Does primary adrenal insufficiency always present initially in patients with X-linked adrenoleukodystrophy?

Primary Adrenal Insufficiency Does Not Always Present Initially in X-Linked Adrenoleukodystrophy

Primary adrenal insufficiency (PAI) is not an invariable initial presentation in X-linked adrenoleukodystrophy (X-ALD), though it is extremely common, affecting approximately 70% of male patients with ALD/AMN phenotypes over their lifetime. 1 The timing and presence of PAI varies dramatically among X-ALD patients despite all carrying ABCD1 gene mutations. 2

Epidemiology and Natural History of Adrenal Insufficiency in X-ALD

• The lifetime prevalence of adrenal insufficiency in male X-ALD patients is approximately 80%, but this develops in an age-dependent pattern rather than uniformly at presentation. 3

• The risk of developing PAI is highest in early childhood (0-10 years), where 46.8% of patients develop adrenal insufficiency, compared to 28.6% between ages 11-40 years, and only 5.6% after age 40. 3

• The median time until development of adrenal insufficiency is 14 years (95% CI, 9.70 to 18.30 years), indicating substantial variability in onset. 3

• Approximately 30% of male X-ALD patients never develop clinically significant adrenal insufficiency despite having the same genetic defect and VLCFA accumulation. 3, 1

Clinical Phenotypes and Presentation Patterns

X-ALD manifests with dramatic phenotypic heterogeneity despite identical genetic mutations, ranging from isolated neurological disease to Addison-only forms to asymptomatic carriers. 1, 2

• Some patients present with cerebral adrenoleukodystrophy (cALD) as the initial manifestation, particularly in childhood, without preceding adrenal symptoms. 4

• Adult adrenomyeloneuropathy (AMN) can be the presenting phenotype, with progressive spastic paraparesis and peripheral neuropathy developing before or without adrenal insufficiency. 5, 2

• The "Addison-only" phenotype exists where PAI is the sole clinical manifestation for years or decades without neurological involvement. 1

• Female heterozygotes rarely develop PAI (only 5% prevalence) but can develop progressive myelopathy and peripheral neuropathy in adulthood. 1, 2

Critical Diagnostic Implications

All males presenting with primary adrenal insufficiency should be screened for X-ALD by measuring very long-chain fatty acids (VLCFA) in serum, regardless of whether autoimmune markers are positive or other autoimmune conditions coexist. 6, 4

• The case report of an 11-year-old boy with type 1 diabetes who developed PAI illustrates this critical point—his PAI was presumed autoimmune given his T1DM history, but 11 months later he was diagnosed with advanced cerebral ALD that rendered him ineligible for life-saving hematopoietic cell transplant. 4

• PAI typically presents before neurological symptoms in X-ALD, making it a crucial window for early diagnosis and intervention. 4

• Timely identification through VLCFA testing when PAI presents allows for early brain MRI surveillance to detect cerebral disease when hematopoietic cell transplant can still be curative. 4

• Adult males with non-autoimmune PAI and any neurological abnormalities (even subtle findings like spastic gait or sensory changes) should undergo VLCFA screening, as X-ALD can be misdiagnosed as multiple sclerosis or idiopathic spastic paraparesis for years. 5

Pathophysiology of Variable Adrenal Involvement

• The mechanism by which only a subset of X-ALD patients develop PAI remains incompletely understood, despite universal VLCFA accumulation in all affected individuals. 1

• Current evidence suggests defective adrenal response to ACTH related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity, but this does not explain the variable penetrance. 1

• No association has been detected between plasma C26:0/C22:0 and C24:0/C22:0 ratios (diagnostic biomarkers) and the risk of developing adrenal insufficiency, spinal cord disease, or cerebral disease. 3

Surveillance Recommendations Based on Age-Dependent Risk

Given the age-dependent risk pattern, X-ALD patients require stratified adrenal surveillance even if initially asymptomatic: 3

• Ages 0-10 years: Adrenal function testing every 4-6 months due to 46.8% cumulative risk. 3

• Ages 11-40 years: Annual adrenal function testing due to 28.6% cumulative risk. 3

• Ages >40 years: On-demand testing only when symptoms manifest, as risk drops to 5.6%. 3

• All age groups should undergo immediate testing if symptoms of adrenal insufficiency develop (hyperpigmentation, hypotension, hyponatremia, fatigue, weight loss). 3

Common Pitfalls to Avoid

• Never assume PAI in a male child or young adult is autoimmune without measuring VLCFA, even when 21-hydroxylase antibodies are positive or other autoimmune conditions coexist. 4

• Do not delay VLCFA testing in males with PAI to "wait and see" if neurological symptoms develop—by the time cerebral disease is clinically apparent, the window for curative transplant may have closed. 4

• Recognize that hyperpigmentation in X-ALD may be present from early childhood (as young as 4 years old) and precede other manifestations by decades. 5

• Female carriers should not be dismissed as unaffected—5% develop PAI and many develop progressive myelopathy in adulthood requiring long-term monitoring. 1, 2