AUTHOR INFORMATION

Section 1 of 12

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	Ian Krantz, MD

eMedicine Journal, November 30 2005, VOLUME 6, Number 11

INTRODUCTION

Section 2 of 12

Background: In 1942, Klinefelter et al published a report on 9 men who had enlarged breasts, sparse facial and body hair, small testes, and inability to produce sperm. In 1959, these men with Klinefelter syndrome were discovered to have an extra sex chromosome (genotype XXY) instead of the usual male sex complement (genotype XY).

Klinefelter syndrome is the most common chromosomal disorder associated with male hypogonadism and infertility. It is defined classically by a 47, XXY karyotype with variants demonstrating additional X and Y chromosomes. The syndrome is characterized by hypogonadism (small testes, azoospermia/oligospermia), gynecomastia at late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules, and elevated urinary gonadotropins.

Pathophysiology: The addition of more than 1 extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is related directly to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected. Skeletal and cardiovascular abnormalities can become increasingly severe. Gonadal development is particularly susceptible to each additional X chromosome, resulting in seminiferous tubule dysgenesis and infertility as well as hypoplastic and malformed genitalia in polysomy X males. Moreover, mental capacity diminishes with additional X chromosomes. The intelligence quotient (IQ) is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are
affected by extra X chromosome material.

The major consequences of the extra sex chromosome, usually acquired through an error of nondisjunction during parental gametogenesis, are hypogonadism, gynecomastia, and psychosocial problems. Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels arising from lack of feedback inhibition by the pituitary gland. Androgen deficiency causes eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, presumably the hormone regulator of follicle-stimulating hormone (FSH) level. The hypothalamic-pituitary-gonadal axis is altered in pubertal patients with Klinefelter syndrome.

Increased incidence of autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, has been reported. This may be due to lower testosterone and higher estrogen levels, since androgen may protect against (and estrogen promote) autoimmunity.

Frequency:

• In the US: Approximately 1 in 500-1,000 males is born with an extra sex chromosome; over 3,000 affected males are born yearly. The prevalence is 5-20 times higher in the mentally retarded than in the general newborn population.

Mortality/Morbidity:

• About 40% of concepti with Klinefelter syndrome survive the fetal period.

• In general, severity of somatic malformations in Klinefelter syndrome is proportional to the number of additional X chromosomes; mental retardation and hypogonadism are more severe in 49,XXXXY than in 48,XXXY.

• Mortality rate is not significantly higher than in healthy individuals.

Race: No racial predilection exists.

Sex: Because of an additional X chromosome on an XY background, this condition is seen in males only.

Age:

• Most males born with Klinefelter syndrome go through life without being diagnosed. Diagnosis, when made, usually occurs in adulthood. The most common indications for karyotyping are hypogonadism and infertility.

CLINICAL

Section 3 of 12

History:

• Infertility and gynecomastia are the 2 most common complaints leading to diagnosis.



• Other complaints include fatigue, weakness, erectile dysfunction, osteoporosis, language impairment, academic difficulty, subnormal libido, poor self-esteem, and behavior problems.

Physical:

• Growth


• • Infants and children have normal heights, weights, and head circumferences. About 25% have clinodactyly. Height velocity is increased by age 5 years, and adult height usually is taller than average. Affected individuals also have disproportionately long arms and legs.
  
  
  
  • Some individuals with Klinefelter variant 49,XXXXY have short stature.
  
  
  
• Central nervous system


• • Most 47,XXY males have normal intelligence. Family background influences 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 developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder.
  
  
  
  • Patients may exhibit behavioral problems and psychological distress. This may be due to poor self-esteem and psychosocial development or a decreased ability to deal with stress.
  
  
  
  • Psychiatric disorders involving anxiety, depression, neurosis, and psychosis are seen more commonly in this group than in the general population.
  
  
  
• Dental


• • Taurodontism (enlargement of the molar teeth by an extension of the pulp) is present in about 40% of patients.

  • Incidence is about 1% in normal XY individuals.
  
  
  
• Sexual characteristics


• • Patients may lack secondary sexual characteristics because of a decrease in androgen production. This results in sparse facial/body/sexual hair, a high-pitched voice, and a female type of fat distribution.

  • By late puberty, 30-50% of boys with Klinefelter syndrome manifest gynecomastia, which is secondary to elevated estradiol levels and increased estradiol/testosterone ratio. The risk of developing breast carcinoma is at least 20 times higher than normal.

  • Testicular dysgenesis (small firm testis, testis size <10 mL) may be present in postpubertal patients.
  
  
  
  • Infertility/azoospermia may result from atrophy of the seminiferous tubules. Infertility is seen in practically all individuals with a 47, XXY karyotype. Patients with Klinefelter syndrome mosaicism (46, XY/47, XXY) can be fertile.
  
  
  
  • Patients may have an increased frequency of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.
  
  
  
• Cardiac and circulatory problems


• • Mitral valve prolapse occurs in 55% of patients.
  
