Anomalía de Möebius y el concepto de secuencia malformativa: Importancia del conocimiento y uso adecuado de la terminología

Dismorfología, Citogenética y Clínica: Resultados sobre los datos del ECEMCA review of the literature shows that a large variety of terms is used to refer to the Möebius anomaly. These include diagnoses such as "Möebius syndrome", "Möebius sequence", "Möebius spectrum", "Möebius syndrome-limb abnormalities" "Möebius sequence-hypogeni- talism-cerebral, and skeletal malformations" and even three types of syndromes numbered "Möebius syndrome 1, 2 and 3", with different chromosomal loci. The Möebius anomaly is believed to comprise paralyses of some cranial nerves and their consequences. Thus, based in the concepts delineated by an International Working Group regarding errors of morphogenesis [Spranger y cols., 1982. J Pediatr 100:160-165], it constitutes a sequence: the "Möebius sequence." As such, it may be observed in different types of malformed infants, whether isolated (with only the Möebius sequence), with multiple congenital anomalies (MCA) patterns, or with different types of syndromes. That is, in multiple clinical presentations with different causes. It is important to keep these concepts in mind, because the term "syndrome" means that all affected infants will have similar characteristics, generally the same cause, and the same recurrence risk. If we do not use the current dysmorphological concepts, the information given to the family may be confuse or, what is worse, erroneous.N

Biología del desarrollo y genética molecular de los síndromes malformativos: Luces y Sombras de un Sistema Altamente Complejo

EditorialN

Clinical analysis of newborn infants with congenital defects registered in ECEMC: Distribution by etiology and ethnic groups

Dismorfología y Genética ClínicaIn this chapter, the information gathered by ECEMC between January 1980 and December 2008 has been analysed. It corresponds to 2,463,134 consecutive newborn infants surveyed, among which 37,545 (1.52%) presented congenital defects detected during the first 3 days of life. When these were distributed by clinical presentation, all the groups showed a statistically significant diminishing trend since the base period, mainly attributable to the impact of termination of pregnancy after the diagnosis of foetal alterations. The distribution by clinical presentation was specifically analysed for 17 congenital defects which are usually monitored, this information being useful in the field of prenatal diagnosis. Blastogenic defects showed a statistically significant decrease in the study period, except in the last 6 years, which could be due to the influence of the immigrant population. All the infants registered were distributed by the causes of the defects, and those with syndromes were also distributed by etiology and frequency in the ECEMC data. Moreover, all infants with congenital defects were distributed by the organic system or area affected, and presented in 3 periods of time. Given the increase in the immigrant population in our country, the distribution of all infants with congenital defects by ethnic group is shown, with whites being distinguished as native or foreigner. This distribution by ethnic group is important for designing specific campaigns for prevention, education and information, according to their real needs. When analysing some selected defects in those groups, with respect to the group of native whites, a lower percentage of cases with neural tube defects was found among blacks; a higher percentage of cases with cardiovascular defects was registered among blacks, gipsies and arabs; a lower percentage of cases with hypospadias was observed among blacks and indoamericans, and a higher percentage of cases with postaxial polydactyly was found among blacks. This data provides useful information for identifying defects for which the gene frequencies of the native population could be modified by immigration, as well as to define specific needs of the different ethnic groups in Spain.N

Present situation in Spain regarding the etiologic diagnosis in foetuses from termination of pregnancy (ToP) due to congenital defects. Guidelines for a minimum protocol

Dismorfología y Genética ClínicaSince the passing of the Spanish law permitting termination of pregnancy (ToP) after the detection of foetal anomalies, in July 1985, the ECEMC has undertaken the commitment to register the maximum information regarding the cases of ToP due to congenital anomalies. This interest is not only prompted by the need of a proper surveillance of these pathologies, what is important for public health purposes, but also for getting an etiologic diagnosis for each case; although this is only possible by retrieving minimum clinical and non-clinical information, depending on each case. This is important, because not achieving an etiologic diagnosis implies not being able to provide the family with information regarding recurrence risk, the risk for possible carriers among their healthy children, and for future pregnancies, planning prenatal diagnosis, and pre-implantation diagnosis or assisted reproduction for certain pathologies. At present, in Spain, there is no official protocol for the study of foetuses from ToP with congenital anomalies, what precludes from getting prevention in all their different levels, starting by the possibility of having a correct diagnosis. To cover that need, and based on the experience of the ECEMC, we highlight a small protocol with the minimal data to be collected to increase the possibilities to reach to a proper diagnosis, and, therefore, provide the parents with complete information. From the point of view of the health practice, this is the correct way, not only for getting the diagnosis, but because this is the only way to also help to diminish the awful situation of couples undergoing ToP due to foetal malformations.N

Other aspects of the epidemiological surveillance performed by ECEMC: Time distribution and distribution by Autonomous Regions of births from the immigrant population in Spain

Aspectos EpidemiológicosIt 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 groupN

