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The advent of high-dimensional imaging offers new opportunities to molecularly characterize diagnostic cells in disorders that have previously relied on histopathological definitions. One example case is found in tuberous sclerosis complex (TSC), a developmental disorder characterized by systemic growth of benign tumors. Within resected brain tissues from patients with TSC, detection of abnormally enlarged balloon cells (BCs) is pathognomonic for this disorder. Though BCs can be identified by an expert neuropathologist, little is known about the specificity and broad applicability of protein markers for these cells, complicating classification of proposed BCs identified in experimental models of this disorder. Here, we report the development of a customized machine learning pipeline (BAlloon IDENtifier; BAIDEN) that was trained to prospectively identify BCs in tissue sections using a histological stain compatible with high-dimensional cytometry. This approach was coupled to a custom 36-antibody panel and imaging mass cytometry (IMC) to explore the expression of multiple previously proposed BC marker proteins and develop a descriptor of BC features conserved across multiple tissue samples from patients with TSC. Here, we present a modular workflow encompassing BAIDEN, a custom antibody panel, a control sample microarray, and analysis pipelines-both open-source and in-house-and apply this workflow to understand the abundance, structure, and signaling activity of BCs as an example case of how high-dimensional imaging can be applied within human tissues., (© 2024 The Author(s). Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)

Abstract: We report a case of a novel phenotypic variant of cerebrotendinous xanthomatosis (CTX) with an adult onset, caused by 2 coexisting mutations involving the CYP7A1 and SLC10A1 genes. A 49-year-old male patient presented with eyelid xanthomatosis associated with dermatochalasis, nystagmus, right-sided paresis with hyperreflexia and atypical parkinsonism. Bilateral xanthomatous plaques involving both Achilles tendons were subsequently detected. Histopathology of the eyelids demonstrated marked diffuse stromal infiltrates of prominent foamy histiocytes. His lipid profile showed only a slightly elevated non-high density lipoprotein cholesterol level but with normal cholesterol and cholestanol levels. By contrast, classic CTX characteristically demonstrates a markedly elevated cholestanol and a mutation involving the CYP27A1 gene for enzyme cholesterol 27-hydroxylase. Unexpectedly, molecular studies on this patient revealed a heterozygous mutation involving 2 different genes, namely, CYP7A1 and SLC10A1 genes. The CYP7A1 gene encodes for the enzyme cholesterol 7α-hydroxylase, which is a rate-limiting enzyme in the cholesterol degradation. The SLC10A1 Na+/taurocholate cotransporter gene is involved in the enterohepatic circulation of bile acids and for the hepatocyte uptake of cholesterol. We are the first to report an unusual case of an adult-onset CTX manifesting with eyelid xanthomas associated with an uncharacteristic lipid profile and a detection of novel heterozygous mutations of CYP7A1 and SLC10A1 genes in this neurocutaneous syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)