Klinefelter SyndromeKlinefelter Syndrome

Imad Fadl-ElmulaImad Fadl-Elmula

Al Neelain UniversityAl Neelain University

HistoryHistory

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

Jacobs Jacobs et alet al., 1959., 1959

FrequencyFrequency 1 in 500-1,000 males. 1 in 500-1,000 males. 3,000 are born yearly. 3,000 are born yearly. 5-20 times higher in mentally retarded.5-20 times higher in mentally retarded.

Mortality and MorbidityMortality and Morbidity About 40% of conception with Klinefelter About 40% of conception with Klinefelter

syndrome survive the fetal period. syndrome survive the fetal period. Mortality rate is not significantly higher than Mortality rate is not significantly higher than

in healthy individuals.in healthy individuals.

EpidemiologyEpidemiology

RaceRace

No racial predilection exists. No racial predilection exists.

AgeAge

Most Most males go through life withoutmales go through life without

being diagnosed until adulthoodbeing diagnosed until adulthood

PhysiopathologyPhysiopathology Primary testicular failurePrimary testicular failure

Elevated gonadotropin levels (arising from lack of feedback Elevated gonadotropin levels (arising from lack of feedback inhibition by the pituitary gland). inhibition by the pituitary gland). Androgen deficiency causesAndrogen deficiency causes 1. Eunuchoid body proportions 1. Eunuchoid body proportions 2. Sparse or absent facial, axillary, pubic, or body hair. 2. Sparse or absent facial, axillary, pubic, or body hair. 3. Decreased muscle mass and strength.3. Decreased muscle mass and strength.4. Feminine distribution of adipose tissue. 4. Feminine distribution of adipose tissue. 5. Gynecomastia. 5. Gynecomastia. 6. Small testes and penis. 6. Small testes and penis. 7. Diminished libido. 7. Diminished libido. 8. Osteoporosis. 8. Osteoporosis. The loss of functional seminiferous tubules and Sertoli The loss of functional seminiferous tubules and Sertoli cellscells3. Stimulating hormone (FSH) level. 3. Stimulating hormone (FSH) level. 4. The hypothalamic-pituitary-gonadal axis is altered. 4. The hypothalamic-pituitary-gonadal axis is altered.

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

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

Sexual characteristicsSexual characteristics

1. 1. Decrease in androgen production.Decrease in androgen production.

2. 2. Elevated estradiol/testosterone ratio levels Elevated estradiol/testosterone ratio levels Body/sexual hair.Body/sexual hair. High-pitched voice.High-pitched voice. Testicular dysgenesis. Testicular dysgenesis. Infertility/azoospermia.Infertility/azoospermia. This results in sparse facial.This results in sparse facial. Female type of fat distributionFemale type of fat distribution Small firm testis, testis size <10 mL.Small firm testis, testis size <10 mL. Atrophy of the seminiferous tubules.Atrophy of the seminiferous tubules.

Lack secondary sexual characteristicsLack secondary sexual characteristics

4747 , ,XXY – Klinefelter syndromeXXY – Klinefelter syndrome

Gynecomastia – Gynecomastia – Male with female features

small testes, inability to produce sperm

Mental retardationMental 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 SyndromeKlinefelter Syndrome

Phenotypic abnormalitiesPhenotypic abnormalities

Gonadal developmentGonadal development

1. Seminiferous tubule dysgenesis.1. Seminiferous tubule dysgenesis.

2. Infertility.2. Infertility.

3. Hypoplastic and malformed genitalia. 3. Hypoplastic and malformed genitalia.

Skeletal and cardiovascular abnormalities.Skeletal and cardiovascular abnormalities.

Mental retardation (related directly to theMental retardation (related directly to the

number X IQ 15 points less). number X IQ 15 points less).

Central nervous systemCentral nervous system Most have normal intelligence (IQ). Most have normal intelligence (IQ). Subnormal intelligence or mental retardation Subnormal intelligence or mental retardation

may be associated with the presence of a may be associated with the presence of a

higher higher number of X chromosomes.number of X chromosomes. About 70% of patients have minor learning About 70% of patients have minor learning

disabilities.disabilities. Patients may exhibit behavioral problems Patients may exhibit behavioral problems

and psychological distress. and psychological distress. Psychiatric disorders involving anxiety, Psychiatric disorders involving anxiety,

depression, neurosis, and psychosis are depression, neurosis, and psychosis are

seen more commonly in this group than in seen more commonly in this group than in

the general population.the general population.

