STEAMBOAT SPRINGS, COLO. – Klinefelter syndrome, the most common cause of hypergonadotrophic hypogonadism in boys, affects 1 in 660 males and is greatly underdiagnosed, according to Dr. Charlotte M. Boney.
"Seventy-five percent of guys with Klinefelter syndrome aren’t diagnosed until they are adults. We are missing the opportunity to diagnose Klinefelter when we could actually intervene in a timely way to promote normal pubertal development," said Dr. Boney, chief of the division of pediatric endocrinology and metabolism at Hasbro Children’s Hospital in Providence, R.I.
Neonates with Klinefelter syndrome look completely normal. But missed opportunities to make the diagnosis later in childhood abound. Among the most common red flags are cryptorchidism, which occurs in 25%-40% of affected boys; language delay, present in more than 40%; learning disabilities, present in more than 75%; and mood and behavior problems, such as attention-deficit/hyperactivity disorder, in more than 25%.
Problems fitting in socially with peers in preschool and kindergarten are also common in boys with Klinefelter syndrome.
"So if you see a boy with an undescended testis at 1 year of age, and that same boy later has language delay, and he’s a wreck in kindergarten, and then in third or fourth grade there are learning disabilities, think about Klinefelter syndrome. I’d like all of us to connect the dots a little better," Dr. Boney said at a meeting on practical pediatrics sponsored by the American Academy of Pediatrics.
She added that since well under 10% of boys should have undescended testes at age 1 year, if at that age she still can’t palpate testes, she’d obtain a karyotype study to rule out Klinefelter syndrome before sending the boy to the urologist to bring down the testes.
Klinefelter syndrome is characterized by delayed puberty, and endocrinologically by high serum FSH and LH and low testosterone levels for the child’s Tanner stage. The majority of affected boys will begin puberty, but it will then turn sluggish and stall.
"Seventy-five percent of guys with Klinefelter syndrome aren’t diagnosed until they are adults."
The diagnosis of Klinefelter syndrome is confirmed by karyotyping. Roughly 90% of individuals with Klinefelter syndrome are 47XXY, 10% are 47XXY/46XY, and less than 1% is 48XXY.
The treatment of Klinefelter syndrome is straightforward: testosterone replacement aimed at achieving normal pubertal development. The goals include a normal-trajectory pubertal growth spurt; normal male muscle mass, body fat distribution, and bone mineralization; induction of secondary sex characteristics; and a sense of psychosocial well-being.
If the boy didn’t virilize normally during puberty, treatment begins with intramuscular injections of a low-dose, long-acting testosterone ester, starting at 50 mg once every 3-4 weeks and working up over the course of a year to 200-300 mg every 2-3 weeks, Dr. Boney said.
Once the patient is in the Tanner 4 range and his serum testosterone climbs above 300 ng/dL, he can transition to maintenance therapy with transdermal testosterone patches. For the patient this is a most welcome event because the patches are self-administered and result in less-dramatic serum testosterone peaks and troughs than with intramuscular injections. Most patients prefer the Androderm patch, which can be placed on the arm, thigh, or back, rather than the Testoderm patch, which has to be stuck on the scrotum, she said.
Testosterone gels that are rubbed into the skin on a daily basis, such as AndroGel or Testim, are another option for replacement therapy. The gels result in impressively smooth serum hormone levels, but they are messy products.
"They have the consistency of ultrasound gel, and a lot of teenagers don’t like them," according to Dr. Boney.
Although a properly diagnosed and treated patient with Klinefelter syndrome will have completely normal sexual functioning, there is at present no way to forestall the death of the patient’s germ cells. In order to preserve the option of parenthood, many large centers are now offering patients with Klinefelter syndrome the option of testicular biopsy to harvest healthy sperm, then banking the sperm for assisted reproduction later in life. But the window for finding healthy sperm in these patients is quite narrow; the biopsy needs to be done when they are roughly 16-20 years old, so the conversation with the patient regarding this option must occur before many teens are emotionally mature, she said.
Dr. Boney reported having no relevant financial disclosures.