title: Hepatocellular Carcinoma in Fanconi-Bickel Syndrome.
abstract: Fanconi-Bickel syndrome is a rare autosomal recessive disorder due to mutations in the facilitative glucose transporter 2 ( GLUT2 or SLC2A2) gene resulting in excessive glycogen storage predominantly in the liver and kidney. Previous case reports of this condition have described liver biopsies with glycogen storage and variable steatosis and/or fibrosis. Unlike in other types of glycogen storage disease, hepatocellular adenomas and carcinomas have not been described to date in this syndrome. A 6-year-old boy with consanguineous parents had short stature, poorly controlled rickets, hepatosplenomegaly, and renal tubular dysfunction clinically consistent with Fanconi-Bickel Syndrome. Sequencing of the SLC2A2 gene showed a homozygous variant of unknown significance [c.474A > C (p.Arg158Ser)] causing a missense mutation in an evolutionarily conserved residue. An incidental single hepatic lesion was discovered on imaging, and subsequent resection showed a 2.6 cm well-differentiated hepatocellular carcinoma with moderate atypia, diffuse immunoreactivity for glypican-3, and nuclear b-catenin, and with focal complete loss of the reticulin framework. The non-neoplastic liver showed marked glycogen accumulation with mild periportal fibrosis, rare bridging fibrosis, and no regenerative or adenomatous nodules. By electron microscopy, tumor cells had pleomorphic nuclei, prominent nucleoli, and scant cytoplasm with numerous mitochondria. Well-developed canaliculi were occasionally seen. The non-neoplastic liver showed glycogenosis with abundant cytoplasmic free (non-membrane bound) glycogen. Hepatocellular carcinoma should be considered as a possible complication of Fanconi-Bickel syndrome. This well differentiated carcinoma did not appear to be associated with hepatic adenomatosis as has been described in some hepatocellular carcinomas associated with other hepatic glycogen storage disorders. The nuclear beta-catenin immunoreactivity indicates a role for the Wnt signaling pathway in the pathogenesis of this tumor.
authors.affiliation: 1 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogoriler
authors.affiliation: 2 Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Allison F
authors.initials: AF
authors.lastname: O'Neill
authors.affiliation: 3 Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.affiliation: 4 Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Shamberger
authors.affiliation: 1 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000209:etiology*; D002648:Child; D005198:Fanconi Syndrome / Q000150:complications / Q000175:diagnosis*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000209:etiology*; D008297:Male
keywords: dysplastic nodule; electron microscopy; glycogen storage disease; glycogenosis; hepatoblastoma; hepatocellular adenoma