Boletín del ECEMC: Revista de Dismorfología y Epidemiología - 2011 - Serie VI Nº 1
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Publication Boletín del ECEMC: Revista de Dismorfología y Epidemiología - 2011 - Serie VI Nº 1(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Instituto de Salud Carlos III. Instituto de Investigación de Enfermedades Raras (IIER)Sumario de Boletín del ECEMC: Revista de Dismorfología y Epidemiología - 2011 - Serie VI Nº 1Publication Boletín del ECEMC: Revista de Dismorfología y Epidemiología - 2011 - Serie VI Nº 1(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Instituto de Salud Carlos III. Instituto de Investigación de Enfermedades Raras (IIER)Número completo de: Boletín del ECEMC: Revista de Dismorfología y Epidemiología - 2011 - Serie VI Nº 1Publication Mecanismos generales del control molecular de la formación de las regiones del cerebro durante el desarrollo(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Martínez, SalvadorPublication Descripción de un nuevo caso de síndrome de Bohring-Opitz (o de Oberklaid-Danks)(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Aldea-Romero, AE; López-Dueñas, A; Rubio-Jiménez, ME; Hernández-Bejarano, MJ; García-García, A; Martinez-Fernandez, Maria Luisa; Bermejo-Sanchez, Eva; Martínez-Frías, María LuisaIn 1999, Bohring et al. reported a new syndrome clinically distinguishable from cases with C syndrome or Opitz trigonocephaly. All the patients showed failure to thrive, microcephaly with metopic suture ridging, nevus flammeus over the forehead, thick hair and forehead hirsutism, shallow orbits with prominent eyes, depressed nasal root, anomalous ears, retrognathia, cleft lip and palate, flexion deformities of the upper limbs with radial head dislocation and ulnar deviation of fingers. Patients have severe developmental delay, sucking and swallowing difficulties starting in the prenatal period, as suggested by the usual polyhydramnios. The brain anomalies include hydrocephaly/large ventricles, agenesis/hypoplasia of corpus callosum, Dandy-Walker malformation, myelin abnormalities, and cortical atrophy. Occasional symptoms are a small or closed fontanel at birth, inguinal hernias and cryptorchidism in males, and intestinal malrotation. Most patients die early in childhood because of bradycardia and apnea. Although there is an overlap between C-like syndrome and C syndrome, different manifestations in these patients suggest a different entity. This new syndrome has been called (apart from C-like syndrome) Bohring-Optiz or Oberklaid-Danks syndrome. Recently, it has been associated in some patients to heterozygous de novo nonsense mutations in ASXL1 gene, which is required for maintenance of both activation and silencing of Hox genes, suggesting that the syndrome is genetically Heterogeneous. Here we describe the first case of this syndrome identified in the Spanish Collaborative Study of Congenital Malformations (ECEMC) Registry, and possibly in Spain. Therefore, its minimal frequency has been estimated in 1:2,648,286 newborn infants.Publication Síndrome de Sorsby: descripción de un caso que representa la segunda familia descrita(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Arroyo-Carrera, I; García-García, MJ; Lozano-Rodríguez, JA; Polo-Antúnez, A; Zunzunegui, JL; Álvarez, T; Martinez-Fernandez, Maria Luisa; Bermejo-Sanchez, EvaIn 1935, Sorsby [Br J Ophthalmol. 1935; 19:65-90] described a family with several affected individuals presenting with bilateral coloboma of macula, type B brachydactyly affecting hands and feet, and unilateral renal agenesis in one of its members. We describe a newborn girl presenting with the same pattern of congenital anomalies as the patients of the family originally described by Sorsby (OMIM 120400). However, the current case has as additional findings a single umbilical artery, and an anomaly of pulmonary vascularization consisting in: a ring in the lower right lobar artery and sequestration of the lower right lung lobe. Therefore, despite that our patient adds new clinical variability, it is not possible to disregard the diagnosis of Sorsby syndrome, because such clinical variability was also observed in the affected members of the original family described by Sorsby and some individuals of the next generations of the same family, according to the report by Thompson and Baraitser [J Med Genet. 