Cardiac and circulatory problemsCardiac and circulatory problems

Mitral valve prolapse in 55% of Mitral valve prolapse in 55% of patients.patients.

Varicose veins in 20-40% of Varicose veins in 20-40% of patients.patients.

Venous ulcers is 10-20 times Venous ulcers is 10-20 times higher than normal.higher than normal.

Deep vein thrombosis and Deep vein thrombosis and pulmonary embolism is increased.pulmonary embolism is increased.

Hormones Hormones

Lower testosterone and higher estrogen levelsLower testosterone and higher estrogen levels

1.1. Increased autoimmune disorders.Increased autoimmune disorders.

2. Systemic lupus erythematosus. 2. Systemic lupus erythematosus.

3. Rheumatoid arthritis.3. Rheumatoid arthritis.

4. Sjögren syndrome.4. Sjögren syndrome.

Variant and mechanismVariant and mechanismChromosomal changesChromosomal changes

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Extra X Mosciacism Structural

0%

10%

20%

30%

40%

50%

60%

Maternal nondisjunction

Paternal nondisjunction

DiagnosisDiagnosis Cytogenetic studiesCytogenetic studies

Between 80% and 90% of patients have 47,XXY.Between 80% and 90% of patients have 47,XXY. About 10% of patients have mosaicism include About 10% of patients have mosaicism include

46,XY/47,XXY, 46,XY/47,XXY,

46,XY/48,XXXY 46,XY/48,XXXY

46,XY/48,XXXY46,XY/48,XXXY

47,XXY/48,XXXY.47,XXY/48,XXXY. Remaining cases represent variants such as the 48,XXYY, Remaining cases represent variants such as the 48,XXYY,

48,XXXY, 49,XXXYY, and 49,XXXXY karyotypes.48,XXXY, 49,XXXYY, and 49,XXXXY karyotypes. About 1% of cases are due to a structurally abnormal X in 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 addition to a normal X and Y, such as 47,X,i(Xq)Y and

47,X,del(X)Y.47,X,del(X)Y.

Karyotypic descriptionsKaryotypic descriptions

ClassicalClassical 47,XXY47,XXY

VariantVariant 48,XXXY48,XXXY48,XXYY48,XXYY 49,XXXYY49,XXXYY

49,XXXXY49,XXXXY MociacismMociacism 46,XY/47,XXY46,XY/47,XXY

StructuralStructural47,X,i(Xq)Y47,X,i(Xq)Y47,X,del(X)Y47,X,del(X)Y

FISHFISH

WCP XWCP Y

Genetic counselingGenetic counseling Prenatal diagnosis……a dilemmaPrenatal diagnosis……a dilemma

Klinefelter syndrome can be detected prenatally Klinefelter syndrome can be detected prenatally

by amniocentesis and cytogenetic analysis of by amniocentesis and cytogenetic analysis of

amniotic fluid. This presents for parents, since amniotic fluid. This presents for parents, since

prognosis is good but the possibility of prognosis is good but the possibility of

phenotypic abnormalities does exist.phenotypic abnormalities does exist. Only few 46,XY/47,XXY mosaics are known to Only few 46,XY/47,XXY mosaics are known to

have fathered a child, in which case there is a have fathered a child, in which case there is a

risk of having a 47,XXY offspring. risk of having a 47,XXY offspring. All 47,XXY individuals are infertile.All 47,XXY individuals are infertile.

ConsultationsConsultationsConsultations should be sought with:Consultations should be sought with: Clinical geneticist. Clinical geneticist. Endocrinologist. Endocrinologist. Surgeon. Surgeon. Psychologist. Psychologist. Speech therapist.Speech therapist.

Activity: Activity: No activity restrictions are required. No activity restrictions are required.

Risk for cancerRisk for cancer1. Gynecomastia (30-50%) of boys with 1. Gynecomastia (30-50%) of boys with

Klinefelter syndrome. The risk of breast Klinefelter syndrome. The risk of breast

cancer is at least 20 times higher. cancer is at least 20 times higher.

