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 cupid's 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.

Prevention, diagnosis and services.

This chapter summarizes how prevention, diagnosis and services can result from the activities of a research programme on the group of rare diseases constituted by congenital anomalies. The Spanish Collaborative Study of Congenital Malformations (ECEMC) is a research programme based on a case-control registry of consecutive newborn infants with congenital anomalies. Its aim is the prevention of this group of rare diseases, through the research on their causes and pathogenesis, combined with the translational activity to transfer the benefits of this knowledge to the general population and health care providers. Its experience could be applied to the research on other rare diseases. The different levels of prevention (primary, secondary, tertiary and quaternary) are briefly defined, and the way in which these levels are being applied or can be applied to congenital defects prevention is reviewed. The main primary prevention measures regarding congenital anomalies are also detailed. To this respect, the benefits derived from the activity of Teratology Information Services (TIS), for the general population as well as for health care providers, are explained. It is finally emphasized how the epidemiological data can contribute to the prevention of that group of rare diseases.

Review of the recently defined molecular mechanisms underlying thanatophoric dysplasia and their potential therapeutic implications for achondroplasia.

Achondroplasia (ACH), thanatophoric dysplasia (TD) types I and II, hypochondroplasia (HCH), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are all due to activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We review the clinical, epidemiological, radiological, molecular aspects, and signaling pathways involved in these conditions. It is known that FGFR3 signaling is essential to regulate bone growth. The signal transducers and activators of transcription (STAT1) pathway is involved in the inhibition of chondrocyte proliferation, and the mitogen-activated protein kinase (MAPK) pathways are involved in chondrocyte differentiation. Hence, FGFR3 signaling is pivotal in chondrocyte differentiation and proliferation through these two different active pathways. Recent studies on the molecular mechanisms involved in chondrocyte differentiation and proliferation, demonstrated that Snail1 participates in the control of longitudinal bone growth and appears to be essential to transduce FGFR3 signaling during chondrogenesis. This result was confirmed in a newborn infant with TD, and suggests new non-surgical therapeutic approaches, that is, Snail1 as a new encouraging therapeutic target.

Epidemiological and clinical analysis of a consecutive series of conjoined twins in Spain.

PURPOSE: The aim of the study was to analyze the frequency and certain epidemiological characteristics of a consecutive series of conjoined twins born in Spain. MATERIAL AND METHODS: We used data from the Spanish Collaborative Study of Congenital Malformations for the period April 1976 to 2006. Because the Spanish law permitting voluntary termination of pregnancies (TOP) when the fetus presented malformations was effective by the end of 1985, we analyzed the data in 4 periods, 2 before 1986 and 2 after. During the first period (1976-1979) only live births were recorded, whereas both still and live births were included in the other three (1980-1985, 1986-1995, and 1996-2006). In the present study, the cases were classified as symmetrical (16 pairs) and asymmetrical (1 pair) conjoined twins. Each pair of conjoined twins was considered as only one case for calculations, regardless of the type of union. RESULTS: Among a total of 2,281,604 consecutive births between 1980 and 2006, there were a total of 15 cases of symmetrical conjoined twins giving a frequency of 0.70 per 100,000 (1/152,107), whereas there was only 1 stillborn asymmetrical conjoined twin pair (0.04/100,000). Among the 13,418 consecutive stillborns surveyed, 6 cases of conjoined twins were identified (either symmetrical or asymmetrical) giving a frequency of 44.72 per 100,000, and 11 pairs were identified among the 2,425,583 total live births surveyed during the first period 1976 to 1979, a frequency of 0.45 per 100,000. Thus, the frequency among stillborn infants is 99.34 times higher than that observed among live births. However, the frequency for the total births (3 last periods) showed a decreasing trend from 1.47 per 100,000 birth in the first period (1980-1985) when TOP was illegal, to a value of 0.09 per 100,000 in the last period, more than 16-fold lower, probably because of the TOP of affected fetuses. Therefore, we consider that the frequencies observed in the period 1980 to 1985 are the basal values in our population. The most frequent type observed was thoracopagus, with an overall prevalence at birth of 0.44 per 100,000 (1/228,160) from 1980 to 2006, representing 58.82% of the total population of symmetric conjoined twin pairs. Diprosopus pairs were the next most common group (11.76%). Most of the cases were females (4 males/11 females), and although this appeared to be mainly because of the thoracopagus pairs (males-females, 2:8), in such a small number of cases, it is not possible to determine the ratios for the other groups. Gestational age was significantly shorter than in control twins for each type studied. CONCLUSIONS: We conclude that it is incorrect to consider that all types of conjoined twins have the same epidemiological characteristics, such as the frequency at birth. The differences observed may be related with the distinct embryo-fetal mortality of each type of conjoined twins in different populations, and the sex ratio, among others.