1988; 25:313-321]. Based on the observed genealogy pattern of affected members in the only family published, it is considered that this syndrome is due to an autosomal dominant gene. The baby described here, is the first case in the family. She had a normal karyotype (~850 bands) and the subtelomeric Multi-FISH was also normal. Her father was 39 years old and, therefore, an age-related new mutation could be evaluated. The frequency of Sorsby syndrome is unknown, since only the original family has been published so far. However, as the case described here is part of the ECEMC Registry, we can estimate that its frequency is at least 1:2,750,000 newborn infants. We consider that, even in the “molecular era”, it remains important to clinically describe those extremely rare syndromes, in order to define their characteristics and clinical expressions. These aspects are essential to define the prognosis, clinical management and information to the family, and can help also to determine the gene(s) or pathogenetic pathways involved in their origin.Publication Análisis clínico-epidemiológico de los recién nacidos con defectos congénitos registrados en el ECEMC: Distribución por etiología y por grupos étnicos(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Martínez-Frías, María Luisa; Cuevas Catalina, María Lourdes; Grupo Periférico del ECEMC; Bermejo-Sanchez, EvaIt is presented here the analysis of the main clinical aspects of the infants with congenital defects registered by ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2010. Among a total of 2,648,286 newborns surveyed, 39,434 (1.49%) had congenital defects detected during the first 3 days of life. This group of infants with congenital anomalies was distributed according to the clinical presentation of their defects as isolated (73.94%), multiply malformed (13.53%), and syndromes (12.53%). The etiologic distribution of infants with congenital anomalies in the ECEMC showed a 20.47% of genetic cause, 20.28% multifactorial, 1.35% produced by environmental causes, and the etiology of the defects was unknown in the remaining 57.90%. The secular distribution of the 3 main groups of clinical presentation (isolated, multiply malformed and syndromes) was studied and all of them showed a decreasing trend along the years, probably as a consequence of the impact of the interruption of pregnancy of some affected foetuses. The different types of syndromes identified and their minimal frequency values are also presented, separated by type of cause (Tables 4-10). Finally, the proportion of cases with birth defects by ethnic groups, first including (Graph 8) and then excluding (Graph 9) two groups of whites, the autochthones and the immigrant whites group. Due to the small samples in most non-white groups, the differences are not statistically significant, except for a significant higher frequency among Gypsies than in the white groups (both native and foreigner), the black group, and the one of Other (including mix groups).Publication Análisis de alteraciones cromosómicas estructurales y su distribución por cromosomas en la serie de recién nacidos con defectos congénitos del ECEMC(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Martinez-Fernandez, Maria Luisa; MacDonald, Alexandra; Aceña, Mª Isabel; Bermejo-Sanchez, Eva; Grupo Periférico del ECEMC; Martínez-Frías, María LuisaThis study was aimed at estimating the frequency of unbalanced structural chromosomal anomalies identified in the consecutive series of newborn infants with congenital defects, registered in the Spanish Collaborative Study of Congenital Malformations (ECEMC). These cases were cytogenetically studied at its laboratory since 1981 up to December 2009. A total of 4,681 cases were studied following a protocol established by ECEMC program, which starts by performing a high resolution karyotype (550-850 bands), and if the results are normal, it is followed by the analysis of subtelomeric regions and depending on the clinical manifestations, some FISH and MLPA analyses were applied in order to also rule out microdeletion syndromes. The parents and other relatives were also studied when necessary, according to ECEMC’s protocol. A total of 136 cases had unbalanced chromosomal structural anomalies. Data were analyzed either globally or in two periods including the years 1981-1994, and 1995-2009 which are before and after starting the use of FISH techniques in the ECEMC`s laboratory. Among the 136 total cases having unbalanced structural anomalies, 71.32% were cytogenetically detected, and the remaining 28.68% by FISH. Each type of anomaly was distributed by involved chromosome separating those affecting p and q arms. In the group of cytogenetically detected anomalies, deletions (42.55% of cases) were 2.1 times more frequent than duplications (20.22%). Deletions affecting short arms were 3 times more frequent than duplications. Among cases detected by FISH techniques, deletions were 15.49 times more frequent than duplications, the 22q11.2 microdeletion being the most common (38.46% of the cases), followed by the deletions in chromosomes 15 (15.38%) and 4 (10.26%). Some of these alterations were identified by the clinical suspicion of their specific syndromes (Wolf-Hirschhorn, Prader-Willi, Williams-Beuren, Miller-Dieker, etc), and