Severe Neonatal Cholestasis in Cerebrotendinous Xanthomatosis
Genetics, Immunostaining, Mass Spectrometry
Jing-Yu Gong
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Kenneth D.R. Setchell
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Address correspondence and reprint requests to Jian-She Wang, The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Rd, Minhang District, Shanghai 201102, China (e-mail: [email protected]); Kenneth D.R. Setchell, Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (e-mail: [email protected]).Search for more papers by this authorJing Zhao
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorWujuan Zhang
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorBrian Wolfe
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorYi Lu
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorKarolin Lackner
Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
Search for more papers by this authorA.S. Knisely
Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
Search for more papers by this authorCorresponding Author
Neng-Li Wang
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Address correspondence and reprint requests to Jian-She Wang, The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Rd, Minhang District, Shanghai 201102, China (e-mail: [email protected]); Kenneth D.R. Setchell, Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (e-mail: [email protected]).Search for more papers by this authorChen-Zhi Hao
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorMei-Hong Zhang
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorJian-She Wang
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorJing-Yu Gong
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Kenneth D.R. Setchell
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Address correspondence and reprint requests to Jian-She Wang, The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Rd, Minhang District, Shanghai 201102, China (e-mail: [email protected]); Kenneth D.R. Setchell, Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (e-mail: [email protected]).Search for more papers by this authorJing Zhao
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorWujuan Zhang
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorBrian Wolfe
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Search for more papers by this authorYi Lu
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorKarolin Lackner
Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
Search for more papers by this authorA.S. Knisely
Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
Search for more papers by this authorCorresponding Author
Neng-Li Wang
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Address correspondence and reprint requests to Jian-She Wang, The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Rd, Minhang District, Shanghai 201102, China (e-mail: [email protected]); Kenneth D.R. Setchell, Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (e-mail: [email protected]).Search for more papers by this authorChen-Zhi Hao
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorMei-Hong Zhang
The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorJian-She Wang
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University
Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China
Search for more papers by this authorThis project was funded by the National Natural Science Foundation of China, Grant Numbers 81361128006 and 81570468 (to J.S.W.); Shanghai Medical Key Specialty Construction Project Number ZK2015A04 (to J.S.W.).
J.-Y.G., K.D.R.S., J.Z., W.Z., and B.W. contributed equally to this article.
K.D.R.S. is a consultant to the Retrophin company and holds a minor equity in Asklepion Pharmaceuticals, LLC. The remaining authors have no relevant financial, professional, and/or personal conflicts of interest with respect to this manuscript.
ABSTRACT
Objectives:
Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The rare reports of CTX manifest as neonatal cholestasis assess the cholestasis as transient, with patient survival. Our experience differs.
Methods:
Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients’ urine samples.
Results:
All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease.
Conclusions:
CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.
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