  
  
  • Varicose veins occur in 20-40% of patients.
  
  
  
  • The prevalence of venous ulcers is 10-20 times higher than normal, and the risk of deep vein thrombosis and pulmonary embolism is increased.
  
  
  
• Klinefelter variants


• • 48,XXYY variant: Patients typically have mild mental retardation, tall stature, eunuchoid body habitus, sparse body hair, gynecomastia, long thin legs, hypergonadotropic hypogonadism, and small testes.

  • 48,XXXY variant: Patients typically have mild-to-moderate mental retardation, speech delay, slow motor development, poor coordination, immature behavior, normal or tall stature, abnormal face (epicanthal folds, hypertelorism, protruding lips), hypogonadism, gynecomastia (33-50%), hypoplastic penis, infertility, clinodactyly, and radioulnar synostosis and benefit from testosterone therapy.

  • 49,XXXYY: Patients typically have moderate-to-severe mental retardation, passive but occasionally aggressive behavior and temper tantrums, tall stature, dysmorphic facial features, gynecomastia, and hypogonadism.

  • 49,XXXXY variant: The classic triad is mild-to-moderate mental retardation, radioulnar synostosis, and hypergonadotropic hypogonadism. Other clinical features include severely impaired language, behavioral problems, low birth weight, short stature in some individuals, abnormal face (round face in infancy, coarse features in older age, hypertelorism, epicanthal folds, prognathism), short or broad neck, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (genu valgus, pes cavus, fifth finger clinodactyly), muscular hypotonia, hyperextensible joints, hypoplastic genitalia, and cryptorchidism. Pea-size testes, micropenis, and infantile secondary sex characteristics are characteristic in patients with 49,XXXXY, whereas patients with 48,XXXY exhibit milder hypogonadism similar to that of patients with 47,XXY.
  
  
  

Causes:

• Klinefelter syndrome is caused by the presence of an additional X chromosome in a male.



• About 50-60% of cases are due to maternal nondisjunction (75% meiosis I errors). In cases in which these maternal meiosis I errors are identified, maternal age is increased. The remaining cases are due to paternal nondisjunction.



• The most common karyotype is 47,XXY (about 80-90% of all cases). Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY, 48,XXXY, 49,XXXYY, and 49,XXXXY, are rare.



• The mosaic forms of Klinefelter syndrome


• • The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote.
  
  
  
  • These forms can arise from a 46,XY zygote or a 47,XXY zygote.
  
  
  
• The variant forms are as follows:


• • 48,XXXY
  
  
  
  • 49,XXXXY
  
  
  
  • 48,XXYY
  
  
  
  • 49,XXXYY
  
  
  

DIFFERENTIALS

Section 4 of 12

Fragile X Syndrome
Hypogonadism
Marfan Syndrome

Other Problems to be Considered:

Kallmann syndrome
46,XX male
Infertility

WORKUP

Section 5 of 12

Lab Studies:

• Cytogenetic studies


• • Between 80% and 90% of patients have 47,XXY.
  
  
  
  • About 10% of patients have mosaicism; karyotypes include 46,XY/47,XXY, 46,XY/48,XXXY, and 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.
  
  
  
• Hormone testing


• • High plasma FSH, luteinizing hormone (LH), and estradiol levels and low plasma testosterone have developed in patients aged 12-14 years.
  
  
  
  • The increase in testosterone in response to administration of human chorionic gonadotropin (hCG) is subnormal.
  
  
  
  • Urinary gonadotropins are increased due to abnormal Leydig cell function.
  
  
  
  • Serum osteocalcin levels are decreased and the hydroxyl-proline/creatinine ratio increased, reflecting decreased bone formation and increased bone resorption.
  
  
  

Imaging Studies:

• Echocardiography is performed to detect mitral valve prolapse.



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

TREATMENT

Section 6 of 12

Medical Care:

• Early identification and anticipatory guidance are extremely helpful (although the syndrome rarely is diagnosed in prepubertal males).



• Treatment should address 3 major facets of the disease: hypogonadism, gynecomastia, and psychosocial problems.



• 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.



• A multidisciplinary team approach will help speech impairments, academic difficulties, and other psychosocial and behavioral problems.



• 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.
  
  
  

Surgical Care: Mastectomy may be indicated for gynecomastia. Gynecomastia places considerable psychological strain on the patient and increases risk of breast cancer.

Consultations: Consultations should be sought with a clinical geneticist, endocrinologist, surgeon, psychologist, and speech therapist.

Diet: No special diet is needed.

Activity: No activity restrictions are required.

MEDICATION

Section 7 of 12

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

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Admission for supportive care is not necessary.

Further Outpatient Care:

• The patient should be monitored by an endocrinologist for testosterone replacement therapy.

In/Out Patient Meds:

• Administer regular testosterone injections.

Complications:

• Risk of breast carcinoma in XXY men may approach 20 times that in healthy men. Other types of neoplasia occur in 1.6% of patients and include acute leukemia, Hodgkin and non-Hodgkin lymphomas, chronic myelogenous leukemia, and other myeloproliferative diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell tumors, teratoma, teratocarcinoma, choriocarcinoma) also may occur.



