Atlas of Genetic Diagnosis and Counseling || Klinefelter Syndrome

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  • Klinefelter Syndrome

    In 1942, Klinefelter et al. published a report on ninemen

    who had enlarged breasts, sparse facial and body hair,

    small testes, and an inability to produce sperm. In 1959,

    thesemenwithKlinefelter syndromewere discovered to

    have an extra sex chromosome (genotype XXY) instead

    of the usual male sex complement (genotype XY).

    Klinefelter syndrome is the most common sex chro-

    mosomal disorder associated with male hypogonadism

    and infertility. Approximately 1 in 5001,000 males is

    born with an extra X chromosome. Over 3,000 affected

    males are born yearly in the USA.

    Synonyms and Related Disorders

    47,XXY syndrome; Klinefelter syndrome mosaicism

    (46,XY/47,XXY, 46,XY/48,XXXY, 47,XXY/48,

    XXXY); Klinefelter syndrome variants (48,XXYY,

    48,XXXY, 49,XXXYY, 49,XXXXY); Klinefelter

    syndrome with structurally abnormal X chromosome

    [47,X,i(Xq)Y, 47,X,del(X)Y]

    Genetics/Basic Defects

    1. Caused by at least an additional X chromosome in

    a male

    2. The XXY form of Klinefelter syndrome

    a. Due to meiotic nondisjunction of the sex chromo-

    somes during gametogenesis in either parent

    b. Responsible meiotic nondisjunction

    i. About 40% occur in the father

    ii. About 60% occur in the mother

    a) Meiosis I errors (75%) when origin is


    b) Presence of maternal age effect in the

    maternally derived cases

    3. The mosaic forms of Klinefelter syndrome

    a. Due to mitotic nondisjunction after fertilization

    of the zygote

    b. Can arise from a 46,XY zygote or a 47,XXY


    4. The variant forms

    a. 48,XXXY: nondisjunction occurring either at the

    first or second meiotic divisions of oogenesis,

    resulting an XXX ovum which is then fertilized

    by a Y bearing sperm

    b. 49,XXXXY: please refer to 49,XXXXY chapter

    c. 48,XXYY and 49,XXXYY: occurrence of non-

    disjunction in paternal meiosis to have two

    Y chromosomes

    i. An X ovum fertilized by an XYY sperm aris-

    ing from successive nondisjunction in the first

    and second meiotic divisions, or

    ii. An XX ovum from 47,XXX mother fertilized

    by a YY sperm

    5. Pathophysiology (Chen 2011)

    a. The X chromosome carries genes that play roles in

    many body systems, including testis function,

    brain development, and growth (Giedd et al. 2007).

    b. The addition of more than one extra X or

    Y chromosome to a male karyotype results in

    variable physical and cognitive abnormalities.

    c. In general, the extent of phenotypic abnormali-

    ties, including mental retardation, is directly

    related to the number of supernumerary

    X chromosomes.

    d. As the number of X chromosomes increases,

    somatic and cognitive development are more

    likely to be affected.

    H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_141,# Springer Science+Business Media, LLC 2012


  • Clinical Features

    1. Growth

    a. Infants and children: normal heights, weights,

    and head circumferences

    b. Adolescents and adults

    i. Eunuchoid body habitus

    ii. Usually taller than average

    iii. Disproportionately long arms and legs

    2. Mild developmental, learning, and behavioral diffi-

    culties (70% of patients)

    a. Delayed speech and language acquisition

    b. Academic and reading difficulties

    c. Attention deficit disorder

    d. Poor self-esteem

    e. Insecurity

    f. Shyness

    g. Poor judgment

    h. Inappropriate assertive activity

    i. Decreased ability to deal with stress

    j. Fatigue

    k. Weakness

    3. CNS

    a. Normal intelligence in most cases

    b. Subnormal intelligence or mental retardation

    associated with a higher number of

    X chromosomes

    c. Diminished short-term memory

    d. Prone to epilepsy and essential tremor

    e. Psychiatric disorders involving anxiety, depres-

    sion, neurosis, and psychosis: more common

    than general population

    4. Taurodontism (enlargement of the molar teeth by an

    extension of the pulp): present in about 40% of

    patients (versus 1% in normal XY individuals)

