María Luisa Martínez-Frías

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Infrequently studied congenital anomalies as clues to the diagnosis of maternal diabetes mellitus.

The aim of this study was to identify congenital anomalies (CA) among infants of women with diabetes mellitus (DM) that, even though infrequent or infrequently reported, may suggest diabetic teratogenesis. Using 1976–2005 data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we compared the frequency of selected CA among 130 infants with CA born to women with pregestational DM (PGDM) and 30,009 infants with CA whose mothers had normal glucose tolerance (NGT). To identify which CA were not only significantly more frequent among infants of mothers with PGDM, but also more specific, we calculated the quotient of their frequencies (frequency ratio: FR). The same analysis was made using data from 927 infants of mothers with gestational DM (GDM). Among the studied defects, several were statistically significantly more frequent among infants of PGDM mothers than among infants of mothers with NGT, although the specificity of their association with DM varied, as indicated by the values of the FR. These included: anorectal atresia/stenosis (FRu2009=u20092.81; Pu2009=u20090.03), hallucal polydactyly (FRu2009=u20093.62; Pu2009=u20090.002), heterotaxy (FRu2009=u20095.70; Pu2009=u20090.049), hypertrophic cardiomyopathy (HCM) (FRu2009=u200961.60; Pu2009=u20090.000000), multicystic dysplastic kidneys (MDK) (FRu2009=u20095.13; Pu2009=u20090.0002), and thymus aplasia/hypoplasia (FRu2009=u200929.62; Pu2009=u20090.000001). The only CA significantly more frequent among infants of women with GDM were HCM (FRu2009=u20098.60; Pu2009=u20090.002) and MDK (FRu2009=u20091.80; Pu2009=u20090.01). Our results suggest that maternal PGDM should be suspected in children with hallucal polydactyly, anorectal atresia/stenosis, heterotaxy, or aplasia/hypoplasia of the thymus. The presence of transient HCM or MDK in a newborn suggests maternal PGDM or GDM. These observations are important in view of the increasing worldwide frequency of DM and the high proportion of individuals with DM in whom the condition remains undiagnosed.

Consumo de tabaco durante el embarazo en España: análisis por años, comunidades autónomas y características maternas

Fundamento y objetivo: Desde hace anos se ha venido informado sobre la conveniencia de que las mujeres embarazadas no fumen. Por ello, hemos estudiado si se ha producido alguna variacion en el habito de fumar durante el embarazo en Espana. Sujetos y metodo: Utilizamos datos de 31.056 madres de ninos sin defectos congenitos, procedentes de todas las autonomias, recogidos con la misma metodologia en todo el pais. Se analiza la evolucion del habito de fumar por anos, comunidades autonomas, caracteristicas y otros habitos maternos. Resultados: En los ultimos anos del estudio (1995-2002), el 30,31% de las madres fumo durante el embarazo, con variaciones entre diferentes grupos etnicos. Se observa un incremento secular de la prevalencia de madres fumadoras entre 1978 y 1991, estabilizandose posteriormente en el 27-28%. No se observa una disminucion secular en los analisis por edades maternas, cantidades y autonomias. Solo las madres de mayor nivel de escolaridad muestran un descenso del habito de fumar en 1993, estabilizandose en alrededor del 23%. Las madres con menos de 25 anos son las que mas fuman en todos los anos. Se ha confirmado la estrecha relacion entre el tabaco, el alcohol y otras drogas comentada por otros autores. Conclusiones: Nuestros datos indican que no ha disminuido la prevalencia de mujeres que fuman durante la gestacion ni por anos ni por comunidades, aunque el 19,19% dejo de hacerlo en los primeros meses de embarazo. Ademas, las madres mas fumadoras en todos los anos son las mas jovenes. Estos resultados muestran la necesidad de aumentar la informacion para que las mujeres dejen de fumar antes del embarazo

Widening the Mutation Spectrum of EVC and EVC2: Ectopic Expression of Weyer Variants in NIH 3T3 Fibroblasts Disrupts Hedgehog Signaling

Autosomal recessive Ellis‐van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis‐van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940−150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5′ splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis‐van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect. Hum Mutat 30:1–9, 2009.

Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case-control study in Spain.

AbstractBackground: Hypospadias is one of the most frequently occurring genital anomalies described in infants prenatally exposed to valproic acid (VA). However, to our knowledge, only one publication has studied a potential causal relationship between VA and hypospadias, only estimating the unadjusted global risk. Here we present the results of a multivariate case-control study aimed at analysing and quantifying the specific risk of hypospadias in newborn infants exposed to VA during the first trimester of pregnancy.n Methods: The data analysed here were derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC), an ongoing, hospital-based, case-control study and surveillance system in which collaborating paediatricians identify case and control infants. The paediatricians collect the same data for both case and control infants, blinded to information on any prenatal exposure. The information includes 312 items related to many prenatal exposures, including drug exposure, reproductive and family history, and other characteristics. The sample analysed included 2393 infants with hypospadias and 12 465 male controls.n Results: The results showed that the unadjusted risk of hypospadias in infants prenatally exposed to VA was 5.23 (95% CI 2.31, 11.86; p < 0.00001). Once adjusted for 13 potential confounding factors using conditional logistic regression analyses, the value of the risk was of a similar magnitude (odds ratio = 5.71; 95% I 1.78, 18.36; p = 0.003). In addition, the frequency of hypospadias in the study population was approximately 1.8/1000 births. This allowed us to calculate the specific risk for an infant with hypospadias to be born to an exposed mother, which was 1 child in 97 births to mothers using VA during the first trimester of pregnancy. We consider this information much more useful for risk assessment than the risk value itself.n Conclusions: An alteration of placental gonadotrophic stimulation caused by changes in gonadotropin-releasing hormone release produced by the effects of VA on GABA is a possible pathogenic mechanism. Our results support the relationship between prenatal exposure to VA and hypospadias.

Postmarketing analysis of medicines: methodology and value of the spanish case-control study and surveillance system in preventing birth defects.

There are many surveillance systems of congenital defects all over the world; several of them have developed specific approaches to generate and test selected hypotheses regarding human teratogens. However, to the best of our knowledge, none of them have a permanent and systematised programme for the study of the risk and safety of drugs.The aim of this article is to describe the research programme on the potential effects of drugs in pregnancy followed by the Spanish Collaborative Study of Congenital Malformations (ECEMC), which is a permanent ongoing case-control study and surveillance system. The programme to analyse drugs includes a continuous and systematic study on the potential effects of medicines used during pregnancy. This programme has several characteristics that make it different from other current systems: (i) the collection of numerous datapoints (up to 312 per infant) in a case-control design; (ii) the use of a versatile and specific coding of birth defects; (iii) a specific programme for the continuous analysis of the potential effects of each type of drugs used during pregnancy that has been developed specifically for the ECEMC methodology, including its dysmorphological coding system.The description of the ECEMC’s approach to surveillance of the effects of drug use during pregnancy may help researches in this area, particularly those using data from birth defects registries.

Characterization of a 8q21.11 Microdeletion Syndrome Associated with Intellectual Disability and a Recognizable Phenotype

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupids bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

Evolución secular y por autonomías de la frecuencia de tratamientos de fertilidad, partos múltiples y cesáreas en España