2. Increased frequency of extragonadal 2. Increased frequency of extragonadal

germ cell tumors such as embryonal germ cell tumors such as embryonal

carcinoma, teratoma, and primary carcinoma, teratoma, and primary

mediastinal germ cell tumor.mediastinal germ cell tumor.

Increased risk of others Increased risk of others neoplasmneoplasm

Acute leukemia.Acute leukemia. Hodgkin and non-Hodgkin lymphomas. Hodgkin and non-Hodgkin lymphomas. Chronic myelogenous leukemia.Chronic myelogenous leukemia. Myeloproliferative diseases. Myeloproliferative diseases. Gonadal and extragonadal germ cell Gonadal and extragonadal germ cell tumors tumors

Associated endocrine diseasesAssociated endocrine diseases Diabetes mellitus. Diabetes mellitus. Hypothyroidism.Hypothyroidism. Hypoparathyroidism.Hypoparathyroidism. Benign prostatic hyperplasia may result Benign prostatic hyperplasia may result

from testosterone supplementation. from testosterone supplementation.

Cerebrovascular diseasesCerebrovascular diseasesAortic valvular disease. Aortic valvular disease.

Berry aneurysm rupture.Berry aneurysm rupture.

Associated endocrine diseasesAssociated endocrine diseases Diabetes mellitus. Diabetes mellitus. Hypothyroidism.Hypothyroidism. Hypoparathyroidism.Hypoparathyroidism. Benign prostatic hyperplasia may result Benign prostatic hyperplasia may result

from testosterone supplementation. from testosterone supplementation.

Cerebrovascular diseasesCerebrovascular diseasesAortic valvular disease. Aortic valvular disease.

Berry aneurysm rupture.Berry aneurysm rupture.

PrognosisPrognosis Increased risk ofIncreased risk of Psychiatric disturbance. Psychiatric disturbance. Criminality.Criminality. Mental retardation. Mental retardation.

XXY babies differ little from other childrenXXY babies differ little from other children Limited academic success. Limited academic success. Life span is presumably normal.Life span is presumably normal. Hypogonadism.Hypogonadism. Low libido.Low libido. Psychosocial problems can be helped by Psychosocial problems can be helped by

Testosterone treatment.Testosterone treatment. Gynecomastia can be corrected by mastectomy.Gynecomastia can be corrected by mastectomy.

Medical/Legal PitfallsMedical/Legal Pitfalls

Failure to inform patient ofFailure to inform patient of

1. An increased risk of 1. An increased risk of breast carcinomabreast carcinoma associated with gynecomastia.associated with gynecomastia.

2. Increased risk of developing 2. Increased risk of developing osteoporosisosteoporosis in in later lifelater life

Failure to refer patients toFailure to refer patients to

1. Endocrinologist for testosterone replacement1. Endocrinologist for testosterone replacement

Medical Care: Medical Care: Early identificationEarly identification? ? Treatment should address 3 major facets of the Treatment should address 3 major facets of the disease:disease:1. hypogonadism1. hypogonadism Androgen therapy is the most important aspect of treatment. Androgen therapy is the most important aspect of treatment. Testosterone replacement should begin at puberty to correct Testosterone replacement should begin at puberty to correct androgen deficiency, provide appropriate virilization, and improveandrogen deficiency, provide appropriate virilization, and improvepsychosocial status. Regular testosterone injections can promote psychosocial status. Regular testosterone injections can promote strengthstrengthand facial hair growth; build a more muscular body type; increase sexual and facial hair growth; build a more muscular body type; increase sexual desire; enlarge size of testes; improve mood, self-image, and behavior; desire; enlarge size of testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis.and protect against precocious osteoporosis.2. Gynecomastia2. GynecomastiaMastectomy may be indicated for gynecomastia. Gynecomastia places Mastectomy may be indicated for gynecomastia. Gynecomastia places considerable psychological strain on the patient and increases risk of considerable psychological strain on the patient and increases risk of breast cancer. breast cancer. 3. psychosocial problems3. psychosocial problemsA multidisciplinary team approach will help speech impairments, A multidisciplinary team approach will help speech impairments, academic difficulties, and other psychosocial and behavioral problems.academic difficulties, and other psychosocial and behavioral problems.

