Consenso de la Rama de Genética de la Sociedad Chilena de Pediatría sobre las anomalías congénitas de mal pronóstico vital (ACMPV): Genetics Consensus Committee / Congenital anomalies of poor prognosis

Introducción: La rama de genética de la Sociedad Chilena de Pediatría, en relación con el proyecto de ley que regula la despenalización de la interrupción voluntaria del embarazo en 3 causales, centrándose en la segunda causal que considera al «embrión o feto que padezca una alteración estructural congénita o genética incompatible con la vida extrauterina¼, se reunió para discutir conforme a la evidencia científica qué anomalías congénitas (AC) podrían ser incluidas en el proyecto de ley. Metodología: Los expertos en genética clínica se centraron en 10 AC. Se efectuó revisión bibliográfica y una reunión extraordinaria para discutirla. Resultados: Se acordó no emplear el término «incompatible con la vida extrauterina¼, pues existen excepciones de sobrevidas más prolongadas y cambiar por «anomalía congénita de mal pronóstico vital (ACMPV)¼. Se evaluaron 10 AC: defectos graves de cierre del tubo neural: anencefalia, iniencefalia y craneorraquisquisis, hipoplasia pulmonar, feto acardio, ectopia cordis, triploidía no mosaico, complejo limb body wall, anomalía body stalk, trisomía 13, trisomía 18 y agenesia renal bilateral. Se analizaron los hallazgos sobre prevalencia, historia natural, métodos diagnósticos prenatales, sobrevida, casos descritos de sobrevida prolongada. Para catalogarlas como ACMPV se consideraron: sobrevida posnatal, existencia de tratamientos y evolución posterior e historia natural sin intervenciones. Conclusión: Las ACMPV incluidas serían: anencefalia, hipoplasia pulmonar severa, feto acardio, ectopia cordis cervical, triploidía no mosaico, complejo limb body wall, anomalía body stalk, trisomía 13 no mosaico, trisomía 18 no mosaico y agenesia renal bilateral. Se requiere para el diagnóstico que toda mujer gestante tenga acceso a evaluaciones ecográficas de anatomía fetal, y en ocasiones a resonancia magnética y estudios citogenéticos y moleculares.

Introduction: The Genetic Branch of the Chilean Society of Paediatrics, given the draft Law governing the decriminalisation of abortion on three grounds, focusing on the second ground, which considers the "embryo or foetus suffering from a congenital structural anomaly or a genetic disorder incompatible with life outside the womb", met to discuss the scientific evidence according to which congenital anomalies (CA) may be included in this draft law. Methodology: Experts in clinical genetics focused on 10 CA, reviewed the literature evidence, and met to discuss it. Results: It was agreed not to use the term "incompatible with life outside the womb", as there are exceptions and longer survivals, and change to "congenital anomaly of poor prognosis (CAPP)". Ten CA were evaluated: serious defects of neural tube closure: anencephaly, iniencephaly and craniorachischisis, pulmonary hypoplasia, acardiac foetus, ectopia cordis, non-mosaic triploidy, "limb body wall" complex, "body stalk" anomaly, trisomy 13, trisomy 18, and bilateral renal agenesis. Findings on the prevalence, natural history, prenatal diagnostic methods, survival, and reported cases of prolonged survival were analysed. Post-natal survival, existence of treatments, and outcomes, as well as natural history without intervention, were taken into account in classifying a CA as a CAPP. Conclusion: A CAPP would be: anencephaly, severe pulmonary hypoplasia, acardiac foetus, cervical ectopia cordis, non-mosaic triploidy, limb body wall complex, body stalk anomaly, non-mosaic trisomy 13, non-mosaic trisomy 18, and bilateral renal agenesis. For their diagnosis, it is required that all pregnant women have access to assessments by foetal anatomy ultrasound and occasionally MRI, and cytogenetic and molecular testing.

