The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration

Context: Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations. Objective: To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD. Design: Retrospective review of medical records. Setting: Two international tertiary referral centers of expertise for ALD. Patients: Male patients with ALD followed at the centers between 2002 and 2016. Main Outcome Measures: The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease. Results: Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival analysis. Median time until adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years). The cumulative proportion of patients who developed adrenal insufficiency was age-dependent and highest in early childhood [0 to 10 years, 46.8% (SEM 0.041%); 11 to 40 years, 28.6% (SEM, 0.037%);.40 years, 5.6% (SEM, 0.038%)]. No association between clinical manifestations and plasma ratios was detected with Cox model or Spearman correlation. Conclusions: Lifetime prevalence of adrenal insufficiency in male patients with ALD is similar to 80%. Adrenal insufficiency risk is time-dependent and warrants age-dependent follow-up. Besides ondemand testing if symptoms manifest, we suggest a minimum of adrenal testing every 4 to 6 months for patients age <= 10 years, annual testing for those age 11 to 40 years, and solely on-demand testing for those age >40 years.