[Alström syndrome: clinical and genetic features, and a diagnostic guide to foresee complications]. / Presentación de un caso con síndrome de Alström: aspectos clínicos, moleculares y guías diagnósticas y anticipatorias.

BACKGROUND AND OBJECTIVE: Alström syndrome is a progressive autosomal recessive genetic disorder affecting multiple organ systems. It may be detected at birth or in early childhood. Clinically, patients with Alström syndrome develop cone-rod dystrophy leading to eventual blindness, sensorineural deafness, and normal intelligence. Patients develop obesity, endocrine disturbances such as type 2 diabetes mellitus, dilated cardiomyopathy and progressive renal and hepatic failure. Alström syndrome is caused by specific mutations in the ALMS1 gene, located at chromosome 2p13. PATIENTS AND METHOD: A case of a 23 year old patient with Alström syndrome, with a previous diagnosis of Laurence-Moon-Bardet-Biedl is described. RESULTS: The subsequent molecular study revealed a mutation on the ALMS1 gene, confirming the diagnosis of Alström syndrome. CONCLUSIONS: The low frequency, the progressive multi-systemic disturbances, and the similarities with other well-known syndromes may difficult the diagnosis of Alström syndrome. Thus, without a careful examination, it may be misdiagnosed and it would not be possible to perform any anticipatory therapeutic approach, with dramatic consequences for the patients and their families. Moreover, as these patients must have a multidisciplinary approach, they may not receive the adequate treatment on time. therefore, it seems important to publish this case in our country, among with the clinical and molecular characteristics of this syndrome, and to spread a diagnostic and anticipatory guidance for its early detection.

Presentación de un caso con síndrome de Alström: aspectos clínicos, moleculares y guías diagnósticas y anticipatorias / Alström syndrome: clinical and genetic features, and a diagnostic guide to foresee complications

FUNDAMENTO Y OBJETIVO: El síndrome de Alström es una entidad genética autosómica recesivaque se caracteriza por un desarrollo evolutivo con afección multisistémica. Su identificación alnacimiento es difícil y generalmente se detecta durante la infancia. Clínicamente se caracterizapor distrofia de los conos y bastones de la retina, que producirá ceguera progresiva, sorderaneurosensorial e inteligencia normal. Además, los pacientes desarrollarán obesidad, alteracionesendocrinas, entre las que destaca la diabetes mellitus tipo 2, miocardiopatía dilatada y fallorenal y hepático progresivos. Este síndrome está causado por mutaciones específicas en elgen ALMS, situado en la región 2p13.PACIENTES Y MÉTODO: Se describe el caso de un paciente de 23 años, con diagnóstico previo deLaurence-Moon-Bardet-Biedl, afectado por el síndrome de Alström.RESULTADOS: El estudio molecular identificó una mutación en el gen ALMS1, la cual, junto conlos rasgos clínicos del paciente, confirma el diagnóstico de síndrome de Alström.CONCLUSIONES: La baja frecuencia, el carácter evolutivo y la alteración multiorgánica de este síndromeno sólo dificultan el diagnóstico, sino la posibilidad de un manejo terapéutico anticipatorio,lo que da lugar a situaciones muy complicadas para los pacientes y sus familias. Por otraparte, por su afección multiorgánica, estos pacientes serán tratados por diferentes especialistas,y pueden no tener una evaluación generalizada. Por todo esto, nos parece importante darloa conocer en nuestro medio, junto con unas guías diagnósticas y anticipatorias

BACKGROUND AND OBJECTIVE: Alström syndrome is a progressive autosomal recessive genetic disorderaffecting multiple organ systems. It may be detected at birth or in early childhood. Clinically,patients with Alström syndrome develop cone-rod dystrophy leading to eventual blindness,sensorineural deafness, and normal intelligence. Patients develop obesity, endocrinedisturbances such as type 2 diabetes mellitus, dilated cardiomyopathy and progressive renaland hepatic failure. Alström syndrome is caused by specific mutations in the ALMS1 gene, locatedat chromosome 2p13.PATIENTS AND METHOD: A case of a 23 year old patient with Alström syndrome, with a previousdiagnosis of Laurence-Moon-Bardet-Biedl is described.RESULTS: The subsequent molecular study revealed a mutation on the ALMS1 gene, confirmingthe diagnosis of Alström syndrome.CONCLUSIONS: The low frequency, the progressive multi-systemic disturbances, and the similaritieswith other well-known syndromes may difficult the diagnosis of Alström syndrome. Thus,without a careful examination, it may be misdiagnosed and it would not be possible to performany anticipatory therapeutic approach, with dramatic consequences for the patients and theirfamilies. Moreover, as these patiens muts have a multidisciplinary approach, they may not receivethe adequate treatment on time. therefore, it seems important to publish this case in ourcountry, among with the clinical and molecular characteristics of this syndrome, and to spreada diagnostic and anticipatory guidance for ist early detection

Preferential associations between oral clefts and other major congenital anomalies.

