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Antecedentes: La náusea sola o en combinación con vómitos puede presentarse en el embarazo (NVE). La náusea es un trastorno común que afecta el 50-70 % de las mujeres embarazadas. NVE es característica del primer trimestre. Alrededor del 2 % de las mujeres embarazadas experimentan la forma más grave de NVE, es la hiperémesis gravídica. Esta patología reduce sustancialmente la calidad de vida de la mujer embarazada. Se puede requerir una intervención con antieméticos hasta que desaparezca.Objetivos: Investigar el porcentaje de mujeres que toman antieméticos durante el embarazo, analizar el potencial riesgo teratogénico y establecer estrategias para el autocuidado.Material y métodos: Se analizaron los datos del Estudio Colaborativo Español de Malformaciones Congénitas de red (ECEMC). Se consideraron como expuestos los lactantes (casos y sus controles) cuyas madres estuvieron expuestas a fármacos antieméticos, durante el primer trimestre del embarazo. Para el análisis de fármacos antieméticos, se consideraron los datos de combinación de doxilamina/piridoxina, metoclopramida y el subgrupo de fenotiazinas (OR=1.69, p=0.017).Resultados: Los datos registrados en el ECEMC un promedio de 49 % de las mujeres embarazadas se ha reportado NVE. El antiemético más consumido fue doxilamina/piridoxina. La metoclopramida fue el segundo antiemético consumido y con pocos casos expuestos el subgrupo fenotiazinas. La combinación de doxilamina / piridoxina no presentó riesgo en la población de mujeres embarazadas españolas (OR=1.02, p = 0.36). La metoclopramida mostró un pequeño pero significativo aumento del riesgo teratogénico (OR = 1.21, p=0.0001), así como las fenotiazinas (OR=1.69, p=0.017). Conclusiones: El impacto de NVE en la salud se relaciona con una baja calidad de vida en las mujeres embarazadas y que tiende a ser minimizado. Esta es la razón por la que debemos tratar a NVE en forma oportuna con medicamentos seguros. Los autocuidados durante el embarazo deben ser mayores y no permitir las complicaciones de la NVE. La combinación de doxilamina / piridoxina usado durante el primer trimestre de embarazo no se asoció con un mayor riesgo de malformaciones.

There are very few publications on the possible relationship between maternal diabetes and infants presenting heterotaxia-asymmetry defects. In mice, there is a relationship between maternal diabetes and heterotaxia, although this is influenced by the fetal genotype. An epidemiological analysis of heterotaxia-asymmetry in children born to diabetic mothers (diabetes mellitus or gestational diabetes) is presented here. The analysis is based in the case-control study of the ECEMC database. However, due to the very small sample size for each type of study of heterotaxia-asymmetry alterations, up to 10 control infants for each case were selected. Although the sample size is small, the results suggest that only maternal diabetes mellitus significantly increases the risk for transposition of great vessels (OR=61.87; CI:7.36-519.82), and transposition of viscera (OR=24.82; CI;1.84-335.44).

A de novo interstitial tandem duplication of 6p12p21.3 was observed in a 7-month-old boy with growth retardation, psychomotor delay and craniofacial, brain, limb, and genital anomalies. Fluorescent in situ hybridization using a chromosome 6 paint probe demonstrated that the extra material belonged to chromosome 6. Although it has been suggested that 6p25 is the critical band involved in the expression of the phenotype of 6p duplication, comparison of the clinical findings of this case with those from the literature cases showed strong similarities.

