Cerebrotendinous Xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene

Abstract Background Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by loss of function variants in the CYP27A1 gene which encodes sterol 27-hydroxylase, on chromosome 2q35. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. The aim of this study is to review the orthopedic findings of the disease by providing an overview of the clinical features of the disease. It is to raise awareness of this condition for which early diagnosis and treatment are important. Methods We retrospectively evaluated the clinical, laboratory, radiological, and genetic findings of eight patients from four families who were admitted to our Orthopedics and Traumatology Department between 2017 and 2022 due to bilateral Achilles tendon xanthomas, were found to have high cholestanol and CYP27A1 gene mutations. Results The mean age of patients was 37, and five of them were male. The mean age at the onset of symptoms was 9.25 years. The mean age of initial diagnosis was 33.75 years. Between symptom onset and clinical diagnosis, an average delay of 24.5 years was observed. All patients had bilateral Achilles tendon xanthoma. Notably, a novel variant (c.670_671delAA) in CYP27A1 gene was identified in three patients who also presented with peripheral neuropathy and bilateral pes cavus. One patient had osteoporosis and four patients had osteopenia. Five patients had a history of bilateral cataracts. Furthermore, three of the patients had early-onset chronic diarrhea and three of the patients had ataxia. Two of the patients had epilepsy and seven of the patients had behavior-personality disorder. All patients had low intelligence, but none of them had cardiac disease. Conclusion We present the diagnostic process and clinical features which the largest CTX case series ever reported from single orthopedic clinic. We suggest that patients with normal cholesterol levels presenting with xanthoma being genetically analyzed by testing at their serum cholestanol level, and that all siblings of patients diagnosed with CTX be examined.