OBJECTIVES: To identify preferential associations between oral clefts (CL = cleft lip only, CLP = cleft lip with cleft palate, CP = cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions. DESIGN AND SETTINGS: Included were 1416 cleft cases (CL = 131, CLP = 565, CP = 720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations. RESULTS: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida. CONCLUSION: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

[Analysis of the frequencies of genotype combinations of 4 polymorphisms of genes acting on the folate cycle in the Spanish population]. / Análisis de las frecuencias de todas las combinaciones genotípicas de 4 polimorfismos de genes implicados en el ciclo del folato en la población española.

BACKGROUND AND OBJECTIVE: Studies on different populations have shown a great variability of the frequencies of different polymorphisms in genes acting in the folate cycle. The present study was aimed to analyze the frequency in the Spanish population of each genotype combination of four polymorphisms, one of them -1561C-T of the glutamate carboxypeptidase II (GCPII) gene- being the first time that is studied in Spain. The study included a meta-analysis of the published data. SUBJECTS AND METHOD: Using the Spanish Collaborative Study of Congenital Malformations (ECEMC) Network, blood samples of 190 mother-child couples with newborns without any congenital defect, were obtained from 15 Spanish autonomous regions. The study polymorphisms were the 677C-T and 1298A-C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR), the 66A-G of the methionine synthase reductase (MTRR), and the 1561C-T polymorphism of the GCPII gene. To estimate the range for the population frequencies, 99% confidence intervals were calculated. RESULTS: The frequencies observed in our country were significantly different from others, being similar to those obtained in countries of the Mediterranean European area. The 1561C-T polymorphism of the GCPII gene has a frequency in Spain of 5.11%, which is also similar to the values observed in France (5%) and in Italy (6%). On the other hand, the frequency of the genotypes CTCC, TTAC is quite few, while the genotype TTCC was not observed in any mother or infants. A meta-analysis was performed for a big sample (23,612 individuals) and the results showed that with a 99% of probability the values for the genotype combinations CTCC, TTAC, and TTCC were within 0.10-0.24; 0.20-0.36; and 0.003-0.05, respectively. CONCLUSIONS: Our results are important to further analyze the relationship with some health problems and individual susceptibilities. Indeed, considering the published observations of the structure and function of the MTHFR enzyme, it is understandable that those genotype combinations that are quite little frequent, may be related to the embryo-fetal viability, and to the life style of each population.

Análisis de las frecuencias de todas las combinaciones genotípicas de 4 polimorfismos de genes implicados en el ciclo del folato en la población española / Analysis of the frequencies of genotype combinations of 4 polymorphisms of genes acting on the folate cycle in the Spanish population

Fundamento y objetivo: Distintas poblaciones muestran diferencias en cuanto a las frecuencias de polimorfismos de genes del ciclo del folato. El objetivo de este estudio ha sido analizar las frecuencias genotípicas de 4 polimorfismos, uno de los cuales -1561C-T del gen de la glutamato carboxipeptidasa II (GCPII)- se analiza por primera vez en España, así como realizar un metaanálisis de los datos publicados. Sujetos y método: Utilizando la Red del Estudio Colaborativo Español de Malformaciones Congénitas (ECEMC) se obtuvieron, en 15 comunidades autónomas, muestras de sangre de 190 parejas madres-recién nacidos sin defectos. Se analizaron los polimorfismos 677C-T y 1298A-C del gen de la metilentetrahidrofolato reductasa (MTHFR); 66A-G del gen de la metionina sintasa reductasa (MTRR), y 1561C-T del gen de la GCPII. Los valores poblaciones se calcularon por los intervalos de confianza del 99%. Resultados: Las frecuencias en nuestro país difieren de las de otras poblaciones, excepto las del área mediterránea europea. La frecuencia del polimorfismo 1561C-T (gen GCPII) en España es del 5,11%, igual que en Francia (5%) e Italia (6%). Las de MTHFR, CTCC y TTAC en España son muy bajas y no se observó ninguna madrehijo con TTCC. El metaanálisis (23.612 individuos) mostró que, con un 99% de probabilidad, las frecuencias poblacionales de CTCC, TTAC y TTCC serían de 0,10-0,24; 0,20-0,36, y 0,003-0,05, respectivamente. Conclusiones: Estos resultados son importantes para estudios sobre la relación de dichos polimorfismos con problemas de salud y susceptibilidad individuales, así como para investigar sus implicaciones biológicas. Tras los últimos hallazgos estructurales y funcionales en la MTHFR pueden entenderse las diferencias, porque los genotipos infrecuentes podrían relacionarse con la viabilidad fetal, las concentraciones de homocisteína materno/ fetal y los estilos de vida