    5. Cardiac and circulatory problems

    a. Mitral valve prolapse (55% of patients)

    b. Varicose veins (2040% of patients)

    i. Venous ulcers

    ii. Deep vein thrombosis

    iii. Pulmonary embolism

    6. A slightly increased risk of autoimmune disorder

    a. Rheumatic diseases (Rovensky et al. 2010)

    i. Inflammatory rheumatic diseases

    ii. Rheumatoid arthritis

    iii. Juvenile idiopathic arthritis

    iv. Psoriatic arthritis

    v. Polymyositis/dermatomyositis

    vi. Systemic lupus erythematosus

    vii. Systemic sclerosis

    viii. Mixed connective tissue disease

    ix. Antiphospholipid syndrome

    x. Ankylosing spondylitis

    b. Thyroid disease

    c. Sjogren syndrome

    d. Diabetes mellitus

    7. Sexual characteristics

    a. Gynecomastia secondary to elevated estradiol

    levels and increased estradiol/testosterone ratio

    i. Develop by late puberty in 3050% of boys

    with Klinefelter syndrome

    ii. Risk of developing breast cancer: at least 20

    times higher than normal

    b. Lack of secondary sexual characteristics second-

    ary to decrease in androgen production

    i. Sparse facial, body, and sexual hair

    ii. High-pitched voice

    iii. Female type of fat distribution

    c. Male psychosexual orientation in most patients

    d. Subnormal libido

    e. Erectile dysfunction

    f. Oligospermia or azoospermia

    g. Testicular dysgenesis in postpubertal patients

    i. Small, firm testes

    ii. Testis size

  • b. Klinefelter variants (Visootsak and Graham


    i. 48,XXYY variant (Tartaglia et al. 2008)

    a) Tall stature.

    b) Disproportionately long lower


    c) Clinodactyly.

    d) Pes planus.

    e) Hypertelorism.

    f) Dental problems.

    g) Gynecomastia.

    h) Intention tremor.

    i) Neurodevelopmental disorders, includ-

    ing developmental delays, ADHD,

    autism spectrum disorders, mood disor-

    ders, and tic disorders.

    j) Unusual dermatoglyphic patterns.

    k) Peripheral vascular disease, especially

    varicose veins and stasis dermatitis.

    l) Poorly developed secondary sexual


    m) Hypogonadism.

    n) Testicular histology similar to that of 47,

    XXY patients.

    o) The sex chromatin pattern indistinguish-

    able from that of the 47,XXY patients

    except two fluorescent Y bodies are pre-

    sent in a high proportion of somatic nuclei.

    ii. 48,XXXY variant

    a) Moderate to severe mental retardation

    b) Behavior: often immature and consistent

    with IQ level, typically described as pas-

    sive, cooperative, and not particularly


    c) Normal to tall stature

    d) Dysmorphic facies

    e) Radioulnar synostosis

    f) Fifth finger clinodactyly

    g) Hypergonadotropic hypogonadism

    h) Small testes

    i) Signs of androgen deficiency

    iii. 49,XXXYY variant

    a) Mental retardation

    b) Somatic anomalies

    c) Small testes

    iv. 49,XXXXY variant: severity and frequency

    of somatic anomalies increase as the number

    of X chromosomes increases

    a) Mental retardation

    b) Microcephaly

    c) Short stature

    d) Hypotonia with lax joints

    e) Facial dysmorphic features: ocular

    hypertelorism, flat nasal bridge, epicanthal

    folds, bifid uvula, or cleft palate

    f) Short neck

    g) Congenital heart defects

    h) Radioulnar synostosis

    i) Genu valgum

    j) Pes cavus

    k) Fifth finger clinodactyly

    l) Hypergonadotropic hypogonadism with

    small genitalia

    m) Behavioral disorders: shy, friendly,

    occasional irritability, temper tantrums,

    low frustration tolerance, and difficulty

    changing routines

    Diagnostic Investigations

    1. Cytogenetic studies

    a. 47,XXY (8090%)

    b. Mosaicism (10%)

