Klinefelter Syndrome and Its variants
Creation date: March 2003
Background
In 1942, Dr. Harry Klinefelter published a report on 9 men with a constellation
of features: testicular dysgenesis, elevated urinary gonadotropins,
microorchidism, eunuchoidism, azoospermia, and gynecomastia. It was
believed to be an endocrine disorder of unknown etiology, until 1959, when
Jacobs et al. recognized that Klinefelter syndrome was a chromosomal
disorder, in which there is an extra X chromosome resulting in the karyotype
of 47,XXY. During the early 1970's, a number of centers began screening
newborns for sex chromatin abnormalities, because there was a need to obtain
accurate information about childhood development in this condition.
Previous studies of XXY individuals were extremely biased toward more severely
affected individuals, since these patients were drawn largely from mental
or penal settings where large numbers of men could be screened.
These earlier studies implied a risk for mental deficiency and behavioral
problems. As prospective, unbiased studied have reported their results
in recent years, it has become clear that most XXY boys demonstrate reductions
in speech and language abilities which are correlated with decreased reading
and spelling achievement. Most, but not all XXY males, are infertile with
small testicles, increased numbers of Leydig cells, tubular sclerosis and
interstitial fibrosis of varying degrees. Their ejaculate is usually
aspermic or azoosperic, and levels of testosterone are typically low.
Diagnostic Criteria
Formal cytogenetic analysis is necessary to make a definite diagnosis,
and more obvious differences in physical features tend to be associated
with increasing numbers of sex chromosomes. Chromosome analysis on
lymphocytes from peripheral blood, or on amniocytes or chorionic villi
from prenatal specimens is used to make this diagnosis.
If the diagnosis is not made prenatally, 47,XXY males may present with
a variety of subtle clinical signs that are age-related. In infancy,
males with 47,XXY may have chromosomal evaluations done for hypospadias,
small phallus or cryptorchidism. The school-aged child may present
with language delay, learning disabilities, or behavioral problems.
The older child or adolescent may be discovered during an endocrine evaluation
for delayed or incomplete pubertal development with eunuchoid body habitus,
gynecomastia, and small testes. Adults are often evaluated for infertility
or breast malignancy.
Differential Diagnosis
The physical manifestations of Klinefelter syndrome are often variable.
When the following features are present in an undiagnosed male, a karyotype
analysis may be indicated:
Diagnostic Testing
Etiology
The extra X chromosome in Klinefelter syndrome results sporadically
from either meiotic nondisjunction where a chromosome fails to separate
during the first or second division of gametogenesis or from mitotic nondisjunction
in the developing zygote. The likelihood of X chromosome nondisjunction
increases with advancing maternal age.
The effects on physical and mental development increase with the number
of extra Xs, and each extra X reduces the overall IQ by 15-16 points, with
language most affected, particularly expressive skills.
Physical Characteristics
Boys with Klinefelter syndrome have variable phenotypic characteristics
and do not have obvious facial dysmorphology; thus, they are indistinguishable
from other boys with normal karyotypes. Small testicular size is
the only consistent physical feature in Klinefelter syndrome. The
presence of gynecomastia and other findings of eunuchoid body habitus and
sparse body hair are variable.
Growth/Stature
Infants and children have normal heights, weights, and head circumferences.
The increase in height is most significant between ages 5 and 8 and results
in the mean final height of 179.2 + 6.2 cm. Affected individuals
have longer arms and legs.
Secondary Sexual Characteristics
Many 47,XXY boys appear to enter puberty normally with a tendency for
testosterone concentrations to decline at late adolescence and early adulthood.
With a decrease in androgen production, secondary sexual characteristics
do not completely develop, and features of eunuchoidism and gynecomastia
can develop. This also results in sparse facial, body, and sexual
hair. The reported incidence of gynecomastia in Klinefelter syndrome
varies widely from 56% to 88%.
Gonads
Features that are constant in Klinefelter syndrome males are small,
soft testes with elevated gonadotropins. Testicular volume is typically
less than 10ml in postpubertal Klinefelter syndrome individuals.
Fertility
Although most patients with Klinefelter syndrome are infertile, there
have been a few patients with reports of pregnancy without assisted medical
technology, typically in mosaic cases. With the introduction of intracytoplasmic
sperm injection, which involves the use of sperm extraction from deep within
the testicles of patients with nonmosaic Klinefelter syndrome, some XXY
men will have an increased chance of fathering a child.