Deleción 14q proximal, presentación de dos casos y revisión de la literatura

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCHere we present two unrelated cases that came to our service for families that are looking for information on the diagnostic on malformation syndromes and infants with congenital defects. Both cases show as common signs psychomotor delay, microcephaly, corpus callosum agenesis and inespecific facial phenotype. We perform a high resolution G-bands karyotypes, and both of them showed a "de novo" deletion in the proximal region of a chromosome 14, with different break points but with a common region deleted. The karyotype of the first case was 46,XY, del(14)(q12;q21.1), and the karyotype of the second case 46,XX del(14)(q11.2;q13.1). We discussed the possible candidates genes that could be related with the phenotype and review the different reported cases.N

Surveillance of congenital anomalies in Spain during the last 24 years

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMCAs a part of the usual surveillance of congenital anomalies performed in the ECEMC (Spanish Collaborative Study of Congenital Anomalies) database, we have analysed the information gathered in the period 1980-2003, during which a total of 1,941,742 newborn infants were surveyed. The ECEMC registry covered 26.48% of total births occurred in Spain in 2002. We have studied the global prevalence of infants with congenital anomalies in 3 different periods: a) before the passing of the law permitting voluntary interruption of gestation -VIG- following prenatal detection of anomalies (1980-85); b) after such passing (1986-2002); and c) year 2003. The baseline frequency of congenital anomalies corresponds to the period 1980-1985. Comparisons with this baseline mainly indicate the impact of VIG on the birth prevalence for defects which are prenatally detectable. The global prevalence continues diminishing over the years, and the significant decrease can also be observed in 13 out of 17 Spanish Autonomic Regions. All these decreases are mostly attributable to the impact of VIG. When studying the time distribution of the frequency of some selected anomalies, as well as their geographical distribution, we have observed that VIG plays an important role. However, it is difficult to get information on VIGs. The problem is that if it is not registered on a routine basis and with complete data on exposures and other variables, it will be impossible to perform analytic studies on the causes of birth defects . A question that has recently raised is the increasing number of immigrants in Spain. We have analysed the distribution of the control group of the ECEMC by country from which the parents come from. On the other hand, we have also analysed the evolution along the time of the proportion of different ethnic groups in the control group. Finally, in spite of the decreasing frequency of congenital anomalies, it should be considered that such decrease is mainly due to the impact of VIG, so we underline the need of investigating in order to reach primary prevention of birth defects, and applying the known preventive measures, getting infants being born healthy.N

Johnson-McMillin syndrome (JMS): description of the first patient in Spain.

Dismorfología y Genética ClínicaThe 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 SpainN

Integration of the clinical aspects into the epidemiological analysis of the newborn infants with congenital defects registered through the ECEMC: 30 years getting ready for the future

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCAn 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.N

Characteristics of mothers following assisted reproductive technologies

Aspectos EpidemiológicosBackground: Assisted reproductive technologies (ART), such as in vitro fertilization, intracytoplasmic sperm injection (ICSI), assisted fecundation, and all the fertility treatments and procedures, have been successfully used to overcome infertility. Indeed, it has been estimated that between 1 and 4% of births in developed countries are conceived trough ART. But at the same time, rising concerns exist on their potential adverse effects on the embryo and fetal development. However, in spite of the huge amount of studies that have been published, big gaps in this knowledge still exist. To assess this association through epidemiological studies, it is necessary to recognize which maternal characteristics, among others, could confound the results. However, some of the maternal characteristics may be related with cultural and social aspects, as well as with other local influences. Therefore, it is advisable to identify those characteristics in the different populations. Objective and methods: Here we present the results of the analysis of several maternal characteristics on data from the cases and controls ´ mothers of the ECEMC database. The analysis included 20,233 mothers of consecutive live born infants with congenital defects, and 19,411 mothers of control infants. The studied characteristics were: maternal age ( 19, 20-30, 31-35, 36), level of education (primary, secondary, and university studies), body mass index (BMI) in three strata (30), maternal chronic diseases, maternal diabetes mellitus, hypertension, gestational diabetes, infectious diseases during pregnancy, tobacco and alcohol consumption while pregnant, multiple births, and caesarean section. Due to the number of analyses performed, the statistical significance was established in p<0.01. Results: We have observed that women undergoing ART are older, with higher educational levels, suffer more chronic diseases, higher frequency of gestational diabetes, and more infectious diseases than mothers with natural conceptions. Most of these results are observed either in cases´ mothers or controls´ mothers, but did no differ when we analyzed cases versus controls´ mothers, all of them using ART for conception. On the other hand, mothers following ART, are less smokers, do not have more frequency of both diabetes mellitus and hypertension. Regarding the BMI, the only statistically significant result is an increased frequency of women having a BMI of <25 among those following ART. Conclusions: Many of the studied characteristics can be confounder factors for epidemiological analyses to identify potential risks of ART to produce birth defects. In addition, although most of the results are similar to those observed in other studies, particularly in Sweden, some of the observed differences may be due to variations in social and educational aspects. Therefore, it is advisable to identify which maternal characteristics can be confounder factors in each population.N