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Disease definition: A Most common sex chromosome abnormality resulting from the addition of one extra X chromosome to the usual male karyotype, 46XY.
Synonyms: 47XXY,
Overview
Most common cause of male hypogonadism and infertility, affecting approximately 1 in 600-1 in 800 male live births. Klinefelter syndrome is usually diagnosed as part of infertility investigations or when antenatal screening is carried out for another reason, for example, increased risk of Down syndrome.
Although the phenotype is very variable, features include testicular dysgenesis, elevated gonadotrophins, microorchidism (hypergonadotrophic hypogonadism, and gynacomastia. These clinical features are not usually present until mid to late adolescence.
Some children may experience a slight delay in motor and language development, with two thirds having a delay in walking. A lag in verbal-intellectual skills, compared with nonverbal skills, may be apparent by the age of four years. By school age, an increased incidence of apraxia and coordination problems may also be observed.
Behaviourally, boys with Klinefelter syndrome tend to be shy and placid with low self confidence. They are often described as non-assertive and may display a greater level of immaturity when compared to their peers. Problems in childhood may lead to psychosocial problems later in life; however, the majority will lead an independent life, forming relationships and gaining employment.
Antenatal diagnosis is associated with improved outcome when compared to individuals ascertained in other ways but this is likely to be the result of ascertainment. However it may alert parents to the condition and allow for appropriate environmental adjustments, which allow individuals to reach their full potential. This may suggest that a supportive and nurturing environment is important for prognosis.
Testosterone treatment improves general well being and is also important to reduce the incidence of cardiovascular disease and osteoporosis, as well as to increase libido.
Inheritance
Klinefelter syndrome usually results from chromosome non-separation during formation of parental eggs or sperm, and there is evidence of an association with increased maternal age. Klinefelter syndrome can also arise from somatic cell division errors after fertilization (resulting in mosaicism, where only a proportion of cells have an abnormal chromosome number). All chromosomal abnormalities associated with Klinefelter syndrome are sporadic events and, therefore, recurrence risk is low.
The diagnosis of Klinefelter syndrome is made when the chromosome complement of an individual is 47XXY; however, variant syndromes such as 48XXXY and mosaicism, are also occasionally observed. 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. Moreover, mental capacity diminishes with additional X chromosomes.
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Chromosome complement |
Phenotype |
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46XY/47XXY |
Klinefelter syndrome but tends to be milder
- The presence of a proportion of normal cells reduces the risk of developmental delay and fertility may be possible
- Testosterone treatment may not be indicated
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48XXYY |
- Boys tend to be taller with long lower extremities
- IQ is generally reduced with speech and motor delay more commonly occurring
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48XXXY |
- May result in a more abnormal phenotype with hypertelorism, epicanthic folds, simple ears and mild prognathism
- Stature is tall and there may be skeletal abnormalities including:
o clinodactyly
o elbow abnormalities
o radioulnar synostosis
- Mild to moderate mental retardation associated with a passive personality is often observed
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49XXXXY |
- As well as the above facial features, the neck may be short and thorax narrow
- Up to a quarter of cases have cardiac defects, usually patent ductus arteriosus (persistence of a normal foetal structure between the left pulmonary artery and the descending aorta)
- Skeletal abnormalities are more common, including hyperextensible joints
- Learning difficulties are more common
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Features of Klinefelter syndrome
The phenotype is very variable and is often not fully expressed.
