American Journal of Medical Genetics 137A:302–304 (2005) Clinical Report Recurrence of Mowat–Wilson Syndrome in Siblings With the Same Proven Mutation Julie McGaughran, 1 * Stephen Sinnott, 2 Florence Dastot-Le Moal, 5 Meredith Wilson, 3 David Mowat, 4 Bridget Sutton, 2 and Michel Goossens 5 1 Queensland Clinical Genetics Service, Royal Children’s Hospital, Brisbane, Queensland, Australia 2 Centre for Fetal Diagnosis and Treatment, Royal Women’s Hospital, Brisbane, Australia 3 Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia 4 Department of Medical Genetics, Sydney Children’s Hospital and School of Paediatrics, University of New South Wales, Sydney, Australia 5 Service de Biochimie et Ge´ne´tique, Unite´INSERM 468, Hoˆpital Henri Mondor,Cre´teil, France Mowat–Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormal- ities, and congenital heart disease. Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS. There have previously been no reports of a sibling recurrence of this syndrome. A brother and sister are described with clinical features of MWS, where both have the same truncating mutation in exon 8 of ZFHX1B. As their parents are phenotypically normal and do not have the mutation in lympho- cyte-derived DNA, the most likely explanation is germ-line mosaicism. ß 2005 Wiley-Liss, Inc. KEY WORDS: Mowat–Wilson syndrome; sibling recurrence; germ-line mosaicism INTRODUCTION Mowat et al. [1998] reported six sporadic patients with microcephaly, mental retardation, and similar dysmorphism, five of whom had Hirschsprung disease (HSCR). This condi- tion, now designated Mowat–Wilson (MWS) syndrome, was subsequently shown to be caused by heterozygous mutations in the ZFHX1B gene [Cacheux et al., 2001; Wakamatsu et al., 2001]. A series of subsequent publications have further delineated the phenotype [Zweier et al., 2002; Mowat et al., 2003; Wilson et al., 2003; Ishihara et al., 2004]. Other common features described in these patients include agenesis of the corpus callosum, congenital heart malformations, and genital and urinary tract anomalies. No convincing sibling pairs with MWS, with or without a proven mutation, have been reported. Here we describe a sister and brother with phenotypic MWS syndrome and the same mutation in ZFHX1B. PATIENTS AND METHODS Patients The female sibling was born to a 20-year-old primigravida mother at 41 weeks gestation. The parents were healthy, Caucasian and non-consanguineous. Antenatal scanning had demonstrated the presence of mild renal pelvic dilatation. She weighed 3.3 kg (10th centile) at birth. She was diagnosed with short segment HSCR and had a pull-through procedure. A postnatal renal tract ultrasound was normal. She was reviewed by a pediatrician at 11 months because of parental concerns about developmental delay. She was assessed as functioning at a 3–4 month level. She was noted to have a divergent strabismus and some dysmorphic features. Cerebral MRI showed agenesis of the corpus callosum. A karyotype was normal, and no syndrome diagnosis was made at this time. During the parents’ next pregnancy, a nuchal translucency scan was reported as normal. Detailed fetal ultrasound examination at 18 weeks-of-gestation showed agenesis of the corpus callosum, which was confirmed on fetal MRI (Fig. 1). The finding of agenesis of the corpus callosum suggested a possible recurrence of the sister’s condition. The mother had a cerebral MRI at the same time as the fetal MRI, which confirmed that she had a normal corpus callosum. There was also concern about the left side of the fetal heart, which appeared to be small. Amniocentesis showed an apparently normal male karyotype. The male baby was delivered at 38 weeks gestation weighing 3.56 kg (60th centile) with an OFC of 34 cm (50th centile). Echocardiogram on day 1 showed coarctation of the aorta down to 2 mm at the ductal origin. This was repaired in the 1st week of life by a patch graft. He developed signs of bowel obstruction and on day 3 at laparotomy, the absence of ganglion cells was noted in sections from bowel distal to the left transverse colon. A transverse colostomy was performed. Ophthalmological assessment demonstrated the presence of colobomas bilaterally. Subse- quent retinal examination showed an aplastic left optic nerve with central chorio-retinal coloboma. On the right only the choroid was affected with a lacuna around the disc. A renal tract ultrasound was normal. The older sibling was first evaluated by a clinical geneticist after the birth of her affected brother. She had not begun walking until over 2 years and had no speech at 30 months. She had no history of epilepsy. She had the typical dysmorphic features seen in Mowat–Wilson syndrome with an open- mouthed, smiling expression. Her eyebrows had disorganized hair growth patterns and she had deep set eyes with the typical nasal tip and prominent chin seen in the condition. She had sparse, fine hair. Her ears had upturned lobes with the central depression typically seen in MWS (Fig. 2). Her brother had *Correspondence to: Julie McGaughran, M.D., Queensland Clinical Genetics Service, Royal Children’s Hospital and Health Service District, Herston, Brisbane 4029, Queensland, Australia. E-mail: Julie_McGaughran@health.qld.gov.au Received 1 November 2004; Accepted 2 June 2005 DOI 10.1002/ajmg.a.30896 ß 2005 Wiley-Liss, Inc.