Consideraciones sobre epigenética perinatal / Considerations about perinatal epigenetics

Se ha reconocido progresivamente que el riesgo de enfermedades del adulto, especialmente el síndrome metabólico, puede estar influenciado por exposiciones ambientales prenatales. El bajo peso de nacimiento, la recuperación del crecimiento durante la infancia, se asocian a un riesgo de obesidad del adulto, así como de enfermedad cardiovascular, y de efectos adversos en las funciones renal y cerebral. La exposición a obesidad materna, o el alto peso de nacimiento también representan un riesgo aumentado para obesidad de la infancia y la adultez. La exposición fetal a determinados químicos o contaminantes ambientales puede afectar la predisposición a enfermedades del adulto. Se aducen mecanismos de programación, que alteren el desarrollo de los órganos, respuestas a señales celulares, y modificaciones epigenéticas (es decir, control de la expresión génica sin modificación de la secuencia de ADN). El cuidado prenatal ha incorporado metas para optimizar la salud materna, fetal y neonatal para prevenir o reducir enfermedades del adulto. El embarazo, cuando el epigenoma está activamente programado es un tiempo vulnerable, es cuando las exposiciones tienen el efecto epigenético más profundo. Los profesionales de la salud que tratan y aconsejan a mujeres en edad reproductiva están en una posición privilegiada para protegerlas de alteraciones epigenéticas y de esa forma prevenir el impacto adverso en el feto en desarrollo que podría manifestarse a lo largo de su vida. El adulto sano es el resultado de una interacción exitosa entre el ambiente materno y el epigenoma fetal en desarrollo...

It has been gradually recognized that the risk of adult diseases, especially metabolic syndrome, can be influenced by prenatal environmental exposures. Low birth weight, growth recovery in childhood are associated with a risk of adult obesity and cardiovascular disease, and adverse effects on kidney and brain functions. Exposure to maternal obesity, or high birth weight also represent an increased risk for obesity in childhood and adulthood. Fetal exposure to certain chemicals or environmental pollutants may affect susceptibility to diseases in adults. Programming mechanisms that alter the development of organs, cellular responses to signals and epigenetic modifications (i.e., control of gene expression without changing the DNA sequence) are adduced. Prenatal care incorporated goals to optimize maternal, fetal, and neonatal health to prevent or reduce adult diseases. Pregnancy, when the epigenome is actively programmed, is a vulnerable time, and when exposures have the deepest epigenetic effect. Health professionals who treat and counsel women of childbearing age are in a privileged position to protect them from epigenetic alterations and thus prevent the adverse impact on the developing fetus that may manifest throughout his life. The healthy adult is the result of a successful interaction between maternal and fetal environment developing epigenome...

Estudio cromosómico en abortos espontáneos / Chromosome study in spontaneous abortions

Aproximadamente 15 por ciento de todos los embarazos clínicos terminan en aborto espontáneo. La causa más frecuente de aborto espontáneo es una anomalía cromosómica fetal, tal como una trisomía autosómica, monosomía X y poliploidía. Desde mayo de 1991 hasta febrero de 2013 hemos realizado 2.416 estudios citogenéticos en restos de aborto en la Sección Citogenética del Laboratorio Clínico de Clínica Alemana de Santiago, Chile. Deseamos compartir la información sobre la distribución de los hallazgos en estos estudios, así como difundir la estrategia que hemos implementado desde febrero de 2010 con estudio de varias sondas de hibridación in situ con fluorescencia (FISH) en aquellos casos en que el cultivo no ha progresado, lo que permite entregar alguna información importante respecto a la presencia o ausencia de ciertas alteraciones cromosómicas en todos los estudios.

Approximately 15 percent of all clinical pregnancies end in spontaneous abortion. The most common cause of spontaneous abortion is a fetal chromosomal abnormality, such as an autosomal trisomy, monosomy X and polyploidy. From May 1991 until February 2013 we performed 2,416 cytogenetic studies in abortion tissues in the Cytogenetics Unit of the Clinical Laboratory Clínica Alemana de Santiago. We want to share information about the distribution of the findings in these studies, and want to disseminate the strategy we have implemented since February 2010 with multiple probes study of fluorescence in situ hybridization (FISH) in cases where the tissue culture had not progressed, allowing to provide some important information regarding the presence or absence of certain chromosomal abnormalities in all studies.

