Neonatal sclerosing cholangitis with novel mutations in DCDC2 (doublecortin domain-containing protein 2) in Chinese children

Abstract

BackgroundNeonatal sclerosing cholangitis (NSC) is a rare and severe autosomal recessive inherited liver disease with mutations in DCDC2, commonly requiring liver transplantation (LT) for decompensated biliary cirrhosis in childhood.MethodsThe information of four Chinese patients with NSC caused by mutations in DCDC2 from Children's Hospital of Fudan University were gathered. The four patients' clinicopathological and molecular features were summarized by clinical data, liver biopsy, immunohistochemical, and molecular genetic analysis.ResultsAll patients presented with jaundice, hepatosplenomegaly, hyperbilirubinemia and bile embolism, and high serum γ-glutamyl transferase activity (GGT). Liver biopsies revealed varying degrees of bile duct hyperplasia, portal-tract inflammation, and/or fibrosis. Whole-exome sequencing (WES) found novel heterozygous variants of c.1024-1G > T /p.? and c.544G > A /p. Gly182Arg in the DCDC2.ConclusionThis study expands the genetic spectrum of DCDC2 in NSC.

Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis

“…UGT1A1 and ABCC2, SLCO1B1/3 mutations result in abnormal bilirubin excretion and metabolism ( Hashimoto et al, 2002 ; van de Steeg et al, 2012 ; Saito et al, 2013 ; Gilbert et al, 2019 ; Hsu et al, 2022 ). DCDC2 mutations are associated with cilia and cause restricted bile acid flow ( Wei et al, 2023 ). ATP7B mutation leads to copper deposition, causing substantial liver damage that disrupts hepatocyte function ( Kwo et al, 2017 ).…”

“…Neonatal sclerosing cholangitis (NSC) is a severe autosomal recessive liver disease that often results in decompensated biliary cirrhosis during childhood, requiring liver transplantation ( Wei et al, 2023 ).…”

“…DCDC2 gene mutations have been strongly associated with this condition ( Wei et al, 2023 ). DCDC2 inhibits the classical WNT signaling pathway, regulates ciliary production and length, and is expressed in most organs, including bile duct epithelial cells.…”

“…The patient exhibited symptoms such as jaundice, hepatosplenomegaly, hyperbilirubinemia, cholestasis, and elevated levels of serum GGT activity. A liver biopsy revealed varying degrees of bile duct hyperplasia, portal inflammation, and/or fibrosis ( Wei et al, 2023 ).…”

“…If left untreated, these children may develop cholestatic cirrhosis and liver failure within 2 years (Schwarz et al, 2013;Lakshminarayanan and Davenport, 2016) Bile acid analogues, drugs that reduce the amount of bile acid in the liver, anti-inflammatory, immunosuppressive agents, anti-fibrotic drugs (Bezerra et al, 2018) Jaundice and cholestatic cirrhosis caused by intrahepatic and intrahepatic bile duct obstruction (Mack and Sokol, 2005) Neonatal sclerosing cholangitis DCDC2 DCDC2 protein is found in the cytoplasm and cilia of cholangiocytes. However, in individuals with neonatal sclerosing cholangitis who have mutations in the DCDC2 gene, the mutant protein accumulates in the cytoplasm and is not present in the cilia, which impair the function of cilia that line the bile duct's epithelial cells, affecting the normal flow of bile (Girard et al, 2016) The patient presented with a combination of symptoms including jaundice, hepatosplenomegaly, hyperbilirubinemia, cholestasis, and elevated levels of serum GGT activity (Wei et al, 2023) Bone marrow transplantation (Girard et al, 2012) (Continued on following page)…”