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 and clinical characteristics of Fraser described in the literature due to its distinctive features. There are syndrome. 1014 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ref: 20102204 D09-03 OTH UK PS.PDF

TABLE I. Prevalence, Prenatal Detection Rate, and Outcome of Pregnancies With Fraser Syndrome in the EUROCAT Congenital Anomaly Registries, 1990–2008 Prenatally detected Study Total Total no. of (no. of patients with Prenatal detection Birth prevalence period births patients available data) rate (%) LB SB TOPFA per 100,000 1990–1999 4,655,793 8 5 (6) 83 4 0 4 0.17 2000–2008 8,230,671 18 12 (14) 86 6 2 10 0.21 1990–2008 12,886,464 26 17 (20) 85 10 2 14 0.20

LB, liveborn; SB, stillborn; TOPFA, terminations of pregnancy for fetal anomaly.

PATIENTS AND METHODS to the prevalence of 0.09 per 100,000 or 1 in 1,091,175 for the rest of Europe (P ¼ 0.0003). The EUROCAT registries cover geographically defined areas and The prevalence rates for 1990–1999 and 2000–2008 were 0.17 are mostly fully population-based, and defined according to the and 0.21 per 100,000 births, respectively (P ¼ 0.56; Table I). residence of the mother. They collect data on all major structural Out of the total of 26 cases, 10 (38%) were liveborn, 14 (54%) congenital anomalies, chromosomal abnormalities, syndromes, pregnancies were terminated following prenatal detection of a and other hereditary conditions presenting prenatally or postna- major anomaly and two (8%) were stillborn. Out of 10 liveborn tally with structural anomalies. Registration covers affected live cases, nine survived the first week of life. There were seven females births, fetal deaths with gestational age (GA) 20 weeks and and 17 males (M/F ¼ 2.4) and in two patients the sex was not terminations of pregnancy for fetal anomaly (TOPFA) following determined (in the third patient with ambiguous genitalia, the sex prenatal diagnosis. was confirmed later by karyotype). In spite of this male prepon- A detailed description of EUROCAT methodology and partic- derance, there was no statistically significant difference in the ipating registries is available elsewhere [www.eurocat-network.eu/ prevalence of Fraser syndrome between boys (1 in 758,027) and content/EUROCAT-Guide-1.3.pdf, Boyd et al., 2011; Greenlees girls (1 in 1,840,923) (P ¼ 0.14). Karyotyping was performed in 16 et al., 2011]. cases and all available results were normal. We received a recent In this study, we used data provided by 34 registries from 16 update on genetic testing for 20 patients. In 13 of them, no genetic European countries for the 1990–2008 period. The data were testing was performed, in four cases the data were not accessible, extracted from the common database on the basis of the ICD/ and in three patients the clinical diagnosis was confirmed by the BPA (759892, 743.0, 743.1, Q87.2, Q11.2) and OMIM (219000) molecular analysis. All mutations involved FRAS1 gene. It is codes assigned to cases of Fraser syndrome that satisfied the possible that some or all of the six cases born in 1995–2005 period diagnostic criteria formulated by Thomas et al. [1986]. Combina- and with no available data on molecular testing, have been part of tions of additional codes (Q110, Q11.1, Q15.8, Q15.9, Q10.3, the study from van Haelst et al. [2008]. Results of postmortem 743.63, 743.8, 743.9, Q70, 755.1, 752, and Q50–Q56) were also examination were available for 11 cases (11/26; 42%). checked for possible unrecognized cases. A medical geneticist A full description of associated congenital anomalies was avail- reviewed the data and contacted the referring registries for addi- able for 24 patients and is presented in Table II. Detailed descrip- tional information if needed. For each case, the following data were tions of the anomalies ascertained postmortem or at birth in evaluated: family history, consanguinity, parental ages, time of prenatally suspected patients were available for 15 cases. Genito- diagnosis, outcome of pregnancy, postmortem examination, urinary anomalies were present in all, bilateral renal agenesis being karyotype/molecular testing, sex of the proband, GA, and weight the most common (12/15; 80%). Thirteen out of 17 patients (76%) at birth, associated anomalies and survival up to 1 week of age. with prenatally detected abnormalities had three or more associated major anomalies. Fourteen (82%) pregnancies with prenatally Statistics diagnosed severe anomalies were terminated at 20.6 2.53 (17– Descriptive data are presented as percentages. Comparisons have 26) weeks of gestation, two resulted in a stillbirth at 37 and 39 been made using the Chi-square test. gestational weeks, respectively, and one resulted in a neonatal death at 34 gestational weeks. RESULTS The frequency of major congenital anomalies in the published series of Fraser syndrome patients and in the present study is shown A total of 26 cases of Fraser syndrome were identified in the in Table III. population of 12,886,464 births during the 19 years under review. In 17 (74%) of 23 patients with known time of diagnosis, first This corresponds to a minimal estimated prevalence of 0.20 per suspicion of an anomaly arose prenatally, while the remaining six 100,000 or 1:495,633 births. Most cases were registered in the cases were detected at birth. The mean GA at detection of anomaly/ western part of Europe, 18/26 (69%) coming from the United anomalies by prenatal ultrasound was 20.4 2.8 (range 16–24) Kingdom, Ireland, Spain, and Portugal. The mean prevalence for gestational weeks. In three cases (15%), prenatal ultrasound was these regions was 0.43 per 100,000 or 1 in 230,695 births, compared performed but did not detect any abnormalities, although two of BARISIC ET AL. 1015 Ref: 20102204 D09-03 OTH UK PS.PDF

