In 1942, Klinefelter et al. published a report on ninemen
who had enlarged breasts, sparse facial and body hair,
small testes, and an inability to produce sperm. In 1959,
thesemenwithKlinefelter syndromewere discovered to
have an extra sex chromosome (genotype XXY) instead
of the usual male sex complement (genotype XY).
Klinefelter syndrome is the most common sex chro-
mosomal disorder associated with male hypogonadism
and infertility. Approximately 1 in 5001,000 males is
born with an extra X chromosome. Over 3,000 affected
males are born yearly in the USA.
Synonyms and Related Disorders
47,XXY syndrome; Klinefelter syndrome mosaicism
(46,XY/47,XXY, 46,XY/48,XXXY, 47,XXY/48,
XXXY); Klinefelter syndrome variants (48,XXYY,
48,XXXY, 49,XXXYY, 49,XXXXY); Klinefelter
syndrome with structurally abnormal X chromosome
1. Caused by at least an additional X chromosome in
2. The XXY form of Klinefelter syndrome
a. Due to meiotic nondisjunction of the sex chromo-
somes during gametogenesis in either parent
b. Responsible meiotic nondisjunction
i. About 40% occur in the father
ii. About 60% occur in the mother
a) Meiosis I errors (75%) when origin is
b) Presence of maternal age effect in the
maternally derived cases
3. The mosaic forms of Klinefelter syndrome
a. Due to mitotic nondisjunction after fertilization
of the zygote
b. Can arise from a 46,XY zygote or a 47,XXY
4. The variant forms
a. 48,XXXY: nondisjunction occurring either at the
first or second meiotic divisions of oogenesis,
resulting an XXX ovum which is then fertilized
by a Y bearing sperm
b. 49,XXXXY: please refer to 49,XXXXY chapter
c. 48,XXYY and 49,XXXYY: occurrence of non-
disjunction in paternal meiosis to have two
i. An X ovum fertilized by an XYY sperm aris-
ing from successive nondisjunction in the first
and second meiotic divisions, or
ii. An XX ovum from 47,XXX mother fertilized
by a YY sperm
5. Pathophysiology (Chen 2011)
a. The X chromosome carries genes that play roles in
many body systems, including testis function,
brain development, and growth (Giedd et al. 2007).
b. The addition of more than one extra X or
Y chromosome to a male karyotype results in
variable physical and cognitive abnormalities.
c. In general, the extent of phenotypic abnormali-
ties, including mental retardation, is directly
related to the number of supernumerary
d. As the number of X chromosomes increases,
somatic and cognitive development are more
likely to be affected.
H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_141,# Springer Science+Business Media, LLC 2012
a. Infants and children: normal heights, weights,
and head circumferences
b. Adolescents and adults
i. Eunuchoid body habitus
ii. Usually taller than average
iii. Disproportionately long arms and legs
2. Mild developmental, learning, and behavioral diffi-
culties (70% of patients)
a. Delayed speech and language acquisition
b. Academic and reading difficulties
c. Attention deficit disorder
d. Poor self-esteem
g. Poor judgment
h. Inappropriate assertive activity
i. Decreased ability to deal with stress
a. Normal intelligence in most cases
b. Subnormal intelligence or mental retardation
associated with a higher number of
c. Diminished short-term memory
d. Prone to epilepsy and essential tremor
e. Psychiatric disorders involving anxiety, depres-
sion, neurosis, and psychosis: more common
than general population
4. Taurodontism (enlargement of the molar teeth by an
extension of the pulp): present in about 40% of
patients (versus 1% in normal XY individuals)
5. Cardiac and circulatory problems
a. Mitral valve prolapse (55% of patients)
b. Varicose veins (2040% of patients)
i. Venous ulcers
ii. Deep vein thrombosis
iii. Pulmonary embolism
6. A slightly increased risk of autoimmune disorder
a. Rheumatic diseases (Rovensky et al. 2010)
i. Inflammatory rheumatic diseases
ii. Rheumatoid arthritis
iii. Juvenile idiopathic arthritis
iv. Psoriatic arthritis
vi. Systemic lupus erythematosus
vii. Systemic sclerosis
viii. Mixed connective tissue disease
ix. Antiphospholipid syndrome
x. Ankylosing spondylitis
b. Thyroid disease
c. Sjogren syndrome
d. Diabetes mellitus
7. Sexual characteristics
a. Gynecomastia secondary to elevated estradiol
levels and increased estradiol/testosterone ratio
i. Develop by late puberty in 3050% of boys
with Klinefelter syndrome
ii. Risk of developing breast cancer: at least 20
times higher than normal
b. Lack of secondary sexual characteristics second-
ary to decrease in androgen production
i. Sparse facial, body, and sexual hair
ii. High-pitched voice
iii. Female type of fat distribution
c. Male psychosexual orientation in most patients
d. Subnormal libido
e. Erectile dysfunction
f. Oligospermia or azoospermia
g. Testicular dysgenesis in postpubertal patients
i. Small, firm testes
ii. Testis size
b. Klinefelter variants (Visootsak and Graham
i. 48,XXYY variant (Tartaglia et al. 2008)
a) Tall stature.
