Differentiating Incidental From Pathologic Brain MRI Findings in Asymptomatic Boys With X-Linked...

X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy with an incidence of 1:15,000 births. Newborn screening has enabled widespread use of serial brain MRI scans for early detection and treatment of cerebral ALD (cALD). Differentiating early cALD lesions from incidental findings remains challenging. We sought to characterize incidental MRI findings during cALD surveillance and describe features that may help distinguish them from early cALD lesions.

MRI reports from boys with ALD followed at the Lucile Packard Children's Hospital and Weill Cornell Medicine from 2012 to 2023 were reviewed. Inclusion criteria were boys with ALD who had at least 1 presymptomatic MRI before the age of 12 and no neurologic symptoms. We analyzed narrative content of available MRI reports, manually verified definite cALD lesions, and classified all other findings as incidental.

Our study included 69 boys with ALD (median age of 6.9 years, interquartile range 4.0-9.5),, with a total of 390 MRI reports reviewed. Participants had either pathogenic ABCD1 variants (45%, n = 31), likely pathogenic variants (9%, n = 6), variants of uncertain significance (39%, n = 27), or a positive family history with confirmatory biochemical testing (7%, n = 5). During surveillance, 11% (n = 8) developed cALD lesions with classical cALD neuroimaging features. Incidental findings were common (74%, n = 51). The most frequent incidental findings included punctate T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in the frontal lobe (29%, n = 20), abnormal T2/FLAIR signal in the periatrial or periventricular white matter (19%, n = 13), prominent perivascular spaces (17%, n = 12), T2/FLAIR hyperintensities in non-frontal lobe regions (14%, n = 10), delayed myelination (14%, n = 10), and stable curvilinear T2/FLAIR hyperintensity in the splenium or genu (13%, n = 9), with the latter requiring follow-up imaging to distinguish from cALD. Only 23% (n = 16) had neither cALD nor incidental findings reported across all time points. Incidental findings were neither statistically associated with genotype classification nor predictive of cALD.

Incidental findings were commonly reported during cALD surveillance, possibly reflecting radiologists' intent to differentiate them from cALD. Incidental findings were distinguishable from true cALD lesions based on anatomic location, stability over time, and persistent absence of contrast enhancement. Our findings provide a practical framework for differentiating incidental findings from cALD lesions during surveillance.