Background and objective: Studies on different populations have shown a great variability of the frequencies of different polymorphisms in genes acting in the folate cycle. The present study was aimed to analyze the frequency in the Spanish population of each genotype combination of four polymorphisms, one of them -1561CT of the glutamate carboxypeptidase II (GCPII) gene- being the first time that is studied in Spain. The study included a meta-analysis of the published data. Subjects and method: Using the Spanish Collaborative Study of Congenital Malformations (ECEMC) Network, blood samples of 190 mother-child couples with newborns without any congenital defect, were obtained from 15 Spanish autonomous regions. The study polymorphisms were the 677C-T and 1298A-C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR), the 66A-G of the methionine synthase reductase (MTRR), and the 1561C-T polymorphism of the GCPII gene. To estimate the range for the population frequencies, 99% confidence intervals were calculated. Results: The frequencies observed in our country were significantly different from others, being similar to those obtained in countries of the Mediterranean European area. The 1561C-T polymorphism of the GCPII gene has a frequency in Spain of 5.11%, which is also similar to the values observed in France (5%) and in Italy (6%). On the other hand, the frequency of the genotypes CTCC, TTAC is quite few, while the genotype TTCC was not observed in any mother or infants. A meta-analysis was performed for a big sample (23,612 individuals) and the results showed that with a 99% of probability the values for the genotype combinations CTCC, TTAC, and TTCC were within 0.10-0.24; 0.20-0.36; and 0.003-0.05, respectively. Conclusions: Our results are important to further analyze the relationship with some health problems and individual susceptibilities. Indeed, considering the published observations of the structure and function of the MTHFR enzyme, it is understandable that those genotype combinations that are quite little frequent, may be related to the embryo-fetal viability, and to the life style of each population

Does single umbilical artery (SUA) predict any type of congenital defect? Clinical-epidemiological analysis of a large consecutive series of malformed infants.

Most studies associating different types of malformations with the presence of a single umbilical artery (SUA) are based on small and selected series. Here, we present the results of a study aimed at identifying the most frequent, and the most specific anomalies related to SUA. We analyzed 19,909 consecutive newborn infants with congenital malformations, from the Spanish Collaborative Study of Congenital Malformations (ECEMC). To estimate the specificity of the relationship of different congenital defects with SUA, we calculated their relative frequencies (RF) by dividing their frequency in infants with SUA by the corresponding frequency in newborn infants without SUA. Using the different levels of the ECEMC coding system, we calculated the RFs in three steps: (a) a group of individual congenital defects, (b) different groups of malformed infants, and (c) each individual malformation by its clinical presentation in some of the studied groups of malformed infants. The defects most specifically associated with SUA were bilateral renal agenesis and imperforate anus, followed by unilateral renal agenesis, and vertebral defects, the RF of which indicated that they were between 7.99 and 9.93 times more frequent among malformed infants with SUA than among malformed infants without SUA. However, these defects were not as frequent in the group of infants with SUA, as cardiovascular anomalies. Regarding the association of SUA in the groups of malformed infants, the most specific groups were body stalk defects and sirenomelia. Finally, we analyzed the association of the individual defects by different groups of malformed infants in order to identify if the individual defects are associated with SUA in any type of clinical presentation, and in relation to some groups of infants with genetic disorders. The results, together with the embryonic development of the umbilical cord, strongly suggest that not all cases of SUA have the same cause, and that all previously suggested mechanisms may be possible but with different frequencies.

Gastroschisis and associated defects: an international study.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

[Dyggve-Melchior-Clausen syndrome: presentation of a case with a mutation of possible Spanish origin]. / Síndrome de Dyggve-Melchior-Clausen: presentación de un caso con una mutación de posible origen español.

