Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported. METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp). RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period. CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

[Descriptive epidemiology of major structural congenital anomalies in Argentina]. / Epidemiología descriptiva de las anomalías congénitas estructurales mayores en Argentina.

The objective of the study is to present the frequency of congenital anomalies (CA) reported to the National Network of Congenital Anomalies of Argentina (RENAC) in the year 2016, as part of its monitoring activities. RENAC is an official, national and hospital-based surveillance system of CA. The case definition includes newborns with major structural CA, external or internal, identified from birth until hospital discharge and detected by physical examination, complementary studies, interventions or autopsy. All live newborns and stillbirths of 500 grams or more were included. The prevalence of CA at birth was calculated as the quotient between the number of live newborns and stillbirths with CA, and the total number of live newborns and stillbirths, for a given period. According to their presentation, the cases with specific CA were classified into isolated, multiple and syndromes. The prevalence at birth of major structural CA was 1.59% (95% confidence intervals 1.55-1.64). The most frequent specific anomalies were: cleft lip and palate, gastroschisis, hydrocephalus, talipes equinovarus, spina bifida, postaxial polydactyly, anorectal malformation, diaphragmatic hernia, renal cysts and esophageal atresia. The most frequent syndrome was Down's. The expected annual cases and the prevalence of selected specific CA were estimated. RENAC data are within values reported in the literature.

Diprosopus: Systematic review and report of two cases.

BACKGROUND: Diprosopus is a subtype of symmetric conjoined twins with one head, facial duplication and a single trunk. Diprosopus is a very rare congenital anomaly. METHODS: This is a systematic review of published cases and the presentation of two new cases born in Argentina. We estimated the prevalence of conjoined twins and diprosopus using data from the National Network of Congenital Anomalies of Argentina (RENAC). RESULTS: The prevalence of conjoined twins in RENAC was 19 per 1,000,000 births (95% confidence interval, 12-29). Diprosopus prevalence was 2 per 1,000,000 births (95% confidence interval, 0.2-6.8). In the systematic review, we identified 31 diprosopus cases. The facial structures more frequently duplicated were nose and eyes. Most frequent associated anomalies were: anencephaly, duplication of cerebral hemispheres, craniorachischisis, oral clefts, spinal abnormalities, congenital heart defects, diaphragmatic hernia, thoracic and/or abdominal visceral laterality anomalies. One of the RENAC cases and three cases from the literature had another discordant nonmalformed twin. CONCLUSION: The conjoined twins prevalence was similar to other studies. The prevalence of diprosopus was higher. The etiology is still unknown. The presence of visceral laterality anomalies may indicate the link between diprosopus and the alteration or duplication of the primitive node in the perigastrulation period (12-15 days postfertilization). Pregnancies of more than two embryos may be a risk factor for diprosopus. Given the low prevalence of this defect, it would be useful to perform studies involving several surveillance systems and international consortiums. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:993-1007, 2016. © 2016 Wiley Periodicals, Inc.

Prenatal detection of congenital anomalies and related factors in Argentina.

Congenital anomalies (CAs) are a leading cause of neonatal death. Many CAs can be diagnosed prenatally. To estimate the prenatal detection rate (PDR) of CA in hospitals participating in the RENAC (National Network of Congenital Anomalies of Argentina) and to analyze the PDR according to different factors. Sources were reports of RENAC from the 2013-2016 period. Congenital anomalies included were those detectable by ultrasound or by a prenatal karyotype. PDR was calculated by region, health subsector, clinical presentation, maternal age, sex, and twining. Using multiple logistic regression analysis, we evaluated predictors of prenatal detection. In total, 9976 cases were defined as prenatal detectable; 5021 were detected (PDR = 50.3%). Multiple presentation increased the chances of prenatal detection (Adj. OR = 1.6; 95%CI 1.4-1.9). Prenatal detection was lower in the public subsector (Adj. OR = 0.8; 95%CI 0.7-0.9) and in the northern regions of the country. PDR was higher than 75% in isolated cases of urinary malformation, anencephaly, and gastroschisis. Prenatal detection increased the chance of birth in higher complexity-level hospitals (Adj. OR = 2.5; 95%CI 2.3-2.8). PDR was within the range previously reported. Heterogeneity between regions and health subsector suggests the need for training to achieve equity in detection.

[16p11.2 Microdeletion: first report in Argentina]. / Microdeleción 16p11.2: primeros casos reportados en Argentina.

The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder. This microdeletion is associated with variable clinical outcome, the phenotypical spectrum ranges from intellectual disability and/or multiple congenital anomalies, autism, learning and speech problems, to a normal Microdeleción 16p11.2: primeros casos reportados en Argentina 16p11.2 Microdeletion: first report in Argentina phenotype. Genomic testing that determines copy number of sequences, such as chromosomal microarray, is used to identify this microdeletion. However, the prediction of the individual phenotype of a patient based only on the location of such deletion remains a challenge, regarding the existence of many genomic variants that might hinder the interpretation of possible functional effects between most of the contributing genes to that region. We describe the clinical findings in two subjects with heterozygous microdeletions at 16p11.2, highlighting the phenotypic and behavioural findings that conditioned the diagnostic strategy. We also discuss the implications of diagnosis, in practical counselling situations.

