Klinefelter Syndrome

1. Klinefelter Syndrome Imad Fadl-Elmula Al Neelain University

2. History Klinefelteret 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 • 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. 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. Gynecomastia Infertility • 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 10-20 times higher than normal. • Deep vein thrombosis and pulmonary embolism is increased.

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

16. Variant and mechanismChromosomal 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 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 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

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: • 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.