Samuels ME, Gallo-Payet N, Pinard S, Hasselman C, Magne F, Patry L, Chouinard L, Schwartzentruber J, René P, Sawyer N, Bouvier M, Djemli A, Delvin E, Huot C, Eugene D,Deal CL, Van Vliet G, Majewski J, Deladoëy J. Bioinactive ACTH Causing Glucocorticoid Deficiency. J Clin Endocrinol Metab 2013; 98: 736-742.

    • Highlighted by an article in lay journal La Presse (31 January 2013), the main French daily journal of the city of Montreal.
    • Interview for Radio-Canada International (6 February 2013)

Description of the study

The two children in the study were hospitalized at the ages of 4 months or 4 years respectively, for hypoglycemia and associated convulsions. A diagnosis of adrenal insufficiency was made and the two children were saved by administering replacement hormones. Their ACTH (the pituitary hormone that controls the adrenal gland) blood concentrations were very high, which seemed to implicate the adrenal gland. The adrenal gland produces two vital hormones: cortisol to regulate glycemia and aldosterone to control minerals. When in doubt, in the event of adrenal insufficiency, both hormone types (cortisol and fludrocortisone, an aldosterone analogue) are prescribed. Nevertheless, fludrocortisone treatment can lead to side effects such as hypertension.

Hoping to better target patient treatment, the investigators went about tracking down the exact cause of adrenal insufficiency. They proceeded to analyze part of the genome that codes for genes in one patient’s DNA (whole-genome sequencing being still too expensive for the time being). To their great surprise, the analysis indicated the presence of two mutations in POMC, the gene that codes for ACTH, in the patient. Direct sequencing of the POMC gene in DNA from the second patient confirmed the occurrence of one of the mutations in that child as well. The researchers then collaborated with Dr. Michel Bouvier (University of Montreal) and Dr. Nicole Gallo-Payet (University of Sherbrooke) to validate the discovery by performing in vitro tests on cells using two synthetic ACTHs produced for the experiment: one normal and the other carrying the mutation observed in both children. These studies showed that, while high levels were detected in the blood, the mutant ACTH was inactive. Due to technical limitations, the standard diagnostic test that detects ACTH was unable to distinguish between the normal and the mutated form found in the patients.

“The genome analysis allowed us to incriminate the POMC gene. Since the gene was not suspect according to the blood tests, we would have missed the cause of the disease without this new technique,” concludes Dr. Deladoëy, a physician and researcher in endocrinology and diabetology.

This case of personalized medicine made possible through novel genomic techniques is just the tip of the iceberg. In the near future, investigators hope to succeed in refining the treatment of many patients using these techniques.