Aspectos Epidemiológicos Congenital anomalies are a leading cause of perinatal mortality (according to EUROCAT’s data, it reaches a prevalence of 9.4 per 10,000 births). Moreover, the most recent Global Burden of Disease Project estimated that congenital anomalies in 2010 accounted for 732,000 Disability Adjusted Life Years Lost (DALYs) in Western Europe, 274,000 in Central Europe and 898,000 in Eastern Europe. Thus, like other Rare Diseases, congenital anomalies are individually rare but collectively a significant public health issue. This report performed by ECEMC (the Spanish Collaborative Study of Congenital Malformations) is the annual update of the congenital anomalies surveillance report, after having analysed data gathered by this research programme between 1980 and 2011, although ECEMC was created in 1976. It is hospital-based and has a case-control design. The report is based on data from 2,735,086 births surveyed, among which a total of 40,329 presented with congenital anomalies detected during the first 3 days of life. Present coverage of the program is 17.95% of total births in Spain. The time distribution, geographical distribution and spacialtemporal distribution of the frequency of congenital anomalies in Spain were studied. The global frequency of infants with congenital defects has significantly decreased along the time, from the basal frequency registered in 1980-1985 (2.22%) to 1.03% in 2011 (Tables 1 and 3), mainly as a consequence of the impact of terminations of pregnancy after the detection of foetal anomalies (ETOPFA), which has been legal in Spain since the end of 1985. This tendency has also been statistically significant in 14 out of 17 Autonomous Regions and in many participating hospitals (Table 3). Only in Extremadura (see Fig. 1) a significant increase was detected, although the frequency registered in 2011 was not significantly different from ECEMC’s global frequency in the same year. After applying the protocol specifically designed at ECEMC for the study of clusters of birth defects, it was concluded that this increase was probably due to both methodological issues during the first years (with some under-registration of birth defects) and the high quality scrutiny and reporting of newborn infants with congenital anomalies, especially in the province of Cáceres). After correcting the frequency in the different hospitals and Autonomic regions by including ETOPFA cases and referrals to tertiary care hospitals, little changes were observed, mainly due to the difficulties to report ETOPFA cases. The time distribution of the frequency of 33 selected birth defects (Table 4) revealed a statistically significant decrease for most of them, although significant increases were also detected for heart/great vessels defects and unilateral renal agenesis, that were interpreted as a result of the availability of better diagnostic procedures. Also, for the annual distribution of 16 selected birth defects (Graphs-1), significant decreases were observed for all global frequencies except for anotia/microtia and gastroschisis. Regarding the temporal-spatial analyses of the frequency of 18 selected defects (Tables 5-10), the global decreases were also evident in many Autonomous Regions. Only an increase was detected for anencephaly in Aragón, where no clue on a local cause for the increase was observed, and where only one case was registered in 2011. Geographical heterogeneity could be detected in 2011 for several defects and was attributable to the birth of a higher than expected number of cases of anencephaly in Aragón, of cleft lip in Galicia, oesophageal atresia/stenosis in the Canary Islands, and hypospadias in Cantabria. All these clusters were analysed and again no local cause was identified and it was concluded that possibly they are stochastic events, although they will be maintained under close scrutiny until the next surveillance report. Since immigration in Spain has been very remarkable in the last years, the ethnic origin of cases and foreign extraction of their parents were analysed. A statistically significant increase along the time in the percentage of foreign parents was detected (Graph 4), and this was more marked among cases than among controls. Also an increase in all ethnic groups except the oriental one was observed (Graph 5). A higher risk for congenital anomalies was observed for all the groups except the Indian group, with respect to the native white group (Graph 6). Some final comments are included regarding the importance of congenital anomalies registries as infrastructure for the research on their causes and prevention, as well as on the exceptional characteristics of ECEMC’s registry and network (including its international activities for birth defects surveillance), and the need for more campaigns for their primary prevention and more research on their causes. In this sense, a reference is made on Kirby and Browne’s 26 consideration of birth defects surveillance as “an essential public health function for primary prevention and health promotion”. No

Dismorfología y Genética Clínica The JMS (OMIM: 147770) is a rare autosomal dominant neuroectodermal disorder characterized by alopecia, ear malformations, conductive hearing loss, anosmia/hyposmia, and hypogonadotropic hypogonadism. Morover, some additional features have been described so far (congenital heart defect, cleft palate, mild facial asymmetry, tendency to caries, and mental retardation). Herein we report on a patient with this condition who exhibits many of the features previously described, including alopecia, malformed auricles, conductive hearing loss, facial asymmetry, and developmental delay. Interestingly, she also has features that have not been reported yet, such as preauricular pits and tags, broad depressions at the external lateral areas close to the eyes, and an abnormal left lower Eyelid. This phenotype supports the involvement of the ectoderm and neuroectoderm of the first two branchial arches in the embryologic basis of this condition. Indeed, alopecia, dental anomalies, defects of the choanae, part of the palatal valves, hypothalamic axis and hypogonadotropic hypogonadism, of epidermic origin, are derived from the ectoderm. Other defects as craniofacial alterations, including inner ear, preauricular tags, ear pits, and even microtia, and facial palsy, are derived from the neural crest, as also are the cardiac malformations. As far as we have known, the patient described here, represents the first case published from Spain No

Otros Resultados: Actividad Traslacional We 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. No

Aspectos Epidemiológicos The 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. No

Dismorfología y Genética Clínica In 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. No

Aspectos Epidemiológicos It 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 group No

Dismorfología y Genética Clínica It 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). No

