been recognized, in which
Hospital, and in the Medical Department M (Diabetes and Endocrinology), patients present with fewer clinical features
and CH Gravholt is a Senior Researcher in the Medical Department M than are observed in the classical phenotype.8
(Diabetes and Endocrinology), Åarhus University Hospital, Denmark. Although the syndrome has been known for
Correspondence
more than 60 years and more than 3,000 arti-
*Department of Clinical Genetics, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark cles on various topics related to Klinefelter
anders.bojesen@dadlnet.dk syndrome have been published, our knowledge
is still limited. This article focuses on aspects
Received 20 November 2006 Accepted 12 January 2007
www.nature.com/clinicalpractice
of epidemiology, endocrinology, cardiology,
doi:10.1038/ncpuro0775 urology and fertility in Klinefelter syndrome,
Table 1 Karyotype distribution among patients diagnosed with Klinefelter syndrome in Denmark.
Karyotype(s) Number of cases Number of cases diagnosed Total number
diagnosed prenatally (%) postnatally (%) of cases (%)
47,XXY 147 (90.2) 714 (89.7) 861 (89.8)
46,XY/47,XXY 15 (9.2) 48 (6.0) 63 (6.6)
48,XXXY 0 11 (1.4) 11 (1.1)
49,XXXXY 1 (0.6) 16 (2.0) 17 (1.8)
47,XXY/48,XXXY 0 2 (0.3) 2 (0.2)
48,XXY + trisomy 0 5 (0.6) 5 (0.5)
of chromosome 18
Total 163 (100) 796 (100) 959 (100)
Permission obtained from The Endocrine Society © 2003, Bojesen A et al. (2003) J Clin Endocrinol Metab 88: 622–626.
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50 – Prevalence
From the earliest published study, Klinefelter
syndrome has been described as “not
Klinetelter syndrome per 100,000 men
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but have not yet been validated for use in Table 2 Abnormalities associated with Klinefelter syndrome and their
newborn babies. If such screening for Klinefelter approximate frequencies.
syndrome is offered, confirmatory karyotype Feature Frequency (%)
tests will be needed. It is also important to have
Adults
an infrastructure that allows for the follow-up
and treatment of patients with sex-chromosome Infertility7 >99
abnormalities, with support services to help Azoospermia7 >95
parents and caregivers deal with the uncertainties Decreased facial hair7 60–80
inherent in this type of diagnosis.
Decreased pubic hair7 30–60
If a fetus is prenatally diagnosed to have a
Abdominal adiposity31 ~50
47,XXY karyotype professional genetic coun-
seling should be offered, which should advise The metabolic syndrome31 46
the parents that their baby has a relatively good Osteopenia52 ~40
prognosis. Despite this favorable prognosis, Type 2 diabetes31 10–39
however, currently 75% of couples in Denmark
Osteoporosis52 10
who discover that they are expecting a child with
Klinefelter syndrome choose termination.12 Mitral valve prolapse46 ≤55
Breast cancer54,55 Increased risk (~50-folda)
Ascertainment bias Children
Ascertainment bias is a major problem in the Learning disabilities6 >75
interpretion of data from studies on different
Gynecomastia6,26 38–75
populations of patients with Klinefelter syn-
drome, because only around 25% of the Delayed speech development6 ≥40
expected men with Klinefelter syndrome are Increased heightb,6 ≥30
actually diagnosed. As mentioned earlier, the Decreased penis size6 10–25
phenotype of a patient diagnosed as having Psychiatric disturbances6 25
Klinefelter syndrome in childhood or at puberty
Mediastinal cancers53 Increased risk (~500-folda)
might be different from that of a patient diag-
nosed as having Klinefelter syndrome in adult- All patients with Klinefelter syndrome
hood. Most published data so far are hampered Small testes (<4 ml)7 >95
by ascertainment bias. The least biased data Increased gonadotropin levels7 >95
currently available are those from prospec-
Decreased testosterone levels7 63–85
tive studies on boys diagnosed at birth, but
the numbers of patients in these studies are Cryptorchidism6,21 27–37
small and there is, therefore, great variability Congenital malformations (cleft palate and ~18
inguinal hernia)59
in the estimates of certain clinical findings. As
a consequence, it is important to interpret the Fractures9,45 Increased risk (2–40-folda)
prevalence data on clinical findings cautiously, aAbove normal. bPrepubertal.
