Klinefelter Syndrome

Article Author:
Evan Los
Article Editor:
George Ford
Updated:
3/20/2018 4:23:34 PM
PubMed Link:
Klinefelter Syndrome

Introduction

Klinefelter syndrome (KS) is the result of 2 or more X chromosomes in a phenotypic male. The clinical phenotype of KS was first described in males with tall stature, small testes, gynecomastia, and azoospermia with the genetic etiology of supernumerary X chromosomes identified in 1959. Extra X chromosomes lead to testicular hyalinization, fibrosis and testicular hypofunction which may result in genital abnormalities, and usually hypogonadism and infertility. Neurocognitive differences associated with KS began to be recognized through the middle and latter part of the 20th century. Often, androgen replacement and neuropsychological and adaptive therapies are beneficial in the medical management of KS. However, deficits in clinical care do exist as there are gaps in diagnosis, lack of standardization of care, and access to treatments are not always available or affordable

Etiology

The most common KS karyotype is 47, XXY (greater than 90%). Mosaic karyotypes such as 46, XY/47, XXY and other aneuploidies such as 48, XXXY and 49, XXXXY have been described. The acquisition of the extra X-chromosome is random and usually due to meiotic nondisjunction or post-zygotic nondisjunction. Overall severity of the phenotype appears to be correlated with the amount of additional X chromosome material present.

Epidemiology

KS is the most common form of aneuploidy, which occurs when an individual has an abnormal number of chromosomes in a cell. KS has an estimated prevalence of between 1:500 to 1:1000 males. KS is not always recognized prior to adulthood and may be diagnosed later. However, recognition of and diagnosis of KS typically occurs after one or more of the items listed below come to clinical attention.

  • By prenatal testing or because of genital abnormalities seen at birth in a child with hypotonia 
  • In an adolescent with learning or behavioral difficulties 
  • In an adolescent evaluated for tall stature, small testicular size or incomplete puberty
  • In adult men evaluated for infertility (3% of all men evaluated for infertility have KS)

However, up to two-thirds of cases of KS may go undiagnosed. Comparative studies suggest that KS may occur more often in the setting of increasing parental age, environmentally-derived errors in meiosis I, or decreased elective termination for prenatally-diagnosed cases. Underdiagnosis is also likely due to variable phenotype with many cases having only subtle findings. It is estimated that approximately a quarter of individuals with KS have no discernable diagnostic features by history or exam. With the increased use of non-invasive prenatal testing (NIPT), the frequency of prenatal diagnosis is expected to increase, resulting in early diagnosis management by health care professionals who care for children.

Pathophysiology

The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in KS are not well characterized. Studies are ongoing to determine the influence of genetic polymorphism, skewed X-inactivation, parental origin of the extra X chromosome, and gene dosage.

Extra X-chromosome material is responsible for testicular hyalinization and fibrosis leading to primary gonadal failure that often evolves through adolescence and young adulthood. If there is early dysfunction, the affected newborn manifests microphallus, hypospadias, cryptorchidism, and unusually small testes. Later, evolving hypogonadism leads to incomplete puberty and gynecomastia. Long-term, hypogonadism and infertility are typical.

The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome leads to tall stature, long limbs, and reduced upper/lower segment ratio. 

The pathophysiology of neuropsychological differences observed in KS is not well-understood.

Histopathology

Seminiferous tubules demonstrate hyalinization and fibrosis in the setting of gonadotropin excess leading to firm, often undersized, testes. Limited studies of testicular biopsies from patients with KS demonstrate reduced germ cell number across the lifespan with a progressive deficit, especially following puberty and only infrequent pockets of spermatogonia in adulthood.

History and Physical

Most patient with KS will present with tall-stature and long limbs, reflected in low upper/lower segment ratio. Mean height is at the 75th percentile with weight and head circumference at the 50th percentile.

In childhood, the phallus and testes may be relatively small. During adolescence, there is discordant pubertal development with fairly normal phallus and pubic hair development, although testes rarely exceed 4 mL and are characteristically firm due to hyalinization and fibrosis. Testosterone levels are usually in the low to the low-normal range. Gynecomastia is common.

