Association of BRAF V600E with Hypothalamic-Pituitary-Adrenal Axis Involvement in Erdheim-Chester Disease

Fady Hannah-Shmouni*, Louisa Boyd, Georgios Z. Papadakis, Amit Tirosh, William A. Gahl, Juvianee I. Estrada-Veras, Kevin O'Brien

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by uncontrolled inflammation resulting in fibro-inflammatory damage of multiple organs, including the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoid insufficiency may occur and is associated with an increased burden of disease and an increased risk of adrenal crisis. Sixty-one ECD subjects (46 males, age 54.3 ± 10.8 years) were evaluated; 56.1% (32/57) harbored a somatic activating BRAF V600E variant. Adrenal gland and sellar or suprasellar involvement was present in 18/57 (31.6%) and 9/57 (15.8%) subjects on computed tomography or magnetic resonance imaging, respectively. The BRAF-positive group was more likely to have adrenal gland involvement (56.2% vs. 20.0%; odds ratio (OR) 5.8, 95% confidence interval (CI) 1.5-17.1, P=0.008), with comparable rates for sellar or suprasellar involvement (28.1% vs. 20.0%; OR 1.6, 95% CI 0.5-5.4, P=0.5) and low random morning cortisol values (37.5% vs. 32.0%; OR 1.3, 95% CI 0.4-3.8, P=0.7). High-sensitivity C-reactive protein was significantly higher in the BRAF V600E-positive group with adrenal involvement when compared to the BRAF V600E-negative group without adrenal involvement (mean concentration: 40 mg/dL vs. 5 mg/dL, P=0.046). HPA axis in ECD tends to involve the adrenal glands in BRAF V600E-positive individuals, without influencing the rates of low cortisol levels, although there is a poor biochemical-radiological concordance in ECD. In this cohort, most subjects with HPA axis involvement did not require glucocorticoid or mineralocorticoid therapy. This study systematically demonstrates an association between the somatic activating BRAF V600E variant and the presence of radiographic and biochemical HPA axis involvement in ECD subjects. TRIAL REGISTRATION:

Original languageEnglish
Article number100051
JournalEndocrine and Metabolic Science
Issue number1-2
StatePublished - Jul 2020


  • Adrenal Insufficiency
  • BRAF
  • Erdheim-Chester Disease
  • Inflammation


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