title: Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance.
abstract: Alagille syndrome is an autosomal dominant disorder affecting multiple organ systems, predominantly the liver, heart, skeleton, eye, face, and kidney. The phenotype in Alagille syndrome is highly variable both within and between families. We report monozygotic twins with Alagille syndrome concordant for a mutation in Jagged1 but discordant for clinical phenotype. The twins' monozygosity was confirmed by molecular testing. A de novo splice site mutation was identified in exon 6 (1329 + 2T --> G) in both children. Both twins display a severe form of Alagille syndrome; however, one twin has a severe pulmonary atresia with mild liver involvement, while the other has tetralogy of Fallot and severe hepatic involvement, which has required liver transplantation. Potential mechanisms for phenotypic variability among monozygotic twins are discussed. This is the first reported case of discordance in phenotype in monozygotic twins with Alagille syndrome. This case implies that genotypic variations alone do not explain the clinical variability seen in Alagille syndrome and supports the contributory role of nongenetic factors in phenotype determination.
authors.affiliation: Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Binita M
authors.initials: BM
authors.lastname: Kamath
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
authors.forename: James E
authors.initials: JE
authors.lastname: Heubi
authors.forename: David A
authors.initials: DA
authors.lastname: Piccoli
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics / Q000503:physiopathology*; D001652:Bile Ducts / Q000002:abnormalities; D002135:Calcium-Binding Proteins; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins; D011506:Proteins / Q000235:genetics; D018633:Pulmonary Atresia / Q000503:physiopathology; D000072099:Serrate-Jagged Proteins; D014430:Twins, Monozygotic
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D000072099:Serrate-Jagged Proteins