• Psychologic and psychiatric complications may occur in individuals with lower-than-average intelligence, hypogonadism, or impotence.



• Vertebral collapse may result from osteoporosis.



• Development of varicose veins and leg ulcers may result from venous stasis.



• Associated endocrine diseases include diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious puberty in association with hCG-producing germ cell tumors.



• Benign prostatic hyperplasia may result from testosterone supplementation. Adults undergoing such therapy should be screened for prostatic enlargement starting at age 30 years.



• In polysomic X males, the mortality rate due to cerebrovascular diseases such as aortic valvular disease and berry aneurysm rupture is more than 6 times greater than the expected rate in males aged 25-84 years. Enhanced platelet aggregation, thrombotic disease, and hypercoagulability have been demonstrated and may be related to increased estrogen levels.

Prognosis:

• Early studies of men with XXY Klinefelter syndrome produced disturbing findings of an increased risk of psychiatric disturbance, criminality, and mental retardation. These results are considered highly questionable due to selection bias from institutionalized populations.



• XXY babies differ little from other children.



• Although boys with 47,XXY may struggle through adolescence with limited academic success, many frustrations, and, in a few instances, serious emotional or behavioral difficulties, most are moving toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning.



• Life span is presumably normal.



• Hypogonadism, low libido, and psychosocial problems can be helped by testosterone treatment.



• Gynecomastia can be corrected by mastectomy.

Patient Education:

• Klinefelter Syndrome and Associates, PO Box 119, Roseville, CA 95678, phone 888-999-9428



• The American Speech, Language, and Hearing Association, 10801 Rockville Pike, Rockville, MD 20852, phone 800-498-2071

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to inform patient of an increased risk of breast carcinoma associated with gynecomastia and increased risk of developing osteoporosis in later life



• Failure to refer patients to an endocrinologist for testosterone replacement

Special Concerns:

• Prenatal diagnosis


• • Klinefelter syndrome can be detected prenatally by amniocentesis and cytogenetic analysis of amniotic fluid. This presents a dilemma 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.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which is a characteristic manifestation of Klinefelter syndrome?

A: Eunuchoidism
B: Hypogonadism
C: Gynecomastia
D: Elevated urinary gonadotropins
E: All of the above

The correct answer is E: Klinefelter syndrome is characterized by eunuchoid body proportions, hypogonadism, gynecomastia, and elevated urinary gonadotropins.

CME Question 2: Which of the following statements regarding Klinefelter syndrome is not true?

A: Most babies born with XXY are never karyotyped.
B: Gynecomastia is a psychological burden, but the chance of developing breast cancer is remote.
C: About 60% of Klinefelter syndrome concepti are miscarried.
D: Fewer than 10% of the estimated number of affected fetuses are detected prenatally.
E: Approximately 1 in 500-1,000 males is born with an extra sex chromosome.

The correct answer is B: By late puberty, 30-50% of boys with Klinefelter syndrome manifest gynecomastia, which causes a considerable psychological burden. The risk of developing breast carcinoma is at least 20 times higher than normal.

Pearl Question 1 (T/F): The 2 most common complaints leading to diagnosis of Klinefelter syndrome are infertility and gynecomastia.

The correct answer is True: Infertility and gynecomastia are the 2 most common presenting symptoms in Klinefelter syndrome.

Pearl Question 2 (T/F): The neuropsychosocial characteristics of patients with Klinefelter syndrome include normal or subnormal intelligence of varying degree, developmental and learning disabilities, and behavior problems and psychosocial distress.

The correct answer is True: Patients with Klinefelter syndrome have normal or subnormal intelligence of varying degree, developmental and learning disabilities, and behavior problems and psychosocial distress.

Pearl Question 3 (T/F): The severity of somatic malformations seen in Klinefelter syndrome is inversely proportional to the number of additional X chromosomes.

The correct answer is False: In general, the severity of malformations is proportional to the number of additional X chromosomes.

Pearl Question 4 (T/F): Adolescent patients with Klinefelter syndrome who complain of weakness, sparse facial hair, low sexual desire, and poor self-image should be treated with regular testosterone injections as soon as possible.

The correct answer is True: Such patients should begin receiving regular testosterone injections.

PICTURES

Section 11 of 12

Caption: Picture 1. Adolescent male with gynecomastia who has Klinefelter syndrome.
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Caption: Picture 2. Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.
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Caption: Picture 3. Klinefelter syndrome. G-banded 47, XXY karyotype.
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Caption: Picture 4. Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.
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BIBLIOGRAPHY

Section 12 of 12

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• Swerdlow AJ, Schoemaker MJ, Higgins CD, et al: Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst 2005 Aug 17; 97(16): 1204-10[Medline].
• Yoshida A, Miura K, Nagao K, et al: Sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility. Int J Androl 1997 Apr; 20(2): 80-5[Medline].
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