Researchers are starting to realise there is more to being an XXY than merely administering exogenous testosterone and having that person virilse. One of several consequences is how exogenous testosterone conceals the underlying impact of having three sex chromosomes in every cell, affecting our entire biological makeup. Not least is a Neurocognitive weakness that makes it difficult for the individual to adequately explain the impact Testosterone has on them, an experience that is especially true in instances concerning children, who completely trust what a parent or doctor expects of them even though this is not always warranted. Researchers now realise that such a pre-symptomatic diagnosis of Klinefelter’s Syndrome is problematic because XXY children who might otherwise develop normally will grow up under specific parental worries and expectations that may ultimately not be confirmed at all.
Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in men. It occurs approximately in one out of 660 males. KS males have one or more extra X chromosomes in addition to normal male 46, XY karyotype. The additional X chromosome can be present in all or only in some of the cells. The classic form of KS (47, XXY) appears in 80%–90% of all the males with KS.
KS is highly underdiagnosed due to large phenotypic variation. According to some studies, less than half of the males with KS are diagnosed during their lifetime. In our unit, the average age at diagnosis of KS was 6.7 years. Only a minority of boys with KS are diagnosed prenatally, usually due to suspicion of other chromosome disorders than KS. A good and efficient alternative to prenatal diagnosis is to involve KS in neonatal screening. Early diagnosis of KS allows for appropriate treatment and helps to prevent possible complications in childhood and later in adolescence.
In newborns with KS, the first signs can appear as microphallus and undescended testes. Growth in height accelerates from the age of 3 years onward, and, on average, adult men with KS are taller than the general population. Learning difficulties, delayed speech development, or problems in relationships with their peers and siblings during childhood are more frequent than in boys with normal karyotype. Among boys with KS, gynecomastia is common at pubertal age, but it is transient in most cases. Testes are smaller in size already in childhood, and in puberty, they fail to grow normally, which leads to small, firm testes in adulthood. KS is the most common reason for male infertility, even though few spermatozoa can be found by testicular sperm extraction technique in more than 40% of males with KS.
In childhood and early puberty, testosterone level stays rather normal in boys with KS while increasing degeneration of germ cells has been observed since the foetal period. The number of germ cells decreases further during puberty when hyalinisation of seminiferous tubules begins and Sertoli cell degeneration and Leydig cell hyperplasia can be seen. The serum levels of follicle-stimulating hormone (FSH) and especially luteinizing hormone (LH) start to increase in early puberty, which stimulates testosterone production. Around mid-puberty, the response of Leydig cells to the increased level of LH fails, which leads to declining testosterone level and relative androgen deficiency. Declining Leydig and Sertoli cell function ultimately leads to hypergonadotropic hypogonadism in which gonadotropin levels stay rather high while testosterone level is low. In addition, testes of KS patients have four times higher expression of aromatase activity than normal, leading to a high estradiol–testosterone ratio.
Some data discrepancies can be found on the timing of the onset and progression of puberty in KS patients. Some researchers have reported on a delayed onset or progression of puberty in boys with KS, while others claim that KS has no effect on the timing of puberty. Therefore, more information about pubertal timing and the progression of boys with KS is needed. The aim of this retrospective study was to examine the onset and progression of puberty and testosterone supplementation in boys with KS in a single tertiary referral centre.
The data of the Children’s Hospital, Helsinki University Hospital, a single tertiary centre of the Helsinki metropolitan area, were investigated from years 2004 to 2018. Altogether, 113 patients with KS born in 1967–2017 were found on the electronic patient registry by using the International Classification of Diseases 10 diagnoses listed in Table. Boys with mosaic KS or more than two X chromosomes and boys with no available data on pubertal development were excluded from the analysis. Altogether, 72 boys with classic KS (47,XXY), who were born between 1986 and 2006, were included in this study. Some data on a small subset of the boys have been published previously. By the end of the data collection in 2018, 72% (52 out of 72) of boys with KS were over 18 years old.Onset and progression of puberty in Klinefelter syndrome
Tanner, Miettinen, Hero,Toppari, Raivio