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Rodríguez-Pinilla, Elvira

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Elvira

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Rodríguez-Pinilla

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ISCIII

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ISCIII::Instituto de Investigación de Enfermedades Raras (IIER)

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Aspectos diagnósticos, etiológicos y genéticos de las ictiosis congénitas al nacimiento
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2004-10) Martínez-Frías, María Luisa; Bermejo-Sanchez, Eva; López Grondona, Fermín; Rodríguez-Pinilla, Elvira; Mendioroz, J; Cuevas Catalina, María Lourdes; Barcia, JM; Oliván del Cacho, MJ; Espinosa, MJ; Gómez, F; Aparicio, P; Félix, V; García, A; García, MJ; Vázquez, MS; Centeno, F; García, MM; Marco, JJ; Galán, E; Gómez, H; Blanco, M; López Soler, JA; Paisán L
The Ichthyoses constitutes a large family of genetic skin diseases characterized by dry skin and variable degrees of blisters and scales. There are at least twenty varieties of ichthyosis, with a wide range of severity and associated symptoms, and genetic heterogeneity (autosomal dominant, autosomal recessive, and X-linked inheritance). The clinical symptoms, which are non-specific, may not be apparent. We have attempted to provide a classification of the ichthyoses and some guidance for the diagnosis and management of these conditions. The present classification is based in the type of alteration of the skin layer, the molecular findings, the biochemical characteristics, and the family history.There are three main categories, which include different subgroups of ichthyoses: 1) Those that are caused by an altered process of keratinocytic diferenciation (altered intermediate filaments/keratins). This category includes the following subgroups: a) Harlequin fetus; b) bullous erythroderma ichthyosiformis congenital; c) Ichthyosis bullosa of Siemens; d) Ichthyosis hystrix of Curth-Macklin; and e) Ichthyosis vulgaris. 2) Those that are caused by a deficient formation of the cornified envelope (transglutaminase 1 enzyme deficiency). In this category we include two main subgrups: a) Lamellar ichthyosis AR, which includes i) ichthyosis lamellar (IL1, IL2, IL3, IL4, and IL5), and ii) ichthyosiform erythroderma congenital nonbullous, and b) Nonlamellar ichthyosis and nonerythrodermic congenital ichthyosis AR. 3) Those caused by an abnormal steroid sulfatase (X-linked Ichtyosis). In spite of having only data at birth and the lack of molecular analysis, we attempted to classify the ECEMC cases according to this classification using available clinical data. We also calculated the frequency of this disease identified at birth, and provide some guidance for the clinical diagnosis, the management of the affected newborn, and the information that should be offered to the parents.
Aspectos Clínico-Epidemiológicos de los recién nacidos con anomalías congénitas registrados en el ECEMC
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2004-10) Bermejo-Sanchez, Eva; Mendioroz, J; Cuevas Catalina, María Lourdes; López Grondona, Fermín; Rodríguez-Pinilla, Elvira; Martínez-Frías, María Luisa
Data gathered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) during the period 1980-2003 have been analyzed to study some clinical aspects of congenital anomalies through an epidemiological point of view. Data of the ECEMC correspond to a consecutive series of newborn infants with congenital anomalies detected during the first 3 days of life. A total of 1,941,742 newborns were surveyed, and 31,646 (1.63%) of them presented with congenital anomalies. Malformed infants were distributed by clinical presentation as isolated, multiply malformed or syndromes, and some other subgroups were also established, according to our own classification system [Martínez-Frías et al, 2002: Rev Dismor Epidemiol V(1):2-8], based on the most modern dysmorphologic concepts. The 3 forms of clinical presentation are significantly decreasing along the time, mostly as a result of the impact of prenatal detection of anomalies and further interruption of some affected pregnancies. We also studied the distribution by clinical presentation of 17 selected defects. Those defects were selected because of their relatively high frequency at birth, or due to the high morbidity/mortality that they bear, and because their frequency at birth is also monitored in other countries and it would permit comparisons if necessary. A high clinical heterogeneity is common, as most of them appear in any clinical presentation. Some, such as gastroschisis, hypospadias, anencephaly, spina bifida, cleft lip, or diaphragmatic hernia, tend to present more frequently in their isolated form, while other, such as anophthalmia/microphthalmia, abdominal wall defects and bilateral renal agenesis, are usually associated to other anomalies. We performed the etiologic distribution of infants with congenital anomalies, and showed the different types of syndromes identified in the ECEMC and their gene map location, based on the OMIM database, also estimating their minimal prevalence at birth, based on our data. We underline the relevance of clinical analysis of malformed infants in order to organize homogeneous groups to which the epidemiological techniques can be applied. For these purposes, it is crucial a fluent contact between clinicians and epidemiologists, to enhance possibilities of statistical findings being also clinically relevant. At present, this is even more important to conduct molecular studies on specific groups of patients for investigating the causes of congenital defects.
