Congenital hepatic fibrosis in 3 siblings with phosphomannose isomerase deficiency

Abstract

Congenital hepatic fibrosis is a rare disorder of intrahepatic bile ducts with the persistence of embryological bile duct structures in ductal plate configuration. Three siblings aged 18, 17 and 14 years old were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme phosphomannose isomerase. The clinical symptoms were recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly. The biochemical abnormalities included elevated serum transferases during attacks, clotting factor deficiencies and persistent hypoalbuminemia. In the youngest patient protein-losing enteropathy was present. Liver biopsies of the three patients taken when they were 1, 3 and 14 years old showed an excess of bile duct structures in ductal plate configuration with mild fibrosis in the portal triads. In one patient the liver biopsy was repeated after 18 years and showed only a mild progression of fibrosis in the portal triads. Duodenal biopsies taken in infancy in two of the three patients did not show any abnormalities. Recognition of phosphomannose isomerase deficiency in association with congenital hepatic fibrosis and protein-losing enteropathy is important, because some of the clinical symptoms are potentially treatable by oral mannose therapy.

A Deficiency in Dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl α3-Glucosyltransferase Defines a New Subtype of Congenital Disorders of Glycosylation

“…However, mutations in only 7 of the genes encoding proteins of the glycosylation pathway have so far been shown to underlie CDG I, and these 7 cases have been classified as CDG I subtypes a-g (Ia, phosphomannomutase 2 (7,8); Ib, phosphomannose isomerase (9, 10); Ic, dolichyl-P-Glc:Man 9 GlcNAc 2 -PP-dolichyl ␣3-glucosyltransferase (11-13); Id, dolichyl-P-Man:Man 5 GlcNAc 2 -PP-dolichyl ␣3-mannosyltransferase (14); Ie, dolichol-P-Man synthase I (15,16); If, the MPDU1 gene product known to facilitate dolichyl-P-Glc and dolichyl-P-Man utilization (17,18); and Ig, dolichyl-P-Man: Man 7 GlcNAc 2 -PP-dolichyl ␣6-mannosyltransferase (19 -21)). Although there are too few patients representing each subtype of the disease to draw precise genotype/phenotype relationships, CDG Ib (PMI deficiency) generally presents as a disease in which central nervous system defects are absent (9,10). Often, PMI deficiency leads to a less severe form of the disease because as well as the PMI-catalyzed conversion of fructose 6-phosphate to mannose 6-phosphate the cell possesses an alternative route for the generation of the latter intermediate.…”

Congenital disorders involving defective N-glycosylation of proteins

“…Other CDG-Ib patients have presented with different PMI mutations [134,135] and similar, but not identical, signs and symptoms. Three siblings were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme PMI and recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly [137]. The phosphomannoisomerase gene (MPI) is composed of eight exons and spans only 5 kb [136].…”

“…Since CDG-Ib is potentially lethal and mannose therapy appears to be curative, patients with idiopathic congenital hepatic fibrosis [137,138], hypoglycemia [139,140], coagulopathies, and failure to thrive should be tested for CDG with a serum transferrin glycoform analysis.…”

Is Congenital Hepatic Fibrosis a Pure Liver Disease?

“…Congenital hepatic fibrosis (CHF) is a rare disorder of intrahepatic bile duct development associated with ductal plate malformation (1). The persistence of excess embryonic bile duct structure in the portal tracts is called ductal plate malformation (DPM), and it is the basic morphologic abnormality in all variants of fibrocystic diseases, such as Caroli's disease, infantile polycystic disease, and adult polycystic disease (2).…”