Dismorfología y Genética Clínica The mouse mutant disorganization (Ds) is an autosomal dominant gene which is lethal in homozygosis, with complete penetrance in heterozygosis. Its expression exhibits an exceptional variety of unusual developmental anomalies in structures derived from various germ layers. Several patients with similar diverse and intriguing anomalies have been reported, raising the possibility of the existence of a human homologue of Disorganization syndrome (DS). In some cases, children with amniotic bands sequence could have a mouse mutant disorganization. Because of this, many children with amniotic bands sequence (ABS) and with abdominal wall defects and other malformations, have been included in cases of DS, concluding that human homologue for DS may be the cause of at least some examples of ABS. Amniotic bands can destroy any structure because they interrupt the blood circulation, leading to encephalocele (actually pseudo-encephalocele), duplication, “cleft lip” and amputations of parts, that stick to other body sites. Before the diagnosis, a detailed analysis should be made to identify primary and secondary malformations. In 1995, the GATA4 gene was mapped at chromosomes 14 and 8 in mice and humans, respectively. GATA4 protein is implicated in the organogenesis processes, particularly in the endoderm and mesoderm formation and their derivatives. The knock-out mice to produce the GATA4 protein are lethal. We describe a female newborn at term presenting with imperforate anus, recto-vestibular fi stula, lipomeningocele and lumbosacral skin appendage with three rudimentary fi ngers. The similarity between the proband´s anomalies, those in previously reported cases and those found in mice support the possibility that this is the fi rst case of Disorganization syndrome in ECEMC. Therefore, its frequency in our registry is less than 1:2,600,000 newborns. No

Citogenética y Genética molecular Arrays are made up of small fragments of DNA from known locations within each chromosome, and labelled probes that bind covalently to a silica or glass surface in a specifi c position (hence the name in silico). Both the sequence and genomic position of each probe are recorded in a database associated with a computer analysis program. These sensors detect changes in gene sequence, particularly in the number of copies, but also in the methylation status or heterozygosity. There are many different types of arrays available and it is possible to differentiate between them in terms of density, distance and the number of probes that they contain, as well as their distribution throughout the genome. In this paper we review the different types of arrays and the current situation in diagnosing patients with birth defects. No

Dismorfología y Genética Clínica Aicardi-Goutières Syndrome (AGS) is a genetic disorder with autosomal recessive aetiology characterized by an early developed encephalopathy with severe physical and mental handicaps. The neonatal form (20% of the cases) shows a phenotype similar to a congenital infection, hence there exists the possibility of misdiagnosis and misinformation to parents about the risk of recurrence. We present a new case of AGS with a neonatal onset and also review clinical patterns, laboratory and neuroimaging findings, and new advances in geneticmolecular diagnosis that have allowed us to delineate the phenotypic spectrum and confirm the aetiology in more than 80% of cases. No

Teratología Clínica The antipsychotic drugs are medications about which a considerable number of telephone calls are received in our teratology information services (SITTE and SITE). We present a review of the literature about the use of this group of drugs during pregnancy. On the other hand, in order to assess the experience in the CIAC, we have studied the intake of antipsychotics in the ECEMC and the queries made on these medications to both teratology information services. Our results show that the intake of antipsychotics during pregnancy is low. However, the number of queries about this type of drugs is increasing, both in the SITTE and in the SITE, probably because of the concern they generate due to the lack of clear information about their use during pregnancy. No

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMC The ECEMC (Spanish Collaborative Study of Congenital Malformations) is a research programme, based on a hospital-based, case-control registry of newborn infants in Spain. It was created in 1976 by María Luisa Martínez-Frías and since then it has surveyed a total population of more than 2.5 million births, and studied more than 38,000 infants with congenital anomalies. The coverage of the registry is 21.18% of total births in Spain. The global frequency of infants with congenital defects in Spain has significantly decreased along the time since the passing of the law (year 1985) permitting termination of pregnancy (ToP) after the diagnosis of fetal defects. Thus, the birth frequency has dropped off from 2.22% in the basal period, to 1.43% in 1986-2006, and 1.17% in 2007. This decrease has also been statistically significant in most of the Spanish Autonomic Regions (see Fig. 1), and in many participating hospitals, and affects most of the defects that are routinely under surveillance. These decreases are considered mainly attributable to the impact of ToP. The only Autonomic Region in which an increase of the frequency was observed, was Extremadura, in which the health care has improved considerably in obstetrics and neonatology, allowing the attention of more complicated pregnancies and infants with serious congenital defects, which in the past were transferred to other regions. With respect to the study of a group of 33 defects, which were selected due to their relatively high base frequency or to the morbidity/mortality that they bear, only the heart/vessels defects and unilateral renal agenesis have increased with time. This must be the result of enhancing possibilities for their diagnosis. From the temporal-spatial analyses, there have been increases in the frequency of anophthalmia/microphthalmia in Baleares, diaphragmatic hernia in Tenerife (Islas Canarias), and omphalocele also in Tenerife. The first one was caused by the birth of just one case in 2007, and no causal agent could be specifically linked to the Balearic Islands. Regarding diaphragmatic hernia in Tenerife, after excluding one case with Brachmann-de Lange syndrome, the increase lost its statistical significance, and apparently there was not any common denominator among the other cases registered. With respect to the increase of omphalocele in Tenerife, this was due to the birth of 2 cases in 2007, without any known common characteristic from which a causal relationship could be inferred. Given that there were 2 defects the frequency of which has increased in Tenerife, it could be thought that they could be somehow related. However, omphalocele and diagphragmatic hernia are etiologically and pathogenetically different, so these findings must rather be independent. As in previous years, the ECEMC system of epidemiological surveillance has demonstrated being the only system in Spain to determine the birth frequency of congenital defects in this country, its evolution along the time, and their comparative geographical as well as temporal-spatial distribution. This is the base for causal studies, for planning of healthcare and social resources, and for designing preventive campaigns. No