BACKGROUND AND OBJECTIVE: The Dyggve-Melchior-Clausen syndrome is a progressive spondyloepimetaphyseal dysplasia characterized by a short trunk dwarfism, barrel chest, sternal protrusion, kyphoscoliosis, severe platyspondyly, with a central constriction, irregular iliac wings with a lacy appearance, rhizomelic shortening of the limbs, microcephaly, coarse face, and variable mental retardation. This condition is extremely rare and the diagnosis is difficult without any previous experience on it. It is inherited as an autosomal recessive condition, its gene (DYM) having been mapped in the 18q12-21.1 chromosomal region. At least 21 different mutations of this gene have been reported. MATERIAL AND METHODS: We describe an affected Spanish child and include his molecular analysis. We also review the current knowledge on this syndrome. RESULTS: The diagnosis of this patient, based on his clinical and radiological features, was later confirmed by analysis of the DYM gene mutations. The patient had two different mutations, one inherited from the mother and the other inherited from the father. CONCLUSIONS: One of the mutations of this patient (exon 8) is extremely rare and has mostly been reported in patients with Spanish ancestors (from Chile, Argentina, Guam islands and a French patient with Spanish ancestors). These observations, together with that of the patient described here, led us to consider this mutation as having a possible Spanish/Portuguese origin. This condition may be more frequent in Spain than previously thought, especially due to misdiagnosis. This is important in order to undertake quaternary prevention, which is quite necessary for rare syndromes with polysystemic affectation.

Pilot study of socioeconomic class, nutrition and birth defects in Spain.

Research has indicated that the appropriate intake of folic acid, a B vitamin, before and during early pregnancy has been shown to prevent 50-70% of neural-tube defects. Increased NTD incidence has long been reported to occur more frequently among women of lower socioeconomic (SES). Since consumption of the folate-rich Mediterranean diet in Spain does not vary by socio-economic status (SES), we hypothesized that there would be no social class effect on NTD occurrence. Using data from a Spanish hospital-based birth defects registry, we studied the risk of Neural Tube Defects (NTDs) in 980 cases and 774 controls between 1980 and 2003. Our analysis showed that the risk of NTDs did not vary by SES. This finding suggests that increased access to folate and nutrition education might benefit women of lower SES in the US.

Síndrome de Dyggve-Melchior-Clausen: presentación de un caso con una mutación de posible origen español / Dyggve-Melchior-Clausen syndrome: presentation of a case with a mutation of possible Spanish origin

Fundamento y objetivo: El síndrome de Dyggve-Melchior-Clausen es una displasia espondiloepimetafisaria progresiva, que se caracteriza por enanismo con tronco corto, tórax ancho, redondeado y protuberante, una grave platispondilia, cifoscoliosis, alas ilíacas con irregularidades que dan aspecto de «encaje», acortamiento rizomélico de las extremidades, microcefalia y retraso mental variable. Es muy poco frecuente y, por lo tanto, de difícil diagnóstico si no se tiene experiencia del síndrome. Su patrón de herencia es autosómico recesivo y el gen responsable, denominado dymeclin (DYM), se ha localizado en 18q12-21.1, y de él se han descrito alrededor de 21 mutaciones. Material y métodos: Se describe el caso de un niño español afectado de este síndrome. Resultados: El diagnóstico clinicorradiológico se confirmó por el estudio de las mutaciones del gen DYM. El paciente tenía 2 mutaciones diferentes, una procedente de la madre y otra del padre. Conclusiones: Una de las mutaciones del paciente (exón 8) es muy poco frecuente y se ha observado mayoritariamente en personas con posible ascendencia española (de Chile, Argentina e isla de Guam, y en un paciente francés con antepasados españoles). Estas observaciones, incluido el caso aquí descrito, han dado lugar a la consideración de que dicha mutación podría ser de origen español/portugués. Creemos que es importante publicar casos de este síndrome para que los profesionales sanitarios lo conozcan, porque podría ser más frecuente y estar infradiagnosticado. Esto es importante para ejercer la prevención cuaternaria, muy necesaria en síndromes raros con afectación polisistémica