Problemática del diagnóstico de los niños malformados cuyas madres son diabéticas
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2004-10) Martínez-Frías, María Luisa; Rodríguez-Pinilla, Elvira; Bermejo-Sanchez, Eva; Grupo Periférico del ECEMC
Taking into consideration that teratogenic agents do not alter the 100% of exposed pregnancies, we posit that each malformed infant born from a diabetic mother should no be automatically consider as having a diabetic embryofetopathy without a deep evaluation of other potential causal agents. The diagnosis of malformed infants whose mothers were diabetic is not always easy. For instance, if the child only have a cardiac defect, this may be due to maternal diabetes, but also to a big amount of other agents either genetics or environmental. In order to facilitate the diagnosis of infants born of diabetic mothers, we calculated and analyzed the concepts of frequency and specificity. To do this, we used the 33,076 malformed infants of the ECEMC (Spanish Collaborative Study of Congenital Malformations) database. Once we excluded 4,069 cases who had well known syndromes, 759 cases because their mothers had gestational diabetic, and 1,006 with not specification of the diabetic status of their mothers, we get 27,242 malformed infants for the present study. This group was divided in three study groups: the first one was made up with the 38 infants diagnoses as having a diabetic embryofetopathy. The second group included 64 malformed infants whose mothers were diabetics but they were not considered as having a diabetic embryofetopathy. Finally, the third group included the rest of 27,140 malformed infants whose mother had not diabetes mellitus or gestational diabetes. For the study we selected the defects and group of defects included in Table 1. We calculated the relative frequency (FR), by dividing the percentage of each of the studied congenital malformations in the two groups of infants whose mothers were diabetic, by the percentage of the same malformation in the group of infants born of non diabetic mothers. Obviously, all the studied defects, but hypospadias, nevus/angiomas, and digestive atresias (which were included as controls, since they are not considered part of the diabetic embryofetopathy), have to be significantly more frequent in the first group, because the infants were diagnosed based in the presence of these defects in their patterns. But this group permit to understand the concepts of frequency and specificity. In fact, Table 1 shows that while the most frequent defect in this consecutive series of infant born with diabetic embryofetopathy, correspond to vertebral anomalies (44.74%), followed by cardiovascular defects (39.47%), the most specific is sacral agenesis/hypoplasia, because it frequency in this group is 131.56 times higher than in the group of infants of non diabetic mothers. In this table, it is also shows that in the group of malformed infants whose mothers were diabetics, some of them may have diabetic embriofetopathy, but were not diagnoses because the lack of some type of information (such as karyotypes, family history, prenatal exposure to others potential related factors, among others). We discussed the importance of performing the diagnosis of malformed infants born to diabetic mothers taking into consideration that among this group of mothers, we can also observed malformed infants with different type of yndromes that in many cases are clinically indistinguishable from the diabetic embryofetopathy (i.e. Jarcho-Levin or Casamassima syndromes, chromosomal abnormalities...), or with isolated malformations (i.e. cardiovascular), that may, or may not, be related with the maternal diabetes. All these consideration are important, not only because the recurrence risk could be much higher than that of the maternal diabetes, but also because the secular increasing trend in diabetic mothers due to the life style.