this could somehow bias their frequencies (see Table 3). In addition, some other unexpected microdeletion syndromes were detected such as two cases with microdeletion 1p36, one case with each of the following microdeletions: 2q23.1, 5q31, and a deletion 12q13.3-q21.2, including the region of the known microdeletion syndrome 12q14, but it is possible that may be other not hitherto identified. To our knowledge, this study represents the first one analyzing the frequency of chromosomal alterations globally and by each one of the 23 chromosomes on a consecutive series of newborn infants with congenital defects which are detectable during the first three days of life. It is also remarkable that all the cases were studied with the same protocol and the same team of specialists.Publication Informe anual del ECEMC sobre vigilancia epidemiológica de anomalías congénitas en España: Datos del período 1980-2010(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Bermejo-Sanchez, Eva; Cuevas Catalina, María Lourdes; Grupo Periférico del ECEMC; Martínez-Frías, María LuisaThe Spanish Collaborative Study of Congenital Malformations (ECEMC) annually undertakes the preparation and updating of the report of epidemiological surveillance of congenital anomalies in Spain. ECEMC is a research programme for congenital anomalies, based on an ongoing registry of births in Spain, which is hospital-based and has a case-control design. It has surveyed about 2.8 million births (Table 1), and gathered data on 41,800 consecutive infants with congenital anomalies and a similar number of healthy controls. Present coverage of the registry is 19.8% of total births in Spain (Table 2). The basal frequency of infants with congenital defects in our country is 2.22% (registered in 1980-1985), and it fell up to 1.07% in 2010, mainly as a result of the impact of elective termination of pregnancy after the detection of foetal anomalies (ETOPFA). ETOPFA has been legal in Spain since the end of the year 1985. Such a statistically significant decrease of the global frequency can be observed (Table 3) in many of the participating hospitals and most Spanish Autonomic Regions (see Fig. 1). Some increases in six hospitals were studied in detail. The only Autonomic Region in which an increase was detected is Extremadura, but this finding is probably due to methodological reasons in the first years, and referrals of high-risk pregnancies to other regions in those years, with considerable further changes that allow a better detection and reporting of cases in this region. The corrected global frequency by hospital and Autonomic Region, taking ETOPFA into account, was also analysed. The evolution of the frequency of a selected group of 33 defects with a relatively high base frequency and/or bearing a high morbidity/mortality was studied (Table 4). Most of them diminished along the time, the only increases being observed for heart/great vessels defects and unilateral renal agenesis, possibly as a result of better diagnostic procedures. Down syndrome is the defect for which a more marked decrease was measured (Graphs-1)A group of 18 defects were selected for the temporal-spatial analyses of the frequency, and also many statistically significant decreases were observed in most Spanish Autonomic Regions (Tables 5-10). The only increase was detected for anencephaly in the Balearic Islands, based on two births, and no clue on a local cause was obtained. Geographical heterogeneity could be detected in 2010 for anencephaly, spina bifida, anal/rectal atresia/stenosis, and hypospadias. For anencephaly, heterogeneity was attributable to the previously mentioned relatively high frequency registered in the Balearic Islands. For spina bifida, it was due to a high frequency observed in La Rioja, but based on the birth of just one case. For anal/rectal atresia/stenosis it was due to the high frequency registered in the quite distant regions of the Balearic Islands and La Rioja, and no common factor was identified as a possible cause. In all these cases it is noticeable that in regions where a small number of births is surveyed, the birth of just one case can bring the frequency to unusually high levels, and this can generate some geographical heterogeneity. For hypospadias, it was due to the low frequency observed in 2010 in the Comunidad Valenciana, and the relatively high frequency registered in Andalucia; all cases were balanic and isolated, and the higher frequency was observed in three hospitals in the provinces of Córdoba, Jaén and Malaga. All these findings will be subject to close scrutiny until the next surveillance report. Due to the importance of immigration in Spain in the last years, the ethnic origin of cases and foreign extraction of their parents were also analysed. The percentage of foreign parents has significantly