Ping Zhang1, Jing Zhao2, Xiao-Min Peng1, Yan-Yan Qian1, Xue-Mei Zhao1, Wen-Hao Zhou3, Jian-She Wang2, Bing-Bing Wu4, Hui-Jun Wang5. 1. Center for Molecular Medicine and Key Laboratory of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China. 2. Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China. 3. Center for Molecular Medicine and Key Laboratory of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China; Department of Neonates, Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China. 4. Center for Molecular Medicine and Key Laboratory of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China. Electronic address: bingbingwu2010@163.com. 5. Center for Molecular Medicine and Key Laboratory of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China. Electronic address: huijunwang@fudan.edu.cn.
Abstract
BACKGROUND: CYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTX patients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive. OBJECTIVE: We aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX. METHODS: From June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records. RESULTS: A total of 17 patients with an average onset age of 8 (1-42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14). CONCLUSION: Based on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.
BACKGROUND:CYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTXpatients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive. OBJECTIVE: We aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX. METHODS: From June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records. RESULTS: A total of 17 patients with an average onset age of 8 (1-42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14). CONCLUSION: Based on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.