Aspectos Clínico-Epidemiológicos de los recién nacidos con anomalías congénitas
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2003-10) Bermejo-Sanchez, Eva; Mendioroz, J; Cuevas Catalina, María Lourdes; López Grondona, Fermín; Rodríguez-Pinilla, Elvira; Martínez-Frías, María Luisa
We have used the data gathered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) during the period 1980-2002, in order to epidemiologically analyze some clinical aspects of a consecutive series of malformed newborn infants. Among a total of 1,838,654 newborns surveyed, 30,531 (1.66%) presented with congenital anomalies detected at birth. Data were analysed before and after the pass of the law permitting voluntary interruption of gestation (VIG) following the detection of anomalies in the fetus. Malformed infants were distributed by clinical presentation as isolated, multiply malformed or syndromes, according to our own classification system [Martínez-Frías et al, 2002: Rev Dismor Epidemiol V(1):2-8]. The 3 forms of clinical presentation are decreasing along the time, as a result of the impact of prenatal detection of anomalies and further VIG in some cases. We also analyzed 17 defects that were selected because of their relatively high frequency at birth, or due to the high morbidity/mortality that they bear, and because their frequency at birth is also monitored in other countries. Most of them show a high clinical heterogeneity, although some (such as gastroschisis, hypospadias, spina bifida, cleft lip, or diaphragmatic hernia) tend to present in their isolated form, while other (such as anophthalmia/microphthalmia) tend to associate to other anomalies. We also performed the etiologic distribution of infants with congenital anomalies in 3 study periods, and showed the number of cases in which the different types of syndromes were identified, as well as the minimal estimate of their frequency at birth and their gene map location, based on the OMIM database. We emphasize the importance of applying all known primary prevention measures, even more during blastogenesis, at the very early stages of pregnancy. On the other hand, we also underline the relevance of clinical analysis of malformed infants in order to organize homogeneous groups to which the epidemiological techniques can be applied. In this way, the statistical findings also will be clinically relevant. This is also important for the molecular studies that may give clues on the causes of congenital defects, as epidemiology of Human Genome can contribute to this kind of research, opening big opportunities in this field.
Defecto de la Zona de Desarrollo primaria del esqueleto axial (Síndrome de Jarcho–Levin, “Fenotipo Jarcho–Levin”)
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2002-10) Martínez-Frías, María Luisa; Bermejo-Sanchez, Eva; Rodríguez-Pinilla, Elvira
We have used data from the Spanish Collaborative Study of Congential Malformations (ECEMC), to epidemiologically analyze anomalies of the axial skeleton, from the clinical, etiological and pathogenetic points of view. Since 1980, a total of 1,847,301 newborn infants were surveyed. Among them, 31,604 were malformed. In 283 infants, anomalies of the spine and/or ribs were observed. The ECEMC´s coding system includes several levels to code defects and patterns of anomalies. This made the present analysis possible. In the first level, each specific defect is coded. The second level has three sublevels to define the global pattern of defects of each infant, as well as the different types of patterns that can be distinguished in infants with multiple defects, whether with or without having a diagnosis of some particular syndrome. This coding system allows to study specific defects or pattern of defects, according with the most modern dysmorphologic concepts. After applying this system to axial skeleton anomalies, we observed that among infants with isolated defects, only 0.14% had the axial skeleton affected. This percentage is higher among infants with MCA patterns (3.59%) and syndromes (1.91%). It is clear the great clinical and causal heterogeneity of these costal–vertebral anomalies. This supports our previous conclusion [Am J Med Genet 1994; 49: 36–44], on that axial skeleton anomalies are one of the results of the dysmorphogenetic reaction of the primary field, which is the whole embryo during blastogenesis. Therefore, the terms spondylo–thoracic dysplasia, spondylocostal dysplasia, costovertebral dysplasia, crab–like thorax, among others, are not diagnoses but different names for the diverse expressions of the primary developmental field of the axial skeleton. It is important the proper use of terminology, based on the current knowledge of developmental biology, in order to provide adequate counselling to families.