increased with time, and was higher among the cases than among the controls (Graph 4). All ethnic groups had a higher risk for congenital anomalies than the native white group (Graph 6) and, except the oriental group, have increased with time (Graph 5). A reflection is included as a final comment, regarding the need of research on causes of birth defects, as expressed by Olshan et al. [Am J Med Genet A. 2011;155:1794–1797]: ‘For future generations, it is essential that we identify causes so that effective public health and clinical prevention programs can be established’. ECEMC, and other programmes worldwide, collaborate with that aim. For that purpose, ECEMC has a considerable background and experience of more than 35 years, as well as enough flexibility to adapt itself to new challenges, working for the prevention of birth defects.Publication Otros aspectos de vigilancia epidemiológica del ECEMC: Evolución temporal y por Comunidades Autónomas, de los nacimientos de la población inmigrante(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Martínez-Frías, María Luisa; Bermejo-Sanchez, EvaIt is well known that immigration has increased along the time in Spain, especially in the most recent years. We have analyzed data from ECEMC in order to quantify this phenomenon in the sample of 35,441 controls (newborn infants without congenital defects) registered by ECEMC in the period 1980-2009, since the group of immigrants usually has a set of characteristics which increase their offspring’s risk for being born with congenital anomalies. ECEMC gathers information on the birth place and ethnic group of parents and grandparents of both controls and cases registered with congenital anomalies. Most of immigrant parents (62.82%) come from non-european countries. Globally, the Autonomous Regions with the higher percentages of immigrant parents were the Balearic Islands (18%), Community of Madrid (15.84%), Comunidad Valenciana (15.16%) and Catalonia (13.08%). In the year 2009, however, the higher percentages were registered in Catalonia, followed by Community of Madrid, Balearic Islands and Comunidad Valenciana. There has been a statistically significant increase of births from immigrants along the time, from 1.89% of total control births in 1980-1985, up to 23.92% in the year 2009. This increase has been more pronounced for the group of immigrants from non-european countries. Since 1996, the proportion of births from non-European countries is higher than the counterpart of infants being born to European immigrants in Spain. Data from the different Autonomous regions mostly reflect this general tendency. In the groups of immigrants, the most frequent ethnic group was that of whites (96.84% among immigrants coming from European countries, and 41.73% among those coming from non-european countries). There is almost total concordance of data from ECEMC with the official data registered by INE (Spanish National Institute for Statististics). Knowing the magnitude of the different groups of immigrants in Spain is very important in order to properly design the different plans for prevention of congenital anomalies, according to the special risks of each population groupPublication Análisis Epidemiológico de las infecciones urinarias y la exposición a Fosfomicina durante el embarazo en madres de niños con y sin defectos congénitos: Distribución por años y por comunidades autónomas(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) García-Benítez, María Regla; Real, María Montserrat; Fernández, Paloma; Bermejo-Sanchez, Eva; Martínez-Frías, María LuisaThe objective of this study was to epidemiologically analyze urinary tract infections (UTI) suffered by pregnant women, and the prenatal exposure to Fosfomycin. To accomplish this objective, data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) were analyzed for the period 1978-2009. A total of 40,060 newborn infants with congenital defects, and a similar number of healthy controls were registered. The proportions of mothers of cases and controls who suffered UTI during the first trimester were 2.69% and 2.56%, respectively. These figures go up to 9.94% and 8.86% when considering UTI at any time during pregnancy. The proportions of mothers who were treated with fosfomycin during the first trimester of pregnancy were 0.67% and 0.69%, respectively for cases and controls, and those figures go up to 2.69% y 2.54% when considering exposures at any time during pregnancy. Use of fosfomycin at any time during pregnancy has progressively increased with time. When studying the geographical distribution of the frequency some differences regarding UTI and use of fosfomycin were detected. The increase in use of fosfomycin has caused a decrease of the use of other antibiotics, and these trends are also observed in several autonomous regions in Spain. The