Diseño de un protocolo de telegenética como asistencia al proceso de diagnóstico y registro de los recién nacidos con anomalías congénitas en las regiones de Los Lagos y de Arica y Parinacota / Design of a telegenetic protocol to assist in the diagnosis and registration process of newborns with congenital anomalies in the Los Lagos and Arica and Parinacota regions

The majority of clinical geneticists in Chile work in the Metropolitan Region (78%). To expand the area of Telemedicine and support the management of the Ministry of Health, we present this Telegenetics development project that includes innovation of assistance and educational nature directed to regions. The implementation of the National Registry of Congenital Anomalies in Chile (RENACH) in the public and private systems, in December 2015, and the obligation to record and describe the anomalies in all newborns, constitutes a favorable scenario that would benefit from the support of clinical geneticists. This proposal brings together a team of 18 specialists and 6 fellows, professionals from different Universities and / or Hospitals of Health Services, in a collaborative project in the area of clinical genetics, which, supported by the HCUCH + CIMT Telemedicine project, will contribute to two regions of Chile better tools for the diagnosis and comprehensive management of newborn patients with congenital anomalies. It can serve as a pilot for a new way to support the registration of malformations throughout Chile and teach clinical genetics concepts. The expected benefits are to improve the quality of care and health management in patients with little-known diseases. (AU)

Fiebre Mediterránea familiar: un diagnóstico a tener en mente / Familial Mediterranean fever: a diagnosis to keep in mind

Familial Mediterranean Fever is a hereditary inflammatory disease of predominantly autosomal recessive inheritance, produced by mutations in the MEFV gene that is found on the short arm of chromosome 16, characterized by recurrent episodes of fever accompanied by peritonitis, pleuritis, arthritis or erysipelaslike erythema. An episode lasts from one to three days, and its frequency is very variable. This disease is more frequent among Mediterranean populations, Jews from North Africa (not Ashkenazi), Armenians, Turks and Arabs. However, in recent years more cases have been reported in countries not related to this area. There are no formal studies of epidemiology in Chile. We present the case of one patient of Egyptian/ Jewish ancestry, and the case of a family of German/Spanish ancestry, all Chileans with semiology and characteristic evolution of familial Mediterranean fever and heterozygous positive molecular study. The absence of diagnosis in non-Mediterranean countries may be due to the lack of awareness of this disease. In Chile there has been a rise in cases given by migrants and their offspring, so it is very important to keep in mind as possible diagnosis in case of pain and fever of unknown origin. On the other hand, the familial Mediterranean fever is mainly of autosomal recessive inheritance, but dominant variants have been described. Both cases described in this work present the variant in which the disease manifests itself in its heterozygous form, generating an autosomal dominant inheritance, which would increase the number of affected individuals in the population.

La fiebre mediterránea familiar es un trastorno auto inflamatorio hereditario de herencia predominantemente autosómica recesiva, producida por mutaciones en el gen MEFV que se encuentra en el brazo corto del cromosoma 16, y que se caracteriza por episodios recurrentes de fiebre acompañada de peritonitis, pleuritis, artritis o eritema tipo erisipela. Un episodio dura entre uno y tres días, y su frecuencia es muy variable. Esta enfermedad es más frecuente entre las poblaciones mediterráneas, judíos del norte de África (no ashkenazíes), armenios, turcos y árabes. Sin embargo, en los últimos años se han reportado más casos en países no relacionados con esta área. No hay estudios epidemiológicos formales en Chile. Presentamos el caso de una paciente de ascendencia egipcia/judía, y el caso de una familia de ascendencia alemana/española, todos chilenos con semiología y evolución característica de fiebre mediterránea familiar y estudio molecular positivo heterocigoto. La falta de diagnóstico en países no mediterráneos puede deberse a la falta de conocimiento de esta enfermedad. En Chile han aumentado los casos dado el aumento de migrantes y sus descendientes, por lo que es importante tener este diagnóstico como posibilidad en caso de dolor y fiebre de origen desconocido. Por otro lado, la fiebre mediterránea familiar es principalmente de herencia autosómica recesiva, pero se han descrito variantes dominantes. Los dos casos descritos en este trabajo presentan la variante en la que la enfermedad se manifiesta en su forma heterocigota, generando una herencia autosómica dominante, lo que aumentaría el número de individuos afectados en la población.