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMC The clinical analysis of the main clinical aspects of the infants with congenital defects registered by the ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2007, has been performed. Among a total of 2,254,439 newborns surveyed, 35,246 (1.56%), had congenital defects detected during the first 3 days of life. This group of malformed infants was distributed according to their clinical presentation as isolated (74.01%), multiply malformed (13.43%), and syndromes (12.56%). The etiologic distribution of infants with congenital anomalies in the ECEMC showed a 20.42% of genetic cause, 21.03% multifactorial, 1.22% produced by environmental causes, and in the remaining 57.33% the etiology of the defects was unknown. 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 fetuses. The different types of syndromes and their minimal frequency values, were also presented separated by type of cause. No

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMC Prader-Willi syndrome (PWS) is a neurogenetic disorder that results from different abnormalities involving chromosome 15, which could have either a (q11-q13) paternal microdeletion, maternal uniparental disomy (UPD) or a defect of the imprinting centre. Recently, it has been observed that the risk of UPD for any chromosome is increased when a supernumerary marker chromosome (SMC) is present. In fact, four mechanisms have been proposed to explain UPD in individuals carrying a SMC: 1) Functional trisomy rescue: In a trisomic zygote one of the three chromosomes undergoes a rearrangement to form a SMC, thereby reducing the chromosome complement to two. 2) Postzygotic reduplication: In a zygote which has inherited a SMC in place of the normal corresponding chromosome, a duplication of the normal chromosome homologue occurs to “rescue” the cell from aneuploidy. 3) Postfertilisation error: a postzygotic formation by either nondisjunction in early mitosis and subsequent reduction of the monosomic chromosome homologue or vice versa. 4) Complementation: fertilisation of a disomic gamete by a gamete having a SMC formed before, or during meiosis. Here we present a malformed newborn girl who presented with arched palate, amimic facies, congenital hips laxity, right talus valgus, marked hypotonia, breathing difficulties and hyaline membrane requiring antibiotics treatment. Cytogenetic analysis on blood culture showed two cellular lines, one normal (93.2% of the cells) and the other with a SMC present in 6.8% of the cells (47, XX, +mar/46,XX). As the clinical features of the patient suggested the PWS, Fluorescence In Situ Hybridization (FISH) analysis with the specific 15(q11-q13) region probe was performed, which gave normal results. However, the FISH and microsatellites analyses demonstrated that the SMC was derived from a chromosome 15, and the presence of maternal UPD for chromosome 15. As far as we know, this is the seventh reported patient with PWS, generated by maternal UPD of the chromosomes 15 due to the presence of a SMC (15). Therefore, we believe that is important to consider the increase risk of UPD in patients with a SMC, which is independent of the SMC origin and size, and the high implication for prenatal diagnosis. No

Teratología Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii infection. Acute infections in pregnant women can be transmitted to the fetus and cause severe illness (mental retardation, blindness, epilepsy…). We present a review of the effectiveness of the treatment of toxoplasmosis during pregnancy and we propose some guidelines for the prevention of congenital toxoplasmosis in pregnant women and for those who are planning to become pregnant No

