1. Imad Fadl-Elmula Al Neelain University
Klinefelter Syndrome
Imad Fadl-Elmula
Al Neelain University

2. History Klinefelter et al., 1942 (9 men). Small testes.
Oligospermia or Azoospermia.
Enlarged breasts (gynecomastia).
Sparse facial and body hair.

3. Jacobs et al., 1959

4. Epidemiology Frequency Mortality and Morbidity 1 in 500-1,000 males.
3,000 are born yearly.
5-20 times higher in mentally retarded.
Mortality and Morbidity
About 40% of conception with Klinefelter syndrome survive the fetal period.
Mortality rate is not significantly higher than in healthy individuals.

5. Most males go through life without being diagnosed until adulthood
Epidemiology
Race
No racial predilection exists.
Age
Most males go through life without
being diagnosed until adulthood

6. 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.

7. Is seen in all individuals with a 47, XXY.
Infertility
Gynecomastia
Is seen in all individuals with a 47, XXY.
Patients with mosaicism (46, XY/47,
XXY) can be fertile.

8. Clinical presentation
Other presentation
Erectile dysfunction.
Subnormal libido.
Osteoporosis.
Language impairment.
Academic difficulty.
Behavior problems.

9. 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.
Lack secondary sexual characteristics

10. 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

11. Klinefelter Syndrome

12. 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).

13. 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.

14. Cardiac and circulatory problems
Mitral valve prolapse in 55% of patients.
Varicose veins in 20-40% of patients.
Venous ulcers is times higher than normal.
Deep vein thrombosis and pulmonary embolism is increased.

15. Hormones 1. Increased autoimmune disorders.
Lower testosterone and higher estrogen levels
1. Increased autoimmune disorders.
2. Systemic lupus erythematosus.
3. Rheumatoid arthritis.
4. Sjögren syndrome.

16. Variant and mechanism Chromosomal changes

17. 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
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.

18. 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

21. FISH
WCP X
WCP Y

22. 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.

23. Consultations Consultations should be sought with:
Clinical geneticist.
Endocrinologist.
Surgeon.
Psychologist.
Speech therapist.
Activity: No activity restrictions are required.

24. 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.

25. Increased risk of others neoplasm
Acute leukemia.
Hodgkin and non-Hodgkin lymphomas.
Chronic myelogenous leukemia.
Myeloproliferative diseases.
Gonadal and extragonadal germ cell tumors

26. Associated endocrine diseases
Diabetes mellitus.
Hypothyroidism.
Hypoparathyroidism.
Benign prostatic hyperplasia may result from testosterone supplementation.
Cerebrovascular diseases
Aortic valvular disease.
Berry aneurysm rupture.

27. Prognosis Increased risk of
Psychiatric disturbance.
Criminality.
Mental retardation.
XXY babies differ little from other children
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.

28. 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

29. Thank you

30. 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.

31. Drug Category: Androgen
-- Exogenous androgen (testosterone) is the treatment of choice for many aspects of Klinefelter syndrome.
Drug Name 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.
Adult Dose 200 mg IM q2-3wk
Pediatric Dose Beginning at 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

32. 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.

33. Imaging Studies
Echocardiography is performed to detect mitral valve prolapse.
Radiographs are performed to detect lower bone mineral density, radioulnar synostosis.

34. Genetic counseling
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.

35. Hormone testing High level of: Luteinizing hormone (LH).
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.