use of fosfomycin during pregnancy seems to be safe, and suffering an UTI is quite common during pregnancy and somehow dangerous for the progress of gestation. It is important to underline that the percentage of mothers without treatment was between 20 and 35%. Therefore, it is advisable to treat UTI as soon as possible, in order to avoid complications both for the mother and fetus.Publication Consumo de Antihistamínicos-H1 durante el primer trimestre del embarazo en España, y estimación del riesgo global para defectos congénitos en el recién nacido(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Arias-Rico, José; Bermejo-Sanchez, Eva; Grupo Periférico del ECEMC; Fernández, Paloma; Martínez-Frías, María LuisaH1 antihistamines (H1A) are drugs that have been used for many years for treatment of allergic diseases, as for the control of nausea and morning sickness in pregnant women. Here it is analyzed the evolution of their global use during gestation and by the different groups of H1A, along the last 31 years in the ECEMC data. In addition, their potential risk on the embryo development regarding congenital defects is analysed. The data belongs to the Spanish Collaborative Study of Congenital Malformations (ECEMC), for the period 1977-2008. The ECEMC is a hospital-based, case-control study and surveillance system, aimed at performing clinical and epidemiological studies on congenital defects, the methodology of which includes the collection of about 310 items on each newborn infant registered, whether case or control, on their pregnancy and family history, and many types of prenatal exposures. During the study period the ECEMC surveyed and examined a total of 2,607,822 consecutive newborns, and a total of 39,561 out of them had congenital defects identifiable during the first three days of life. After having excluded those cases diagnosed centrally at ECEMC as presenting with syndromes, the studied samples were 33,056 cases and 32,258 controls. The total data of the different tables may not be the same because they include only the cases and controls with each data specified. The analysis of the evolution of H1A consumption by pregnant women in Spain along the years showed a statistically significant increasing trend, from 12.66% and 11.51% for cases and controls, respectively, in 1977 to 13.90% and 15.86%, respectively, in 2008. This increase has occurred at the expense of doxilamine (combined with vitamin B6) used as an antiemetic, and of three subgroups of H1A used in the control of allergic processes (Alquilamines, Piperazines, and Piperidines). None of the subgroups of H1A has shown an increased risk for birth defects (after its use during the first trimester of pregnancy), except the group of Piperidines (OR=6.83; p=0.003). However, due to the small samples of exposed infants, it is not possible to perform any type of multivariate analysis to control for possible confounders. Hence, we cannot rule out that the observed risk could be due to uncontrolled factors. If a pregnant woman had allergic problems and needs to be treated, she has to be treated because the risks for her and for the embryo overwhelm the ones derived from the treatment if any. For such treatment, if the allergic process only can be controlled with a piperidine, this product could be used, although not as the first option. On the other hand, the combination of doxilamine and pyridoxine (vitamin B 6) is a safe option for the control of nausea and vomiting during pregnancy.Publication Actividad de los Servicios de Información sobre Teratógenos (SITTE y SITE) durante el año 2010(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Fernández-Martín, P; García-Benítez, Mª Regla; Real-Ferrero, M Monserrat; Bermejo-Sanchez, Eva; Martínez-Frías, María LuisaWe present a summary of the activity of the two Teratology Information Services: SITTE (for health professionals) and SITE (for the general population) during the year 2010. The total number of calls received in both services was 5,087 (814 received by SITTE and 4,273 by SITE). We present the distribution of calls along the years, as well as by the types of health professionals who performed the calls and the types of questions. Also, we show the distribution by different groups of exposures, including maternal diseases and their treatments, professional exposures, life styles, and others. Quantitatively, drug use has been the main reason for these queries. In addition, we have analyzed for the first time, the question regarding paternal diseases, treatments and professional exposures.Publication Pósteres presentados en la XXXIV Reunión Anual del ECEMC, celebrada en Albacete durante los días 27-29 de octubre de 2011(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2011-12) Instituto de Salud Carlos III. Instituto de Investigación de Enfermedades Raras