RESUMEN

BACKGROUND AND AIMS: Rhabdomyosarcoma (RMS) is a pediatric tumor whose classification is based on histological criteria according to two main subgroups, embryonal RMS (ERMS) and alveolar RMS (ARMS). The majority but not all ARMS carry the specific PAX3(7)/FKHR translocation. The type of translocation in patients with ARMS defines the prognosis. METHODS: We retrospectively analyzed 30 cases of ARMS in Mexican patients and evaluated the fusion status of the genes using RT-PCR and fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissues (FFPET). RESULTS: From 25 samples (83%) with optimal RNA quality, RT-PCR revealed 15 cases (50%) with the t(2;13)/PAX3-FKHR. Only one case (3%) was positive to t(1;13)/PAX7-FKHR and nine cases (30%) were fusion-negative. Correspondingly, using FISH, the t(2;13)/PAX3-FKHR was found positive in 19 cases (63.5%), one case (3%) revealed the t(1;13)/PAX7/FKHR and ten cases (33.5%) were fusion-negative by this method. Five cases were not evaluable by RT-PCR but recovered by FISH. Only four of the total revealed t(2;13); the other was fusion-negative. CONCLUSIONS: FISH technique is more sensitive when FFPET is used to describe the chromosomal translocation of ARMS. These Latino patients showed an association of the t(2;13) in older patients (mean: 9 years) and negative translocation in younger patients (mean: 4 years) (p <0.05). Both t(2;13) and negative-fusion were present in patients with clinical stages III and IV (p <0.05). There was a nonsignificant trend of t(2;13) to lower overall survival than negative-fusion status.

Asunto(s)

Hibridación Fluorescente in Situ/métodos , Proteínas Recombinantes de Fusión/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Rabdomiosarcoma/genética , Niño , Formaldehído , Humanos , Estimación de Kaplan-Meier , México , Adhesión en Parafina , Estudios Retrospectivos , Rabdomiosarcoma/clasificación , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/patología

RESUMEN

There are limited data on mitochondrial DNA (mtDNA) variation in the Mexican mestizo population. To examine the genetic diversity and matrilineal ancestry, the full mtDNA hypervariable regions I and II were sequenced in 270 unrelated mestizos from different regions of Mexico. A total of 202 different haplotypes were identified and the haplotype diversity was 0.9945. Amerindian haplotypes predominated in the sample with a proportion of 93.3%, followed by European (6.0%) and African haplotypes (0.7%). The frequency of the Amerindian haplogroups A2, B2, C1 and D1 was 51.1, 17.8, 18.5 and 5.9%, respectively. The frequency of Amerindian haplogroups was higher in the central region than in Mexico City, whereas it was the contrary for European haplogroups. This difference was accounted principally by the high frequency of B2 haplotypes in the central region. The minimum spanning network, the mismatch distribution and Tajima's D neutrality test suggest a population expansion for each Amerindian haplogroup, which could be initiated more recently for haplogroups A2 and D1. The present knowledge combined with other nuclear genetic markers will be essential in future association studies to correct for genetic substructure in mestizo populations.

Asunto(s)

ADN Mitocondrial/genética , Variación Genética , Haplotipos , Indígenas Norteamericanos/genética , Población Negra/genética , ADN Mitocondrial/química , ADN Mitocondrial/clasificación , Frecuencia de los Genes , Genética de Población , Geografía , Humanos , México , Filogenia , Análisis de Secuencia de ADN , Población Blanca/genética

RESUMEN

17alpha-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene. This condition shows considerable clinical and biochemical variation. Molecular characterization of novel mutations in the CYP17A1 gene and detailed study of their structural, enzymatic, and clinical consequences are required to fully understand enzyme behavior. Here, we present the first molecular characterization of two novel mutations in CYP17A1 in a 15-year-old female Mexican mestizo 46,XY female with primary amenorrhea and lack of pubertal development and severe hypertension that manifested only after surgery. A complete clinical and biochemical evaluation was compatible with 17OHD. Structural anomalies in the CYP17A1 gene were discovered by direct automated sequencing, which revealed a novel compound heterozygous K110X/R362H mutation that leads to a complete lack of enzyme activity. Immunohistochemical analyses performed to determine protein expression and localization showed that cytochrome P450 17A1 was completely absent in the patient's testicular tissue. Studies of novel mutations, such as those described here, provide important information that allows us to better understand the effect of a given mutation on enzyme function and to observe the impact of the mutation on clinical phenotype.