Background and objective: The Dyggve-Melchior-Clausen syndrome is a progressive spondyloepimetaphyseal dysplasia characterized by a short trunk dwarfism, barrel chest, sternal protrusion, kyphoscoliosis, severe platyspondyly, with a central constriction, irregular iliac wings with a lacy appearance, rhizomelic shortening of the limbs, microcephaly, coarse face, and variable mental retardation. This condition is extremely rare and the diagnosis is difficult without any previous experience on it. It is inherited as an autosomal recessive condition, its gene (DYM) having been mapped in the 18q12-21.1 chromosomal region. At least 21 different mutations of this gene have been reported. Material and methods: We describe an affected Spanish child and include his molecular analysis. We also review the current knowledge on this syndrome. Results: The diagnosis of this patient, based on his clinical and radiological features, was later confirmed by analysis of the DYM gene mutations. The patient had two different mutations, one inherited from the mother and the other inherited from the father. Conclusions: One of the mutations of this patient (exon 8) is extremely rare and has mostly been reported in patients with Spanish ancestors (from Chile, Argentina, Guam islands and a French patient with Spanish ancestors). These observations, together with that of the patient described here, led us to consider this mutation as having a possible Spanish/Portuguese origin. This condition may be more frequent in Spain than previously thought, especially due to misdiagnosis. This is important in order to undertake quaternary prevention, which is quite necessary for rare syndromes with polysystemic affectation

Evolución secular y por comunidades autónomas de la frecuencia de síndrome de Down al nacimiento en hijos de madres jóvenes / Trends in the frequency of Down syndrome in the infants of young mothers in the autonomous communities of Spain

Introducción: Hay una relación universalmente probada entre la edad materna y el riesgo para tener hijos con síndrome de Down (SD), que es mayor a medida que aquélla aumenta. El grupo de madres con más de 34 años (entre un 9 y un 14% del total) tiene globalmente 10 veces más riesgo que el grupo con menos de 35 años. Por ello, las madres con 35 años o más han sido la población diana para el diagnóstico prenatal del SD. Como consecuencia de ello, la frecuencia de recién nacidos con SD en este grupo de madres va disminuyendo con el tiempo. Sin embargo, el desarrollo de nuevas técnicas de cribado ha facilitado también la detección de grupos de riesgo para SD en las madres con menos de 35 años. El objetivo de este trabajo era estudiar la evolución de la frecuencia de SD en los recién nacidos de madres menores de 35 años en España, durante 28 años y por comunidades autónomas. Material y métodos: Se han utilizado los datos registrados por el Estudio Colaborativo Español de Malformaciones Congénitas (ECEMC) entre 1976 y 2003, procedentes de todas las comunidades autónomas. El ECEMC es un programa de investigación clínico-epidemiológica sobre las causas de los defectos congénitos, estructurado como un sistema permanente de registro con un diseño de tipo casos y controles y de base hospitalaria. Para el análisis de la tendencia temporal se ha utilizado el test de tendencia lineal (χ² con un grado de libertad) y la χ² con k-2 grados de libertad para detectar desviaciones de la linealidad. Resultados: La frecuencia global de SD en el grupo de madres menores de 35 años ha disminuido de forma estadísticamente significativa con el tiempo (p = 0,03), fundamentalmente los últimos años. Dicho descenso es estadísticamente significativo en Cataluña (p = 0,002) y Galicia (p = 0,01). Sin embargo, no se alcanza la significación estadística para los descensos observados en Andalucía, Islas Baleares, Madrid y País Vasco. En la Comunidad Foral de Navarra y en La Rioja no se ha podido evaluar la tendencia más reciente porque estas comunidades interrumpieron temporalmente su participación en el estudio. En el Principado de Asturias hemos detectado un incremento secular significativo, y en el resto de las comunidades no se aprecian tendencias destacables. Además, el porcentaje de madres con más de 34 años ha aumentado progresivamente hasta alcanzar el 20,54% del total de madres en 2003, mientras que el número y el porcentaje de niños con SD que nacieron de madres con más de 34 años ha ido disminuyendo hasta ser inferior al de niños con SD hijos de madres con menos de 35 años. Discusión: La evolución global con el transcurso del tiempo de la frecuencia de SD en hijos de madres con menos de 35 años muestra ya un descenso significativo, pero éste no es igual en todas las comunidades autónomas. Este hecho puede ser consecuencia de la aplicación de planes diversos, que se deberían homogeneizar, dirigidos a la detección prenatal del SD en el grupo de madres de menor riesgo

