Is Central Adrenal Insufficiency Over-diagnosed in Prader-Willi Syndrome?

Columbus, OH — November 2017

There are no consensus guidelines for the evaluation of central adrenal insufficiency (CAI) in patients with Prader-Willi syndrome, at least in part because previous studies have shown little consistency in CAI rates in that population. Studies using various testing methods for CAI suggest rates as low as 0 percent; a study using a different test found a rate of 60 percent.

Research led by endocrinologists at Nationwide Children’s Hospital appears to be the first to examine how two tests for CAI can lead to different conclusions in the same patient – suggesting that one test may have a high false-positive rate. The findings were presented in September at the 10th International Meeting of Pediatric Endocrinology in Washington D.C.

“Clinicians have a dilemma over how to screen for central adrenal insufficiency in their patients with Prader-Willi syndrome,” says Kathryn Obrynba, MD, a member of the Section of Endocrinology at Nationwide Children’s, a member of the hospital’s Prader-Willi Syndrome Clinic physician team and lead author of the study. “That, in turn, leads to a dilemma about the need for steroid treatment during times of physical stress or illness.”

A total of 21 patients (median age 13.9 years) with Prader-Willi syndrome, who had not been previously diagnosed with CAI, completed the study. Each completed a low-dose adrenocorticotropic hormone (ACTH) stimulation test and then a single-dose overnight metyrapone test (OMT).

The OMT was considered the “gold standard” for comparison as it directly assesses the response of the entire hypothalamic-pituitary-adrenal (HPA) axis, and therefore is ideal to evaluate central hormonal deficiencies and ACTH reserve.  The low-dose ACTH stimulation test does not directly assess the HPA axis, but rather relies on indirect assessment of adrenal gland function. This test is readily available, quick, inexpensive, and safe, and therefore has become the accepted method for assessing for CAI in most patients.

Twenty of the patients passed the OMT and one was considered inconclusive, so none had evidence of CAI. In contrast, only 15 passed the low dose ACTH stimulation test, meaning 29 percent had evidence of CAI, suggestive of a high false-positive rate.

These discrepancies in testing methods have been shown in earlier studies, but never before in the same patients, says Manmohan Kamboj, MD, interim chief of Endocrinology at Nationwide Children’s and senior author of the study.

“In an effort to avoid over diagnosis and treatment, OMT may be the preferred method of screening for CAI in Prader-Willi syndrome,” she says.

Obrynba K, Hoffman R, Repaske D, Bucker J, Anglin K, Coshway L, Cazeau R, Lozano R, Pyle-Eiola A, Kamboj M. Could we be over diagnosing central adrenal insufficiency in Prader-Willi Syndrome? International Meeting of Pediatric Endocrinology; 2017 Sept 14-17; Washington D.C.