Unilateral renal agenesis 4 17 TABLE II. Type and Frequency of Anomalies in Fraser Syndrome Renal dysplasia 1 4 Atresia/hypoplasia of bladder 2 8 Patients Cloacal exstrophy 1 4 Patients Genitalia 8 33 Type of anomaly (N ¼ 24) % Ambiguous genitalia 3 13 Nervous system Cryptorchidism 2 8 Spina bifida 1 4 Underdevelopment of male 28 Head and neck genitalia Eyes 20 83 Absence of female genitalia 1 4 Cryptophthalmos 18 75 Hypoplastic uterus 1 4 Microphthalmos/anophthalmos 8 33 Ovarian dysgenesis 1 4 Congenital cataract 2 8 Numbers in columns do not add up because cases had usually more than one anomaly Coloboma of iris 1 4 listed in the subgroup. Coloboma of eyelid 1 4 Malformation of eyelids 2 8 Retinal dysplasia 2 8 Ear 7 29 these cases presented major anomalies that could easily have been Anotia 2 8 detected by prenatal ultrasound. The prenatal detection rate was Absence of external auditory 28thus 85% (17/20) with no significant trend over the two time canal periods, 1990–1999 and 2000–2008 (P ¼ 0.56; Table I). Misshapen ear 3 13 In liveborn babies, the mean GA at birth was 37.3 2.1 gesta- Nose 2 8 tional weeks (range 34–40). The mean birth weight was Bifid nose 1 4 2,534 654 g for males and 2,126 714 g for females. Overall Other 1 4 live births had a less severe clinical presentation. Five out of 10 Mouth 5 21 live births (50%) had three major anomalies. There was one case of Cleft lip/palate 2 8 bilateral renal agenesis resulting in neonatal death, and three cases Hypoglossia/microglossia 2 8 of unilateral renal agenesis. Ankyloglossia 1 4 Mandible The mean paternal age was 31.3 4.7 years and the mean Micrognatism 1 4 maternal age was 28.8 5.2 years. The maternal age distribution Retrognatism 1 4 did not differ significantly from that for the total EUROCAT Respiratory system 8 33 population, based on the available maternal age (known for 72% Laryngeal stenosis/hypoplasia 5 21 of the EUROCAT total birth population or for 9.3 million births out Stenosis of subglottic area 1 4 of approximately 12.9 million births). Lung hypoplasia 2 8 Parental consanguinity was present in seven families (27% of Unspecified lung anomaly 1 4 cases) that all came from Western European countries. In five cases, Heart 3 13 the parents were first cousins, and in two cases second cousins. Four ASD 1 4 families already had one affected child. One pair of siblings was VSD 1 4 included in the present study. Anomalies of pulmonary artery 1 4 Digestive system 10 42 Diaphragmatic hernia 1 4 DISCUSSION Large bowel obstruction 1 4 Agenesis of anus 3 13 This article reports the epidemiological and clinical features of a Imperforate anus 3 13 series of Fraser syndrome patients recorded in the European con- Atresia of anus 1 4 genital anomaly registries in the period 1990–2008. Stenosis of rectum 1 4 Ectopic anus 2 8 Hands/digits 14 58 Prevalence Syndactyly 14 58 We have found that the minimal estimated prevalence of Fraser Ectrodactyly 1 4 syndrome in Europe is 0.20 per 100,000 or 1:495,633 births and that Agenesis of phalanges 1 4 Hand anomaly 1 4 the prevalence has been stable since 1990. Fraser syndrome includes Skeletal 3 13 severe and distinctive malformations that are easily detected pre- Skull ossification defect 1 4 natally or at birth and it is unlikely that a significant number of cases Malformation of spine not 14were missed at birth or diagnosed later in infancy. It is, however, specified possible that some of the fetuses with severe anomalies were Clubfoot 1 4 terminated or resulted in stillbirth without syndrome diagnosis, Urinary system 18 75 particularly when there is no postmortem examination. Therefore, Bilateral renal agenesis 12 50 the established prevalence represents a minimal estimate. 1016 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ref: 20102204 D09-03 OTH UK PS.PDF

