European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

Abstract

Background Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. Objective To create the first European Academy of Andrology (EAA) guidelines on KS. Methods An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone‐related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. Conclusion These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.

Strategies to improve early diagnosis of Klinefelter syndrome

“…Prenatal diagnosis has also the possible risk of increasing the abortion rate. Therefore, the best way to increase the diagnostic rate at birth is to perform karyotype analysis in newborns with bilateral cryptorchidism (above all when spontaneous descent does not occur in the first year) and micro-penis (Table 1), as per guidelines [18].…”

“…Although the clinical signs are quite nonspecific in this period, some features (and above all their combination) might be useful for clinical suspect. The common feature of Klinefelter syndrome includes primary testicular failure starting from mid-puberty, with testicular hypotrophy and elevated gonadotropins, associated in about half of the cases with low testosterone and signs of hypogonadism [18]. Therefore, diagnosis should be suspected in cases characterized by normal starting of puberty, followed by its arrest, lack of testicular growth and hypergonadotropic hypogonadism or compensated hypogonadism (elevated gonadotropins with still normal testosterone levels).…”

“…Therefore, diagnosis should be suspected in cases characterized by normal starting of puberty, followed by its arrest, lack of testicular growth and hypergonadotropic hypogonadism or compensated hypogonadism (elevated gonadotropins with still normal testosterone levels). In these cases karyotype analysis is recommended [18]. Gynecomastia, increased fat/lean mass proportion and other signs of hypogonadism, such as long legs and tall stature or eunuchoid proportion and reduced virilization, as well as nonspecific behavioral, social and psychological difficulties might be present in some cases and further increase clinical suspect (Table 1).…”

“…General pediatricians, pediatric endocrinologists, but also sport doctors or school doctors, could have a great opportunity for early diagnosing Klinefelter syndrome in this period of life. An early diagnosis is possible and advisable pre-pubertally, but in children the clinical signs are actually few and often vague, and there is no consensus for recommendation of karyotype analysis based on clinical signs [18]. Reduced testis volume, long legs and tall stature, tendency to overweight and increased fat/lean mass proportion, speech and learning difficulties, deficits in cognitive and executive functioning could be observed [2] ( Table 1).…”

“…Diagnostic rate could be increased in adulthood, but obviously this is not by definition early diagnosis. Higher rate of diagnosis could be achieved if recommendations for karyotype analysis would be regularly followed [18] (Table 1). Importantly, a better awareness of the suggestive signs (Table 1) not only in specialists (endocrinologists/andrologists) but especially non-specialists (family, school, sport doctors) could increase diagnostic rate.…”