Estudios genéticos sobre espina Bífida en Chile: por dónde comenzar?: [revisión] / Genetic studies of spina bifida in Chile: where do we start?: [review]

Neural tube defects (NTDs) are a group of congenital anomalies that affect the central nervious system. Spina Bifida (SB) is the most frecuent NTD in live births andi t is usually associated to disease, disability; and mortality. NTDs are considered as a multifactorial disease. Women who use folic acid periconceptionally are at a 50-70% reduced risk for NTD-affected pregnancies. More than 80 candidates genes to SB are been studied, someones related to folic acid metabolic pathway. MTHFR gene is the gene more studied in NTDs. Its allele 677T is asóciate to higher risk to NTD. It is important to study polymorphisms in MTHFR gene in Chile because Chilean population has dfferent ethnic origen from others previous studied populations.

Genética del cáncer de colon / Genetics of colon cancer

Colon cancer (CC) is a prevalent disease, with 800,000 new cases annually worldwide. In Chile the mortality is 6.2 per 100,000 inhabitants, which has increased in recent years, being more common in developed countries. Although, CC are most sporadic forms (70 percent), there are patients with family history (30 percent) and 10 percent have a hereditary component, with a predisposition to the formation of tumors, including CC, the most studied syndrome are: Familial Adenomatous Polyposis (FAP), Peutz-Jeghers syndrome and hereditary non-polyposis colon cancer (HNPCC).The progresses made by the human genome sequencing have allowed to known mutations in oncogenes and tumor suppressor genes that occur in a cell of the normal intestinal mucosa and lead to carcinogenic transformation. This review is an update of the known genes related to the sporadic form of the CC, as well as the most common inherited forms of CC. It is important that health professionals, be aware of developments in this area, because they are who should promote in the community a timely screening for patients with increased risk factors for CC, with the aim of giving an accurate counseling for decrease the morbidity and mortality of this condition.

Principales factores que producen fragilidad cromosómica transitoria en los pacientes referidos para estudio citogenético / Main factors that produce transitory chromosomic fragility in the patients referred for cytogenetic study

The fragile sites are specific loci that show fractures during karyotyping perform under specific laboratory conditions. Are present in normal individuals and are classified by their population frequency. These sites have been associated with an increase in chromosome fragility, fractures and other chromosomal abnormalities. In recent years, the fragile sites have taken great importance because they represent regions in the genome that are particularly sensitive to replicative stress and are frequently rearrenged in tumor cells. Multiple risk factors endogenous and exogenous have been involved in the increase in chromosome fragility, including microorganisms, drugs, illegal drugs and toxins. The fragile sites have provided insight into understanding of the effects of replicative stress on DNA damage and genomic instability in cancer cells. In this work we aim to summarize the limited information available about the topic, and the clinical significance of fragile sites in vivo in the laboratory.

[Scientific and ethical perspectives of perinatal and fetal medicine]. / Consideraciones científicas y éticas en las perspectivas diagnósticas y terapéuticas en medicina fetal.

This review emphasizes the importance of recent developments and knowledge on cell biology and human genetics than have integrated, through a basic-clinical concept to an emerging branch of medicine, called Perinatal and Fetal Medicine. We discuss the possible role of fetal cells and DNA in the diagnosis and treatment of diseases in the intrauterine environment The associated bioethical issues associated to these medical actions are discussed, considering the imminent use of these agents in the human species.

Consideraciones científicas y éticas en las perspectivas diagnósticas y terapéuticas en medicina fetal / Scientific and ethical perspectives of perinatal and fetal medicine

This review emphasizes the importance of recent developments and knowledge on cell biology and human genetics than have integrated, through a basic-clinical concept to an emerging branch of medicine, called Perinatal and Fetal Medicine. We discuss the possible role of fetal cells and DNA in the diagnosis and treatment of diseases in the intrauterine environment. The associated bioethical issues associated to these medical actions are discussed, considering the imminent use ofthese agents in the human species.