Asunto(s)

Hiperplasia Suprarrenal Congénita/enzimología , Mutación , Esteroide 17-alfa-Hidroxilasa/genética , Acantosis Nigricans/diagnóstico , Adolescente , Hiperplasia Suprarrenal Congénita/diagnóstico , Hormona Adrenocorticotrópica , Secuencia de Bases , ADN/sangre , ADN/química , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Disgenesia Gonadal/enzimología , Disgenesia Gonadal/genética , Heterocigoto , Humanos , Hidrocortisona/sangre , Hormona Luteinizante/sangre , Masculino , Fenotipo , Pubertad , Testículo/enzimología , Testosterona/sangre

RESUMEN

Gonadoblastoma (GB) is an in situ tumor consisting of a heterogeneous population of mature and immature germ cells, other cells resembling immature Sertoli/granulosa cells, and Leydig/lutein-like cells, may also be present. GB almost exclusively affects a subset of patients with intersex disorders and in 30% of them overgrowth of the germinal component of the tumor is observed and the lesion is term dysgerminoma/seminoma. Several pathways have been proposed to explain the malignant process, and abnormal OCT3/4 expression is the most robust risk factor for malignant transformation. Some authors have suggested that OCT3/4 and beta-catenin might both be involved in the same oncogenic pathway, as both genes are master regulators of cell differentiation and, overexpression of either gene may result in cancer development. The mechanism by which beta-catenin participates in GB transformation is not completely clear and exploration of the E-cadherin pathway did not conclusively show that this pathway participated in the molecular pathogenesis of GB. Here we analyze seven patients with mixed gonadal dysgenesis and GB, in an effort to elucidate the participation of beta-catenin and E-cadherin, as well as OCT3/4, in the oncogenic pathways involved in the transformation of GB into seminoma/dysgerminoma. We conclude that the proliferation of immature germ cells in GB may be due to an interaction between OCT3/4 and accumulated beta-catenin in the nuclei of the immature germ cells.

Asunto(s)

Cadherinas/fisiología , Disgerminoma/etiología , Disgenesia Gonadal Mixta/complicaciones , Gonadoblastoma/etiología , Factor 3 de Transcripción de Unión a Octámeros/fisiología , Neoplasias Ováricas/etiología , Neoplasias Testiculares/complicaciones , beta Catenina/fisiología , Adolescente , Transformación Celular Neoplásica , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Masculino

RESUMEN

PURPOSE: To describe the molecular defects in the Norrie disease protein (NDP) gene in two families with Norrie disease (ND). METHODS: We analysed two families with ND at molecular level through polymerase chain reaction, DNA sequence analysis and GeneScan. RESULTS: Two molecular defects found in the NDP gene were: a missense mutation (265C > G) within codon 97 that resulted in the interchange of arginine by proline, and a partial deletion in the untranslated 3' region of exon 3 of the NDP gene. Clinical findings were more severe in the family that presented the partial deletion. We also diagnosed the carrier status of one daughter through GeneScan; this method proved to be a useful tool for establishing female carriers of ND. CONCLUSION: Here we report two novel mutations in the NDP gene in Mexican patients and propose that GeneScan is a viable mean of establishing ND carrier status.

