Klinefelter syndrome

Harry Klinefelter first described a syndrome in patients with gynecomastia, small testes, sterility, and increased excretion of FSH – later to be named Klinefelter syndrome (Klinefelter et al. 1942). Klinefelter syndrome occurs in approximately 1 in 500 live births and is the most common genetic cause of hypogonadism and male infertility (Lanfranco et al. 2004). This syndrome is caused by congenital aneuploidy of the sex chromosomes, with the majority (80%) of patients having the 47‐XXY karyotype (Figure 9.4), and the remainder having mosaic 47‐XXY/46‐XY (different chromosome number in different cells), supernumerary X chromosome aneuploidy (48‐XXY; 49‐XXXXY) or additional Y‐chromosomes (48‐XXYY). These chromosomal abnormalities are due to chromosomal nondisjunction during maternal and paternal gametogenesis (Tüttelmann and Gromoll 2010).

Clinical presentations of Klinefelter syndrome are small firm testes, low serum testosterone concentrations, and azoospermia. However, some men with mosaicism can have normal testicular size and active spermatogenesis at puberty, but spermatogonial stem cells are progressively lost over time, reducing mature sperm counts dramatically. Patients with Klinefelter syndrome may also display symmetrical gynecomastia and tall stature with long legs and a short trunk. Beard growth and other secondary sexual hair growth are often sparse (see Figure 9.3 for a summary). Diagnosis of Klinefelter syndrome is confirmed by karyotyping (Figure 9.4) (Lanfranco et al. 2004; Nieschlag 2013).

Treatment of Klinefelter syndrome involves testosterone replacement therapy, which can attain increased masculinity including increased muscle mass and strength, increased bone density, and thicker secondary hair growth. Increased libido and a decrease in erectile dysfunction and depressive moods and are also achieved (Vignozzi et al. 2010).

Although fertility cannot be restored in men with Klinefelter syndrome, biological fatherhood can be achieved, in some cases, using surgical sperm retrieval and intracytoplasmic sperm injection (ICSI) (Bakircioglu et al. 2011; Greco et al. 2013).

A recent study has demonstrated that during reprogramming to induced pluripotent stem cells (iPSC), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome, by a phenomenon termed trisomy‐biased chromosome loss. The resulting euploid XY iPSCs can then be differentiated into functional sperm that can be used in ICSI to produce chromosomally normal, fertile offspring. The findings have relevance to overcoming infertility and other trisomic phenotypes, like Klinefelter syndrome (Hirota et al. 2017).

Y‐chromosome microdeletions

The Y chromosome is the smallest chromosome containing 60 million base pairs, and is divided into a long arm (Yq) and a short arm (Yp). The genetic information on the Y chromosome contains the SRY gene, which is important for male sex determination, and different spermatogenesis loci named azoospermia factors (AZFa, b, and c – see Figure 9.5). Deletions in these regions remove one or more of the candidate genes (DAZ, RBMY, USP9Y, and DBY) and cause severe testiculopathy leading to male infertility and decreased or absent spermatogenesis (Chandley 1998; Li, Haines and Han 2008; Krausz and Casamonti 2017). A fourth AZF region, between AZFb and AZFc, termed AZFd, has been described and found in patients with mild oligozoospermia or even normal sperm counts and abnormal sperm morphology (Kent‐First et al. 1999; Müslümanoglu et al. 2005).

Approximately 7% of men with severe oligospermia and 13% of men with azoospermia have microdeletions of the Y chromosome (Najmabadi et al. 1996). Deletions removing the entire AZFa or AZFb regions (complete deletions) are associated with azoospermia due to Sertoli cell‐only syndrome and spermatogenic arrest, respectively. The partial deletions of AZFa and AZFb are associated with residual sperm production. The complete AZFc deletions are associated with a variable semen sperm content ranging from oligozoospermia (fewer than 2 million sperm/mL) to azoospermia (sperm absent in semen). In hormone analysis, concentrations of testosterone and LH in serum are generally normal, but FSH concentration is raised because of decreased production of inhibin B and loss of negative feedback (Krausz and Casamonti 2017). In some cases of Y chromosome, microdeletions can present with cryptorchidism (Foresta et al. 1999).

The diagnosis of microdeletions is performed by multiplex polymerase chain reaction (PCR) amplification of selected regions of the long arm of the Y chromosome from genomic DNA derived from white blood cells. Lack of PCR amplification suggests the presence of a microdeletion, which should be confirmed by a separate PCR reaction based on different primers (Nakashima et al. 2002; Hopps et al. 2003).

