Klinefelter syndrome management

Klinefelter syndrome is the most common chromosomal aberration in humans. Most of the men have one additional X chromosome, however some men may have more than 2 X chromosomes. It seems that the higher the number of additional X chromosomes the more pronounced affects on the testicular and cognitive function.

 

Management of Klinefelter syndrome should be individualized since not all boys with KS have the same spectrum of problems. The principals of management focus on help with academic, social and endocrine development as well as preservation of fertility.

Because many genes which are expressed in brain and testis are X-linked, thus it is not surprising that the men with KS have mild impairment of cognitive function – especially language and auditory processing, as well as spermatogenic failure. The exact mechanisms of the negative effects of X chromosome disomy on brain and testicular development are not clear.

 

 The natural history of Klinefelter syndrome is poorly understood and significant controversy exists about frequency of hypogonadism during childhood and among young adults.  However from our experience we estimate that at least one third of pubertal boys and two third of the adults will have low testosterone. Thus we recommend that every child who is diagnosed prenatally have testosterone FSH and LH checked during first 3 months of life together with measurement of the penile lenght.

 

Since there is only minimal amount of circulating testosterone from the time 6 months of life to the initiation of puberty, there is no need to replace testosterone prior to puberty. Testosterone therapy should be initiated only if an adolescent or adult men is diagnosed with hypogonadism.  This is based on the fact that majority of children with Klinefelter syndrome will go through puberty at normal age. However over 50% of boys will have poor progression of puberty and will require supplementation.

 

It is our practice to normalize hormonal levels in boys >10 year old with Klinefelter syndrome to reflect the hormone levels seen in normal boys of similar age with 46 XY. Recently it has been suggested that early supplementation with testosterone may actually have negative impact on testicular function especially when injectable testosterone is used. This may be secondary to either aromatization of testosterone or suppression of LH and FSH production.

 

We are not supporting the use of oral testosterone prior to puberty – since there is no clear benefit of supplementing testosterone during childhood. Based on the fact that boys and adolescents with Kallmann syndrome – who suffer from severe hypogonadism, have normal cognitive function, as well as considering growing evidence that abnormal expression of X-linked genes is responsible for mental retardation in many other syndromes, it is very unlikely that the testosterone supplementation in prepubertal children will have significant impact on academic, social and physical development in prepubescent boys with KS.

 

Regarding fertility in men with Klinefelter syndrome until a decade ago all men with Klinefelter syndrome were considered sterile however with advancement of new microsurgical techniques and in vitro fertilization, approximately 50 to 70% of men with Klinefelter syndrome will have sperm found in side the testis – which can be obtained  during testicular sperm extraction, a microsurgical procedure.  The only way of achieving pregnancy at this point in adult men who do not have sperm present in ejaculate is to perform testicular sperm extraction and if sperm is found to use fresh sperm for in vitro fertilization using ICSI.  At the same time patient’s partner needs to be ready for an oocyte retrieval.  There is no reliable test which would allow us to predict presence of sperm in testes in men with Klinefelter syndrome.

 

Currently we are performing magnetic resonance imaging study and MR spectrometry to determine if those techniques will be useful in identifying areas of spermatogenesis within the testes in men with KS. We should have results of this study by the end of 2008.

 

Based on our initial experienced as well as reports of testicular biopsy in children and adolescents with Klinefelter syndrome, it  seems that the majority if not all boys with Klinefelter syndrome actually do have spermatogonia present in the testis.  It is not known what triggers massive spermatogonial loss during puberty, however based on preliminary research done in our laboratory, we believe that during early puberty and initiation of first wave of spermatogenesis spermatogonia undergo programmed cell death called apoptosis.  This observation is supported by our report that in some children who are early in pubertal development and whose FSH is below 20 we actually found viable and motile sperm which were able to cryopreserved. 

 

This opens a new and fundamentally different approach to preservation of fertility in adolescents with Klinefelter syndrome.  It is our practice to check FSH, LH, testosterone and estradiol every 6 months starting at around age of 9 in boys and adolescents with Klinefelter syndrome.  We see patients on annual or semiannual basis to identify a window of opportunity when they start producing sperm however when there is still enough spermatogonia present.  Most of adolescents at this time practice self- stimulation and are willing to deliver semen sample. The discussion about fertility preservation and examining semen sample is preferentially initiated by the parents and after obtaining informed consent the patient delivers the semen sample in the office.  Sample is checked for presence of the sperm.  If sperm is present then the sample is cryopreserved.  Semen can be cryopreserved and used for in vitro fertilization for more than 20 years.

If patient has no sperm found however he is progressing through puberty and his FSH is below 20 then we discuss with obtaining testicular sample through the testicular  biopsy since it is likely that the we will at least find round spermatids which can also be useful in vitro fertilization.

 

We have also ongoing studies looking at different methods of hormonal manipulation which hopefully would prevent damage to spermatogonia during puberty.  In addition we are actively involved in maturing of spermatogonia in animal models for potential use in the future.

 

The are of fertility preservation in children and adolescents with childhood malignancies is a very active area of clinical and basic science research.  The interest in fertility preservation has stemmed from the increasing survival of children with malignancies who underwent chemotherapy and radiation therapy.

 

Most of children who are survive aggressive cancers of childhood and adolescence require aggressive chemotherapy and radiation therapy and by some estimates over 90% of children and adolescents undergoing bone marrow transplant and total body irradiation will be sterile.  Thus most of the pediatric oncologist and fertility specialist recommend now an active role all of male reproductive health specialists in preservation of fertility in children or adolescents who will undergo chemotherapy or radiation therapy.  The same principal is applied to children born with chromosomal abnormalities which affect mainly reproductive function. Thus for younger boys and adolescents with KS we advocate early discussion about fertility preservation.

 

During adolescents we focus on assuring normal progression of puberty by checking testosterone and pubertal development. During this period especial attention needs to be placed on increase in levels of physical activities and at the same time restricting caloric intake to avoid obesity which can contribute to development of lipomastia – breast enlargement and potential diabetes in adulthood.

 

Since many of our patients attend college we try to see them every 6 months to help with any social adjustments and academic, development issues which may be accentuated by separation from family and typical support system the young men is used to.

 

In late teens and during twenties and 30s we check bone mineral density to prevent development of osteoporosis.

 

Overall KS is becoming easy to manage chronic condition which if diagnosed early and with managed with long term plan, can make the life of boy or a man with KS as normal as any other of his peers.

 

It is important to remember that KS doesn’t typically affect many other organs and that erectile, ejaculatory, or sexual dysfunction are NOT typically seen in adolescents and young adults with KS, unless their testosterone is very low.