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMC This chapter summarizes the main results of the current epidemiological surveillance of congenital anomalies performed in the Spanish Collaborative Study of Congenital Malformations (ECEMC). This is a research programme developed as a hospital-based case-control study and surveillance system, aimed at investigating the characteristics and causes of congenital defects. It started in 1976, with a common methodology for all the participants in the programme. According to the most recent data, it covers 22.96% of births in Spain. It has been found that the general tendency of the neonatal frequency of congenital defects in Spain is decreasing since the passing, in 1985, of the law allowing voluntary termination of pregnancy (TOP) after the detection of fetal anomalies. The frequency has fallen from the base frequency registered in 1980-1985 (2.22%) up to 1.16% in the year 2006. This general tendency has also been proven for most of the defects under systematic surveillance in the ECEMC. The most noticeable decrease has been observed for the global frequency of Down syndrome, and this decrease is even more pronounced for the oldest maternal ages, as a result of the impact of TOPs. In the analyses by Autonomous Regions (look at the map in Figure 1 to see their location), there was only a statistically significant increase of the global frequency, in Extremadura, that can be attributable to the improvements in the neonatal and obstetrical care in this region, not being necessary to move deliveries at risk to other Autonomous Regions. Regarding the frequency of specific defects, there have been increases in the frequency of esophageal atresia/stenosis in Castilla-La Mancha, anal-rectal atresia/stenosis in Tenerife (Islas Canarias), gastroschisis also in Tenerife, and hypospadias in Castilla y León. For the first two defects, after excluding cases with syndromes with multiple congenital anomalies, they lost statistical significance. For gastroschisis in Tenerife, there were some risk factors among the cases (young maternal age, change in paternity of the different infants of the mother) that could account for the cluster, although it will be closely followed up. For hypospadias, there has not been found any common denominator in the cases that could be considered as the cause of the cluster in Castilla y León, that will also be closely monitored. In conclusion, the ECEMC system of epidemiological surveillance has demonstrated being effective in determining the birth frequency of congenital defects in Spain, its secular trend and geographical distribution, as well as for detecting several increases in the frequency of some congenital defects, leading to a close monitoring of the clusters, which is important for determining their causes and for the prevention of congenital defects, apart from their usefulness in the planning of health and social resources. No

Teratología Vitamin A plays a key role in many essential biological processes, such as the embryonic development, regulation of proliferation and diferentiation of many cell types. The present article reviews the biochemistry, metabolism and mode of action of retinoides (including vitamin A), as well as their role in the embryo development and their teratogenic effect on animal and human beings. No

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMC In this chapter, the most recent results from the main analyses of epidemiological surveillance carried out systematically in the ECEMC are shown. There has not been any remarkable change with respect to the results of the analyses performed in 2005. The decrease in the neonatal prevalence of the congenital defects that are usually included in the surveillance, continues being a constant, mainly attributable to the impact of the voluntary interruption of gestations (VIG) after the detection of foetal anomalies. It has not been detected any increase in the prevalence that could be correlated to any known variation in the causal factors of congenital defects in Spain. The ability of the ECEMC to break down the data gathered in different periods, and to group them in the diverse geographical-administrative areas, has shown to be useful to correlate the variations in the frequencies with some circumstances contributing to the reality of the problem of congenital defects in our country. For instance, the fact of having gathered data since the previous period to the passing of the law regulating VIGs in Spain, has let to estimate their impact on the neonatal frequency of congenital defects. Moreover, grouping data by Spanish Autonomous Regions, has laid the foundations to assess, even comparatively, the different plans of action and intervention developed in each region. Another important issue is that the immigrant population is getting a considerable fraction of the Spanish population, being very similar the percentage registered by the ECEMC to that published by the INE in the official statistics. Additionally, the availability of data in the ECEMC regarding a wide group of about 312 variables per infant registered, confers a great power and versatility to this programme of epidemiological surveillance, as it allows trying to confirm or rule out the possible relationship of those variables with the incidental variations detected in the frequency or congenital defects. No