TABLE III. Frequency of Congenital Anomalies in Previously Published Reviews Compared to Present Series of Fraser Syndrome Patients Thomas et al. Gattuso et al. Slavotinek and Tifft van Haelst et al. [1986] [1987] [2002] [2007] Our study Cryptophtalmos 80/94 (85%) 63/68 (93%) 103/117 (88%) 50/59 (85%) 18/24 (75%) Syndactyly 65/82 (79%) 37/68 (54%) 72/117 (61.5%) 56/59 (95%) 14/24 (58%) Laryngeal abnormalities 24/29 (83%) 14/68 (21%) 48/117 (41%) 29/59 (49%) 6/24 (25%) Renal agenesis 31/37 (84%) 25/68 (37%) 53/117 (53%) 45/59 (76%) 16/24 (67%) Bladder abnormalities — 7/68 (10%) 20/117 (17%) 10/59 (17%) 3/24 (13%) Genital anomalies 57/71 (80%) 33/68 (49%) — 39/59 (66%) 8/24 (33%) Ambiguous genitalia 10/64 (15.6%) 4/68 (6%) 20/117 (17%) — 3/24 (13%) Ear abnormalities 57/68 (84%) 30/68 (44%) — 44/59 (74%) 7/24 (29%) Nose anomalies 56/66 (85%) 20/68 (29%) — 31/59 (53%) 2/24 (8%) Cleft lip/palate 7/65 (11%) 5/68 (7%) 13/117 (11.1%) 5/59 (9%) 2/24 (8%) CHD 5/86 (5.8%) 4/68 (6%) 14/117 (11.9%) 6/59 (10%) 3/24 (13%) Anorectal anomalies 2/86 (2.3%) 4/68 (6%) 41 (35%) 19/59 (32%) 10/24 (42%)

CHD, congenital heart defect. ‘‘—’’ presentation of this set of data in the original articles was such that it did not permit comparison with our data and data from other studies.

The present study reveals considerable heterogeneity in the [2004], the proposed diagnostic criteria for Fraser syndrome are prevalence rates, with significantly higher rates in the west Euro- not applicable to the cases diagnosed prenatally, because several pean countries compared to the rest of Europe. Majority of cases major criteria, for example, syndactyly and abnormal genitalia, are were registered in the United Kingdom, Ireland, Spain, and Portu- only observed with difficulty in the presence of oligohydramnios. gal. Due to the rarity of Fraser syndrome, reports on the possible On the other hand, renal agenesis, a minor diagnostic criterion, is differences in geographical distribution are not available. The only easily detectable on prenatal ultrasound and was the most impor- epidemiological study performed to date was conducted in a tant prenatal diagnostic marker in our series of patients. Spanish population. The reported prevalence of 0.49 per 100,000 Early diagnosis is important for the timely counselling of affected live births and stillbirths is comparable to the prevalence 0.43 per couples regarding the option of pregnancy termination for cases 100,000 births that we found in the registries of Western Europe. with a major anomaly. The 25% recurrence risk and the possibilities Geographical differences may be explained by ethnic differences, of genetic testing and prenatal molecular diagnosis in future with consanguinity being common in some immigrant and Roma pregnancies should also be considered. Prenatal detection resulted populations of Western Europe [Bundey et al., 1990; Martınez-Frıas in the termination of pregnancy in 82% (14/17) of cases. This is and Bermejo, 1992]. Possible differences of ascertainment methods approximately half of all recorded cases with Fraser syndrome in between registries could be another potential reason for the differ- this study, which shows the important impact of prenatal diagnosis ence in prevalence between west and east of the Europe. on the birth prevalence of Fraser syndrome in Europe.