and to avoid extrapolating prevalence rates
found in one population to all patients with
Klinefelter syndrome.
fifth finger as the most frequent abnormality.20
CONGENITAL MALFORMATIONS The same survey found major congenital
Reaching a diagnosis of Klinefelter syndrome abnormalities in 18% of boys with Klinefelter
at birth on the basis of clinical findings is syndrome; cleft palate, inguinal hernia and
unlikely, as the syndrome has no specific clinical testis retention were the most frequent find-
features that are apparent in newborn babies ings.20 Further evidence of a highly increased
(unlike Turner syndrome or Down syndrome); prevalence of testis retention in this syndrome
however, an increased incidence of congenital comes from a large, cross-sectional study
malformations has been found in babies with undertaken in an andrology clinic, where 27%
Klinefelter syndrome. Minor congenital abnor- of patients with Klinefelter syndrome had a
malities were found in 26% of babies diagnosed history of undescended testes, compared to 8%
with Klinefelter syndrome at birth in a sex- of the total number of patients who attended
chromosome survey, with clinodactyly of the the same clinic.21
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CANCER
was found, but the mortality from ischemic Whether gynecomastia leads to an increased risk
heart disease was significantly decreased.9 Data of developing breast cancer remains a matter of
from a study on castrated men also corrobo- debate. A Danish study of cancer registry data
rate this theory; these men had a decreased risk on men with Klinefelter syndrome did not show
of dying from acute myocardial infarction, in that these patients had an increased risk of breast
spite of a generally increased mortality risk.43 cancer;53 however, a Swedish karyotype study54
It seems plausible that a vicious circle could that evaluated nonmetastatic lymph nodes from
exist, in which hypogonadism leads to abdom- men with breast cancer showed a 47,XXY karyo-
inal obesity, which in turn leads to insulin type in 7.5% of the examined patients, which
resistance that might further aggravate the was equivalent to a 50-fold increase in risk of
hypogonadism (Figure 2).44 breast cancer. An increased risk of breast cancer
has been confirmed in a study on mortality and
CARDIOVASCULAR DISEASE incidence of cancer in a large cohort of patients
Mortality from cardiovascular diseases is with Klinefelter syndrome (n = 3,518), which
increased in patients with Klinefelter syn- showed that these patients’ risk of breast cancer
drome,9,45 even though their mortality from was significantly elevated.55
ischemic heart disease is reduced.9 One reason The Danish register study on cancer inci-
for this increased cardiovascular mortality dence in men with Klinefelter syndrome did
could be mitral valve prolapse, which has been not show an overall increased risk of cancer, but
described to affect a large proportion of patients those patients did have a significantly increased
with Klinefelter syndrome in one study;46 mitral risk of mediastinal germ-cell tumors.53 By
valve prolapse is related to an increased risk of contrast, patients with Klinefelter syndrome in
sudden death. Patients’ risk of hypostatic leg the most recent UK study (published in 2005)
ulcers can be significantly increased,47 which had an increased mortality risk from lung
might cause serious morbidity and mortality cancer (albeit with only marginal statistical
from pulmonary embolism.9 Dysfunction of significance), breast cancer and non-Hodgkin’s
the fibrinolytic system has been proposed as a lymphoma, and a significantly decreased risk
reason for this association, and one study has of death from prostate cancer.55 The UK study
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could not, however, confirm the increased risk in the left temporal lobes of five untreated
of mediastinal tumors found in the Danish patients with Klinefelter syndrome, compared
study. The finding of a decreased risk of to five patients with Klinefelter syndrome who
death from prostate cancer probably reflects were treated with testosterone, and to normal
the frequent hypogonadism in Klinefelter controls.63 Another study on brain perfusion in
syndrome, because most prostate cancers are patients with Klinefelter syndrome, which used