Síndromes muy poco frecuentes
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2002-10) Martínez-Frías, María Luisa; Bermejo-Sanchez, Eva; Rodriguez, Laura; Rodríguez-Pinilla, Elvira; Blanco, M; Foguet, A; Goñi, C; Sanchis, A; Ayala, A; Cuevas Catalina, María Lourdes; López Grondona, Fermín
Many of the malformation syndromes are as very few frequent, that are rarely known by most of the paediatricians and geneticists or our population. This is an important difficulty to establish such diagnoses in affected patients that can remain undiagnosed for a long time, or even never been diagnosed. Moreover, the advances in the field of prenatal diagnosis and the possibility of interrupting the gestation if there are anomalies in the fetus, make such syndromes even be less frequent. For these reasons the experience of the young paediatricians and geneticists will become more and more limited. It is noteworthy that the ECEMC Registry is gathering data on infants with congenital defects since 26 years ago. The database includes more than 32,000 malformed infants, many of them with photos, X-ray, and others images. Besides, in the ECEMC laboratory, the karyotype with high resolution band (850 bands) and FISH techniques, is currently performed. Consequently, we have these studies for most of the multiply malformed infants. Systematically, the ECEMC group make a detailed clinical study on each malformed baby in order to identify syndromes and causes. Furthermore, the group is expert in evaluation of potential human teratogens. The group is participating internationally in the clarification and development of the concepts in dysmorphology, and describing syndromes. Taking all these points into considerations, we think that will be very useful to include a new section in the "Boletín del ECEMC", to present syndromes of extremely low frequency in our country. In this new section, we are presenting six very rare syndromes that, in our data, have a frequency of 1/1,887,538 newborn infants. However, some of then may be under-recognized due to their great variability in clinical expression.
Vigilancia Epidemiológica de Anomalías Congénitas en España durante el período 1980–2001
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2002-08) Rodríguez-Pinilla, Elvira; Bermejo-Sanchez, Eva; Cuevas Catalina, María Lourdes; Mejías, C; Martínez-Frías, María Luisa
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.
Aspectos clínicos y distribución etiológica de los recién nacidos con defectos congénitos registrados en el ECEMC
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2007-10) Rodríguez-Pinilla, Elvira; Bermejo-Sanchez, Eva; Mendioroz, J; Cuevas Catalina, María Lourdes
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 2006, has been performed. Among a total of 2,254,439 newborn 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 cause, 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.
Aspectos Clínico–Epidemiológicos
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2002-10) Martínez-Frías, María Luisa; Bermejo-Sanchez, Eva; Rodriguez, Laura; Cuevas Catalina, María Lourdes; López Grondona, Fermín; Rodríguez-Pinilla, Elvira
We have used data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) to epidemiologically analyze some clinical aspects of infants with congenital anomalies. For this purpose all infants of the ECEMC database were classified following the Program ´s methodology, which is explained in detail in another work of this issue [Martínez–Frías et al., 2002]. Data were analysed in three periods: the first one includes the years 1980–1985 (before the passing of the law allowing voluntary interruption of gestation (VIG) due to prenatal detection of anomalies in the fetus); the second period corresponds to the years 1986–2000, and the last one is for the year 2001, which is the year analysed in this issue. In this paper, we show the distribution of infants in the three main groups of clinical presentation (isolated, multiple, and syndromes), as well as some specific types of defect patterns identified among the three main groups. In addition, we studied the distribution by clinical presentation of 17 selected congenital defects. These defects were selected because of their frequency, or the morbidity/mortality that they bear. The etiologic distribution of infants with congenital defects is also analysed in the three study periods. Moreover, we have specified all the syndromes identified in the ECEMC database, as well as the number of cases with each syndrome, their birth frequency, and their gene map location when possible (based on the OMIM database). It is important to underline that all the presented figures for syndromes and the study defects, are minimal estimations of the real frequency, because of several reasons. First, because of the possibility to perform a VIG after the prenatal detection of fetal anomalies, which is possible in Spain since 1985. Second, because some modern diagnostic procedures were not available in the first years of the study. Moreover, unfortunately, the results of some complementary studies are not available for review in some cases, being impossible to reach to a final diagnosis. Finally, because of the difficulty to identify some syndromes at birth. We emphasize that, for some of the environmental syndromes (such as fetal alcohol syndrome, diabetic mbryofetopathy, and those due to some maternal infectious diseases), primary prevention is possible if a proper information and education is provided to the population.