Asunto(s)

Ceguera/congénito , Proteínas del Ojo/genética , Pérdida Auditiva Sensorineural/genética , Discapacidades para el Aprendizaje/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia , Niño , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Tamización de Portadores Genéticos , Heterocigoto , Humanos , Masculino , Biología Molecular , Linaje , Reacción en Cadena de la Polimerasa , Retina/anomalías

RESUMEN

We report a Mexican boy with isolated ectrodactyly (split hand malformation) in whom a new mutation was identified in exon 3 of the TP63 gene. In contrast to previously reported patients with isolated split hand/foot anomaly and mutations in the DNA binding domain of Tp63, the mutation described herein induce an amino acid substitution (R97C) in the canonical transactivation (TA) domain. To our knowledge, this is the first naturally occurring mutation described so far in this part of the protein. Based on the genotype-phenotype correlation observed in our patient, we hypothesize that integrity of the TA domain of Tp63 is critical for normal limb development.

Asunto(s)

Deformidades Congénitas de la Mano/genética , Mutación Missense , Fosfoproteínas/genética , Transactivadores/genética , Secuencia de Bases , Sitios de Unión/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Genes Supresores de Tumor , Deformidades Congénitas de la Mano/patología , Heterocigoto , Humanos , Lactante , Masculino , Factores de Transcripción , Activación Transcripcional/genética , Proteínas Supresoras de Tumor

RESUMEN

Gonadoblastoma is an unusual mixed germ cell-sex cord-stromal tumor that has the potential for malignant transformation and 30% of all patients with gonadoblastoma develop germ cell tumors mainly dysgerminoma/seminoma. An additional 10% gives rise to other malignant germ cell neoplasms. This tumor affects a subset of patients with intersex disorders. The age at diagnosis is variable ranging from birth to the fourth decade, but around 94% of cases are diagnosed during the first three decades of life and there are few cases with gonadoblastoma diagnosed in infants. In this paper, we present the histological and molecular findings of four patients with gonadal dysgenesis who developed gonadoblastoma in the first 2 years of life and one case with bilateral dysgerminoma diagnosed at 15 years of age. The sex chromosomes of mosaic patients do not distribute homogenously in dysgenetic gonads; however, statistical analysis of FISH results revealed significant differences between the XY cell line in the gonadoblastoma compared with the dysgenetic testis. Our cases demonstrate that tumors could be present at a very early age, so the prophylactic removal of the gonads is advised.

Asunto(s)

Cromosomas Humanos Y/genética , Disgenesia Gonadal Mixta/genética , Gonadoblastoma/patología , Neoplasias Ováricas/patología , Neoplasias Testiculares/patología , Testículo/anomalías , Adolescente , Preescolar , Femenino , Disgenesia Gonadal Mixta/patología , Gonadoblastoma/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Neoplasias Ováricas/genética , Neoplasias Testiculares/genética

RESUMEN

In the year 2002, the population of Mexico was approaching 103 million inhabitants. Approximately 74% of them live in the cities with a continuous migration from rural to urban areas. Genetic departments are concentrated in the capital and other big cities. In this paper we review the current status of genetic departments in Mexico City, emphasizing the main areas of genetic services offered to the public and involved in research. We also comment on the deficiencies identified and suggest recommendations to improve the quality of the genetic services offered to the Mexican population.

Asunto(s)

Servicios Genéticos/organización & administración , Anomalías Congénitas/prevención & control , Atención a la Salud/organización & administración , Atención a la Salud/normas , Enfermedades Genéticas Congénitas/prevención & control , Servicios Genéticos/ética , Servicios Genéticos/normas , Empleos en Salud/educación , Humanos , México

RESUMEN

The World Health Organization sponsored a Consultation on Community Genetic Services and a Regional Network of Medical Genetics in Latin America in Porto Alegre, Brazil, on June 19, 2003. The main recommendations of the meeting included: (a) the call for government funding of services, research and education in medical genetics; (b) the conduct of epidemiological research on the prevalence and types of birth defects, genetic disorders and genetic predispositions to common diseases; (c) the education of health professionals in genetics; (d) the education of genetic professionals in community health and public health genetics; (e) the fostering of interactions between clinical geneticists, public health personnel, primary health care workers and community organizations, and (f) a better planning of regionalized services to avoid duplication and inefficiency.