La microdeleción 16p11.2 se relaciona, habitualmente, con discapacidad intelectual y trastornos del espectro autista. El rango fenotípico incluye un espectro que se extiende desde discapacidad intelectual con o sin autismo, alteraciones del aprendizaje y del lenguaje hasta fenotipos normales. El diagnóstico de la microdeleción se realiza mediante estudios genómicos capaces de identificar variación en número de copias, como la hibridación genómica comparativa en microarreglos, conocida como arrayCGH. Sin embargo, la predicción del fenotipo de un individuo basada únicamente en la localización de dicha deleción sigue siendo un desafío, ya que la existencia de un gran número de variantes en el genoma dificulta la interpretación de posibles efectos funcionales de los genes que contribuyen a dicha región. Se describen dos casos clínicos de pacientes con microdeleción heterocigota en 16p11.2 y se destacan los hallazgos fenotípicos y conductuales que dificultaron la estrategia diagnóstica. También se discuten las implicancias del diagnóstico para el asesoramiento genético familiar.

Neurologic dysfunction and genotoxicity induced by low levels of chlorpyrifos.

Chlorpyrifos (CPF) is an organophosphorus cholinesterase inhibitor widely used as an insecticide. Neuro and genotoxicity of this agent were evaluated following daily subcutaneous injections at 0.1, 1 and 10mg/kg or its vehicle to laboratory rats during one week, at the end of which somatosensory evoked potentials (SEP) and power spectrum of the electroencephalogram (EEGp) were recorded under urethane anesthesia. In another group of conscious animals, auditory startle reflex (ASR) was evaluated followed, after euthanasia, with measurements of plasma B-esterases, and genotoxicity with the alkaline comet assay (ACA) at the same CPF doses. The results indicated a CPF dose related inhibition of B-esterases. Enhanced inhibition of the ASR by a subthreshold pre-pulse was observed at all doses and ACA showed a significant higher DNA damage than vehicle controls in animals exposed to 10mg/kg CPF. A trend to higher frequencies of EEGp and an increase in amplitude of the first negative wave of the SEP were found at all doses. The first positive wave of the SEP decreased at the CPF dose of 10mg/kg. In summary, a shift to higher EEG frequencies and alterations of somatosensory and auditory input to the central nervous system were sensitive manifestations of CPF toxicity, associated with depression of B-esterases. The changes in electrical activity of the cerebral cortex and DNA damage observed at doses that do not elicit overt toxicity may be useful in the detection of CPF exposure before clinical signs appear.

Epidemiología descriptiva de las anomalías congénitas estructurales mayores en Argentina / Descriptive epidemiology of major structural congenital anomalies in Argentina

El objetivo del trabajo es presentar las frecuencias de anomalías congénitas (AC) estructurales mayores obtenidas por la Red Nacional de Anomalías Congénitas de Argentina (RENAC) correspondientes al año 2016, como parte de sus actividades de vigilancia de salud pública de AC. La RENAC es un sistema de vigilancia de AC oficial, nacional y de base hospitalaria. La definición de caso corresponde a recién nacidos con AC estructurales mayores, externas o internas, identificadas desde el nacimiento hasta el alta del hospital y detectadas en el examen físico, estudios complementarios, intervenciones o autopsia. Se incluyeron todos los recién nacidos vivos y los fetos muertos de 500 gramos o más. La prevalencia de AC al nacimiento se calculó como el cociente entre el número de recién nacidos vivos y fetos muertos con AC, y el número total de recién nacidos vivos y fetos muertos, en un período determinado. Según su presentación los casos con AC específicas fueron clasificados en aislados, múltiples y síndromes. La prevalencia al nacimiento de AC estructurales mayores fue de 1.59% (Intervalo de confianza del 95%: 1.55-1.64). Las anomalías específicas más frecuentes fueron: fisuras labiopalatinas, gastrosquisis, hidrocefalia, talipes equinovarus, espina bífida, polidactilia postaxial, malformación anorrectal, hernia diafragmática, quistes renales y atresia de esófago. El síndrome más frecuente fue Down. Se estimaron los casos anuales esperados y la prevalencia de AC específicas seleccionadas. En general, los datos de RENAC están dentro de los valores informados en la literatura.

