Letter to the Editor from Erdoğan Özbuğday and Karakurt: “Primary adrenal insufficiency resulting in diagnosis of rare ABCD1 pathogenic variant in X-linked adrenoleukodystrophy”

Dear Editor,

We read with great interest the case report by Jin, Bhatnagar, Bryant, and Soe, entitled “Primary adrenal insufficiency resulting in diagnosis of rare ABCD1 pathogenic variant in X-linked adrenoleukodystrophy” [1]. The authors highlight an important clinical message: adrenoleukodystrophy (ALD) should be considered in the differential diagnosis of unexplained primary adrenal insufficiency in male patients. Their report also underscores the value of endocrine evaluation in uncovering underlying peroxisomal disorders.

However, the clinical spectrum of adult ALD is remarkably heterogeneous, and the diagnostic pathway does not invariably begin with adrenal dysfunction. Recent studies have demonstrated substantial phenotypic variability among adult patients, with neurological and endocrine manifestations often emerging at different stages of the disease course [2].

In this context, we would like to share a case that provides an additional clinical perspective on the phenotypic diversity of adult ALD. A 41-year-old man had been under neurological evaluation for ∼3 years because of progressive gait impairment, balance difficulties, and sensory disturbances in the lower extremities. Neurological examination revealed findings consistent with progressive spastic paraparesis and peripheral neuropathy. Despite extensive investigations, brain magnetic resonance imaging remained unremarkable, and no definitive diagnosis could be established. During the diagnostic workup for his neurological symptoms, an adrenal incidentaloma was identified, prompting endocrine assessment. Biochemical evaluation revealed primary adrenal insufficiency, a finding that was confirmed on repeat testing with persistently elevated adrenocorticotropic hormone concentrations and concordant adrenal hormone profiles. Further genetic analysis identified a hemizygous pathogenic variant in the ABCD1 gene, establishing the diagnosis of ALD.

This case illustrates that primary adrenal insufficiency may not only represent an early manifestation of ALD but can also serve as a critical diagnostic clue in patients with longstanding unexplained neurological symptoms. Furthermore, it emphasizes that normal brain imaging does not exclude the diagnosis of adult ALD and that clinical suspicion should be maintained in individuals presenting with progressive spastic paraparesis or myelopathy, particularly when accompanied by evidence of adrenal dysfunction [3].

We fully agree with the authors that unexplained primary adrenal insufficiency in men should prompt consideration of ALD. At the same time, our experience highlights another clinically important presentation of ALD: in some adult patients, neurological manifestations may predominate for years, with the diagnosis becoming apparent only after the recognition of concomitant adrenal insufficiency. Systematic assessment of adrenal function in patients with unexplained progressive spastic paraparesis or myelopathy may therefore facilitate earlier recognition of ALD and reduce diagnostic delay.

Funding

No funding was received for this work.

Disclosures

The authors declare no conflict of interest.