b) Disproportionately long lower
d) Pes planus.
f) Dental problems.
h) Intention tremor.
i) Neurodevelopmental disorders, includ-
ing developmental delays, ADHD,
autism spectrum disorders, mood disor-
ders, and tic disorders.
j) Unusual dermatoglyphic patterns.
k) Peripheral vascular disease, especially
varicose veins and stasis dermatitis.
l) Poorly developed secondary sexual
n) Testicular histology similar to that of 47,
o) The sex chromatin pattern indistinguish-
able from that of the 47,XXY patients
except two fluorescent Y bodies are pre-
sent in a high proportion of somatic nuclei.
ii. 48,XXXY variant
a) Moderate to severe mental retardation
b) Behavior: often immature and consistent
with IQ level, typically described as pas-
sive, cooperative, and not particularly
c) Normal to tall stature
d) Dysmorphic facies
e) Radioulnar synostosis
f) Fifth finger clinodactyly
g) Hypergonadotropic hypogonadism
h) Small testes
i) Signs of androgen deficiency
iii. 49,XXXYY variant
a) Mental retardation
b) Somatic anomalies
c) Small testes
iv. 49,XXXXY variant: severity and frequency
of somatic anomalies increase as the number
of X chromosomes increases
a) Mental retardation
c) Short stature
d) Hypotonia with lax joints
e) Facial dysmorphic features: ocular
hypertelorism, flat nasal bridge, epicanthal
folds, bifid uvula, or cleft palate
f) Short neck
g) Congenital heart defects
h) Radioulnar synostosis
i) Genu valgum
j) Pes cavus
k) Fifth finger clinodactyly
l) Hypergonadotropic hypogonadism with
m) Behavioral disorders: shy, friendly,
occasional irritability, temper tantrums,
low frustration tolerance, and difficulty
1. Cytogenetic studies
a. 47,XXY (8090%)
b. Mosaicism (10%)
d. Structural abnormal X in addition to a normal
X and Y
2. Endocrinologic studies
a. A variable degree of feminization and insuffi-
i. Elevated plasma FSH, luteinizing hormone,
and estradiol levels
ii. Low plasma testosterone levels in patients
age 1214 years
b. Subnormal increased testosterone in response to
human chorionic gonadotropin administration
3. Imaging studies
a. Echocardiography to demonstrate mitral valve
Klinefelter Syndrome 1233
i. Lower bone mineral density
ii. Radioulnar synostosis
a. Small, firm testes
b. Seminiferous tubular hyalinization, sclerosis,
and atrophy with focal hyperplasia of mostly
degenerated Leydig cells
c. Deficient or absent germ cells
d. Rare spermatogenesis (azoospermia)
e. Progressive degeneration and hyalinization of
seminiferous tubules after puberty in mosaic
1. Recurrence risk
a. Patients sibs: recurrence risk not increased for
b. Patients offspring
i. Recurrence risk not increased since all 47,
XXY individuals are infertile
ii. Report of paternity in nonmosaic 47,XXY
males (no other tissues were examined for
possible mosaicism with a 46,XY cell line)
c. A risk of having a 47,XXY offspring in a few 46,
XY/47,XXY mosaic patients who fathered
2. Prenatal diagnosis
a. Cytogenetic analysis of fetal cells obtained from
amniocentesis and CVS.