Introduction: There is a universally proven relationship between maternal age and the risk of having an infant with Down syndrome (DS); the risk is greater as maternal age increases. The overall risk is increased almost 10-fold in mothers aged more than 34 years (traditionally accounting for 9-14% of all mothers) than in those aged less than 35 years. For this reason, mothers aged 35 years or older have constituted the target population for prenatal diagnosis of DS and, consequently, the frequency of newborn infants with DS in this age group has clearly decreased over time. However, the development of new prenatal screening techniques has allowed groups with a higher risk to be detected among young mothers. The aim of this study was to analyze trends in the frequency of DS in the infants of mothers aged less than 35 years old in Spain over the last 28 years by autonomous communities in Spain. Material and methods: Data from the Spanish Collaborative Study of Congenital Malformations (Estudio Colaborativo Español de Malformaciones Congénitas [ECEMC]) corresponding to the period 1976-2003, and obtained from all the autonomous communities in Spain, were used. The ECEMC is a clinical-epidemiological research program on the causes of congenital defects, structured as a permanent registration system with a case-control design. The program is hospital-based. For the analysis of time trends, the lineal trend test (χ² with 1 degree of freedom) was used. To detect deviations from linearity, a χ² test with k-2 degrees of freedom was used. Results: The overall frequency of DS in mothers younger than 35 years significantly decreased over time (p = 0.03), mainly in the last few years. This decrease was statistically significant in the autonomous communities of Catalonia (p = 0.002) and Galicia (p = 0.01), but was nonsignificant in Andalusia, Balearic Island, Madrid and the Basque Country. In Navarre and La Rioja, the most recent tendency could not be evaluated because these regions temporarily interrupted their participation in the study. A statistically significant increase was found in the Principality of Asturias. No notable tendencies were found in the remaining regions. The percentage of mothers older than 34 years progressively increased, accounting for 20.54% of all mothers in 2003, while the number and percentage of infants with DS born to mothers older than 34 decreased and was lower those of infants with DS born to mothers younger than 35 years. Discussion: Although the time trend of the frequency of DS in the infants of mothers aged less than 35 years showed a significant overall decrease, differences were found in the distinct autonomous communities. This finding could be a result of the application of different programs for the prenatal detection of DS in lower-risk maternal age groups. Therefore, homogenizing these programs would seem advisable

Análisis comparativo de las frecuencias de ciertos defectos congénitos y su evolución secular en 11 comunidades autónomas / Comparative analysis of the frequencies of diverse congenital birth defects and their time trends in 11 autonomous communities in Spain

Fundamento y objetivo: El conocimiento de la frecuencia de los distintos defectos congénitos a lo largo del tiempo y en las diferentes comunidades autónomas es importante, no sólo para cuantificar la magnitud del problema y planificar los recursos necesarios, sino para disponer de sistemas de vigilancia y analizar el impacto de las diversas actuaciones sanitarias. El objetivo de este trabajo ha sido analizar comparativamente en las 11 comunidades autónomas que participan en la REpIER (Red Epidemiológica de Investigación en Enfermedades Raras) las frecuencias de 6 tipos de defectos congénitos. Sujetos y métodos: Se han utilizado los datos del ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas) correspondientes a las 11 autonomías que participan en la REpIER (Andalucía, Aragón, Canarias, Cantabria, Castilla-La Mancha, Cataluña, Comunidad de Madrid, Comunidad Valenciana, Extremadura, La Rioja y el Principado de Asturias), en el período 1980-2003. El ECEMC es un programa de investigación clínico-epidemiológico acerca de las causas de los defectos congénitos, estructurado como un sistema permanente de registro, con un diseño de tipo caso-control y de base hospitalaria. Los defectos estudiados han sido: anencefalia; espina bífida; labio leporino, con o sin fisura del paladar; sólo fisura del paladar; defectos por reducción de extremidades, y síndrome de Down en hijos de mujeres con más de 34 años. Para el análisis de la tendencia temporal en cada autonomía se ha utilizado la prueba de tendencia lineal (χ2con 1 grado de libertad) y la χ2 con k-2 grados de libertad para detectar desviaciones de la linealidad. Resultados: La distribución temporal de las frecuencias no es igual para todos los defectos estudiados ni en todas las comunidades. La mayor concordancia entre las 11 autonomías estudiadas se observa para la disminución secular del síndrome de Down en madres de más de 34 años, que es significativa en 8 comunidades. La anencefalia disminuye significativamente en 6 autonomías, y en otras 2 no se registró ningún caso. La espina bífida muestra descensos estadísticamente significativos en 6 circunscripciones autonómicas. La distribución secular de las frecuencias de los otros 3 tipos de malformaciones estudiadas no presenta tendencias significativas en la mayoría de las autonomías. Conclusiones: Desde que hay en España la posibilidad legal de realizar una interrupción voluntaria del embarazo tras la detección prenatal de anomalías, se observa un claro descenso de las frecuencias al nacimiento de los defectos para los que es posible el diagnóstico prenatal. Dicho descenso no ha sido igual en todas las comunidades, ni en lo que se refiere a su comienzo ni en cuanto a su intensidad, lo que puede estar poniendo de manifiesto, entre otros factores, diferencias en cuanto a la atención sanitaria