A wide range of intelligence quotients (IQs) has been described; however, mean full-scale IQ is between 85 to 90. Verbal IQ is higher than performance due to problems with expressive language and auditory processing. Behavioral difficulties including immaturity, insecurity, shyness, poor judgment, and the formation of meaningful peer relationships may be affected. Between 20% to 50% of individuals with KS have an intention tremor.

Evaluation

Diagnosis of KS is typically made by prenatal or postnatal karyotype or chromosomal microarray. Non-invasive prenatal testing for cell-free DNA can identify sex chromosome abnormalities. Published positive predictive values in the detection of KS via NIPT are 67%. Additional prenatal testing or postnatal testing is suggested to confirm any suspected case.

The initial evaluation of KS may include a workup for hypogonadism or infertility. In KS, gonadotropins are usually elevated when testicular hyalinization and fibrosis is present, though this may evolve over adolescence. The finding of hypogonadotropic hypogonadism indicates primary gonadal failure. FSH elevation typically predominates over LH, though both are elevated above normal. Testosterone concentrations are usually low or low-normal in both adolescents and adults. A minority of children may demonstrate low inhibin B and elevated AMH reflecting abnormal Sertoli cell function, but it is unclear whether identifying these differences is predictive of future gonadal failure.

Treatment / Management

Earlier diagnosis of KS (often in utero) has permitted earlier developmental evaluation and intervention services to assist with neuropsychological development. Speech-language delays and motor skills delays are present in 50% to 75% of cases; therefore, proactive measures to screen for and address these delays are recommended. Speech delays that are not addressed may limit self-expression and impact tolerance for frustration and contribute to behavioral issues. Hypotonia with hypermobility, pes planus, and genu valgum can affect motor development including handwriting and self-care; therefore, physical, occupational therapy and adaptive treatments such as orthotics may be needed.

Supplemental testosterone treatment under the supervision of a pediatric endocrinologist may prevent some of the physical manifestations of the "classic KS phenotype." Hypogonadism in KS may start early in the fetus, and it plays a role in underdeveloped genitalia, cryptorchidism, reduced germ-cell number, small testicular size, and blunted "mini-puberty" of infancy. Some providers give supplemental testosterone during the first few months of life for treatment of microphallus, though limited retrospective data suggests possible cognitive and behavioral benefits; prospective studies are ongoing. If cryptorchidism or an inguinal hernia is present, the infant should be referred to a pediatric urologist.

In adolescence, most boys with KS will enter puberty normally, and endogenous testosterone usually supports virilization with penile enlargement and pubic hair development. However, these individuals may not have as much facial or body hair as expected. Supplemental testosterone may help minimize gynecomastia that often develops during adolescence. Other treatments for gynecomastia either have not been effective (aromatase inhibitors), have limited published data in KS (tamoxifen), or are invasive (surgery) and are at risk of recurrence. To be properly educated about these issues, to build rapport, and to outline future monitoring and treatment plans, boys and their parents should establish care with a pediatric endocrinologist around the onset of puberty. The age at which to start androgen replacement is not standard and should be individualized. It may start at the time of pubertal onset or be delayed until there is clear evidence of hypogonadism which may be late adolescence or early adulthood. Guidelines for hormone replacement for men with hypogonadism are available from the Endocrine Society.

Advanced reproductive technology such as testicular sperm extraction (micro-TESE) has been successful in allowing up to half of the men with KS deemed "infertile" to have an opportunity to have a biologic child. Small pockets of gonadal tissue producing sperm may be identified, extracted and then injected by intracytoplasmic sperm injection into an ovum for fertilization.

Long-term, men with KS are more likely to develop disorders related to insulin resistance such as type-2 diabetes, dyslipidemia, and fatty liver disease as well as peripheral vascular disease and thromboembolic disease. Careful screening and aggressive preventive measures are recommended. Bone mineral density may also be negatively affected, likely related to hypogonadism, so attention to bone health is important. Some studies have documented higher rates of autoimmune disorders. Finally, the risk for certain malignancies is increased. These include breast cancer, extragonadal germ cell tumors, and non-Hodgkin lymphoma. Although the overall frequencies are still very low, and no routine screening is warranted, suspicious symptoms should be investigated.