Treatment of men with Y‐chromosome microdeletions will depend on the region deleted on the Y chromosome, with successful biological fatherhood achieved in some cases through the use of surgical sperm retrieval and ICSI. However, Y chromosomal microdeletions can be transmitted from a father to a son via ICSI suggesting that the microdeletions may be expanded during such transmission. It is imperative, therefore, that genetic counselling is offered for infertile couples contemplating ICSI in cases where the male carries Y chromosomal microdeletions (Komori et al. 2002).

Noonan Syndrome

Noonan syndrome is a relatively common genetic disorder (1 in 1000 to 1 in 2500) with multiple congenital abnormalities. It is characterized by short stature and broad webbed neck, facial dysmorphia, sternal deformity (pectus carinatum and/or excavatum), and congenital heart disease (Tafazoli et al. 2017). Noonan syndrome is genetically heterogeneous with approximately half the cases caused by activating germline mutations in the PTPN11 gene, but other cases have since been shown to be because of gain‐of‐function mutations in KRAS,6 SOS1,7,8 and RAF1.9 (Tartaglia et al. 2001).

Cryptorchidism has been reported in 80% of boys with Noonan syndrome. In many cases LH and testosterone levels are essentially normal in men, while FSH levels are raised in the men with cryptorchidism. Although sexual function is not affected in men with Noonan syndrome, the onset of sexual activity can be delayed with late onset of puberty. Bilateral cryptorchidism appears to be the main factor contributing to impairment of fertility in men with Noonan syndrome, which can result in azoospermia or oligozoospermia (Elsawi et al. 1994). However, in other reports, men with normal testicular descent displayed signs of Sertoli cell dysfunction, indicating that bilateral cryptorchidism may not be the main contributing factor to impairment of testicular function in Noonan syndrome (Marcus et al. 2008).

Acquired Primary Hypogonadism

Chemical insult, injury, or infection of the testis can result in testicular dysfunction and impaired spermatogenesis resulting in infertility. See Chapter 13 for more detail on the pathologies of the testis and how this can impact on testicular function. Chapter 14 covers the impact of infection on fertility and Chapter 17 details the impact of environmental exposures on testicular function. The following is a brief description of factors responsible for primary hypogonadism.

Orchitis

Infections and inflammations of the testis (orchitis) are responsible for the most frequent causes of reduced sperm quality. Bacterial infections can result in activation of the immune cells and mediators involved in the inflammatory processes, inducing irreversible damage to seminiferous tubules leading to reduced spermatogenesis and corresponding decline of sperm quality and number (Trojian et al. 2009). Infection of the testis that spreads to the epididymis is referred to as epididymo‐orchitis (Kaver et al. 1990). Bacterial testicular infection may result in permanent azoospermia or oligospermia, which can lead to male infertility (Osegbe 1991; Schuppe 2010). In men under 35 years of age, epididymo‐orchitis is most commonly caused by sexually transmitted Neisseria gonorrhoeae or Chlamydia trachomatis infection. In those younger than 14 years or older than 35 years, epididymo‐orchitis is generally caused by infection with common urinary tract pathogens, such as Escherichia coli (Walker and Challacombe 2013).

The symptoms of orchitis are often difficult to differentiate from those of other acute testicular conditions such as testicular torsion, which is the most important differential diagnosis of acute testicular pain, especially in younger men (Arap et al. 2007). If there is any suspicion of testicular torsion, the patient should be referred to secondary care immediately as surgery is required within 4–6 h. Patients who are in severe pain or systemically unwell should be referred for analgesia, intravenous antibiotics, and hydration (Walker and Challacombe 2013).

Mumps‐Related Orchitis

Mumps (epidemic parotiditis) is a highly contagious viral disease caused by a single‐stranded RNA virus belonging to the genus Rubulavirus and the family Paramyxoviridae. This virus can spread from human to human by direct contact, airborne droplets, and from fomites contaminated saliva. The clinical presentations of mumps are headache, malaise and low‐grade pyrexia, followed by unilateral or bilateral parotid swelling in 60–70% of infections, and in 95% of patients are symptomatic. In prepubertal males the most common symptoms are those associated with infectious parotitis. Since the implementation of widespread vaccinations, the presentation of orchitis related to mumps is seen in pubertal and postpubertal males (Philip et al. 2006; Singh et al. 2006). Orchitis is seen in 15–30% of men with mumps and presents as painful testicular enlargement.

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