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMC An epidemiological analysis of the main clinical aspects of the infants with congenital defects registered by the ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2005, has been performed. It is remarkable that the ECEMC programme is defined, as stated in its Operating Manual, as a clinical and epidemiological research program on congenital defects, based on an ongoing case-control, hospital-based registry of newborn infants in Spain. The analyzed material corresponds to 2,152,479 total newborns surveyed, of which 34,066 (1.58%) had congenital defects detected during the first 3 days of life. All these infants with congenital anomalies were analyzed by applying the classification system developed in the ECEMC [Martínez-Frías et al., 1991: Am J Med Genet 41:192-195; Martínez-Frías and Urioste, 1994: Am J Med Genet 49:36-44; Martínez-Frías et al., 2000: Am J Med Genet 90:246-249], based on the most modern concepts in Dysmorphology [Martínez-Frías et al., 1998: Am J Med Genet 76:291-296]. Infants registered were distributed according to their clinical presentation as isolated, multiply malformed, and syndromes, and other subgroups into these 3 groups. The time distribution of the 3 main groups of clinical presentation was studied and all of them have decreased along the years, probably as a consequence of the impact of interruption of pregnancy of some affected fetuses. Apart from the study for all infants with congenital defects, the clinical presentation of a group of 17 defects (selected according to: their relatively high frequency at birth, or the high morbidity/mortality that they bear, and their monitoring in other countries) was also analysed. There was a considerable clinical heterogeneity in most of them, although some (gastroschisis, hypospadias, or anencephaly) tend to present as isolated anomalies, and other (anophthalmia/microphthalmia, abdominal wall defects and bilateral renal agenesis) appear more frequently associated to other defects. The etiologic distribution of infants with congenital anomalies in the ECEMC resulted similar to that shown by other authors, and the lists of syndromes, classified by their etiology, is also provided, detailing their gene map locations if known (OMIM database accessed in June 2006), and their minimum birth prevalence in Spain (according the ECEMC database). To conclude, a commentary is made on the possibility of including not only clinical and genetic information, but also molecular data in the registries coding systems, in order to integrate all the available biological knowledge in the epidemiological approach to identify the causes of congenital defects, to be prevented. No

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMC Under the term "Epidermolysis Bullosa" (EB), there is a heterogeneous group of vesicular disorders that are generally congenital and of genetic origin, and affect skin and often mucosas. It is remarkable the extreme fragility of these epithelia; the vesicles arise spontaneously as well as induced by even slight trauma or the influence of high temperatures. Their content is sero-hemorrhagic and in the scarring can be very difficult. As a consecuence of the scarring processes, joint contractures and fusion of digits (pseudo-syndactyly) can occur. Pathogenetically, EB is caused by abnormal blistering at the basement membrane zone in the dermal-epidermal attachment zone and its surroundings. This is due to alterations in the attachment complexes, and some mutations have been identified in a total of 10 genes expressed in such level. Four main types of EB can be distinguished (simple, junctional, dystrophic and hemidesmosomal), depending on the level at which the cleavage that forms the bulla takes place, although about 30 subtypes have been described. The clinical characteristics or optic microscopy are not adequate for diagnosis, and it is mandatory to perform electron microscopy, immunofluorescent and immunohistochemical studies, as well as mutation analysis if available. Regarding the epidemiological aspects, in the Spanish Collaborative Study of Congenital Malformations (ECEMC), since 1976 up to December 2004, a total of 2,204,264 liveborn infants were controlled and, among them 27 cases have been identified, for a minimum frequency of 0.12 per 10,000 (95% confidence interval:0.08-0.18). It seems generally accepted that the determination of the frequency of EB is subject to multiple biases and registration of cases is always incomplete. We have also reviewed the issues related to management of EB patients by clinicians. No

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMC In an attempt to facilitate the knowledge of the malformation syndromes that have very few frequencies to pediatricians and first health care physicians, particularly to those of rural areas, we have selected six new syndromes. As in previous years, the syndromes are selected from the ECEMC database registry. In this Boletín we include the following syndromes: Townes-Bröcks, MMT, Smith-Lemli-Opitz, Coffin-Siris, Espleno-gonadal fusion, and Silver-Russell syndromes. For each syndrome, we described the most important clinical characteristics, and the present knowledge of their causal factors. No

Dismorfología, Citogenética y Clínica: Resultados sobre los datos del ECEMC Pure 1p36 deletion is considered a new delineated syndrome that probably is a contiguous gene syndrome, presenting a pattern of clinical manifestation that may be recognizable. This includes moderate to severe psychomotor retardation, hypotonia, microcephaly, postnatal growth retardation, seizures and craniofacial dysmorphism (deep set eyes, low nasal bridge, large anterior fontanelle, midface hypoplasia) which should lead to perform a chromosomal study particularly focussed on this type of deletion. Terminal region 1p is difficult to visualize and its alterations will only be detected in a High Resolution G-band karyotype, followed by Fluorescence in situ Hybridization techniques (FISH). Here we present a case which was diagnosed as having a 1p36.22 deletion with High Resolution G-band karyotype confirmed by telomeric FISH. No

