(EAA) GUIDELINES ON KLINEFELTER SYNDROME

madman

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European Academy of Andrology (EAA) GUIDELINES ON KLINEFELTER SYNDROME Endorsing Organisation: 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 the 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 hypogonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psycho-social 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 are diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood, or adolescence. The pediatric 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.





GENETIC ISSUES
CHILDREN AND PRE-PUBERTAL BOYS WITH KS
ADOLESCENTS WITH KS
ADULTS WITH KS
GENERAL DEMANDS





1. INTRODUCTION


Klinefelter Syndrome (KS) is the most frequent chromosome disorder in men, exhibiting a karyotype of 47, XXY. Symptoms in KS are highly variable. Nevertheless, frequent characteristics are small testes, azoospermia, and hypergonadotropic hypogonadism. Also neurocognitive and psycho-social manifestations can be seen as well as cardiovascular, metabolic, and bone-related conditions of adverse nature. Generally, morbidity and mortality are increased in KS compared to men with a karyotype of 46, XY. Both hypogonadism and genetic effects seem to contribute to this clinical spectrum. Among physicians, knowledge about KS regarding diagnosis and treatment is distributed unevenly. KS is not fully known to many physicians and there is a marked need for a respective improvement of medical curricula.

Whereas KS is usually considered in all guidelines dealing with the management of hypogonadism, no specific guideline and recommendation have ever been published to care for patients with KS in various developmental stages. The aim of the present study is to summarize the available evidence on KS providing a list of suggestions and recommendations on behalf of the European Academy of Andrology (EAA) and endorsed by the European Society of Endocrinology in order to correctly manage patients with KS from prenatal period to adulthood.





2. METHODOLOGY OF THE GUIDELINE COMPOSITION

2.1. Data identification
2.2. Levels of evidence and grades of recommendation
2.3. Aetiology
2.4. Prevalence
2.5. Low diagnostic rate




3. CLINICAL PICTURES, DIAGNOSTIC STEPS, AND THERAPY

3.1. Genetics

3.2. Developmental issues in infants and prepubertal children

3.2.1. Testicular development and function of the hypothalamic-pituitary-testicular axis
3.2.2. Growth
3.2.3. Bone mineralization
3.2.4. Body composition
3.2.5. Psychological aspects




4.4. Developmental issues in puberty and adolescence

4.4.1. Spermatogenesis
4.3.2. Function of the hypothalamic-pituitary-testicular axis

4.3.3. Cognitive and psychological aspects



3.3. Pathophysiology and clinics in adults

3.4. 4.4.1. Hypogonadism
4.4.2. Infertility

4.4.3. Metabolic disorders, body composition, cardiovascular risk and thrombosis
4.4.4. Bone disorders
4.4.5. Psychological and psychiatric conditions/ Gender incongruence
4.4.6. Risk of neoplasia
4.4.7. Other disorders




5. GENERAL DEMANDS




6. CONCLUSIONS AND FUTURE DIRECTIONS


KS is the most common sex chromosomal disorder in men. It affects patients with both hypogonadism and infertility. In addition, men with KS are afflicted with a higher risk of having cardiovascular, metabolic, psychiatric, and other comorbidities. Providing the patient with KS and, if deemed adequate, his parents with suitable and balanced information as well as assistance for various aspects of his life after receiving the diagnosis is suggested. Prevention and treatment of the medical complications and comorbidities associated with KS should be standardized as far as possible. Also minimizing neurodevelopmental dysfunction, i.e. verbal deficits, learning difficulties, behavioral problems should be aimed at. These measures are likely to promote the patients’ self-esteem, assure the quality of life, and improve his social adaption. Finally, preservation of the fertility potential, i.e. cryopreservation of spermatozoa from ejaculate or testicular tissue is an option now widely available.

The pathological conditions in patients with KS are most likely of a combined endocrine, genetic, and epigenetic origin. Further research in a coordinated fashion is needed. KS is vastly underdiagnosed and an increment of general knowledge, as well as establishment of standard care in multidisciplinary networks, is mandatory. These are the first guidelines to take a step towards this goal.
 

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Nelson Vergel

Founder, ExcelMale.com

 

madman

Member
Table 1. Summary of the most important parameters to be tested and/or related to therapeutical approaches from childhood to adolescence in patients with KS
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madman

Member
Table 2. Summary of the most important parameters to be tested and/or related therapeutical approach in an adult with KS
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madman

Member
Figure 1
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Legend to Figure 1 Signs and symptoms of Klinefelter Syndrome (KS) at various stages in life. It is indicated that these symptoms may be seen in some or many patients with KS, depending on their age. Most of these symptoms are not inherent to KS and are, therefore, not specific. Small firm testes can, however, be considered quite specific. Also, the combination of symptoms in adults can be considered specific and promote the diagnosis of KS.
 
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madman

Member
Fig 2a
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Legend to Figure 2a-c Figure 2a Testicular histology in an adult patient with Klinefelter Syndrome. The biopsy is dominated by Sertolicell-only tubules, Leydig cell hyperplasia with one large Leydig cell nodule (*), and completely hyalinized “ghost” tubules (white dotted circles). Note two types of Sertoli cell-only seminiferous tubules; type A which contains differentiated Sertoli cells (A), and type B which contain incompletely differentiated Sertoli cells (B). Periodic acid-Schiff staining. The bar denotes 100 µ. Courtesy of Lise Aksglaede
 
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madman

Member
Fig 2b
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Figure 2b Testicular histology (right testis) of a young adult/adolescent patient (age 18 years) with non-mosaic 47, XXY Klinefelter Syndrome. b: section with various types of tubules, containing elongated spermatids but also a „ghost“ tubule
 
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madman

Member
Fig 2c
Screenshot (2004).png

Figure 2c Testicular histology (right testis) of a young adult/adolescent patient (age 18 years) with non-mosaic 47, XXY Klinefelter Syndrome. c: section with almost intact tubules, containing more elongated spermatids. PAS-staining. The bar denotes 100µ
 
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