Abstract:

CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a familial or sporadic vascular disorder caused by a NOTCH3 gene mutation resulting in abnormal accumulation of NOTCH3 in vascular smooth muscle cells. As clinical and radiological findings can be non-specific, diagnosis often rests on a combination of pathologic evaluation of skin and/or brain tissue, molecular studies and detailed clinical-pathologic correlation. Electron microscopy reveals granular osmiophilic deposits in the vascular media with cellular degeneration but this technique is highly specialized and costly. In contrast, NOTCH3 immunohistochemistry (IHC), especially if performed on skin tissue, is easier and cost effective with high sensitivity and specificity. However, when faced with a patient requiring a skin biopsy for CADASIL, we found little guidance in the literature regarding best biopsy practices. We describe the case of a 50-year-old woman with a family history of CADASIL as well as clinical, imaging and molecular findings highly suggestive of CADASIL who was referred for skin biopsy to support the diagnosis. Two telescoping punch biopsies of normal abdominal skin were obtained which appeared unremarkable on routine microscopy. Positive granular NOTCH3 immunostaining was patchy and most prominent in the deep muscular dermal and subcutaneous arteries and absent in the superficial plexuses in both biopsies. This observation suggests multiple and generous skin samples, to include deep muscular arteries in the dermis and subcutis, increases yield for positive NOTCH3 IHC. Submitting clinicians seeking confirmatory skin findings for CADASIL should be advised of these biopsy parameters to optimize diagnosis.

Financial Disclosure:
No current or relevant financial relationships exist.

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Nizar Belgasem, MBBCh, FRCPC