Cáncer hereditario de colon: Aportes del diagnóstico genético molecular / Molecular and genetic studies for hereditary colon cancer in two patients and their families

Background: About 30 percent of cases of colon cancer (CC) have a family history of CC, and only 5 percent are hereditary forms. Hereditary forms have an increased risk of CC and other tumors. Aim: To report the molecular and genetic study in two families with hereditary CC. Material and Methods: Molecular analysis of the adenomatous polyposis coli (APC) gene of familial adenomatous polyposis (FAP), was done in a patient with multiple benign polyps and his children. Molecular analysis was performed for MLH1 gene mutation of hereditary non-polyposis colon cancer (HNPCC) in an asymptomatic patient with family history of multiple cancers and his mother with a confrmed mutation in the MLH1 gene. Results: The patient with FAP had an insertion of 17 base pairs in exon 9 of the APC gene and two of his children had the same mutation. The patient with history of HNPCC did not have the family mutation on MLH1. Conclusions: In the case of FAP, molecular study was performed in his children since manifestations in carriers of the mutation may begin in childhood. If the second patient would have had the mutation, the study of his children could have been postponed until the age of 18, when the risk for CC is increased.

Marcadores genéticos en hipertensión esencial / Genetic markers in essential hypertension

Essential hypertension (HTA) is a multifactorial disease and in Chile, its prevalence is 33.7 percent. There is a genetic predisposition to develop hypertension, whose magnitude is approximately 30 to 50 percent. At present, some factors are known to increase the risk for cardiovascular disease, but widely accepted biomarkers for screening are missing. The frst studies that looked for candidate genes have focused on the reninangiotensin - aldosterone, aducina, adrenoreceptors ß, G protein subunits, G protein signaling regulators, kinases associated with G proteins and Rho kinases. Studies of DNA sequencing, search for polymorphisms and variants through single nucleotide polymorphisms, have been used to seek partnerships with complex or multifactorial diseases, like HTA. Examples of these are: components of collagen proteins, genes related to cell myocardial proteins belonging to cytochrome P450 and growth factors, among others. It is still unlikely to count in a near future with a universal marker. Most probably, a series of markers that confer susceptibility to a specifc individual will have to be used in prevention programs or personalized therapy.

Hipertensión arterial infantil de origen monogénico / Hypertension Infant monogenic origin

La hipertensión arterial (HTA) es una patología frecuente en el adulto, en cambio, en pediatría es una patología subdiagnosticada y con una prevalencia del 1 al 2 por ciento. La hipertensión arterial de origen monogénico, representa a menos del 1 por ciento del total, sin embargo es importante su diagnóstico debido a que puede tener riesgo de recurrencia en la familia y ser transmitida a la descendencia. En esta revisión se describen los elementos de sospecha de HTA de origen monogénico, las causas principales, etiopatogenia molecular, clínica, técnicas diagnósticas, modos de herencia y tratamientos. Además se comenta el estado del arte sobre los genes candidatos en la HTA esencial. Conclusión: la HTA de origen monogénico es una señal de alerta de una condición subyacente, la historia personal, los antecedentes familiares y los exámenes de laboratorio, condicionarán el diagnósitco y el asesoramiento genérico para el paciente, como también una búsqueda dirigida en sus familiares.

Servicios para la atención y la prevención de defectos congénitos: Síntesis de una reunión de la Organización Mundial de la Salud y la Fundación March of Dimes / Services for the care and prevention of birth defects. Reduced report of a World Health Organization and March of Dimes Foundation meeting