Epidemiología y Teratología: Resultados sobre los datos del ECEMC In this study we analyzed the evolution of maternal age along time (the last 26 years) and by Spanish Regions. We also estimated the sex ratio by each year of maternal age in the first pregnancy and in women with more than one previous pregnancy. The results showed that in all Spanish Regions, with some differences among them, there was an important increase in maternal age as the number of sibs increased. We also observed throughout the country an increase in the number of women working outside of the home. Additionally, the sex ration in the first pregnancy by each year of maternal age showed a high proportion of males in each maternal age from 15 years of, age to 36, but from 37 onwards, there were more females than males. This inversion was not observed in mothers with more than one previous pregnancy, who had more males than females in almost all ages. The progressive incorporation of women to the workforce is one of the factors used to explain the observed increasing age for the first pregnancy. This increasing maternal age could have different consequences, such as the alleged potential effect on the sex ratio at birth. Several authors have tried to explain these changes by applying the Trivers and Willard's model that hypothesizes that vertebrates adaptively vary the sex ratio of their offspring in response to the mother´s physical condition. We posit that this relationship is more complex than this. The notable advances in biomedical scientific knowledge and obstetric care have had a marked influence on human beings, not only as it relates to reproduction but also during all the stages of their lives. This influences all adaptive biological mechanisms that, together with the physiological differences with animals including primates, does not make it possible to apply the Trivers and Willard model to human beings. No

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMC We have analysed data from the ECEMC database, gathered in the period 1980-2002, during which a total of 1,838,654 newborn infants were surveyed. The ECEMC programme covered 25.6% of total births occurred in Spain in 2001. We have calculated the global frequency of infants with congenital anomalies in different periods of time (before or after the passing of the law permitting voluntary interruption of gestation -VIG- following prenatal detection of anomalies). This allows to figure out the baseline frequency of congenital anomalies (corresponding to the period 1980-1985), and to assess the impact of VIG on the birth prevalence by comparing the baseline frequency of congenital anomalies with the frequency registered after 1985. The global frequency is decreasing over the years, and in 11 out of 17 Spanish Autonomic Regions we have also observed significant decreases of the frequency along the time. All those decreases are attributable to VIG. We have also studied the time distribution of the frequency of some selected anomalies, as well as their geographical distribution, and both are highly influenced by VIG. Nevertheless, the information on VIG is rather scarce. We consider that if it is not registered on a routine basis, it will be impossible to perform analytic studies on the causes of birth defects and to evaluate any preventive measure. Another question that will have to be approached in years to come is the distribution of birth defects depending on the country the parents come from, as immigration from other countries is increasing in Spain. Finally, we consider that even though the birth prevalence of these pathologies is decreasing as a consequence of the prenatal diagnosis and the possibility of voluntarily interrupting the gestation, it is necessary to search for primary prevention measures in order to get infants being born healthy. No

Dismorfología, Citogenética y Clínica: Resultados sobre los datos del ECEMC This section is based on two facts: First, that the majority of the malformation syndromes are very few frequent. Second, the progressive generalization in our country of the prenatal diagnosis with a high resolution echography performed to all women between 18-20 weeks of gestation as a Service of the National Health System, together with the possibility of voluntary interruption of gestation if fetal anomalies are detected. Thus, the impact of prenatal diagnosis is that the frequency at birth of these syndromes shows an important and progressive decreasing trend. For these reasons, in addition to the difficulty for pediatricians and geneticists or our population to diagnose these usually rare syndromes, the impact of prenatal diagnosis increases the usual difficulties that the young pediatricians and geneticists have to identify these pathologies. This increases the possibility that some affected patients can remain undiagnosed for a long time, or even never be diagnosed. As started last year in this section of the "Boletín del ECEMC", we present other six syndromes of low frequency in our country. No

Epidemiología y Teratología: resultados de estudios sobre los datos del ECEMC We used data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), to analyse some clinical and epidemiological aspects of congenital ocular defects. During the study period (April 76 to March 2000) and after excluding infants with Down síndrome (because all of them had epicanthal folds), a total of 1,257 had ocular defects, for a birth prevalence of 7,5 per 10,000 liveborn infants. This figure is similar to that observed by other authors. Microphthalmia is the most frequent ocular defect identified in the ECEMC data base (1,56 per 10,000). The frequency distribution of the ocular anomalies has been quite stable along time. Regarding the distribution by clinical presentation of ocular defects, the most frequent group is that of infants with multiple congenital anomalies (51,63%), followed by those with syndromes (33,97%). In relation to the etiological distribution of the ocular defects, we observed that these defects can be caused by environmental agents (3,74%), or genetic disorders. These last ones can be of monogenic origin (15,83%) of any type of inheritance, or caused by different types of chromosomal anomalies. Taking into account all these observations, some guidances could be delineated with respect to infants with congenital ocular defects. A careful examination searching for other associated anomalies must be performed, particularly of the central nervous system (CNS). On the other hand, after excluding the possibility that the defects could have been caused by an nvironmental factor, a chromosomal study with high resolution (850 bands) techniques has to be done, as well as FISH techniques if indicated, together with a complete family history. All these data together with the early detection of the ocular and other anomalies, are important for treatment and prognosis of the affected patients and to give counselling to the family. Moreover, in infants with CNS anomalies, an ophthalmologic examination should be mandatory and vice versa. Based in the results of our population, we consider extremely important to inform the population about the harmful effects of alcohol drinking during pregnancy, vaccinations and other preventive measures with respect to some infections during gestation.