The objective of the study is to present the frequency of congenital anomalies (CA) reported to the National Network of Congenital Anomalies of Argentina (RENAC) in the year 2016, as part of its monitoring activities. RENAC is an official, national and hospital-based surveillance system of CA. The case definition includes newborns with major structural CA, external or internal, identified from birth until hospital discharge and detected by physical examination, complementary studies, interventions or autopsy. All live newborns and stillbirths of 500 grams or more were included. The prevalence of CA at birth was calculated as the quotient between the number of live newborns and stillbirths with CA, and the total number of live newborns and stillbirths, for a given period. According to their presentation, the cases with specific CA were classified into isolated, multiple and syndromes. The prevalence at birth of major structural CA was 1.59% (95% confidence intervals 1.55-1.64). The most frequent specific anomalies were: cleft lip and palate, gastroschisis, hydrocephalus, talipes equinovarus, spina bifida, postaxial polydactyly, anorectal malformation, diaphragmatic hernia, renal cysts and esophageal atresia. The most frequent syndrome was Down´s. The expected annual cases and the prevalence of selected specific CA were estimated. RENAC data are within values reported in the literature.

Microdeleción 16p11. 2: primeros casos reportados en Argentina / 16p11. 2 Microdeletion: first report in Argentina

La microdeleción 16p11.2 se relaciona, habitualmente, con discapacidad intelectual y trastornos del espectro autista. El rango fenotípico incluye un espectro que se extiende desde discapacidad intelectual con o sin autismo, alteraciones del aprendizaje y del lenguaje hasta fenotipos normales. El diagnóstico de la microdeleción se realiza mediante estudios genómicos capaces de identificar variación en número de copias, como la hibridación genómica comparativa en microarreglos, conocida como arrayCGH. Sin embargo, la predicción del fenotipo de un individuo basada únicamente en la localización de dicha deleción sigue siendo un desafío, ya que la existencia de un gran número de variantes en el genoma dificulta la interpretación de posibles efectos funcionales de los genes que contribuyen a dicha región. Se describen dos casos clínicos de pacientes con microdeleción heterocigota en 16p11.2 y se destacan los hallazgos fenotípicos y conductuales que dificultaron la estrategia diagnóstica. También se discuten las implicancias del diagnóstico para el asesoramiento genético familiar.

The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder. This microdeletion is associated with variable clinical outcome, the phenotypical spectrum ranges from intellectual disability and/or multiple congenital anomalies, autism, learning and speech problems, to a normal phenotype. Genomic testing that determines copy number of sequences, such as chromosomal microarray, is used to identify this microdeletion. However, the prediction of the individual phenotype of a patient based only on the location of such deletion remains a challenge, regarding the existence of many genomic variants that might hinder the interpretation of possible functional effects between most of the contributing genes to that region. We describe the clinical findings in two subjects with heterozygous microdeletions at 16p11.2, highlighting the phenotypic and behavioural findings that conditioned the diagnostic strategy. We also discuss the implications of diagnosis, in practical counselling situations.

Estudio de prevalencia y búsqueda de agregados geográficos de las fisuras labio alvéolo palatinas (FLAP) en Argentina con información del Registro Nacional de Anomalías Congénitas (RENAC) / Prevalence study and search for geographic aggregates of cleft lip and palate (FLAP) in Argentina with information from the Registro Nacional de Anomalías Congénitas (RENAC)

Las fisuras labio alvéolo palatinas (FLAP) son anomalías congénitas (AC) estructurales mayores frecuentes, con gran impacto en la salud, que requieren cuidados multidisciplinarios. La Red Nacional de Anomalías Congénitas de Argentina (RENAC) es un sistema de vigilancia de AC creado en 2009, que actualmente incluye 180 maternidades de Argentina. Dentro de las AC que se reportan a RENAC se encuentran las FLAP. Los objetivos del presente trabajo son describir la prevalencia de FLAP en recién nacidos, estimar el número total de casos anuales esperados, buscar agregados geográficos (clusters) de FLAP y comparar las prevalencias con las de otros países; para contribuir a la planificación de los servicios de salud para su tratamiento, la definición de intervenciones para su prevención y la generación de hipótesis sobre posibles causas. MÉTODOS Se realizó un estudio observacional y descriptivo, con datos provenientes de los hospitales de la RENAC. Se calculó la prevalencia y se estimaron los casos anuales esperados. Se identificaron agregados geográficos de alta prevalencia. Se comparó la prevalencia observada en la RENAC con la de otros registros. RESULTADOS Entre 2009 y 2015 se examinaron 1.358.158 nacimientos. La prevalencia total de FLAP fue 15,0 por 10.000 (IC 95%: 14,4-15,7). Neuquén, Salta, Jujuy, Chubut y Santa Cruz presentaron la mayor prevalencia. Se identificaron 2 clusters de alta prevalencia, uno que incluye algunos hospitales de Capital Federal y otro en el Noroeste del país. DISCUSIÓN Se observó mayor prevalencia de FLAP en la RENAC que en otros registros, lo que podría explicarse por el componente amerindio y el menor nivel socioeconómico de algunas regiones del país, asociados con esta anomalía. El cluster de alta frecuencia en Salta y Jujuy coincide con lo reportado previamente por ECLAMC. La región Noroeste presenta una estructura poblacional con mayor componente amerindio y diferencias socioeconómicas que podrían explicar en parte la alta frecuencia observada