Asunto(s)

Servicios Genéticos/normas , Genética Médica/normas , Guías como Asunto , Organización Mundial de la Salud , Redes Comunitarias , Servicios Genéticos/organización & administración , Técnicas Genéticas , Pruebas Genéticas , Genética Médica/organización & administración , Humanos , América Latina

RESUMEN

Sex differentiation in humans depends on the presence of the Y-linked gene SRY, which is activated in the pre-Sertoli cells of the developing gonadal primordium to trigger testicular differentiation. Occasionally testicular formation can take place in subjects lacking a Y chromosome resulting in a 46,XX sex reversal condition. True hermaphroditism (TH) is a rare form of intersexuality characterized by the presence of testicular and ovarian tissue in the same individual. Genetic heterogeneity has been proposed as a cause of dual gonadal development in some cases and recently, hidden mosaicism was reported to cause TH in some 46,XX SRY negative patients. Here we report a TH case in which hidden mosaicism for the Y and X chromosome was detected by PCR and FISH in peripheral blood and gonadal tissue, supporting the fact that mosaicism may cause TH and that molecular analysis of gonadal tissue should be performed in all 46,XX cases.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Trastornos del Desarrollo Sexual/genética , Mosaicismo , Aberraciones Cromosómicas Sexuales , Niño , Femenino , Genes sry/genética , Genitales Femeninos/anomalías , Genitales Femeninos/cirugía , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Testículo/anomalías , Testículo/cirugía

RESUMEN

INTRODUCTION: Müllerian agenesis, also named the Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) or vaginal aplasia, is the second most common cause of primary amenorrhea. It is characterized by the congenital absence of the Müllerian structures including the Fallopian tubes, the uterus, and the internal portion of the vagina in an otherwise normally feminized 46,XX subject. Most cases are sporadic in inheritance, but the occurrence of some patients with chromosomal translocations or even familial aggregates suggest a genetic basis for the disease, although the etiology of the disease is still unknown. It has been suggested that activating mutations in the anti-Müllerian hormone (AMH) or in its receptor (AMHRII) are potential sources for the defect. METHODS: In this study we describe the molecular analysis of both the AMH and AMHR genes in a group of 15 patients with Müllerian agenesis. After sequencing all exons and exon/intron junctions of both genes, we were not able to detect any deleterious mutation. RESULTS: Five new polymorphisms, 2 of them in the AMHRII gene and 3 of them in the AMH gene, were identified. No significant differences between patients and controls were observed in the frequency of a given polymorphism. CONCLUSION: This work reinforces the view that molecular defects in the AMH or AMHR are unlikely sources for the MRKHS syndrome.

Asunto(s)

Trastornos del Desarrollo Sexual/genética , Conductos Paramesonéfricos/anomalías , Hormona Antimülleriana , Estudios de Casos y Controles , Femenino , Glicoproteínas/genética , Humanos , Polimorfismo Genético , Receptores de Péptidos/genética , Receptores de Factores de Crecimiento Transformadores beta , Síndrome , Hormonas Testiculares/genética , UTP-Hexosa-1-Fosfato Uridililtransferasa/genética

RESUMEN

True hermaphroditism (TH) is an unusual form of sex reversal, characterized by the development of testicular and ovarian tissue in the same subject. Approximately 60% of the patients have a 46,XX karyotype, 33% are mosaics with a second cell line containing a Y chromosome, while the remaining 7% are 46,XY. Molecular analyses have demonstrated that SRY is present in only 10% of TH with a 46,XX karyotype; therefore, in the remaining 90%, mutations at unknown X-linked or autosomal sex determining loci have been proposed as factors responsible for testicular development. True hermaphroditism presents considerable genetic heterogeneity with several molecular anomalies leading to the dual gonadal development as SRY point mutations or SRY hidden gonadal mosaicism. In order to identify genetic defects associated with subjects with the disease, we performed molecular analyses of the SRY gene in DNA from blood leukocytes and gonadal tissue in 12 true hermaphrodites with different karyotypes. Our results using PCR and FISH analyses reveal the presence of hidden mosaicism for SRY or other Y sequences in some patients with XX true hermaphroditism and confirms that mosaicism for SRY limited to the gonads is an alternative mechanism for testicular development in 46,XX true hermaphrodites.

