RESEARCH ARTICLE Ref: 20102204 D09-03 OTH UK PS.PDF Fraser Syndrome: Epidemiological Study in a European Population Ingeborg Barisic,1* Ljubica Odak,1 Maria Loane,2 Ester Garne,3 Diana Wellesley,4 Elisa Calzolari,5 Helen Dolk,2 Marie-Claude Addor,6 Larraitz Arriola,7 Jorieke Bergman,8 Sebastiano Bianca,9 Patricia A. Boyd,10 Elizabeth S Draper,11 Miriam Gatt,12 Martin Haeusler,13 Babak Khoshnood,14 Anna Latos-Bielenska,15 Bob McDonnell,16 Anna Pierini,17 Judith Rankin,18 Anke Rissmann,19 Annette Queisser-Luft,20 Christine Verellen-Dumoulin,21 David Stone,22 and Romano Tenconi23 1Children’s Hospital Zagreb, Clinical Hospital Centre Sisters of Charity, Medical School University of Zagreb, Zagreb, Croatia 2EUROCAT Central Registry, Centre for Maternal, Fetal and Infant Research, University of Ulster, Newtownabbey, United Kingdom 3Pediatric Department, Hospital Lillebaelt, Kolding, Denmark 4University Hospitals Southampton Faculty of Medicine and Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom 5Istituto di Genetica Medica, University of Ferrara, Ferrara, Italy 6Division of Medical Genetics, Lausanne, Switzerland 7Public Health Division of Gipuzkoa, Instituto BIO-Donostia, Basque Government, CIBER Epidemiologıa y Salud Publica—CIBERESP, Gipuzkoa, Spain 8University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 9Registro ISMAC, Catania, Italy 10National Perinatal Epidemiology Unit, University of Oxford, Oxford, United Kingdom 11Department of Health Sciences, University of Leicester, Leicester, United Kingdom 12Department of Health Information and Research, Gardamangia, Malta 13Medical University of Graz, Graz, Austria 14INSERM U953, Paris, France 15Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland 16Health Service Executive, Dublin, Ireland 17CNR Institute of Clinical Physiology, Pisa, Italy 18Institute of Health and Society Newcastle University, Newcastle upon Tyne, United Kingdom 19Medical Faculty, Malformation Monitoring Centre Saxony-Anhalt, Magdeburg, Germany 20University Medical Center of the Johannes Gutenberg University, Mainz, Germany 21Institut de Pathologie et de Genetique, Charleroi, Belgium 22Paediatric Epidemiology & Community Health (PEACH) Unit, Yorkhill Hospital, University of Glasgow, Glasgow, United Kingdom 23Genetica Medica, Dip. Pediatria, Padova, Italy Manuscript Received: 19 April 2012; Manuscript Accepted: 9 December 2012 Abbreviations: EUROCAT, European Surveillance of Congenital Anomalies; GA, gestational age; TOPFA, terminations of pregnancy for fetal anomaly; EDMP, EUROCAT Data Management Program; ICD, International Classification of Diseases; BPA, British Pediatrics Association; OMIM, Online Mendelian Inheritance in Man. Grant sponsor: EC (Executive Agency for Health & Consumers); Grant number: 20102204. *Correspondence to: Ingeborg Barisic, M.D., Ph.D., Professor of Pediatrics Children’s Hospital Zagreb, Medical School University of Zagreb, Klaiceva 16, Zagreb 10 000, Croatia. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 26 March 2013 DOI 10.1002/ajmg.a.35839 Ó 2013 Wiley Periodicals, Inc. 1012 BARISIC ET AL. 1013 Ref: 20102204 D09-03 OTH UK PS.PDF Fraser syndrome is a rare autosomal recessive disorder charac- terized by cryptophthalmos, cutaneous syndactyly, laryngeal, How to Cite this Article: and urogenital malformations. We present a population-based Barisic I, Odak L, Loane M, Garne E, Wellesley epidemiological study using data provided by the European D, Calzolari E, Dolk H, Addor M-C, Arriola L, Surveillance of Congenital Anomalies (EUROCAT) network of Bergman J, Bianca S, Boyd PA, Draper ES, birth defect registries. Between January 1990 and Gatt M, Haeusler M, Khoshnood B, Latos- December 2008, we identified 26 cases of Fraser syndrome in Bielenska A, McDonnell B, Pierini A, Rankin the monitored population of 12,886,464 births (minimal esti- J, Rissmann A, Queisser-Luft A, Verellen- mated prevalence of 0.20 per 100,000 or 1:495,633 births). Most Dumoulin C, Stone D, Tenconi R. 2013. cases (18/26; 69%) were registered in the western part of Europe, Fraser syndrome: Epidemiological study in a where the mean prevalence is 1 in 230,695 births, compared to the European population. prevalence 1 in 1,091,175 for the rest of Europe (P ¼ 0.0003). Am J Med Genet Part A 161A:1012–1018. Consanguinity was present in 7/26 (27%) families. Ten (38%) cases were liveborn, 14 (54%) pregnancies were terminated following prenatal detection of a serious anomaly, and 2 (8%) were stillborn. Eye anomalies were found in 20/24 (83%), syn- more than 250 published case reports of prenatally or postnatally dactyly in 14/24 (58%), and laryngeal anomalies in 5/24 (21%) diagnosed patients. The diagnostic criteria were