On 17-19 May 2006, the World Health Organization (WHO) and the March of Dimes Birth Defects Foundation held a meeting in Geneva: The Management of Birth Defects and Haemoglobin Disorders. Meeting participants included 18 experts from developing and industrialized countries, including the author and nine staff from WHO Headquarters. The meeting had five goals: (A) ratify the data on the global toll of birth defects presented in the MOD Global Report; (B) agree upon a definition of terms; (C) develop a collaborative plan for strengthening care and prevention of birth defects; (D) develop a plan for strengthening care and prevention of haemoglobin disorders; and (E) determine how potential stakeholders could contribute to these efforts. The consensus for each of the goals were: a) Participants endorsed the estimates in the MOD Global Report, b) Participants concluded that the term "birth defect" is synonymous with the term "congenital disorder", whereas the term "congenital anomalies" should be avoided, c) Participants agreed that 70 percent of birth defects could be prevented, ameliorated or treated effectively, by the strengthening of medical genetic services, d) Participants agreed that efforts must be made to improve the control of hemoglobin disorders in developing countries, and e) Progress will require the combined efforts and political will of the WHO.

Edad materna y defectos del tubo neural: evidencia para un efecto mayor en espina bífida que anencefalia / Influence of maternal age on the risk for neural tube defects, a meta analysis

Background: Recent evidence from birth order data suggest that maternal factors can differently influence anencephaly and spina bifida. Aim: To study the influence of maternal age on the risk for neural tube defects. Material and methods: A meta-analysis of published data on neural tube defects (NTDs) was carried out to determine whether there is an increased risk to have a child with NTDs for younger and older mothers and if this risk differs depending on the type of NTD. All data available with information regarding the frequency of live births and NTDs cases by maternal age (five- or ten-year intervals) were included in the analysis. Effect sizes calculations were performed. Results: The analysis supports the hypothesis that there is an increased risk of having an offspring with NTDs for mothers 40 years of age or older. However, this effect is stronger for spina bifida than for anencephaly. There is also evidence that mothers 19 years old or younger have a higher risk for having a child with spina bifida. Conclusions: Maternal age influences the risk of having an offspring with neural tube defects.

Análisis mutacional del gen Homeobox de segmento muscular 1 (MSX1) en chilenos con fisuras orales / Mutational analysis of the muscle segment homeobox gene 1 (MSX1) in Chilean patients with cleft lip/palate

Background: Mutations of the MSX1 gene may contribute to nonsyndromic forms of cleft lip and/or cleft palate. Aim: To search for mutations of MSX1 coding regions, including one highly conserved non-coding region in the single intron, among Chilean patients with cleft lip/palate. Patients and Methods: We studied 45 patients with cleft lip/palate and their parents. Oral mucosa samples were obtained with a swab. DNA was extracted and amplified by PCR. Results: Two missense mutations (G16D and G34A) were identified in this study that may be useful for future admixture studies. The G16D mutation appears to disrupt a possible splicing site and may contribute to clefting in this population. Conclusions: Rare MSX1 mutations are found in some cases of cleft lip and/or cleft palate but others remain to be found most likely in other regulatory regions of the gene.

Síndrome de Williams: estudio clínico, citogenético, neurofisiológico y neuroanatómico / Williams syndrome: clinical, cytogenetic, neurophysiological and neuroanatomic features in 44 patients

Background: Williams syndrome (WS) is a genetically based disorder caused by deletion of elastin and contiguous genes on chromosome 7q11.23. This syndrome is characterized by multiorganic involvement with dysmorphic facial features and a distinctive cognitive profile. It is an interesting model for elucidation of relationships between brain, cognition and genes. Patients have a visual-spatial cognition impaired with relative strengths in social and language abilities. Aim: To report clinical, cytogenetic, neurophysiological and neuroanatomic features in 44 patients referred as WS. Patients and methods: Forty four patients, aged 2 to 17 years, with the clinical diagnosis of Williams syndrome were studied with fluorescence in situ hybridization (FISH). In three cases, electrophysiological and neuroimaging studies were performed. Result: The deletion was confirmed in 23 patients. In three patients with neurophysiological studies, event related potentials suggested a cognitive difficulty in detecting and processing visual stimuli. Magnetic resonance imaging showed normal brain morphology. SPECT showed hypoperfusion of the right frontal lobe and bilateral anterior cingulum hyperperfusion. Conclusions: There are functional alterations in the brains of patients with Williams, which may be related to the cognitive deficits