Fundamento y objetivo Los tratamientos de fertilidad, los partos multiples y las cesareas estan relacionados con la edad materna. Por ello, al haber aumentado esta en Espana, es de esperar que hayan aumentado esas variables. Analizamos su evolucion secular y por edades maternas en todo el pais y por comunidades autonomas. Sujetos y metodo Se ha estudiado una muestra de 30.956 madres de todo el pais cuyos recien nacidos entre 1977 y junio de 2002 no tenian defectos congenitos. Resultados El porcentaje de tratamientos de fertilidad muestra un incremento secular estadisticamente significativo en todas las edades maternas, aunque es superior en mujeres mayores de 34 anos, en las que tambien se ha incrementado la frecuencia de partos multiples (pxa0=xa00,01). Las mismas tendencias se observan por comunidades autonomas, aunque con diferencias entre ellas. En la Comunidad Valenciana se observa la mayor frecuencia de tratamientos de fertilidad, mientras que la mayor edad materna se registra en Aragon. En Galicia la proporcion de partos multiples es de las mas bajas y la de los tratamientos de fertilidad es similar a la de las otras comunidades. El porcentaje de cesareas (globalmente superior al 25%) muestra un incremento progresivo y significativo en todas las edades maternas, y es maximo en las madres mayores de 39 anos. Conclusiones El incremento de la edad materna implica mayor utilizacion de tratamientos de fertilidad, mayor numero de partos multiples y de cesareas. Todas estas variables presentan en Espana variaciones significativas a lo largo del tiempo y entre comunidades autonomas.

Unusual congenital abdominal wall defect and review

Abdominal wall defects distant from the umbilicus are very unusual. We describe a patient with a congenital defect adjacent and external to the lateral border of the recti muscles, rounded in shape, bilateral and symmetrical, but affecting different structures in each side, musculocutaneous agenesis in the left side and only muscle agenesis in the right one. The morphologic characteristics of the defect and the absence of associated anomalies, suggest that this anomaly may be the result of an event acting during phenogenesis. We consider that this defect is different from other structural abnormalities of the anterior abdominal wall which occur much earlier at certain periods of the embryogenesis. Though the etiology is speculative, we could postulate a disruptive origin of the defect of unknown cause.

Adecuación de las dosis de ácido fólico en la prevención de defectos congénitos

Fundamento y objetivo El acido folico (AF) sintetico (usado en medicamentos y en la fortificacion) esta en forma de pteroilmonoglutamato (PGA), que no existe en la naturaleza, donde se encuentra como pteroilpoliglutamatos, especialmente en forma de 5-metiltetrahidrofolato. El organismo transforma el PGA en 5-metiltetrahidrofolato, y parece que este proceso de biotransformacion del PGA se satura con dosis de 0,4 mg. Recientemente ha surgido la preocupacion por el uso de dosis altas, ya que se superaria la capacidad metabolica del organismo, con la consiguiente acumulacion plasmatica de AF sintetico no metabolizado. El objetivo de este estudio es analizar las dosis de AF sintetico que se estan utilizando en Espana y su evolucion tanto temporal como espacial. Pacientes y metodo Se ha analizado a 16.761 madres de recien nacidos sin defectos congenitos (controles) del Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC). Se han considerado todas las formas de folatos sinteticos (folico o folinico), que denominamos globalmente como AF. Resultados Aunque se ha observado un significativo incremento secular de la proporcion de madres que utilizaron AF en el ultimo periodo (2003-2004), solo un 17,37% tomo AF desde antes del embarazo. Del resto, un 71,13% lo tomo cuando ya estaban embarazadas y un 11,50% no lo tomo nunca. Ademas, de las madres que tomaron AF, mas del 70% ingirio dosis de 4 mg o superiores. Los resultados por autonomias son muy similares a los globales, y en la mayoria de las comunidades mas del 50% de las madres del ultimo periodo tomaron dosis medias diarias entre 12,5 y 20 veces superiores a la recomendada de 0,4xa0mg/dia. Conclusiones La mayoria de las mujeres toman AF cuando ya estan embarazadas o no lo toman nunca. La mayoria de las mujeres que toman AF ingieren dosis mucho mas altas que las recomendadas. Los resultados de este trabajo muestran la necesidad de realizar una importante difusion de estos aspectos entre los profesionales sanitarios.