Recurrence of Mowat–Wilson syndrome in siblings with a novel mutation in the ZEB2 gene

To the Editor:Mowatetal.[1998]describedaseriesofsixisolatedpatients with microcephaly, mental retardation,and a peculiar facial phenotype. Five patients hadHirschsprung disease (HSCR) [Mowat et al., 1998].The disorder, which was designated by the eponymMowat–Wilson syndrome (MWS, OMIM #235730),was demonstrated to be caused by heterozygousmutations in the Zinc finger E-box-Binding homeo-box 2 gene (ZEB2, also known as ZFHX1B orSMADIP1) [Cacheux et al., 2001; Wakamatsu et al.,2001;Yamadaetal.,2001].Molecularanalysishelpedto delineate the cardinal features of MWS (facialgestalt and delayed psychomotor development)as well as several variably associated congenitalanomalies, including HSCR, agenesis of the corpuscallosum, seizures, eye anomalies, heart malforma-tions, genital, and urinary tract defects [reviewed byAdam et al., 2006; Garavelli and Mainardi, 2007].To date, there are approximately 180 mutation-positivepatientswithMWSintheliterature,with100different ZEB2 mutations reported [Zweier et al.,2005]. Three cases of recurrence in siblings havebeen reported [McGaughran et al., 2005; Zweieret al., 2005; Ohtsuka et al., 2008]. We describe twosisters with clinical features of MWS in whom thesame nonsense mutation in the ZEB2 gene wasfound.Theoldersiblingisnow6yearsold.Shewasbornby spontaneous delivery at 39 weeks of gestation.Antenatalscanningperformedat20weekssuggestedagenesis of the corpus callosum. Birth weight was3,670g(75thcentile),lengthwas52cm(75thcentile).Head circumference at birth was not measured.Hypotonia and feeding difficulties were present inthe neonatal period. Growth was normal. Psycho-motor development was delayed: she walked at30monthsofageandstillpronounces4–5words.At18 months an episode of febrile seizures occurred,followed by afebrile tonic-clonic seizures treatedwith valproate. Postnatal cerebral MRI confirmedagenesisofthecorpuscallosum.Ultrasoundscansoftheheartandabdomenandkaryotypewerenormal.Constipation was never reported. The clinicaldiagnosis of MWS was first raised when she was5 years of age by the presence of her facial gestalt(Fig. 1A–C). Length was 112 cm (50–75th centile),weight18kg(25thcentile),headcircumferencewas51 cm (50th centile).The sister was born at 39 weeks of gestation byspontaneous delivery. Again probable agenesis ofthe corpus callosum was noted on the antenatalultrasound scan (20th week of gestation). At birthweight was 4,010 g (90th centile), length 52 cm(75th centile), head circumference was not meas-ured. Echocardiography on day 3 revealed a com-plex heart malformation: aortic coarctation andvalvularstenosis,pulmonaryvalvestenosis,multiple