Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly. Subjects affected by the condition are almost always phenotypically male, with common complications such as infertility and small, poorly functioning testicles. Although this is one of the most common chromosomal disorders, symptoms are often noticed only at puberty. The birth prevalence of KS in the State of Victoria, Australia, was estimated to be 223 per 100,000 males. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s, along with his colleagues at Massachusetts General Hospital.
The syndrome is defined by the presence of at least two X chromosomes in addition to a Y chromosome, yielding a total of 47 or more chromosomes rather than the usual 46. Sometimes certain chromosome anomalies such as 48,XXXY, 48,XXYY or 49, XXXYY are considered variants of Klinefelter syndrome.
Klinefelter syndrome occurs randomly. An older mother may have a slightly increased risk of a child with KS. The syndrome is diagnosed by the genetic test known as karyotyping.
Signs and symptoms
Klinefelter syndrome has different manifestations and these will vary from one patient to another. Among the primary features are infertility and small testicles. Often, symptoms may be subtle and many people do not realize they are affected. In other cases, symptoms are more prominent and may include weaker muscles, greater height, poor motor coordination, less body hair, gynecomastia (breast growth), and low libido. In the majority of the cases, these symptoms are noticed only at puberty.
Prenatal Chromosomal abnormalities, including Klinefelter syndrome, are the most common cause of spontaneous abortion. Generally, the severity of the malformations is proportional to the number of X chromosomes present in the karyotype. For example, patients with 49 chromosomes (XXXXY) have more extreme manifestations than those with 48 chromosomes (XXXY).
Physical manifestations
Prepubertal At birth, bodily length, weight and head circumference are slightly lower on average than in males without XXY, though still generally within the normal range. Subtle featural changes may be observed, such as fifth finger clinodactyly (a curved fifth finger), high-arched palate, epicanthal folds and hypertelorism (increased distance between the eyes). In infancy, micropenis and cryptorchidism (an undescended testis or testes) are more frequent than in males without XXY, but still uncommon (<10%).
As babies and children, those with XXY chromosomes may have lower muscle tone and reduced strength. They may sit up, crawl, and walk later than other infants. An average KS child will start walking at 19 months of age. They may also often have less muscle control and coordination than other children of their age.
Pubertal and post-pubertal During puberty, KS subjects show less muscle mass, less facial and body hair, and broader hips as a consequence of low levels of testosterone. Delays in motor development may occur. As teens, persons with XXY may develop more breast tissue, have weaker bones, and a lower energy level than others. Testicles are affected and are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4 ml in volume.
By adulthood, individuals with KS tend to become taller than average, with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, and narrower shoulders. Some will show few or no symptoms, a lanky, youthful build and facial appearance, or a rounded body type. Gynecomastia (increased breast tissue) in males is common, occurring in up to 80% of cases. Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery.
Individuals with KS are often infertile or have reduced fertility. Advanced reproductive assistance is sometimes required in order to produce offspring since approximately only 50% of males with Klinefelter syndrome can produce sperm.
Psychological characteristics
Cognitive development Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions. It is estimated that 10% of those with Klinefelter syndrome are autistic. Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.
Language milestones may also be delayed, particularly when compared to other people their age. Between 25% and 85% of persons with XXY have some kind of language problem, such as delay in learning to speak, trouble using language to express thoughts and needs, problems reading, and auditory processing issues. They may also have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers.
Behavior and personality traits Compared to individuals with a typical number of chromosomes, males affected by Klinefelter syndrome may display behavioral differences. These are phenotypically displayed as higher levels of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood, and low frustration tolerance. These neurocognitive disabilities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.
In 1995, a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. It demonstrated that children with XXY tend to be quiet, shy and undemanding; they are less self-confident, less active, and more helpful and obedient than other children their age. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other children.
As adults, they live lives similar to others without the condition; they have friends, families, and normal social relationships. Nonetheless, some individuals may experience social and emotional problems due to problems in childhood. Persons with XXY show a lower sex drive and low self-esteem, in most cases due to their feminine physical characteristics.
Concomitant illness Those with XXY are more likely than others to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. Nonetheless, the risk of breast cancer is still below the normal risk for women. These patients are also more prone to develop cardiovascular disease due to the predominance of metabolic abnormalities such as dyslipidemia and type 2 diabetes. It has not been demonstrated that hypertension is related with KS.
In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in those with XXY than in those without, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.
SRY-negative Klinefelter syndrome Different to typical Klinefelter syndrome, SRY-negative Klinefelter syndrome is extremely rare. People with SRY-negative Klinefelter syndrome have normal female phenotype and are able to get pregnant.
Cause
Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases and from the father in the other 50%. Maternal age is the only known risk factor. Women at 40 years have a four-times-higher risk of a child with Klinefelter syndrome than women aged 24 years.
The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II, also known as gametogenesis. The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY or Klinefelter offspring. Fertilizing a double X egg with a normal sperm also produces an XXY or Klinefelter offspring.
Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in approximately one in 500 live male births.
In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed.
Variations The condition 48,XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births. These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, urinogenital and other anomalies. Thirteen cases of individuals with a 47,XXY karyotype and a female phenotype have been described.
Mosaicism Approximately 15–20% of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only approximately 10 cases of 47,XXY/46,XX have been described in literature.
Random versus skewed X-inactivation
Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelter's, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.
Pathogenesis The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, testicular growth also is arrested.
Destruction and hyalinization of the seminiferous tubules cause a reduction in the function of Sertoli cells and Leydig cells, leading to decreased production of FSH and testosterone. This results in impaired spermatogenesis and further endocrine dysfunction.
Diagnosis