known to be testosterone-dependent, and anti- single-photon-emission computed tomography
androgens have proven to be effective tools in (SPECT), described a diminished left lateraliza-
the treatment of this common cancer. Although tion of perfusion (compared with the pattern
testis retention (a well-known risk factor for seen in normal controls) and a negative corre-
testicular cancer) is very common in Klinefelter lation between reduced perfusion in regions
syndrome, no increase in testicular cancer has involved in language processing and scores in
been described. verbal tests.64 These observations might, in part,
In summary, the available data from several explain the decreased verbal performance seen
sources indicate that men with Klinefelter in patients with Klinefelter syndrome. Although
syndrome have a grossly elevated risk of cancer these results were based on a small sample of
of the breast, mediastinal germ-cell tumors and patients, they also point towards a possible posi-
non-Hodgkin’s lymphomas. Additional studies tive effect of testosterone-replacement therapy
will be needed to elucidate whether they also on verbal performance in men with Klinefelter
have an increased risk of other cancers. syndrome. This potential positive effect is in
accordance with the findings of a study on verbal
COGNITIVE DISTURBANCES intelligence, pubertal development and testo-
In the early 1960s several investigators reported sterone levels, which showed a positive associ-
an increased prevalence of Klinefelter syndrome ation between testosterone levels and verbal
among inmates of prisons and institutions intelligence.65 Interestingly, a study published
for the mentally retarded.3,56,57 This finding led in 2006 showed impaired learning and memory
to the conclusion that Klinefelter syndrome was function as well as testicular failure in an XXY
associated with criminal behavior and low intel- mouse model.66
ligence. This belief was challenged by prospec-
tive studies in newborn babies screened for PSYCHIATRIC ILLNESS
sex-chromosome disorders during the 1970s. In Studies from the late 1960s that were primarily
later studies with long-term follow up,5,6,58 the based on screening for sex-chromosome abnor-
overall intelligence of patients with Klinefelter malities among inmates of penal institutions,
syndrome was found to be near-normal, but psychiatric hospitals and institutions for the
they had decreased verbal abilities, delayed mentally retarded reported an increased inci-
development of speech and a high proportion dence of psychiatric illness in individuals with
of educational problems.59,60 A study of patients Klinefelter syndrome.57 Ratcliffe’s long-term
with Klinefelter syndrome who were prenatally follow-up study of patients with Klinefelter
diagnosed showed remarkably good outcomes in syndrome who were identified by a chromo-
relation to intellectual performance,61 but this somal survey of newborn babies also revealed
finding might reflect elevated socioeconomic an increased frequency of referrals for psychi-
status and increased motivation among parents atric treatment.6 A survey of sex-chromosome
who chose to continue with the pregnancy aberrations among patients with schizo-
despite the Klinefelter syndrome diagnosis. phrenia found a 4–5-fold increased incidence
One study on adults who had sex-chromosome of Klinefelter syndrome, compared with the
abnormalities that were detected at birth showed expected incidence in the normal population.67
that the decreased verbal intelligence and Our epidemiological study on hospital admis-
reading impairment of patients with Klinefelter sions in patients with Klinefelter syndrome
syndrome persisted in adulthood,62 but there showed that these individuals had a significantly
was a large variation in educational and voca- increased risk of discharge from hospital with a
tional achievement. The reason for the delay in psychiatric diagnosis.35 Moreover, patients with
speech development and decreased verbal intel- Klinefelter syndrome might show an increased
ligence is unclear, but an MRI study of the whole incidence of pathological symptoms and traits
brain found diminished grey matter volumes associated with schizophrenia, compared to a
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Table 3 Testosterone preparations available and their suggested doses for adult patients with Klinefelter syndrome.