Múltiple FISH y múltiple BAND: técnicas de citogenética molecular en cinco casos / Application of the cytogenetic techniques multiple FISH and multiple BAND: report of 5 cases

The techniques of multiple FISH (M-FISH) or fluorescence in situ hybridization with different color assignment for all and each of the human chromosomes, and multiple BAND (M-BAND) or hybridization with different color assignment for each chromosomal band, allow the identification of some alterations that would not be possible to distinguish with classical banding techniques, like the origin of the chromosomal material that constitutes a (non identifiable) marker chromosome or confirming the constitution of the multiple and simultaneous aberrations that occur in cancer cells. We communicate five complex cytogenetic cases that benefited by the employment of this diagnostic strategy, allowing to corroborate or reformulate a previous given conclusion

Progeria / Progeria

La progeria o síndrome de Hutchinson-Gilford es un síndrome poco frecuente. Consiste en la aparición de signos de envejecimiento en niños entre su primer y segundo año de vida. La mayoría de los casos de progeria son esporádicos, lo cual plantea la posibilidad de un patrón de herencia autosómico dominante por mutación de novo. El diagnóstico diferencial de esta entidad debe plantearse con cualquiera de los otros síndromes progeroides descritos en la literatura. Se presenta una revisión actualizada sobre el tema haciendo énfasis en la aproximación diagnóstica del cuadro

Síndrome de Coffin Siris: 2 casos clínicos y revisión de la literatura / Coffin Siris syndrome: 2 clinical cases and literature review

Presentamos los casos clínicos de 2 pacientes de sexo femenino de 10 y 5 años de edad, que tenían retraso del crecimiento de inicio posnatal, retardo mental, cabello ralo, hirsutismo corporal, facies tosca, cejas pobladas, nariz ancha, filtrum largo, boca grande, micrognatia, escoliosis, braquidactilia de predominio distal, pulpejos prominentes e hipoplasia ungueal del quinto dedo bilateral. El cariograma en sangre fue normal 46XX. Considerndo las características clínicas de ambas pacientes se realizó el diagnóstico de síndrome de Coffin-Siris, enfermedad genética de la que existen menos de 100 casos publicados. La forma de herencia de este síndrome, al parecer autosómica dominante, aún se encuentra en discusión. El síndrome de Coffin-Siris debe ser considerado en el diagnóstico diferencial del retardo mental asociado a rasgos toscos

Frecuencia de los defectos de cierre del tubo neural en las maternidades públicas de Santiago durante el año 1999 / Frequency of neural tube defects in Chilean maternity hospitals during 1999

Background: Fortification of wheat flour with folic acid in Chile, started in January 2000. This fortification should decrease the incidence of neural tube defects. Aim: To study the incidence of neural tube defects among Chilean newborns, during 1999. Material and methods : The records of all newborns and stillbirths with a birth weight over 500 g from 9 public maternity hospitals in Santiago in 1999, were reviewed. All neural tube defects, associated or not to other malformations were taken into account. Results: During the study period, 59.627 newborns and 455 stillbirths were analyzed. The global incidence of neural tube defects was 1.56 per 1.000 born (57 percent women, 42 percent men and 1percent ambiguous sex). Spina bifida was the most frequent neural tube defect found. Conclusion: These baseline data will be useful to assess the impact of folic acid fortification of wheat flour

Desarrollo puberal espontáneo en una mujer con disgenesia gonadal pura 46, XY / Spontaneous puberal development in a woman with pure gonadal dysgenesis 46, XY