Síndrome de Cornelia de Lange / Cornelia de Lange syndrome

El Síndrome de Cornelia de Lange (SCL) es un cuadro malformativo poco frecuente, caracterizado por la presencia de retraso del crecimiento, microcefalia, retardo mental, hirsutismo, dismorfias faciales características y defectos en las extremidades. Se estima una incidencia de 1:10.000 a 1:40.000 recién nacidos vivos, siendo la mayoría casos esporádicos, aunque algunos pocos se han publicado con una herencia de tipo autosómico dominante. Existen dos genes responsables del SCL: el NIPBL, que ha sido recientemente identificado y mapeado en 5p13.1, y el SMC1L1 en Xp11.22 –p11.21, descubierto también recientemente en varios sujetos afectados y con herencia ligada al X. Mutaciones en el gen NIPBL se han encontrado en el 40 por ciento a 50 por ciento de los pacientes afectados clínicamente por el cuadro. En esta revisión presentamos el caso de una paciente de seis años de edad, con diagnóstico clínico de SCL, con el objetivo de dar a conocer esta patología malformativa, que forma parte del diagnóstico diferencial de los cuadros clínicos con retardo mental.

Cornelia de Lange Syndrome (CdLS) is a rare malformative disease. It is characterized by the presence of growth retardation, microcephaly, mental retardation, hirsutism, facial alterations and defects in the extremities. Incidence is 1:10,000 to 1:40,000 in newborns. Most cases are sporadic, although some cases have been published with autosomal dominant inheritance. Two recently identified genes are responsible for CdLS: NIPBL, located on 5p13.1, and SMC1L1, located on Xp11.22 –p11.21 and present in several affected subjects, and with X-linked inheritance. Mutations of NIPBL genes are described in 40 to 50 percent of patients. We present the case of a six year old patient, with clinical diagnosis of CdLS, with the purpose of presenting this malformative disease, which is part of the differential diagnosis of clinical manifestations associated to mental retardation.

Estudio genético de una familia chilena con tres fenotipos dentales diferentes / Genetic studies of a Chilean family with three different dental anomalies

Background: Congenital dental anomalies can affect up to 25 percent of the population. Aim: To report the genetic study of a family with dental anomalies. Material and methods: We studied a Chilean family presenting with three independent dental phenotypes: third molar agenesis, supernumerary teeth, and dentinal dysplasia type I. We searched for mutations in candidate genes proposed for tooth agenesis and supernumerary teeth: IRF6, FGFR1, MSX1, MSX2, PAX9, PRDM16 and TGFA. We also studied DSPP as a candidate gene for dentinal dysplasia type I. Results: We did not find mutations in FGFR1, MSX2, PAX9, PRDM16, or TGFA. We found a MSX1 mutation (G16D) in both affected and unaffected family members. Also, we found a genetic variation not described before in IRF6 in the dentinal dysplasia type I case. Conclusions: Further investigation is necessary to evaluate if these variants are functional in nature. Finally, we are reporting a mutation in DSPP in an asymptomatic 2-year-old child, which illustrates the ethical pitfalls of interpreting molecular data for genetic counseling of young and/or asymtomatic individuals.

[Genetic studies of a Chilean family with three different dental anomalies]. / Estudio genético de una familia chilena con tres fenotipos dentales diferentes.

BACKGROUND: Congenital dental anomalies can affect up to 25% of the population. AIM: To report the genetic study of a family with dental anomalies. MATERIAL AND METHODS: We studied a Chilean family presenting with three independent dental phenotypes: third molar agenesis, supernumerary teeth, and dentinal dysplasia type I. We searched for mutations in candidate genes proposed for tooth agenesis and supernumerary teeth: IRF6, FGFR1, MSX1, MSX2, PAX9, PRDM16 and TGFA. We also studied DSPP as a candidate gene for dentinal dysplasia type I. RESULTS: We did not find mutations in FGFR1, MSX2, PAX9, PRDM16, or TGFA. We found a MSX1 mutation (G16D) in both affected and unaffected family members. Also, we found a genetic variation not described before in IRF6 in the dentinal dysplasia type I case. CONCLUSIONS: Further investigation is necessary to evaluate if these variants are functional in nature. Finally, we are reporting a mutation in DSPP in an asymptomatic 2-year-old child, which illustrates the ethical pitfalls of interpreting molecular data for genetic counseling of young and/or asymtomatic individuals.