Substance Brand name (manufacturer) Format Route of Suggested dose
administration
Testosterone Andriol® (Organon, Oss, the Netherlands) Capsule Oral 120–160 mg per day
undecanoate
Testosterone Nebido® (Schering, Berlin, Germany) Injection Intramuscular 1 g every 10–14 weeks
undecanoate
Testosterone enantate Testoviron® (Schering, Berlin, Germany) Injection Intramuscular 250 mg every 2–3 weeks
Testosterone Striant® (Columbia Laboratories, Livingston, Buccal adhesive Buccal 60 mg per day
NJ, USA)
Testosterone Testim® (Ipsen, Paris, France) Gel Skin 50 mg per day
Testosterone Testogel® (Laboratoires Besins, Paris, Gel Skin 50 mg per day
France)
Testosterone Androderm® (Watson Pharma Inc., Corona, Transdermal patch Skin 2.5–7.5 mg per day
CA, USA)
Testosterone Testoderm® (Alza Corp., Mountain View, Transdermal/ skin/scrotal skin 4–6 mg per day
CA, USA) scrotal patch
the patient, especially in order to avoid the tran- Box 1 Proposed assessment and follow-up program for patients with
sient, high levels of testosterone that can occur Klinefelter syndrome.
with injected formulations of testosterone, and At first assessment visit
which can cause discomfort. ■ Confirm karyotype, if necessary
Some testosterone preparations currently ■ Test sex hormone levels: testosterone, estrogen, sex-hormone-binding
available are shown in Table 3. A possible nega- globulin, follicle-stimulating hormone and luteinizing hormone
tive effect of exogenous testosterone on fertility
■ Measure fasting glucose and lipids
(or on the outcome of TESE and ICSI) has
been reported, and that study also described ■ Assess thyroid status, hemoglobin, hematocrit and serum PSA
the use of aromatase inhibitors and human ■ Physical examination, including assessment of blood pressure, height,
choriogonadotropin to increase intratesticular weight, waist size, testes size, gynecomastia and varicose veins
testosterone in order to increase the chance of
■ Bone densitometry (dual-energy X-ray absorbtiometry), vitamin D status,
sperm recovery by TESE.32 These interesting
and serum calcium phosphate levels
data are based on the observation that sperm
recovery by TESE failed in five patients with ■ Echocardiography
Klinefelter syndrome who were taking long-term ■ Provide information to the patient (and family) about the syndrome
testosterone treatment; these findings should,
■ Initiation of testosterone treatment (injected, transdermal or oral administration)
however, be confirmed in a randomized setting,
before testosterone treatment is withheld from ■ Answer patient’s questions about wellbeing, physical activity, energy, sexual
young men with Klinefelter syndrome. activity, libido
A clinical outpatient program for the manage- At routine follow-up assessment (initially every 3 months, then annually)
ment of patients with Klinefelter syndrome is ■ Physical examination, including assessment of blood pressure, height,
suggested in Box 1. Patients who are given testo- weight, waist, testes size, gynecomastia and varicose veins
sterone treatment should initially be followed
■ Test sex hormone levels: testosterone, estrogen, sex-hormone-binding
up with clinic visits every 3 months, until their globulin, follicle-stimulating hormone and luteinizing hormone (nadir values)
testosterone dose has been titrated to achieve
serum levels of testosterone and LH in the ■ Measure fasting glucose and lipids
middle of the normal ranges and according to ■ Assess thyroid status, hemoglobin, and serum PSA
the patients’ symptoms, and annually thereafter.
■ Answer patient’s questions about wellbeing, physical activity, energy, sexual
activity, libido
CONCLUSION
Not a single randomized, placebo-controlled At 2, 5 and 10 years, and then probably every 5 years thereafter
■ Bone densitometry (dual-energy X-ray absorbtiometry), vitamin D status
study on the effects of testosterone-replacement
and serum calcium phosphate levels
therapy in patients with Klinefelter syndrome
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