firstly formulated by patients. Ambiguous genitalia were observed in 3/24 (13%) cases. Thomas et al. [1986]. Major criteria were defined as cryptophthal- Bilateral renal agenesis was present in 12/24 (50%) and unilateral mos, syndactyly, abnormal genitalia, and a positive family history. in 4/24 (17%) cases. The frequency of anorectal anomalies was Minor criteria included congenital anomaly of the nose, ears, or particularly high (42%). Most cases of Fraser syndrome (85%) larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal are suspected prenatally, often due to the presence of the asso- agenesis, and intellectual disability in survivors. Diagnosis was based ciation of renal agenesis and cryptophthalmos. In the European on the presence of at least two major and one minor criterion, or one population, a high proportion (82%) of pregnancies is termi- major and four minor criteria. These criteria, largely adopted in nated, thus reducing the live birth prevalence to a third of the clinical practice, have recently been modified, based on data from total prevalence rate. Ó 2013 Wiley Periodicals, Inc. one literature review and one clinical multicentric study that have further refined the phenotypic spectrum [Slavotinek and Tifft, 2002; Key words: Fraser syndrome; epidemiology; prevalence; congen- van Haelst et al., 2007]. In a more recent study, the diagnostic criteria ital abnormalities; prenatal diagnosis; induced abortion were tested on a set of patients who underwent a standardized evaluation by clinical geneticists, including a detailed questionnaire, INTRODUCTION postmortem reports and clinical photographs. Diagnostic criteria found to be most specific for Fraser syndrome (major criteria) Fraser syndrome (cryptophthalmos-syndactyly syndrome, OMIM included cutaneous syndactyly, cryptophthalmos, ambiguous gen- 219000) is a rare autosomal recessive disorder characterized by italia, urinary, and respiratory tract anomalies and a positive family variable expression of cryptophthalmos, cutaneous syndactyly, and history. Less specific congenital anomalies (minor criteria) were ear laryngeal and urogenital anomalies. Various other anomalies and nose anomalies, anorectal abnormalities, skull ossification including craniofacial, anorectal, skeletal, and heart defects may defects, and an umbilical hernia [van Haelst et al., 2007]. All studies be also present [Fraser, 1962; Thomas et al., 1986; Slavotinek and agreed that there was marked clinical variability and that none of the Tifft, 2002; van Haelst et al., 2007]. major criteria were mandatory for diagnosis. The pathogenesis of Fraser syndrome is thought to be related to a In contrast to the obvious clinical interest, no population-based failure of the programmed cell necrosis or to defects in epidermal epidemiological studies on Fraser syndrome have been published. adhesion which result in the formation of large blisters during The only exception is the study by Martınez-Frıas et al. [1998] where embryonic development [Short et al., 2007; Pavlakis et al., 2011]. the minimal frequency of Fraser syndrome in a Spanish population Mutations in FRAS1 (607830.0001) and FREM2 (608945.0001) was estimated to be 0.43 per 100,000 live births and 11 per 100,000 genes have been previously found to be responsible for about half of stillbirths, based on the seven cases identified in the multi-hospital cases [McGregor et al., 2003; Jadeja et al., 2005; Shafeghati et al., based study of the consecutive series of 1,405,374 liveborn and 9,042 2008; van Haelst et al., 2008]. Recently, mutations in GRIP1 gene stillborn children. have also been identified to cause Fraser syndrome in humans Population-based epidemiological studies of rare genetic syn- [Vogel et al., 2012]. Mutations in these genes are responsible for the dromes can give further perspective to reports of hospital-based disruption of the epithelial–mesenchymal interactions leading to series of patients, but are very difficult to perform, because they the Fraser syndrome phenotype. The potential involvement of require large populations, standardized data collection, and genetic several other genes such as Hemicentin1 (HMCN1), Furin, and expertise. In this report, we have used a large European database for Fibrillin2 that interact in basement membrane anchorage has been population-based surveillance of congenital anomalies (EUROCAT) proposed based on the study of zebrafish, suggesting further genetic to present our findings regarding the prevalence of all birth out- heterogeneity [Carney et al., 2010]. comes, prenatal diagnosis, associated congenital anomalies, survival, Although Fraser syndrome is considered to be rare, it is often and other epidemiological