Presentamos el caso de una mujer de 26 años que tuvo su menarquia a los 16 seguida de dos ciclos menstruales espontáneos y luego amenorrea. Su examen físico mostró una estatura normal, proporciones corporales eunucoides, desarrollo mamario adulto, distribución pilosa normal, genitales externos femeninos normales sin virilización, útero hipoplásico y anexos no palpables, lo que fue confirmado por ecografía. Su cariotipo fue 46, XY. Tenía niveles plasmáticos elevados de FSH y normales de testosterona. Con el diagnóstico de disgenesia gonadal pura XY en su forma completa, se realizó gonadectomía bilateral. El estudio microscópico, demostró presencia de tejido fibroso tipo estroma ovárico con múltiples calcificaciones nodulares, sin estructuras foliculares, ni células de Leydig. Sertoli o carácter maligno. El cariotipo de ambas gónadas fue 46, XY. El estudio molecular de su ADN genoma mostró ser SRY positivo. Se discuten las bases del diagnóstico de disgenesia gonadal completa XY en este caso y los posibles mecanismos etiopatogénicos involucrados

Anomalías cromosómicas y citometría de flujo en adenocarcinoma de vesícula biliar / Chromosome rearrangements and flow cytometry in gallbladder carcinoma

Background: Gallbladder carcinoma is the first cause of cancer deaths among chilean women. The few cytogenetic studies performed in these tumors have not found specific or primary chromosome abnormalities. Also, no relationships with specific oncogenes have been found. Aim: To perform cytogenetic studies in gallbladder carcinoma. Material and Methods: A chromosomal study and measurement of dna content, was performed in 38 samples of advanced gallbladder carcinoma and in 40 samples of gallbladders without malignant changes. Results: Hyperploidies were found in the karyotype of 15 carcinomas (near triploidies and near teraploidies). These findings were confirmed in the cytometric study. Multiple structural chromosome abnormalities were found in 11 and 15 samples, such as translocations, deletions, inversions, isochromosomes, rings and markers. Some chromosome alterations such as interstitial deletion of chromosome 4, deletion of distal region of chromosome 12, deletion of distal segment of the short arm of chromosome 17 with a fracture point in p12 and rearrangement of chromosome 6 were repeated in 2 or more cases. Conclusions: Hyperploidies in gallbladder carcinoma are an alteration that appears in advanced stages of the tumor. Chromosomal abnormalities may be a primary or specific alteration of this tumor, whose prognostic or diagnostic role should be explored. There are ongogenes related to some mentioned chromosomal fracture points, that should be explored with molecular techniques

Hernia diafragmática congénita y malformaciones asociadas / Congenital diaphragmatic hernia and associated malformations

La hernia diafragmática congénita (HDC) continúa siendo una patología que pone en peligro la vida a pesar de los adelantos en su manejo. Las malformaciones congénitas asociadas resultan ser uno de los factores más importantes que contribuyen a elevar las tasas de mortalidad en estos pacientes. En este trabajo presentamos nuestra experiencia con relación a esta anomalía, la cual forma parte del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC), enfocado principalmente en la asociación de la HDC con otras malformaciones congénitas, y revisamos los aspectos relacionados con el patrón de herencia involucrado en los casos familiares de HDC. En este estudio encontramos que las malformaciones mayores, especialmente las cardíacas y un bajo peso al nacer confieren un mal pronóstico a los recién nacidos con HDC

Arteria umbilical única y malformaciones asociadas: experiencia en el Hospital Clínico de la Universidad de Chile / Single umbilical artery and associated malformations: experience at Hospital Clínico, Universidad de Chile

La arteria umbilical única (AUU) es una malformación centinela que debe orientar a la búsqueda más exhaustiva de malformaciones asociadas que pueden no ser siempre evidentes, ya sea que estas se presenten en forma de síndromes o bien con un patrón desconocido. Este estudio incluye a los casos registrados de AUU en la Unidad de Neonatología del Hospital Clínico de la Universidad de Chile desde enero de 1978 hasta abril de 1998. Observamos, como se ha reportado en la literatura, que la AUU aislada o asociada a malformaciones menores tiene buen pronóstico en contraposición a lo que ocurre cuando se acompaña de una o más malformaciones mayores. Se encontró a la AUU como parte de un síndrome en un 36,4 por ciento de los casos y se detectaron causas cromosómicas en 10,9 por ciento de ellos. Es importante intentar realizar un diagnóstico preciso, de manera de estimar el riesgo de recurrencia que puedan tener los padres en futuros embarazos