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http://www.emedicine.com/ped/topic1252.htm#
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Klinefelter Syndrome
Last Updated: November 2, 2001 |
| Synonyms and related keywords:
XXY male, XXY syndrome, XXXY syndrome, XXYY syndrome,
XXXXY syndrome, XXXYY syndrome |
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| Author: Harold
Chen, MD, MS, FAAP, FACMG, Chief,
Professor, Department of Pediatrics, Section of
Perinatal Genetics, Louisiana State University Medical
Center
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| Harold Chen, MD, MS, FAAP, FACMG, is a member of the
following medical societies: American
Academy of Pediatrics, American
College of Medical Genetics, American
Medical Association, American
Society of Human Genetics, and Teratology
Society
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| Editor(s): Ian Krantz, MD, Assistant
Professor, Department of Pediatrics, University of
Pennsylvania and Children's Hospital of Philadelphia; Robert
Konop, PharmD, Clinical Assistant Professor,
Department of Pharmacy, Section of Clinical
Pharmacology, University of Minnesota; Margaret
McGovern, MD, PhD, Vice Chair, Associate
Professor, Department of Human Genetics, Mount Sinai
School of Medicine; Paul D Petry, DO, FACOP,
Assistant Professor, Department of Pediatrics, Division
of Maternal Child Health, Northeast Regional Medical
Center; and Bruce Buehler, MD,
Chairman, Department of Pediatrics, Professor,
Departments of Pediatrics and Pathology, University of
Nebraska Medical Center |
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| Background: In
1942, Klinefelter et al published a report on 9 men who had
enlarged breasts, sparse facial and body hair, small testes, and
inability to produce sperm. In 1959, these men with Klinefelter
syndrome were discovered to have an extra sex chromosome
(genotype XXY) instead of the usual male sex complement
(genotype XY).
Klinefelter syndrome is the most common chromosomal disorder
associated with male hypogonadism and infertility. It is defined
classically by a 47, XXY karyotype with variants demonstrating
additional X and Y chromosomes. The syndrome is characterized by
hypogonadism (small testes, azoospermia/oligospermia),
gynecomastia at late puberty, psychosocial problems,
hyalinization and fibrosis of the seminiferous tubules, and
elevated urinary gonadotropins.
Pathophysiology: The addition of more than 1
extra X or Y chromosome to a male karyotype results in variable
physical and cognitive abnormalities. In general, the extent of
phenotypic abnormalities, including mental retardation, is
related directly to the number of supernumerary X chromosomes.
As the number of X chromosomes increases, somatic and cognitive
development are more likely to be affected. Skeletal and
cardiovascular abnormalities can become increasingly severe.
Gonadal development is particularly susceptible to each
additional X chromosome, resulting in seminiferous tubule
dysgenesis and infertility as well as hypoplastic and malformed
genitalia in polysomy X males. Moreover, mental capacity
diminishes with additional X chromosomes. The intelligence
quotient (IQ) is reduced by approximately 15 points for each
supernumerary X chromosome, but conclusions about reduced mental
capacity must be drawn cautiously. All major areas of
development, including expressive and receptive language and
coordination, are affected by extra X chromosome material.
The major consequences of the extra sex chromosome, usually
acquired through an error of nondisjunction during parental
gametogenesis, are hypogonadism, gynecomastia, and psychosocial
problems. Klinefelter syndrome is a form of primary testicular
failure, with elevated gonadotropin levels arising from lack of
feedback inhibition by the pituitary gland. Androgen deficiency
causes eunuchoid body proportions; sparse or absent facial,
axillary, pubic, or body hair; decreased muscle mass and
strength; feminine distribution of adipose tissue; gynecomastia;
small testes and penis; diminished libido; decreased physical
endurance; and osteoporosis. The loss of functional seminiferous
tubules and Sertoli cells results in a marked decrease in
inhibin B levels, presumably the hormone regulator of
follicle-stimulating hormone (FSH) level. The
hypothalamic-pituitary-gonadal axis is altered in pubertal
patients with Klinefelter syndrome.
Increased incidence of autoimmune disorders, such as systemic
lupus erythematosus, rheumatoid arthritis, and Sjögren
syndrome, has been reported. This may be due to lower
testosterone and higher estrogen levels, since androgen may
protect against (and estrogen promote) autoimmunity.
Frequency:
- In the US: Approximately 1 in 500-1,000
males is born with an extra sex chromosome; over 3,000
affected males are born yearly. The prevalence is 5-20 times
higher in the mentally retarded than in the general newborn
population.