    i. 46,XY/47,XXY

    ii. 46,XY/48,XXXY

    iii. 47,XXY/48,XXXY

    c. Variants

    i. 48,XXYY

    ii. 48,XXXY

    iii. 49,XXXYY

    iv. 49,XXXXY

    d. Structural abnormal X in addition to a normal

    X and Y

    i. 47,X,i(Xq)Y

    ii. 47,X,del(X)Y

    2. Endocrinologic studies

    a. A variable degree of feminization and insuffi-

    cient androgenization

    i. Elevated plasma FSH, luteinizing hormone,

    and estradiol levels

    ii. Low plasma testosterone levels in patients

    age 1214 years

    b. Subnormal increased testosterone in response to

    human chorionic gonadotropin administration

    3. Imaging studies

    a. Echocardiography to demonstrate mitral valve


    Klinefelter Syndrome 1233

  • b. Radiography

    i. Lower bone mineral density

    ii. Radioulnar synostosis

    iii. Taurodontism

    4. Histology

    a. Small, firm testes

    b. Seminiferous tubular hyalinization, sclerosis,

    and atrophy with focal hyperplasia of mostly

    degenerated Leydig cells

    c. Deficient or absent germ cells

    d. Rare spermatogenesis (azoospermia)

    e. Progressive degeneration and hyalinization of

    seminiferous tubules after puberty in mosaic


    Genetic Counseling

    1. Recurrence risk

    a. Patients sibs: recurrence risk not increased for

    nonmosaic patients

    b. Patients offspring

    i. Recurrence risk not increased since all 47,

    XXY individuals are infertile

    ii. Report of paternity in nonmosaic 47,XXY

    males (no other tissues were examined for

    possible mosaicism with a 46,XY cell line)

    c. A risk of having a 47,XXY offspring in a few 46,

    XY/47,XXY mosaic patients who fathered

    a child

    2. Prenatal diagnosis

    a. Cytogenetic analysis of fetal cells obtained from

    amniocentesis and CVS.

    b. Dilemma for parents since prognosis for the

    fetus with XXY is good but the possibility of

    phenotypic abnormalities does exist.

    c. Explanation to each couple the genetic risks

    resulting from intracytoplasmic sperm injection

    (ICSI) (increased risk of sex chromosome and

    autosome abnormalities).

    d. Preimplantation genetic diagnosis by embryo

    biopsy offers an efficient tool for embryo selec-

    tion (Friedler et al. 2001).

    3. Management

    a. Speech therapy.

    b. Physical therapy.

    c. Occupational therapy.

    d. Educational services.

    e. Reassurance of patients that most of the clinical

    features can be explained by the diminished

    ability of the testes to produce testosterone.

    f. Testosterone replacement: Optimal time to

    initiate therapy is at age 1112 years of age to

    allow for the maximum effect and permit

    boys to experience pubertal changes with their


    i. Corrects hormone imbalance (symptoms of

    androgen deficiency)

    ii. Improves self-image

    iii. Positive effect on mood and behavior

    iv. Increase in masculinity

    v. Increase in strength

    vi. Increase in libido

    vii. Increase in facial and pubic hair

    viii. Diminish fatigue and irritability

    ix. No positive effect on infertility

    g. Management of gynecomastia

    i. Androgen replacement therapy effective in

    achieving regression of less severe gyneco-

    mastia in some patients

    ii. Reduction mammoplasty or liposuction for

    severe or psychologically disturbing


    h. Management of infertility (Lanfranco et al.


    i. Nowadays patients with Klinefelter syndrome,

    including the nonmosaic type, need no longer

    be considered irrevocably infertile because

    intracytoplasmic sperm injection offers an

    opportunity for procreation even when there

    are no spermatozoa in the ejaculate.

    ii. In a substantial number of azoospermic

    patients, spermatozoa can be extracted

    from testicular biopsy samples, and

    pregnancies and live births have been achieved.

    iii. The frequency of sex chromosomal hyper-

    ploidy and autosomal aneuploidies is higher

    in spermatozoa from patients with

    Klinefelter syndrome than in those from nor-

    mal men. Thus, chromosomal errors might in

    some cases be transmitted to the offspring of

    men with this syndrome.

    iv. The genetic implications of the fertilization

    procedures, including pretransfer or prenatal

    genetic assessment, must be explained to

    patients and their partners.

    1234 Klinefelter Syndrome

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