Transcript Klinefelter Syndrome - Fadl

Klinefelter Syndrome
Imad Fadl-Elmula
Al Neelain University
History
Klinefelter et al., 1942 (9 men).
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Small testes.
Oligospermia or Azoospermia.
Enlarged breasts (gynecomastia).
Sparse facial and body hair.
Jacobs et al., 1959
Epidemiology
Frequency
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1 in 500-1,000 males.
 3,000 are born yearly.
 5-20 times higher in mentally retarded.
Mortality and Morbidity
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About 40% of conception with Klinefelter
syndrome survive the fetal period.
 Mortality rate is not significantly higher than
in healthy individuals.
Race
No racial predilection exists.
Age
Most males go through life without
being diagnosed until adulthood
Physiopathology
Primary testicular failure
Elevated gonadotropin levels (arising from lack of
feedback inhibition by the pituitary gland).
Androgen deficiency causes
1. Eunuchoid body proportions
2. Sparse or absent facial, axillary, pubic, or body hair.
3. Decreased muscle mass and strength.
4. Feminine distribution of adipose tissue.
5. Gynecomastia.
6. Small testes and penis.
7. Diminished libido.
8. Osteoporosis.
The loss of functional seminiferous tubules and
Sertoli cells
3. Stimulating hormone (FSH) level.
4. The hypothalamic-pituitary-gonadal axis is altered.
 Is seen in all individuals with a 47, XXY.
 Patients with mosaicism (46, XY/47,
XXY) can be fertile.
Other presentation
 Erectile dysfunction.
 Subnormal libido.
 Osteoporosis.
 Language impairment.
 Academic difficulty.
 Behavior problems.
Sexual characteristics
1. Decrease in androgen production.
2. Elevated estradiol/testosterone ratio levels
 Body/sexual hair.
 High-pitched voice.
 Testicular dysgenesis.
 Infertility/azoospermia.
 This results in sparse facial.
 Female type of fat distribution
 Small firm testis, testis size <10 mL.
 Atrophy of the seminiferous tubules.
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Lack secondary sexual characteristics
47, XXY – Klinefelter syndrome
Gynecomastia –
Male with female features
small testes,
inability to produce sperm
Mental retardation
is related directly to the number
of supernumerary X chromosomes
(-15 IQ unit per 1 extra X).
1 out of 500 or 1000 males;
most go through life undiagnosed
40% of embryos survive to birth
Klinefelter Syndrome
Phenotypic abnormalities
Gonadal development
1. Seminiferous tubule dysgenesis.
2. Infertility.
3. Hypoplastic and malformed genitalia.
Skeletal and cardiovascular abnormalities.
Mental retardation (related directly to the
number X IQ 15 points less).
Central nervous system
 Most have normal intelligence (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 learning
disabilities.
 Patients may exhibit behavioral problems
and psychological distress.
 Psychiatric disorders involving anxiety,
depression, neurosis, and psychosis are
seen more commonly in this group than in
the general population.
Cardiac and circulatory problems
 Mitral
valve prolapse in 55% of
patients.
 Varicose veins in 20-40% of
patients.
 Venous ulcers is 10-20 times
higher than normal.
 Deep vein thrombosis and
pulmonary embolism is increased.
Hormones
Lower testosterone and higher estrogen levels
1. Increased autoimmune disorders.
2. Systemic lupus erythematosus.
3. Rheumatoid arthritis.
4. Sjögren syndrome.
Variant and mechanism
Chromosomal changes
60%
90%
80%
50%
70%
40%
60%
50%
30%
40%
20%
30%
20%
10%
10%
0%
0%
Extra X
Mosciacism
Structural
Maternal nondisjunction
Paternal nondisjunction
Diagnosis
Cytogenetic studies
Between 80% and 90% of patients have 47,XXY.
 About 10% of patients have mosaicism include
46,XY/47,XXY,
46,XY/48,XXXY
46,XY/48,XXXY
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.
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Karyotypic descriptions
Classical
47,XXY
Variant
48,XXXY
48,XXYY
49,XXXYY
49,XXXXY
Mociacism 46,XY/47,XXY
Structural
47,X,i(Xq)Y
47,X,del(X)Y
FISH
WCP X
WCP Y
Genetic counseling
Prenatal diagnosis……a dilemma
Klinefelter syndrome can be detected prenatally
by amniocentesis and cytogenetic analysis of
amniotic fluid. This presents 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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Consultations
Consultations should be sought with:
 Clinical geneticist.
 Endocrinologist.
 Surgeon.
 Psychologist.
 Speech therapist.
Activity: No activity restrictions are required.
Risk for cancer
1. Gynecomastia (30-50%) of boys with
Klinefelter syndrome. The risk of breast
cancer is at least 20 times higher.
2. Increased frequency of extragonadal
germ cell tumors such as embryonal
carcinoma, teratoma, and primary
mediastinal germ cell tumor.
Increased risk of others neoplasm
Acute leukemia.
 Hodgkin and non-Hodgkin lymphomas.
 Chronic myelogenous leukemia.
 Myeloproliferative diseases.
 Gonadal and extragonadal germ cell tumors
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Associated endocrine diseases
 Diabetes
mellitus.
 Hypothyroidism.
 Hypoparathyroidism.
 Benign prostatic hyperplasia may result
from testosterone supplementation.
Cerebrovascular diseases
Aortic valvular disease.
Berry aneurysm rupture.
Prognosis
Increased risk of
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Psychiatric disturbance.
 Criminality.
 Mental retardation.
XXY babies differ little from other children
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Limited academic success.
 Life span is presumably normal.
 Hypogonadism.
 Low libido.
 Psychosocial problems can be helped by
Testosterone treatment.
 Gynecomastia can be corrected by mastectomy.
Medical/Legal Pitfalls
Failure to inform patient of
1. An increased risk of breast carcinoma
associated with gynecomastia.
2. Increased risk of developing osteoporosis in
later life
Failure to refer patients to
1. Endocrinologist for testosterone replacement
Medical Care:
Early identification? Treatment should address 3 major facets of the
disease:
1. hypogonadism
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.
2. Gynecomastia
Mastectomy may be indicated for gynecomastia. Gynecomastia places
considerable psychological strain on the patient and increases risk of
breast cancer.
3. psychosocial problems
A multidisciplinary team approach will help speech impairments,
academic difficulties, and other psychosocial and behavioral problems.
Drug Category: Androgen
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-- Exogenous androgen (testosterone) is the treatment of choice for many
aspects of Klinefelter syndrome.
 Drug Name Testosterone enanthate (Delatestryl) or cypionate (DepoTestosterone) -- Major therapeutic aims are to reduce serum gonadotropin
concentrations to the upper limits of normal and to induce virilization
gradually.
 Adult Dose
200 mg IM q2-3wk
 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
 Contraindications
Documented hypersensitivity; severe renal, hepatic,
or cardiac disease; prostate or breast cancer in males; hypercalcemia
 Interactions Increases effects of warfarin; increases propranolol
clearance
 Pregnancy
X - Contraindicated in pregnancy
 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
Histologic Findings
Findings include
seminiferous tubular hyalinization
sclerosis
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.
Imaging Studies
 Echocardiography
is performed to detect
mitral valve prolapse.
 Radiographs are performed to detect lower
bone mineral density, radioulnar
synostosis.
Genetic counseling
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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.
Hormone testing
High level of:
• FSH.
• Luteinizing hormone (LH).
• Estradiol levels.
 Urinary gonadotropins are increased
due to abnormal Leydig cell function.
 Serum osteocalcin levels are
decreased and the hydroxyl-proline/
creatinine ratio increased.