Mechanism of pancreatic and liver malformations in human fetuses with short-rib polydactyly syndrome.

BACKGROUND The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. METHODS The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. RESULTS Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord). CONCLUSION In SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal-epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549-562, 2016. © 2016 Wiley Periodicals, Inc.