Mortality/Morbidity:
- About 40% of concepti with Klinefelter syndrome survive
the fetal period.
- In general, severity of somatic malformations in
Klinefelter syndrome is proportional to the number of
additional X chromosomes; mental retardation and
hypogonadism are more severe in 49,XXXXY than in 48,XXXY.
- Mortality rate is not significantly higher than in healthy
individuals.
Race: No racial predilection exists.
Sex: Due to an additional X chromosome on an
XY background, this condition is seen in males only.
Age:
- Most males born with Klinefelter syndrome go through life
without being diagnosed. Diagnosis, when made, usually
occurs in adulthood. The most common indications for
karyotyping are hypogonadism and infertility.
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History:
- Infertility and gynecomastia are the 2 most common
complaints leading to diagnosis.
- Other complaints include fatigue, weakness, erectile
dysfunction, osteoporosis, language impairment, academic
difficulty, subnormal libido, poor self-esteem, and behavior
problems.
Physical:
- Infants and children have normal heights, weights, and
head circumferences. About 25% have clinodactyly. Height
velocity is increased by age 5 years, and adult height
usually is taller than average. Affected individuals also
have disproportionately long arms and legs.
- Some individuals with Klinefelter variant 49,XXXXY have
short stature.
- Most 47,XXY males have normal intelligence. Family
background influences IQ. Subnormal intelligence or mental
retardation may be associated with the presence of a higher
number of X chromosomes.
- About 70% of patients have minor developmental and
learning disabilities. These may include academic
difficulties, delayed speech and language acquisition,
diminished short-term memory, decreased data-retrieval
skills, reading difficulties, dyslexia, and attention
deficit disorder.
- Patients may exhibit behavioral problems and psychological
distress. This may be due to poor self-esteem and
psychosocial development or a decreased ability to deal with
stress.
- Psychiatric disorders involving anxiety, depression,
neurosis, and psychosis are seen more commonly in this group
than in the general population.
- Taurodontism (enlargement of the molar teeth by an
extension of the pulp) is present in about 40% of patients.
- Incidence is about 1% in normal XY individuals.
- Patients may lack secondary sexual characteristics because
of a decrease in androgen production. This results in sparse
facial/body/sexual hair, a high-pitched voice, and a female
type of fat distribution.
- By late puberty, 30-50% of boys with Klinefelter syndrome
manifest gynecomastia, which is secondary to elevated
estradiol levels and increased estradiol/testosterone ratio.
The risk of developing breast carcinoma is at least 20 times
higher than normal.
- Testicular dysgenesis (small firm testis, testis size
<10 mL) may be present in postpubertal patients.
- Infertility/azoospermia may result from atrophy of the
seminiferous tubules. Infertility is seen in practically all
individuals with a 47, XXY karyotype. Patients with
Klinefelter syndrome mosaicism (46, XY/47, XXY) can be
fertile.
- Patients may have an increased frequency of extragonadal
germ cell tumors such as embryonal carcinoma, teratoma, and
primary mediastinal germ cell tumor.
- Cardiac and circulatory problems
- Mitral valve prolapse occurs in 55% of patients.
- Varicose veins occur in 20-40% of patients.
- The prevalence of venous ulcers is 10-20 times higher than
normal, and the risk of deep vein thrombosis and pulmonary
embolism is increased.
- 48,XXYY variant: Patients typically have mild mental
retardation, tall stature, eunuchoid body habitus, sparse
body hair, gynecomastia, long thin legs, hypergonadotropic
hypogonadism, and small testes.
- 48,XXXY variant: Patients typically have mild-to-moderate
mental retardation, speech delay, slow motor development,
poor coordination, immature behavior, normal or tall
stature, abnormal face (epicanthal folds, hypertelorism,
protruding lips), hypogonadism, gynecomastia (33-50%),
hypoplastic penis, infertility, clinodactyly, and radioulnar
synostosis and benefit from testosterone therapy.
- 49,XXXYY: Patients typically have moderate-to-severe
mental retardation, passive but occasionally aggressive
behavior and temper tantrums, tall stature, dysmorphic
facial features, gynecomastia, and hypogonadism.