Background and objective: Knowledge of the frequency of the distinct congenital defects over time in the various Autonomous Communities in Spain is important, not only to quantify the scope of the problem and to plan the necessary resources, but also to have surveillance systems and analyze the impact of the diverse health interventions. The aim of this study was to analyze the comparative frequencies of 6 types of congenital defect in the 11 Autonomous Communities participating in the Epidemiological Network on Rare Disease Research (REpIER). Subjects and methods: We analyzed data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) corresponding to the 11 Autonomous Communities participating in REpIER (Andalusia, Aragon, the Canary Islands, Cantabria, Castilla-La Mancha, Catalonia, the Autonomous Community of Madrid, the Autonomous Community of Valencia, Extremadura, La Rioja, and the Principality of Asturias) from 1980 to 2003. The ECEMC is a clinical-epidemiological research program on the causes of congenital defects, structured as a permanent registration system with a case-control design. The program is hospital-based. The defects studied were anencephaly, spina bifida, cleft lip with or without cleft palate, cleft palate only, limb reduction defects, and Down syndrome in infants born to mothers aged 34 years or older. To analyze the time trends in each Autonomous Community, the lineal trend test (chi-square with 1 degree of freedom) and chi-square with k-2 degrees of freedom to detect deviations from linearity were used. Results: The time trend of the frequencies was not the same for all the defects studied or for all the Autonomous Communities. The highest concordance between the 11 Autonomous Communities analyzed was observed in the decreasing secular trend for Down syndrome in infants born to mothers aged 34 years or older, which was statistically significant in 8 Autonomous Communities. The frequency of anencephaly significantly decreased in 6 Autonomous Communities, and in a further 2 no cases were registered. The frequency of spina bifida significantly decreased in 6 Autonomous Communities. The secular distribution of the frequencies of the other 3 types of malformations studied showed no significant trends in most of the regions. Conclusions: Since pregnancy terminations after prenatal detection of anomalies became legal in Spain, the frequency of prenatally diagnosable birth defects has clearly decreased. This decrease has not been equal in all the regions. Differences were found in the time the decreases began and in their intensity, which may reveal, among other factors, differences in health care

Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

This study was aimed at analyzing the effect of mutations in three non-synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hcy), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case-control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Using a general lineal model in a backwards step, we performed the analyses including the different mutations, maternal age, the fact that each mother had a DS or a control infant, and all possible interactions of these variables, in the models, being maternal Hcy the continuous dependent variable. In another model, maternal folic acid intake during the third trimester of pregnancy was added. The results from both models were essentially the same: Hcy levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hcy variance, as it does the statistical interaction between the mutations MTRR66A > G and MTHFR1298A > C in the mother. In this sense, the interaction between different polymorphisms may totally modify their individual effects, and some of those effects are different in mothers of DS children and in controls' mothers. For instance, only two mutations in MTRR66 (GGAA) in mothers of control infants increase the reference maternal Hcy level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hcy level in 12.74 units. However, the presence of the four mutations (GGCC) interacts giving a statistically significant decrease in 6.00 units in the level of Hcy in control mothers. On the contrary, in mothers of DS infants, the sole presence of two mutations in one of these two genes decreases the levels of Hcy (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hcy in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy in an irreversible way, and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS. This fact, as well as others influencing Hcy levels (such as nutrients interactions and lifestyle), together with the fetal genotype, suggest that their relationship with DS could be through an effect on fetal survival up to birth. Three possible mechanisms are considered by evaluating the results in the light of the present knowledge on cytology and molecular biology.

Respuesta de los autores. Posibles sesgos metodológicos en estudios de prevalencia del hábito de fumar durante el embarazo en España / Autors’ reply. Methodologic bias in prevalence studies of smoking habit during pregnancy

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Growth deficiency, facial anomalies, and brachydactyly (Frías syndrome): a second family.

A second family with the condition first described by Frías et al. in 1975 is presented. Those authors examined a mother and her son affected with short stature, facial anomalies (epicanthic folds, downward palpebral fissures, hyperthelorism, and eyelid ptosis), cup-shaped and posteriorly rotated ears, hand and foot defects, and delayed bone age. In the family we are presenting here, a girl, her mother, the mother's brother, and the propositus' maternal grandmother, were affected. This supports autosomal dominant inheritance, as proposed by (Frías et al. [1975] BDOAS 11:30-33), although with variable expressivity.