Managing delayed or altered puberty in boys

BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e7913 (Published 03 December 2012) Cite this as: BMJ 2012;345:e7913

Re: Managing delayed or altered puberty in boys

Dr Fiona Godlee
Editor BMJ

Dear Dr Godlee,

I was surprised to see not only the cover of the BMJ 5th January linking delayed puberty with Klinefelter’s syndrome (karyotype 47,XXY) but also an editorial and clinical practice article on this subject both of which contain serious errors. It is abundantly clear from the follow up studies of children identified at birth as having sex chromosome aneuploidy by newborn screening programmes (including the UK MRC Edinburgh study in which I participated), hence an unbiased source of evidence, that boys with Klinefelter syndrome have an onset of pubertal development within the normal range as noted in all other boys by testicular enlargement >3ml (1). I practice as an adolescent endocrinologist with a special interest in disorders of puberty and currently run the only national specialist referral service for boys with Klinefelter’s syndrome in the UK. The onset and progress of puberty has been the subject of my research and clinical interest over the past 28 years including my doctoral thesis (2).

The primary presentation of the delayed onset of puberty arising as a result of Klinefelter’s syndrome is so rare almost to the extent that single cases presenting denovo are exceptional. I usually pick up new cases of 47,XXY in adolescence, even then rarely, on account of concern over the lack of pubertal progress and not over the delayed onset. Klinefelter’s syndrome is not part of the 5-10% of boys with delayed puberty resulting from hypergonadotrophic hypergonadism quoted by Professor Pitteloud (p5). A delayed onset of puberty may occur in more complex karyotypes eg 48,XXYY or 48,XXXY or 49,XXXXY or in 47,XXY boys with other congenital or clinical problems, but these boys are usually identified beforehand on account of learning difficulties and speech delay or these other congenital problems. This finding has been verified in several recent publications and in the proceedings from the international Congress of Klinefelter’s syndrome organized by Professor Anders Juul in 2010 (3).

Testosterone should not be given, as loosely described by CH Blevins (p33), at the start of puberty, but in a much more considered manner. My research and that of others subsequently has clearly showed that testosterone fails to rise adequately in late puberty (Tanner stages 4 and 5) and this can only be detected accurately by evaluating testosterone concentrations in the early morning. Initiation of testosterone supplementation at the onset of puberty has been shown to restore the sex dimorphic changes to fat deposition where this is required in obese individuals (4), and may also prevent the development and persistence of significant gynaecomastia, present in up to 60% of boys- and this is the subject of my current research. Testosterone is not required in early puberty in most Klinefelter syndrome boys as a deficiency is not usually present at that stage.

I find the perpetuation of the myth that Klinefelter syndrome causes the delayed onset of puberty, highlighted by a colour picture of the karyotype and erroneous wording on the front of the BMJ extremely frustrating (including using the term ‘late’ rather than ‘delayed’ as it should have stated), having spent the best of the last 30 years trying to present an accurate picture of this common yet too frequently unrecognized condition. I shall be submitting a separate letter on the terminology used and the new UK approach to the evaluation of puberty and growth on the new UK 2-18 RCPCH growth charts (www.growthcharts.rcpch.ac.uk) with my other colleagues in this venture. ‘Late’ in this context refers to an extreme of normal variation, whereas the new UK charts and Professor Pitteloud’s correctly worded article title use the term ‘delayed’ to highlight concern.

I feel it is mandatory that this Journal publishes an accurate representation and a prominent correction of the errors made about Klinefelter’s syndrome in puberty. I would be happy to assist the Journal in correcting these errors.

Yours sincerely,

Gary Butler

Professor Gary Butler MD FRCPCH
Professor and Consultant in Paediatric & Adolescent Medicine and Endocrinology,
University College Hospital, London & UCL Institute of Child Health.
Chairman, European Society for Paediatric Endocrinology Clinical Practice Committee.

Email: gary.butler@ucl.ac.uk

1. Ratcliffe SG, Paul N Eds. Prospective studies on children with sex chromosome aneuploidy. March of Dimes Birth Defects Foundation. Birth Defects: Original Article Series. New York: Alan R Liss, 1986; 22 Number 3.

2. Butler GE. Changes in gonadal function and their effect on pubertal development and growth in normal, XXY, and XYY boys, determined by the estimation of testosterone in saliva. MD Thesis; University of London 1993.

3. Juul A, Aksglaede L, Bay K, Grigor K Skakkebaek N. Proceedings of the International Workshop on Klinefelter Syndrome 2010. Ed Acta Paediatrica 2011

4. Ratcliffe S G, Butler G E, Jones M.
Edinburgh study of growth and development of children with sex chromosome abnormalities IV.
In: Evans J A, Hamerton J L, Robinson A, Eds. Children and young adults with sex chromosome aneuploidy. Follow-up, clinical and molecular studies. March of Dimes Birth Defects Foundation. Birth Defects: Original Article Series. New York: Wiley-Liss, 1991; 26 Number 4: 1-44.

Competing interests: No competing interests

09 January 2013
Gary E Butler
Professor of Paediatric Endocrinology
UCL Hospital and UCL Institute of Child Health
250 Euston Rd London NW1 2PQ