- 49,XXXXY variant: The classic triad is mild-to-moderate
mental retardation, radioulnar synostosis, and
hypergonadotropic hypogonadism. Other clinical features
include severely impaired language, behavioral problems, low
birth weight, short stature in some individuals, abnormal
face (round face in infancy, coarse features in older age,
hypertelorism, epicanthal folds, prognathism), short or
broad neck, gynecomastia (rare), congenital heart defects
(patent ductus arteriosus is most common), skeletal
anomalies (genu valgus, pes cavus, fifth finger clinodactyly),
muscular hypotonia, hyperextensible joints, hypoplastic
genitalia, and cryptorchidism. Pea-size testes, micropenis,
and infantile secondary sex characteristics are
characteristic in patients with 49,XXXXY, whereas patients
with 48,XXXY exhibit milder hypogonadism similar to that of
patients with 47,XXY.
Causes:
- Klinefelter syndrome is caused by the presence of an
additional X chromosome in a male.
- About 50-60% of cases are due to maternal nondisjunction
(75% meiosis I errors). In cases in which these maternal
meiosis I errors are identified, maternal age is increased.
The remaining cases are due to paternal nondisjunction.
- The most common karyotype is 47,XXY (about 80-90% of all
cases). Mosaicism (46,XY/47,XXY) is observed in about 10% of
cases. Other variant karyotypes, including 48,XXYY, 48,XXXY,
49,XXXYY, and 49,XXXXY, are rare.
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Fragile
X Syndrome
Hypogonadism
Marfan
Syndrome
Other Problems to be Considered:
Kallmann syndrome
46, XX male
Infertility
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Lab Studies:
- Between 80% and 90% of patients have 47,XXY.
- About 10% of patients have mosaicism; karyotypes include
46,XY/47,XXY, 46,XY/48,XXXY, and 47,XXY/48,XXXY.
- Remaining cases represent variants such as the 48,XXYY,
48,XXXY, 49,XXXYY, and 49,XXXXY karyotypes.
- About 1% of cases are due to a structurally abnormal X in
addition to a normal X and Y, such as 47,X,i(Xq)Y and
47,X,del(X)Y.
- High plasma FSH, luteinizing hormone (LH), and estradiol
levels and low plasma testosterone have developed in
patients aged 12-14 years.
- The increase in testosterone in response to administration
of human chorionic gonadotropin (hCG) is subnormal.
- Urinary gonadotropins are increased due to abnormal Leydig
cell function.
- Serum osteocalcin levels are decreased and the hydroxyl-proline/creatinine
ratio increased, reflecting decreased bone formation and
increased bone resorption.
Imaging Studies:
- Echocardiography is performed to detect mitral valve
prolapse.
- Radiographs are performed to detect lower bone mineral
density, radioulnar synostosis, and taurodontism.
Histologic Findings: Findings may include small,
firm testes with seminiferous tubular hyalinization, sclerosis,
and atrophy with focal hyperplasia of mostly degenerated Leydig
cells. Germ cells are markedly deficient or absent.
Spermatogenesis is demonstrated rarely. In patients with mosaicism,
progressive degeneration and hyalinization of seminiferous tubules
take place after puberty despite presence of normal-sized testes
and spermatogenesis at puberty. Histology of gynecomastic breasts
shows hyperplasia of interductal tissue.
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Medical Care:
- Early identification and anticipatory guidance are extremely
helpful (although the syndrome rarely is diagnosed in
prepubertal males).
- Treatment should address 3 major facets of the disease:
hypogonadism, gynecomastia, and psychosocial problems.
- Androgen therapy is the most important aspect of treatment.
Testosterone replacement should begin at puberty to correct
androgen deficiency, provide appropriate virilization, and
improve psychosocial status. Regular testosterone injections
can promote strength and facial hair growth; build a more
muscular body type; increase sexual desire; enlarge size of
testes; improve mood, self-image, and behavior; and protect
against precocious osteoporosis.
- A multidisciplinary team approach will help speech
impairments, academic difficulties, and other psychosocial and
behavioral problems.
- The recurrence risk is not increased above that of the
general population.
- Physicians should provide parents with information from
unbiased follow-up studies of children with Klinefelter
syndrome.
- The best time to reveal the condition to an affected male
is probably mid-to-late adolescence when he is old enough to
understand his condition.
Surgical Care: Mastectomy may be indicated for
gynecomastia. Gynecomastia places considerable psychological
strain on the patient and increases risk of breast cancer.
Consultations: Consultations should be sought
with a clinical geneticist, endocrinologist, surgeon,
psychologist, and speech therapist.
Diet: No special diet is needed.
Activity: No activity restrictions are
required.
