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. © 2002 Wiley‐Liss, Inc.

Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy

“…Cholestatic liver disease is present in nearly all individuals with AGS, as originally defined, and in the past has been considered to be an essential criterion for the AGS diagnosis. However, reports that first-degree relatives of AGS patients can have cardiac and other organ defects typical of AGS in the absence of overt liver disease, and a recent report of a series of Jagged 1 mutations in individuals with isolated congenital cardiac defects, suggest that the spectrum of defects caused by Jagged 1 mutations is broad (Elmslie et al, 1995;Emerick et al, 1999;Kamath et al, 2002b;McElhinney et al, 2002).…”

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

“…(2) Phenotypic discordance in miscellaneous syndromes and diseases. A wide variety of conditions has been described in which there are examples of phenotypic discordance within MZ twin pairs, including: Proteus syndrome, male [Biesecker et al, 1998;Brockmann et al, 2008]; tibial aplasia with ectrodactyly, female [Dayer et al, 2007]; lymphedema-distichiasis [Kumar et al, 2007]; microphthalmia, syndromic 3, male [Zenteno et al, 2006]; Melnick-Needles syndrome, female [Robertson et al, 2006]; Klippel-Feil syndrome, female [Toyoshima et al, 2006]; Klippel-Trenaunay syndrome, male [Hofer et al, 2005]; frontonasal dysplasia, five discordant pairs [Mohammed et al, 2004]; Alagille syndrome 1 [Kamath et al, 2002]; Leopard syndrome 1 [Rudolph et al, 2001]; Fryns syndrome [Vargas et al, 2000]; Joubert syndrome, female [Raynes et al, 1999]; orofaciodigital syndrome 1, female [Shotelersuk et al, 1999]; trichorhinophalangeal syndrome 1, female [Naselli et al, 1998]; Sotos syndrome [Brown et al, 1998]; Aicardi syndrome, female [Costa et al, 1997] Table IV [Sommer et al, 2002]. Twelve pairs were concordantly right-handed (RH/ RH) and 13 pairs were discordantly handed, that is, right-handed/nonright-handed (RH/NRH).…”

Differential changes in platelet reactivity induced by acute physical compared to persistent mental stress

“…The matrix-metalloproteinases MMP-2 [4] and MMP-9 [5] as well as the immune-modulatory molecule CD40L [6] are found mainly in the cytosol of platelets and are released upon platelet activation. The secretion of molecules by platelet degranulation allows for interaction with other platelets, immune cells and endothelial cells [7].…”