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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by pathogenic variants in the CYP27A1 gene encoding the mitochondrial enzyme sterol 27-hydroxylase. Patients with CTX can present with a wide range of symptoms, but most often have evidence of tendon xanthomas along with possible cataracts, atherosclerosis, or neurological dysfunction. Regardless of clinical phenotype, CTX patients typically exhibit levels of cholestanol and bile acid precursors in the circulation that are many fold increased over normal control concentrations. Here we report two siblings, one with the rare spinal xanthomatosis phenotype and the other with a very mild form of CTX manifesting as minor tendon xanthomatosis and gastrointestinal complaints who both carry compound heterozygous variants in CYP27A1 : NM_000784.3: c.410G > A (p.Arg137Gln) and c.1183C > T (p.Arg395Cys). However, biochemical analysis of these patients revealed normal levels of serum cholestanol and relatively mild elevations of the bile acid precursors 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one. The atypical biochemical presentation of these cases represents a diagnostic challenge for a disorder once thought to have a sensitive biomarker in cholestanol and highlight the need for thorough investigation of patients with symptomatology consistent with CTX that includes bile acid precursor biochemical testing and molecular analysis., Competing Interests: A. D. has received Honoraria from Leadiant Biosciences and Retrophin, as well as grant funding from Retrophin. The OHSU Foundation and Chemical Physiology and Biology Department have received gifts from Retrophin. These gifts, which have not been made specifically in connection with this research, have been reviewed by the OHSU integrity office. All other authors declare no conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)