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMC We analysed the data gathered by the ECEMC Program since 1980 till 2001, in order to study the frequency of congenital defects (CD) among more than 1.800.000 newborn infants in Spain, its evolution over the time, and the birth prevalence of CD in the different Spanish Autonomic Regions (AR). The analysis also included the birth prevalence of series of selected CD (because of their relatively high frequency, or the mortality/morbidity they bear), their time distribution, their combined distribution by time and AR, and the impact of the voluntary interruption of gestation (VIG) after prenatal detection of anomalies in the fetus. We analysed the data in 3 periods: 1980–1985, which is the period preceding the pass in Spain of the law allowing VIGs before the 22 weeks of gestation due to congenital defects in the fetus. 1986–2000, which is the period following the pass of the mentioned law, and 2001, which is the year we are analysing. The prevalence figures in the first period can be considered as de baseline frequencies in our population, since the VIG was not permitted by law. We have observed statistically significant decrease of the global frequency of CD, which was 1.14% in 2001, being 2.22% in the base period. The main cause of this decrease frequency, are VIGs after prenatal detection of CD in the fetus. We have also analysed the data gathered on VIGs due to CD, but the results are not substantially modified, since not all the articipating hospitals can report data on VIGs. Regarding the global prevalence observed in the different AR, we detected significantly decreases in 11 of the 17 AR. Only Extremadura experiment a significant increase trend, which is attributable to the improvements in the neonatal care units permitting to take care of infants that in the past were born in other Regions after prenatal diagnosis of CD after the 22 weeks of gestations. Among the 16 selected CD, 12 show a statistically significant decreasing trend along the time. These are: anencephaly, spina bifida, encephalocele, hydrocephaly, anophthalmia/ microphthalmia, cleft palate, cleft lip, diaphragmatic hernia, hypospadias, omphalocele, limb reduction defects, and Down syndrome. Some others defects shown a tendency to diminish, but without reach the statistical significance. It is important to comment that hypospadias, that have had a stable frequency along the time until 1995, showed an important decreasing frequency in 1996, and since that moment have been stable but in low levels of frequency. A specific study is being conducted nowadays in order to figure out the cause of such change in their prevalence. Six defects (anencephaly, spina bifida, cleft palate, cleft lip, limb reduction defects, and Down syndrome), show a generalized tendency to diminish their frequency at birth over the time in the different AR, although in some of them the tendency is not statistically significant yet. In conclusion, it is clear from our data, the great impact of VIGs on the birth prevalence of CD. However, we could consider that some other factors, such as the primary prevention of neural tube defects and other anomalies with periconceptional intake of folic acid may also affect to the decrease birth frequencies. Other measures, as the better planning and care of pregnancies, may also act as a primary prevention. However, at present times, it is near impossible to analyse their individual contribution.

Resultados de otras actividades del ECEMC We present the results of the calls received by the Spanish Teratology Information Services, (SITTE directed to health professionals and SITE directed to general population) during 2001. The total number of calling has been of 5.753, corresponding 1.438 of them to the SITTE and 4.315 to the SITE. This number has suffered an increasing in comparison with the year 2000. Calls from all the Spanish Regions (Comunidades Autonómas) have been received. The most frequent enquiry in both services was the drugs during pregnancy. Among them, the psycholeptics and psychoanaleptics are the more often type of drug consulted.

Adams and Oliver (1945) described a family with several affected individuals with terminal transverse limb reduction defects and aplasia cutis congenita of the scalp. The clinical expression was highly variable and the pattern showed a family transmission compatible with an autosomal dominant condition. Since the first description, many cases have been published with this pattern of anomalies being known as Adams-Oliver syndrome. Here we present five affected patients ascertained among the 21,835 malformed infants registered by the Spanish Collaborative Study of Congenital Malformations (ECEMC). Epidemiological aspects and clinical features of the patients are presented and compared with data from the literature.