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

Christine K.C. Loo; Tamara N. Pereira; Mette Ramsing; Ida Vogel; Olav B. Petersen; Grant A. Ramm

doi:10.1002/bdra.23495

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

Christine K.C. Loo, Tamara N. Pereira, Mette Ramsing, Ida Vogel, Olav B. Petersen, Grant A. Ramm^*

^*Corresponding author af dette arbejde

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Birth Defects Research Part A - Clinical and Molecular Teratology
Vol/bind	106
Udgave nummer	7
Sider (fra-til)	549-562
ISSN	1542-0752
DOI	https://doi.org/10.1002/bdra.23495
Status	Udgivet - 2016
Udgivet eksternt	Ja

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10.1002/bdra.23495

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@article{56f7a4d4941847de8d483cfcccfacae3,

title = "Mechanism of pancreatic and liver malformations in human fetuses with short-rib polydactyly syndrome",

abstract = "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.",

keywords = "ciliopathy, ductal plate malformation, human fetus, short-rib polydactyly",

author = "Loo, {Christine K.C.} and Pereira, {Tamara N.} and Mette Ramsing and Ida Vogel and Petersen, {Olav B.} and Ramm, {Grant A.}",

year = "2016",

doi = "10.1002/bdra.23495",

language = "English",

volume = "106",

pages = "549--562",

journal = "Birth Defects Research Part A - Clinical and Molecular Teratology",

issn = "1542-0752",

publisher = "Wiley",

number = "7",

}

TY - JOUR

T1 - Mechanism of pancreatic and liver malformations in human fetuses with short-rib polydactyly syndrome

AU - Loo, Christine K.C.

AU - Pereira, Tamara N.

AU - Ramsing, Mette

AU - Vogel, Ida

AU - Petersen, Olav B.

AU - Ramm, Grant A.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - ciliopathy

KW - ductal plate malformation

KW - human fetus

KW - short-rib polydactyly

U2 - 10.1002/bdra.23495

DO - 10.1002/bdra.23495

M3 - Journal article

C2 - 26970085

AN - SCOPUS:84960387260

SN - 1542-0752

VL - 106

SP - 549

EP - 562

JO - Birth Defects Research Part A - Clinical and Molecular Teratology

JF - Birth Defects Research Part A - Clinical and Molecular Teratology

IS - 7

ER -

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

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