Displasia ectodérmica hipohidrótica: caso clínico y revisión de la literatura / Hypohydrotic ectodermal dysplasia: a clinical case and review of the literature

La displasia ectodérmica hipohidrótica (DEH) es un trastorno genético que se caracteriza por hipohidrosis, hipotricosis e hipodoncia. Comúnmente afecta a varones con una herencia recesiva ligada al X, aunque existen otras formas con herencia autosómica dominante y recesiva. Los pacientes afectados pueden presentar intolerancia al calor, fiebre, hipertermia grave e incluso muerte súbita. Objetivo: Presentan el caso clínico de un paciente portador de DEH, y actualizar el conocimiento de la etiología y medidas terapéuticas de esta patología. Caso clínico: Se reporta el caso de una niña de 7 años de edad, que presenta escaso vello, alteraciones dentarias, amastia y escasa sudoración, compatible con una DEH y una probable herencia autosómica recesiva. Se comenta su evolución y manejo clínico, junto a aspectos embriológicos, genéticos, diagnósticos y el consejo genético de esta enfermedad.

Síndrome de morquio (mucopolisacaridosis tipo IV) y embarazo / Morquio syndrome (Mucopolysaccharidosis type IV) and pregnancy

Se presenta el caso de una paciente embarazada, portadora de Síndrome de Morquio (Mucopolisacaridosis tipo IV), que evoluciona con polihidroamnios y disnea. Se comenta el manejo y resolución del caso.

Endometriosis familiar: reporte de una familia con herencia mendeliana / Family endometriosis: report of a family with mendelian inheritance

La endometriosis es una causa importante de dolor pélvico e infertilidad en las mujeres premenopáusicas. Aunque poco se conoce sobre su etiopatogenia, se considera como un trastorno multifactorial donde se conjugan elementos endocrinológicos, inmunológicos, ambientales y genéticos. El estudio de genes candidatos no ha sido exitoso en la ubicación de genes de susceptibilidad. Se reporta una familia con tres hermanas afectadas de endometriosis, se comenta su evolución y posibles implicancias genéticas.

Aplicación de técnicas de biología molecular en la investigación médica en Chile / Molecular biology techniques in clinical research in Chile

Medical investigation in Chile is beginning to applymolecular biology methods as diagnostic tools and in studies establishing the prevalence of pathologies with Mendelian or multifactorial genetic origin. In this way,we are getting nearer to the strategies used worldwide for these purposes. Two studies published in this journal, 1 about hemophilia A where an analysis of intron-18 and intron-7 of the Factor VIII gene was applied as strategy for the diagnosis of carrier state in a Chilean population and the other one, about insulin-dependent diabetes mellitus in Santiago, Chile, with an analysis from immunogenetics to some environmental risk factors, constitute good examples about this integration

Estudio de paternidad aplicando el polimorfismo de DNA: evaluación en relación a los métodos convencionalmente usados en Chile / Paternity study applying DNA polimorphism: evaluation in relation to conventional methods used in Chile

Simultaneous detection of several VNTR loci using a single DNA probe is the basis of the technique called DNA fingerprint (DNAfp) of increasing application in parenthood identification. According to the data gathered by different laboratories worldwide, father exclusion can be made in a larger number of cases when compared with the customary tests based on erythrocyte antigens. The question could then be whether DNAfp will completely replace erythrocyte antigen tests. We report here our experience in applying DNAfp to 92 samples corresponding to 34 paternity cases and comparing these with the results obtained with the antigens of the systems ABO, Rh. MNSs, Duffy and Kidd. Most of the HaeIII/digested DNA samples produced 13 to 16 bands larger than 4,3 Kb (average 14,0761ñ2,205). Average band sharing between pairs of unrelated individual was 1,907ñ1,083. Two cases presenting an a posteriori probability of being the father of 80.7 percent and 76.5 percent by erythrocyte antigens were clearly excluded by DNAfp. All exclusions made by antigens were confirmed by DNAfp. In the cases reported as father probable (28 cases) by DNAfp, these shared with the child 6,7407ñ1,7 bands on average. Because of time, cost and simplicity we favor a procedure starting with the antigens test and continuing with DNAfp only when an exclusion is not possible. Economy will increase as the number of exclussions increases