Drug Category: Drug Category: AndrogenAndrogen -- Exogenous androgen (testosterone) is the treatment of choice for many -- Exogenous androgen (testosterone) is the treatment of choice for many

aspects of Klinefelter syndrome. aspects of Klinefelter syndrome. Drug NameDrug Name Testosterone enanthate (Delatestryl) or cypionate (Depo-Testosterone enanthate (Delatestryl) or cypionate (Depo-

Testosterone) -- Major therapeutic aims are to reduce serum gonadotropin Testosterone) -- Major therapeutic aims are to reduce serum gonadotropin concentrations to the upper limits of normal and to induce virilization concentrations to the upper limits of normal and to induce virilization gradually. gradually.

Adult DoseAdult Dose 200 mg IM q2-3wk 200 mg IM q2-3wk Pediatric DosePediatric Dose Beginning at 11-12 years: 50 mg IM every mo; increase 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 dosage yearly in accord with the patient's state of well-being, degree of virilization, growth, and serum gonadotropin concentrations; eventually virilization, growth, and serum gonadotropin concentrations; eventually reaching adult dose reaching adult dose

ContraindicationsContraindications Documented hypersensitivity; severe renal, Documented hypersensitivity; severe renal, hepatic, or cardiac disease; prostate or breast cancer in males; hepatic, or cardiac disease; prostate or breast cancer in males; hypercalcemia hypercalcemia

InteractionsInteractions Increases effects of warfarin; increases propranolol Increases effects of warfarin; increases propranolol clearance clearance

PregnancyPregnancy X - Contraindicated in pregnancy X - Contraindicated in pregnancy PrecautionsPrecautions Initiation of therapy may be associated with priapism Initiation of therapy may be associated with priapism

(rare); other adverse effects include salt and water retention with edema (rare); other adverse effects include salt and water retention with edema and hypertension, polycythemia, and transient or increased gynecomastia; and hypertension, polycythemia, and transient or increased gynecomastia; large doses in older patients may produce prostatic hypertrophy leading to large doses in older patients may produce prostatic hypertrophy leading to acute bladder outlet obstructionacute bladder outlet obstruction

Histologic FindingsHistologic FindingsFindings includeFindings includeseminiferous tubular hyalinizationseminiferous tubular hyalinizationsclerosissclerosisatrophy with focal hyperplasia of mostly degenerated atrophy with focal hyperplasia of mostly degenerated Leydig cells. Leydig cells. Germ cells are markedly deficient or absent. Germ cells are markedly deficient or absent. Spermatogenesis is demonstrated rarely. Spermatogenesis is demonstrated rarely. In patients with mosaicismIn patients with mosaicism progressive degeneration and hyalinization of progressive degeneration and hyalinization of seminiferous tubules take place after puberty despite seminiferous tubules take place after puberty despite presence of normal-sized testes and spermatogenesis at presence of normal-sized testes and spermatogenesis at puberty. Histology of gynecomastic breasts shows puberty. Histology of gynecomastic breasts shows hyperplasia of interductal tissue. hyperplasia of interductal tissue.

Imaging StudiesImaging Studies

Echocardiography is performed to detect Echocardiography is performed to detect mitral valve prolapse.mitral valve prolapse.

Radiographs are performed to detect lower Radiographs are performed to detect lower bone mineral density, radioulnar bone mineral density, radioulnar synostosis.synostosis.

Genetic counselingGenetic counseling The recurrence risk is not increased The recurrence risk is not increased

above that of the general population. above that of the general population. Physicians should provide parents with Physicians should provide parents with

information from unbiased follow-up information from unbiased follow-up studies of children with Klinefelter studies of children with Klinefelter syndrome. syndrome.

The best time to reveal the condition to The best time to reveal the condition to an affected male is probably mid-to-late an affected male is probably mid-to-late adolescence when he is old enough to adolescence when he is old enough to understand his condition.understand his condition.

Hormone testingHormone testing Hormone testingHormone testing High level of:High level of:• FSH.FSH.

• Luteinizing hormone (LH).Luteinizing hormone (LH).

• Estradiol levels. Estradiol levels. Urinary gonadotropins are increased Urinary gonadotropins are increased

due to abnormal Leydig cell function.due to abnormal Leydig cell function. Serum osteocalcin levels are Serum osteocalcin levels are

decreased and the hydroxyl-proline/ decreased and the hydroxyl-proline/

creatinine ratio increased.creatinine ratio increased.