Porcentaje de la recurrencia de los defectos del tubo neural (DTN) y sus frecuencias en España: Evolución temporal de las mismas y su posibles causas
(Instituto de Salud Carlos III (ISCIII). Instituto de Investigación de Enfermedades Raras (IIER), 2002-10) Martínez-Frías, María Luisa; Bermejo-Sanchez, Eva; Rodríguez-Pinilla, Elvira; Sanchis, A
We analysed the birth prevalence of the different types of neural tube defects (NTD) in Spain in four periods of time, as well as their recurrence in our population and their variation along the time and causes. We have used data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), with a total population of 1,703,322 births surveyed since 1980 till June 2001. After excluding those cases with syndromes of any etiology, and those with two different types of NTD, or the presence of discordant NTD in different sibs, a total of 937 infants with NTD were available for the present study. Birth prevalence of all forms of NTD show diminishing trends since 1985, when the law allowing voluntary interruption of gestations (VIG) with congenital defects was passed in Spain (Table 1, and Graph 1). The tendency is more marked for anencephaly and encephalocele than for spina bifida (Table 2). The recurrence (measured as pre–ocurrence) has also decreased with time, being 3.33% for NTD (Table 3) in the basal period (1980–1985), and 3.14% for anencephaly, 5.71% for encephalocele, and 2.31% for spina bifida. However, since the year 1985, the recurrence of anencephaly and encephalocele was cero, while for spina bifida (Table 4) decreases in 99.77% in the following period (1986–1992), and 100% in the other two consecutive studied periods. We also analysed the proportion ofmothers of cases and controls who received folic acid supplementation at least during the first trimester of pregnancy. Although we started asking for pre–conceptional intake of folic acid since 1998, the question was included in the questionnaires in the year 2001. Based on those data, only 2 mothers of cases and 3 of controls, used the folic acid before the current pregnancy. It is difficult to determine whether the decreases of the birth prevalence and recurrence figures are due to the impact of VIG or, in some degree, due to the periconceptional supplementation with folic acid. However, we consider that the group of mothers who have had a previous affected pregnancy, should constitute the group of population with a more adequate ingestion of folic acid. Nevertheless, the dramatic decrease of the recurrence in our population must be in part due to a secondary prevention produced by the VIG (which does not avoid the alteration of prenatal development) and, in part, to the primary prevention (which prevents the alteration of prenatal development) produced by the folic acid supplementation. In fact, the frequency of spina bifida, decreases “only” in a 56.95% in the last study period of time (Table 2), while its recurrence decreased in a 100%. We consider that there is no reason for not prescribing the adequate doses of folic acid to all women planning pregnancy, or not informing women at childbearing age about the convenience of starting supplementation before getting pregnant. However, to be sure that the prevention reach to thewhole population, includingmarginal groups, and those 50 and older, the Health Authorities of our country, should consider, as soon as possible, the necessity to fortify a generally used food like the flour. To paraphrase Oakley [2002], the opportunity to implement inexpensive passive population intervention to prevent severe human diseases come rarely, and fortification of flour is one of those rare opportunities.