Had he been practising some forty years ago, pediatric endocrinologist David Cooke’s profile of patients who are 47XXY would have differed sharply from today’s view. Then, late-adolescent boys would have comprised most of Cooke’s patients. Now, with amniocentesis and prenatal karyotyping more routine, however, Cooke, as the pediatric endocrinologist with the Johns Hopkins Klinefelter Syndrome Center, also sees far younger boys—babies, even—whose extra X chromosome signals the variation.
“Before puberty, there’s little that cries out, oh, this is a child with Klinefelter syndrome,” Cooke says. Nothing commonly sets the boys apart. If slightly weaker muscles or cognitive or social delays surface, he adds, they tend toward the low-end-of-normal. In mid-puberty the syndrome’s phenotype gains strength—luteinizing and follicle stimulating hormones rise above normal; plasma testosterone drops. Still, few early-teen boys know they have Klinefelter. The characteristic mildly enlarged breasts, sparse chest hair or tallness can seem unremarkable. Mid-puberty, however, opens a brief and perhaps critical window of opportunity to address adult problems that can follow. What prompts the “perhaps” is research’s lag in nailing down best practices, says Cooke.
Here he comments on current issues in treating and studying Klinefelter syndrome:
Androgen replacement therapy (ART) typically starts when a peri-pubertal XXY boy shows low testosterone, yes? That seems clear-cut.
Not quite. First, you need to know: Is testosterone truly low or is a patient just not yet in puberty? Clearly, puberty’s a moving target: Some start around age 10 with a testosterone level at 100 ng/dl that reaches 500 ng/dl by age 13. Others hover at a level near zero until into their teens. A physical exam helps decide, but it’s more clear if you follow the LH level. If LH exceeds the normal level seen in an adult male, then you know the body expects more testosterone than it’s getting.
And the benefits of ART?
In XXY adults, the benefits of testosterone therapy overwhelmingly relate to sexual health—normal libido, erections. Therapy also increases energy, muscle mass and strength. That’s true as well in XXY adolescent boys. But it can be hard to know what effects to expect in treating them.
Do you mean there are no data to show ART can bring these things about? Or is it that some of these benefits occur, but it’s difficult to predict which ones for a particular patient?
Both. I am not aware of any controlled trials that have studied testosterone treatment in boys with Kleinfelter. We know the effects of testosterone, for example, in boys or men who make no hormone if their testes completely fail from another cause. But adolescents with Kleinfelter make some testosterone. We can’t predict the effect of increasing levels from slightly low to mid-normal for a given patient. In general, no one knows the best approach for sure in testosterone therapy—when, optimally, to begin it, how long to treat, what dosage is best or if better options exist.
Some clinicians talk about low-dose testosterone before puberty.
Without evidence, I don’t know what to make of that.
Until research comes through, what do you offer to boys with Klinefelter during puberty?
Two things. Once LH levels rise above normal, ART should be considered. For some boys, this will be needed for lagging sexual characteristics. For other boys, we discuss what might be expected with ART and decide whether such treatment is appropriate. The other issue we address is fertility preservation. The approach to infertility in individuals with Klinefelter now includes consideration of harvesting sperm for storage at the earliest signs of testicular failure, and before starting testosterone treatment. This approach is felt to lead to greater success.
What is the most appropriate clinical setting for patients with Klinefelter Syndrome?
Because patients with KF vary widely in symptoms and biology, not surprisingly a multidisciplinary clinic offers the best diagnostics and therapeutics for these patients. Here at the Johns Hopkins Klinefelter Syndrome Center, we see both adult men and children with this not-uncommon chromosome anomaly—the only such dual centre in this country. Our staff include experts in pediatric and adult internal medicine and endocrinology, urologists who address infertility, a neuropsychologist skilled in treating cognitive or mood problems, speech therapists, genetic counsellors, and surgeons who specialize in male breast reduction. You really do need this type of centre to provide best practices care for these patients.