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Growth and feeding |
- Neonates with Klinefelter syndrome are generally unremarkable with normal growth parameters
- Height velocity tends to be increased by 5 years of age; therefore, individuals tend to be taller than their peers, with an increase in leg length
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Development and behaviour
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- Slight delay in motor development possible —approximately two thirds have a delay in walking
- Language milestones may also be delayed, particularly when compared to siblings
- By 4 years of age, verbal-intellectual skills lag behind nonverbal skills
- Overall IQ tends to be lower than that of siblings
- However, development is variable with some boys showing no delay at all
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Personality characteristics |
- Shyness, lack of assertiveness and immaturity are common features — the delay in language skills is thought to be a contributing factor
- Aggressive behaviour has been reported due to frustration, but is not characteristic
- Some report an increased incidence of attention deficit and hyperactivity disorder
- Adolescents may lack confidence, which can limit academic and physical success
- Due to problems in childhood, some individuals may experience social and emotional problems later in life
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Endocrine |
- Sexual development is normal in infancy and childhood
- The normal adolescent elevation of testosterone tends to plateau at 14 years of age. Serum levels remain low and so by mid-puberty, FSH and LH gonadotrophin levels have risen
- Testicular growth is arrested, resulting in a reduced testicular size throughout adulthood
- Progressive hyalinisation and fibrosis and reduced number of Leydig cells result in low levels of testosterone and infertility
- Sexual function is normal but the ejaculate contains no sperm
- Gynacomastia can occur in adolescents, which may or may not regress
- Although facial, axillary and pubic hair growth is observed, this is to a lesser extent than would be expected in normal males
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Cardiovascular |
- Increased incidence of mitral valve prolapse, as well as an increased risk of cardiovascular disease due to increased cholesterol levels — can be reduced with testosterone treatment
- Research indicates an increased incidence of chronic leg ulcers, possibly associated with testosterone deficiency or vascular abnormality
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Immunological |
- There is an increased incidence of certain autoimmune diseases including systemic lupus erythematosis, diabetes mellitus and thyroid disturbances
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Neoplasia |
- Recent studies have not shown an overall increased risk of cancer in klinefelters syndrome. however there is an increased incidence (<1%) of extragonadal germ cell tumours:
o Usually occur in the mediastinum
o Individuals may present with respiratory symptoms, particularly between adolescence and the age of 30
o In younger boys these tumours may result in precocious puberty
- Increased risk of breast cancer — ~20 times higher than that of the normal male population
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Dental |
- Taurodontism (enlarged tooth size with reduced root size) and early tooth decay may occur
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Diagnosis
Differential diagnosis:
- Kallman syndrome: characterised by hypogonadotrophic hypogonadism and anosmia (absent sense of smell); similar physical features to Klinefelter syndrome are also observed.
Chromosome analysis can be used to determine the number of X chromosomes present and provides a definite diagnosis of Klinefelter syndrome.
Testing
Karyotyping can be carried out postnatally on blood lymphocytes or fibroblasts (from skin biopsy), or prenatally from amniocytes or chorionic villi.
Referral
Once a diagnosis of Klinefelter syndrome has been made, individuals should be referred to an endocrinologist who can monitor sexual development and initiate testosterone treatment at the appropriate stage of development. Growth and development can also be monitored.
Referral to a clinical geneticist, both in pre and postnatally diagnosed cases, may also be useful. Despite Klinefelter syndrome being regarded as a relatively benign condition, up to 70% of pregnancies are terminated following a positive diagnosis. Studies have shown that the termination rate is lower if parents are referred for genetic counselling. Recurrence risks may also be of concern to parents.
When a diagnosis of Klinefelter syndrome is made in a man, referral to an infertility specialist may be appropriate. A number of techniques such as intracytoplasmic sperm injection (ICSI) have now been developed to enable some such individuals to have biological children.
In all age groups, psychosocial problems may prompt referral to a psychologist. In conjunction with body image problems, some men may also have psychological and social problems due to personal characteristic and developmental delays.
Management
Prompt recognition and management significantly improves the patient’s quality of life. Children with Klinefelter syndrome should be treated as normally as possible; however, it is important to safeguard against complications, particularly those associated with testosterone deficiency.
Referral to an endocrinologist at the age of 10 is reasonable. Lifelong testosterone replacement therapy may be indicated when serum concentrations are low and should be initiated as early as possible. Testosterone treatment can be administered in various forms and should be undertaken by an endocrinologist. Baseline gonadotrophin FSH and LH levels should be obtained at 12-13 years of age or at diagnosis if later than this age.
Early testosterone replacement results in increased masculinity, strength, libido, bone mineral density and body hair. It also has a positive effect on self esteem and general well being, which may reduce the risk of psychosocial problems in adult life.
Testosterone treatment also has a positive effect on cardiovascular and vascular endothelial complications, and anaemia. Cholesterol levels should be checked as testosterone treatment can reduce plasma concentrations.
Testosterone treatment does not affect fertility; this must be managed by an infertility specialist who may be able to offer solutions such as ICSI following sperm extraction. Testosterone therapy also has little effect on gynaecomastia, but this can be treated surgically if necessary.
The growth and development of children with Klinefelter syndrome should be monitored as normal and referral made only if necessary, for example to a physiotherapist or speech and language therapist if delays are apparent.
Early intervention is recommended for individuals with learning difficulties to allow them to reach their full potential. Parents and carers should facilitate successful experiences, and build self esteem and self confidence.
Patients should also be made aware of the existence of self help and support groups. |