Prenatal Diagnosis Associated Anomalies Prenatal ultrasound diagnosis of Fraser syndrome is possible at The description of our patients is not entirely compatible with 18 weeks of gestation, but mainly carried out in cases with a family literature reviews, some of which include detailed lists of minor history [Feldman et al., 1985; Schauer et al., 1990; Rousseau et al., anomalies. Minor anomalies are not systematically coded in 2002; Vijayaraghavan et al., 2005]. In most cases, the definitive EUROCAT registries and those with no specific code are missed diagnosis is reached at postmortem examination or after birth. The if text descriptions are missing. This may account for the lower characteristic prenatal ultrasonographic signs include the combi- frequency of mild ear, nose, and genital anomalies in our nation of cryptophthalmos/microphthalmia, syndactyly, enlarged population-based case series (Table III). Postmortem results were echogenic lungs, and oligohydramnios [Berg et al., 2001]. unavailable for some patients, which could also be the reason for This study is the first to provide population-based data on underreported anomalies not detected by prenatal ultrasound. prenatal diagnosis and termination of pregnancy for Fraser syn- Finally, some anomalies, for example, laryngeal stenosis, are diffi- drome. When performed, prenatal ultrasound examination cult to diagnose in TOPFA which accounted for about half of cases detected the presence of at least one major anomaly in 85% of in our series. the European patients. The prenatal detection rate of associated In addition to the high rate of cryptophthalmos and syndactyly, anomalies did not substantially change during the study period. The which are considered to be the hallmark of the syndrome, we found combination of bilateral renal agenesis and cryptophthalmos, a high rate of urinary tract anomalies. They were present in 80% of observed in 10/15 patients, was the most common one. Most of our patients, which is comparable with 84%, 70%, and 93% the prenatally detected patients had at least three major anomalies reported by Thomas et al. [1986], Slavotinek and Tifft [2002], indicating phenotype severity. As observed by Maruotti et al. and van Haelst et al. [2007], respectively (Table III). This high rate BARISIC ET AL. 1017 Ref: 20102204 D09-03 OTH UK PS.PDF of urinary tract anomalies is mostly due to the high frequency of digital cosmetic surgery are usually needed [Saleh et al., 2009]. bilateral renal agenesis. We also observed a high frequency of Developmental delays/intellectual disability is present only in a anorectal anomalies which were present in 42% of our patients. proportion of cases. Of these, anal atresia/stenosis was the most common (Table II). A In conclusion, this is the first large population study on Fraser significantly higher frequency of anorectal anomalies was also syndrome that includes all types of birth outcomes. Large studies as found by Slavotinek and Tifft [2002] (35%) and van Haelst et al. this one always imply some heterogeneity of case ascertainment. In [2007] (32%) when compared to the low frequency of 2.3% and 6% the EUROCAT network, minor anomalies are not systematically recorded in the studies by Thomas et al. [1986] and Gattuso et al. recorded and most of the registries do not routinely record infor- [1987], respectively (Table III). mation on the long-term outcome of recorded patients. However, van Haelst et al. [2007] suggested adding airway and urinary tract the benefits of this network include a large population, standardized anomalies to the major criteria of Thomas et al. [1986]. This is data collection and the use of genetic expertise, thus providing an supported by the data from our study. Cleft lip and/or palate, opportunity to increase our knowledge of rare genetic disorders. cardiac malformations, and musculoskeletal anomalies are uncom- We have found that Fraser syndrome is a rare genetic disorder mon. As most of the EUROCAT registries only follow patients up to with a minimal estimated prevalence of 0.20 per 100,000 births, and 1 year of age, we were not able to evaluate the frequency of marked regional variation. A high rate of consanguinity confirms intellectual disability among Fraser syndrome patients. recessive inheritance. Our data point to a high rate of urinary tract, airway malformations, and anal stenosis/agenesis. Most cases of Consanguinity Fraser syndrome are suspected prenatally due to the presence of characteristic anomalies which are mostly severe and often include Consanguineous marriage is customary in many parts of the world, the association of bilateral agenesis and cryptophthalmos. In our leading to an increased birth prevalence of infants with recessive European population, a high proportion of pregnancies are termi- disorders. Although consanguineous marriages are most common nated, thus reducing the live birth prevalence to a third of the total in the Middle East, North Africa, Western Asia, and South India, prevalence rate. they are also present in immigrant populations and resident Roma communities of Western Europe, leading to regional differences in the prevalence of rare recessive disorders. Our data confirm a high ACKNOWLEDGMENTS incidence of consanguinity (27%) in families with Fraser syndrome, This study is a part of the EUROCAT Joint Action funded by the EC, which was also observed by Slavotinek and Tifft [2002] (24.8%) and under the framework of EU Health Programme 2008-2013, Grant is much higher than the incidence of 15% that was found in the Agreement 20102204 (Executive Agency for Health & Consumers). original series of patients from Thomas et al. [1986]. Of the seven We thank doctors Berenice Doray, Karin Kallen Carlos Matias Dias, Fraser syndrome patients described in a study of the Spanish Vera Nelen, Mary OMahony, Joaquin Salvador, Gioacchino population by Martınez-Frıas et al. [1998], four came from Scarano, David Tucker, Leonore Abramsky, Christine Francannet, Roma families. The consanguinity rate in this study was also and Carmen Mosquera-Teneiro for providing data for the present high (28.6%). The proportion of endogamous marriages in Spanish study. We also thank the many people throughout Europe involved Roma population is about 30% [Martınez-Frıas and Bermejo, in providing and processing information, including affected 1992] and the estimated prevalence of Fraser syndrome in the families, clinicians, health professionals, medical record clerks, Roma population is 1:22,065 [Martınez-Frıas et al., 1998]. All and registry staff. consanguineous cases in our series came from Western Europe. The most common consanguineous union referred to first cousins. REFERENCES

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