b. Dilemma for parents since prognosis for the
fetus with XXY is good but the possibility of
phenotypic abnormalities does exist.
c. Explanation to each couple the genetic risks
resulting from intracytoplasmic sperm injection
(ICSI) (increased risk of sex chromosome and
d. Preimplantation genetic diagnosis by embryo
biopsy offers an efficient tool for embryo selec-
tion (Friedler et al. 2001).
a. Speech therapy.
b. Physical therapy.
c. Occupational therapy.
d. Educational services.
e. Reassurance of patients that most of the clinical
features can be explained by the diminished
ability of the testes to produce testosterone.
f. Testosterone replacement: Optimal time to
initiate therapy is at age 1112 years of age to
allow for the maximum effect and permit
boys to experience pubertal changes with their
i. Corrects hormone imbalance (symptoms of
ii. Improves self-image
iii. Positive effect on mood and behavior
iv. Increase in masculinity
v. Increase in strength
vi. Increase in libido
vii. Increase in facial and pubic hair
viii. Diminish fatigue and irritability
ix. No positive effect on infertility
g. Management of gynecomastia
i. Androgen replacement therapy effective in
achieving regression of less severe gyneco-
mastia in some patients
ii. Reduction mammoplasty or liposuction for
severe or psychologically disturbing
h. Management of infertility (Lanfranco et al.
i. Nowadays patients with Klinefelter syndrome,
including the nonmosaic type, need no longer
be considered irrevocably infertile because
intracytoplasmic sperm injection offers an
opportunity for procreation even when there
are no spermatozoa in the ejaculate.
ii. In a substantial number of azoospermic
patients, spermatozoa can be extracted
from testicular biopsy samples, and
pregnancies and live births have been achieved.
iii. The frequency of sex chromosomal hyper-
ploidy and autosomal aneuploidies is higher
in spermatozoa from patients with
Klinefelter syndrome than in those from nor-
mal men. Thus, chromosomal errors might in
some cases be transmitted to the offspring of
men with this syndrome.
iv. The genetic implications of the fertilization
procedures, including pretransfer or prenatal
genetic assessment, must be explained to
patients and their partners.
1234 Klinefelter Syndrome
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Klinefelter Syndrome 1235
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1236 Klinefelter Syndrome
Fig. 1 A child with Klinefelter syndrome (47,XXY) showingnormal phenotype
Fig. 2 (a, b) A child with Klinefelter syndrome (47,XXY) showing pectus excavatum and multiple fractures of ribs in the neonatalperiod during hospital stay
Klinefelter Syndrome 1237
Fig. 3 The previous child at 14 years of age
a b c d
Fig. 4 (ad) A child with Klinefelter syndrome (47,XXY)associated with paralyzed diaphragm requiring intubation. The
photos were taken at early childhood, 9 and 12 years of age
showing pectus excavatum, long extremities with
hyperextended elbow, and kyphoscoliosis.
1238 Klinefelter Syndrome
Fig. 5 (ad) Two adolescent boys and two adults with Klinefelter syndrome (47,XXY) showing gynecomastia
Fig. 6 (ac) A 13-year-old boy, an adolescent boy and an adult male with Klinefelter syndrome (47,XXY) showing femaledistribution of pubic hair (last two patients) and small scrotum containing atrophic testicles
Klinefelter Syndrome 1239
Fig. 7 Interphase FISH showing two copies of CEPX (green),one copy of CEPY (orange), and two copies of CEP18 (aqua),which was confirmed by chromosome karyotype of 47,XXY
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Fig. 8 A G-bandedKaryotype showing 47,XXY
1240 Klinefelter Syndrome
Klinefelter SyndromeSynonyms and Related DisordersGenetics/Basic DefectsClinical FeaturesDiagnostic InvestigationsGenetic CounselingReferences