Psychological Characteristics
Intelligence
A wide range of IQs has been noted and extends from well below average
to well above average. Based on the Wechsler Intelligence Test, Verbal
IQ is usually lower than Performance IQ. Most of the differences
between Verbal IQ and Performance IQ appear to relate to deficits in verbal
abilities and to decreased auditory memory and processing.
Language Development
Several longitudinal studies of Klinefelter syndrome subjects have
revealed a tendency for language deficits that often causes academic difficulties
during the school years. Most 47,XXY boys have a lag in language
skills with mildly delayed expression of single words. These individuals
also demonstrated that the production of language is affected more than
that of comprehension. The pattern of deficits includes problems
in understanding of complex grammatical constructions, problems in oral
language production, and deficits in morphology, word retrieval abilities,
and oral narrative construction. The variability of their speech
and language deficits is reflected in the lower mean verbal scales scores
being significantly lower than performance scale scores.
Behavior and Personality
The personalities of 47,XXY males are variable. One study characterized
47,XXY males as timid, immature, and reserved, with difficulty relating
to their peer group, whereas other studies described 47,XXY subjects as
friendly, kind, helpful, and relates well with other people. Most are described
to be quiet, sensitive, and unassertive. The majority of 47,XXY males
rate themselves as more sensitive, apprehensive, and insecure than their
peers. The language difficulty experienced by these males possibly
contributes to the social immaturity.
Complications
Risk of acquiring breast carcinoma in 47,XXY males may approach 20
times than the normal male. The estimated frequency of breast cancer
in Klinefelter syndrome males is 3.7%.
Associated endocrine complications include diabetes mellitus, hypothyroidism,
and hypoparathyrodism.
Autoimmune diseases, such as systemic lupus erythematosus, Sjogren
syndrome, and rheumatoid arthritis, are common in Klinefelter syndrome.
Development of varicose veins and leg ulcers may result from venous
stasis.
Decreased bone density occurs in 25% of patients with Klinefelter syndrome
and possibly reflects decreased bone formation and increased bone resorption.
Medical Management
Testosterone treatment
Androgen replacement therapy should begin at puberty, around age 12
years, in increasing dosage sufficient to maintain age appropriate serum
concentrations of testosterone, estradiol, FSH, and LH. Androgen
replacement promotes normalization of body proportions and development
of normal secondary sex characteristics and helps prevent the development
of gynecomastia. Testosterone replacement also results in general
improvement in behavior and work performance. Testosterone
also has beneficial long- term effects that might reduce the risk of osteoporosis,
autoimmune disease, and breast cancer.
Speech therapy
Early identification and anticipatory guidance are important in boys
with 47,XXY. Language therapy is particularly essential in helping
the child to develop skills in the understanding and production of more
complex language.
Genetic Counseling
The recurrence risk is not increased above that of the general population.
There is no evidence to suggest that a chromosomal nondisjunction process
is likely to repeat itself in a particular family.
Antenatal Diagnosis
Klinefelter syndrome can be detected prenatally by amniocentesis and
cytogenetic amniotic fluid. Parents should be counseled based on
recent prospective and unbiased information.
Klinefelter syndrome variants
- 48,XXYY
Males with 48,XXYY are often tall, with an adult height above 6 feet.
They have an eunuchoid habitus with long legs, sparse body hair, small
testicles and penis, hypergonadotropic hypogonadism, and gynecomastia.
Peripheral vascular disease may result in leg ulcers and varicosities.
Their IQ level is in the range of 60-80, with delayed speech and their
behavior appears to be more disturbed than that in XXY boys. They
are usually shy but can be aggressive and impulsive.
- 48,XXXY
Males with 48,XXXY chromosome complement can be average or tall stature
with ocular hypertelorism, flat nasal bridge, radioulnar synostosis, fifth-finger
clinodactyly, and small penis and testicles with hypergonadotropic hypogonadism.
Their IQs are usually between 40 and 60, with severely delayed speech.
Their behavior is often immature and consistent with their IQ level, and
they are typically described as passive, cooperative, and not particularly
aggressive.
- 49,XXXXY
Males with 49,XXXXY are severely affected. They manifest microcephaly
with short stature, ocular hypertelorism, flat nasal bridge, and upslanting
palpebral fissures. They may also have a bifid uvula, cleft palate,
heart defect (usually patent ductus arteriosus), radioulnar synostosis,
genu valgum, pes cavus, fifth-finger clinodactyly, hypotonia with lax joints,
and small genitalia with hypergonadotropic hypogonadism. Their IQ
ranges between 20 to 60. They tend to be shy and friendly, with occasional
irritability and temper tantrums, low frustration tolerance, and difficulty
changing routines.
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