Estudio de elementos traza en embarazadas controladas en Hospital Roy H. Glover de Chuquicamata: evaluación en relación a pérdida reproductiva y aparición de malformaciones congénitas / Study of tracer elements in controlled pregnant women in Roy H. Glover Hospital from Chuquicamata: abortion and congenital abnomalities related

Los habitantes de la mina Chuquicamata, en el norte de Chile, están dispuestos al polvo, humo y otros agentes derivados de los procesos de extracción y tratamiento del mineral. Estudiando la composición de polución ambiental entre Chuquicamata y Calama, una ciudad cercana, se observaron diferencias para selenio, zinc, plomo, manganeso, fierro y cobre, los que indicaban un decaimiento del nivel a mayor distancia de la fuente emisora. El Departamento de Control de Calidad de la Corporación Nacional del Cobre ha desarrrollado técnicas para analizar concentraciones de metales en muestras orgánicas: orina, sangre, pelo, uñas, en base a dos métodos: espectrometría de emisión con fuente de plasma y absorción atómica con generación de hidruros. Diversos tejidos y líquidos corporales investigados para niveles de arsénico en madres y sus hijos recién nacidos revelaron valores más altos en los niños, especialmente en pelo y uñas. Para estudiar el impacto teratogénico de los contaminantes de esta área, buscamos una correlación entre niveles aumentados de elementos traza de las embarazadas que acudan a su control en Chuquicamata y un dsenlace patológico: pérdida reproductiva y/o presencia de malformaciones en mortinatos y recién nacidos. Se intenta establecer un diágnostico lo más preciso posible con estudio anatomopatológico, cromosómico y otros

Antecedentes perinatales en trisomía 18 / Perinatal antecedents in trisomy 18

La T:18 tiene una incidencia de uno en 3000 a uno en 8000 RN vivos. Muchos se pierden como AE o MN. Los RN afectados tienen una pobre sobrevida. Se revisan los antecedentes clínicos de 32 RN vivos con T:18, nacidos entre los años 1980 y 1994, enviados a nuestro Laboratorio para estudio cromosómico. El objetivo es describir algunas características de la gestación, parto y período de RN y lactante. El promedio de edad materna fue significativamente mas alto que el de la población general. De los RN vivos la mayoría fueron de sexo femenino. Los antecedentes prenatales más comunes fueron: PHA, RCIU, onfalocele; síntomas de aborto o parto prematuro. Más del 50 por ciento nacieron por cesárea. Tenían presentación podálica cuatro de seis. El Apgar al minuto fue bajo tres en más del 50 por ciento de los RN vivos. Trece de 21 fueron prematuros y 50 por ciento fueron (PEG). Las malformaciones más frecuentes fueron las cardíacas, las gastrointestinales y las genitourinarias. La sobrevida promedio fue de 52 días. Damos énfasis en la importancia del diagnóstico temprano de la T:18 para que de este modo los padres y neonatólogos tomen las decisiones adecuadas en relación al manejo

Alteraciones cromosómicas en niños referidos para estudio citogenético / Chromosomal abnormalities in children submited for cytogenetic study

Entre los años 1981 y 1993 se realizaron 1.473 cariogramas en pacientes de 0 a 15 años en un centro de estudios citogenéticos de la Universidad de Chile. Los diagnósticos de referencia fueron síndrome de Down (30,8 por ciento), malformaciones múltiples (19,1 por ciento), retraso psicomotor (10,5 por ciento), síndrome de Turner (9,3 por ciento), alteraciones del desarrollo sexual (7,6 por ciento), talla baja (7,1 por ciento), trastornos del desarrollo de lenguaje (2 por ciento) y síndromes diversos (14,9 por ciento). El rendimiento del examen varía según la categoría clínica del diagnóstica: síndrome de Down (94 por ciento), malformaciones múltiples (24,8 por ciento), retraso psicomotor (13,4 por ciento), síndrome de Turner (56,9 por ciento), alteraciones del desarrollo sexual (13,4 por ciento), trastornos del lenguaje (10 por ciento) síndromes diversos (9,1 por ciento). El estudio cromosómico permite comprobar una hipótesis clínica estableciendo el diagnóstico o si da resultados normales, puede obligar a estudiar otras etiologías, no cromosómicas, que expliquen los tratornos del paciente. El objetivo final es contribuir al consejo genético óptimo para la familia afectada