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Drug Category: Androgen
-- Exogenous androgen (testosterone) is the treatment of
choice for many aspects of Klinefelter syndrome.
Drug Name
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Testosterone enanthate
(Delatestryl) or cypionate (Depo-Testosterone) -- Major
therapeutic aims are to reduce serum gonadotropin
concentrations to the upper limits of normal and to induce
virilization gradually.
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| Adult Dose |
200 mg IM q2-3wk
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| Pediatric Dose |
Beginning at 11-12
years: 50 mg IM every mo; increase dosage yearly in accord
with the patient's state of well-being, degree of
virilization, growth, and serum gonadotropin
concentrations; eventually reaching adult dose
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| Contraindications |
Documented
hypersensitivity; severe renal, hepatic, or cardiac
disease; prostate or breast cancer in males; hypercalcemia
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| Interactions |
Increases effects of
warfarin; increases propranolol clearance
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| Pregnancy |
X - Contraindicated in
pregnancy
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| Precautions |
Initiation of therapy
may be associated with priapism (rare); other adverse
effects include salt and water retention with edema and
hypertension, polycythemia, and transient or increased
gynecomastia; large doses in older patients may produce
prostatic hypertrophy leading to acute bladder outlet
obstruction
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Further
Inpatient Care:
- Admission for supportive care is not necessary.
Further Outpatient Care:
- The patient should be monitored by an endocrinologist for
testosterone replacement therapy.
In/Out Patient Meds:
- Administer regular testosterone injections.
Complications:
- Risk of breast carcinoma in XXY men may approach 20 times
that in healthy men. Other types of neoplasia occur in 1.6% of
patients and include acute leukemia, Hodgkin and non-Hodgkin
lymphomas, chronic myelogenous leukemia, and other
myeloproliferative diseases. Gonadal and extragonadal germ
cell tumors (mediastinal germ cell tumors, teratoma,
teratocarcinoma, choriocarcinoma) also may occur.
- Psychologic and psychiatric complications may occur in
individuals with lower-than-average intelligence, hypogonadism,
or impotence.
- Vertebral collapse may result from osteoporosis.
- Development of varicose veins and leg ulcers may result from
venous stasis.
- Associated endocrine diseases include diabetes mellitus,
hypothyroidism, empty sella syndrome, hypoparathyroidism, and
precocious puberty in association with hCG-producing germ cell
tumors.
- Benign prostatic hyperplasia may result from testosterone
supplementation. Adults undergoing such therapy should be
screened for prostatic enlargement starting at age 30 years.
- In polysomic X males, the mortality rate due to
cerebrovascular diseases such as aortic valvular disease and
berry aneurysm rupture is more than 6 times greater than the
expected rate in males aged 25-84 years. Enhanced platelet
aggregation, thrombotic disease, and hypercoagulability have
been demonstrated and may be related to increased estrogen
levels.
Prognosis:
- Early studies of men with XXY Klinefelter syndrome produced
disturbing findings of an increased risk of psychiatric
disturbance, criminality, and mental retardation. These
results are considered highly questionable due to selection
bias from institutionalized populations.
- XXY babies differ little from other children.
- Although boys with 47,XXY may struggle through adolescence
with limited academic success, many frustrations, and, in a
few instances, serious emotional or behavioral difficulties,
most are moving toward full independence from their families
as they enter adulthood. Some have completed graduate
education and have a normal level of functioning.
- Life span is presumably normal.
- Hypogonadism, low libido, and psychosocial problems can be
helped by testosterone treatment.
- Gynecomastia can be corrected by mastectomy.
Patient Education:
Klinefelter
Syndrome and Associates, PO Box 119, Roseville, CA 95678,
phone 888-999-9428
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Medical/Legal Pitfalls:
- Failure to inform patient of an increased risk of breast
carcinoma associated with gynecomastia and increased risk of
developing osteoporosis in later life
- Failure to refer patients to an endocrinologist for
testosterone replacement
Special Concerns:
- Klinefelter syndrome can be detected prenatally by
amniocentesis and cytogenetic analysis of amniotic fluid.
This presents a dilemma for parents, since prognosis is good
but the possibility of phenotypic abnormalities does exist.
- Only few 46,XY/47,XXY mosaics are known to have fathered a
child, in which case there is a risk of having a 47,XXY
offspring. All 47,XXY individuals are infertile.
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this article from other sources prior to use. In particular, all
drug doses, indications, and contraindications should be confirmed
in the package insert.
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