Assessment of Skin Biopsy as a Diagnostic Biomarker in CSF1R-Related Disorder

ObjectivesTo validate a recently published study in which skin biopsy was reported as a valuable alternative to brain biopsy in diagnosing CSF1R-related disorder (CSF1R-RD).MethodsBlinded evaluation of skin samples was performed by independent reviewers using light and electron microscopy collected from a group of CSF1R variant carriers (n = 10) with various genotypes (mono and biallelic), different stages of the disease (asymptomatic and symptomatic), and exposed to different therapies (glucocorticoids, hematopoietic stem cell transplantation, and TREM2 agonist), and from a group of healthy controls (n = 5).ResultsBiopsies from patients with CSF1R-RD at various disease stages were indistinguishable from controls determined using light microscopy and electron microscopy.DiscussionWe found no distinctive axonal pathology in skin biopsies collected from CSF1R variant carriers at all stages of the disease. Our results are consistent with clinical and neurophysiologic features of the CSF1R-RD, in that peripheral nervous system involvement has not been reported. Studies aiming to discover new biomarkers are important, but the results must be validated with larger numbers of patients and healthy controls. Based on blinded light and electron microscopic studies of skin biopsies, there is no evidence that CSF1R-RD is associated with distinctive changes in cutaneous peripheral nerves. This suggests that skin biopsy is not useful in diagnosis of CSF1R-RD.Classification of EvidenceThis study provides Class III evidence that skin biopsy does not distinguish those with CSF1R-RD, or carriers, from normal controls.