Asunto(s)

Cromosomas Humanos Y/genética , Trastornos del Desarrollo Sexual/genética , Genes sry , Mosaicismo , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Reacción en Cadena de la Polimerasa , Diferenciación Sexual/genética

RESUMEN

La discordancia entre el sexo cromosómico y gonadal-fenotípico se conoce como reversión sexual (varones XX y mujeres XY). Un ejemplo es la disgenesia gonadal pura 46,XY que se caracteriza por fenotipo femenino, amenorrea primaria y ausencia de caracteres sexuales secundarios. En la forma completa existen estrías fibrosas bilaterales y en las formas parciales el fenotipo depende del grado del daño testicular. Una explicación plausible para esta patología son mutaciones en el gen SRY que interfieren con el desarrollo testicular. Sin embargo sólo 10-15 por ciento de las pacientes con disgenesia gonadal XY completa presentan mutaciones o deleciones en SRY, particularmente en la caja HMG. El resto de los casos son probablemente resultado de mutaciones en genes autosómicos o ligados al X que también participan en la cascada de diferenciación sexual. En los últimos años se reconocía que mutaciones en genes responsables de síndromes genéticos bien definidos, tales como WT1, SOX9, DSS y SF1, resultan en reversión sexual. Estos datos muestran la heterogeneidad genética y la variabilidad clínica de la reversión sexual XY y permiten reconocer la participación y la jerarquía de cada uno de estos genes en la cascada de la diferenciación sexual

Asunto(s)

Humanos , Masculino , Femenino , Heterogeneidad Genética , Variación Genética , Disgenesia Gonadal 46 XY/genética , Diferenciación Sexual

Asunto(s)

Conocimientos, Actitudes y Práctica en Salud , Medicina , Genética

RESUMEN

La revisión sexual 46, XX es un estado patológico poco frecuente, genéticamente heterogéno, que se caracteriza por la presencia de desarrollo testicular en ausencia de cromosoma Y. Clínicamente, los pacientes pueden ser categorizados en tres tipos: varones XX con genitales normales, varones XX con ambigüedad genital y hermafroditas verdaderos con tejido ovárico y testicular y genitales anormales. En este trabajo se estudiaron cinco pacientes con revisión sexual 46,XX. El diagnóstico clínico, endocrinológico y ultrasonográfico en tres individuos correspondió a varones XX y en los dos restantes a hermafroditismo verdadero. El análisis del gen determinante testicular (SRY) en DNA genómico reveló la presencia de éste en dos varones XX, en cambio el tercero y los dos hermafroditas verdaderos fueron SRY-negativos. Los datos moleculares confirman que el desarrollo testicular en la mayoría de los varones 46,XX se debe a la presencia del gen SRY en el genoma de estos sujetos. Los pacientes SRY-negativos, un varón XX y dos hermafroditas verdaderos, sugieren que en estos casos la diferenciación testicular es consecuencia de mutaciones en genes autosómicos o ligados al X que participan en la cascada que conduce a la diferenciación sexual

Asunto(s)

Humanos , Masculino , Femenino , Lactante , Preescolar , Adulto , Aberraciones Cromosómicas Sexuales/etiología , Trastornos del Desarrollo Sexual , Trastornos del Desarrollo Sexual/diagnóstico , Trastornos del Desarrollo Sexual/fisiopatología , Cromosoma Y , Ultrasonografía , Análisis Mutacional de ADN , Genética

RESUMEN

In this report we show the chromosomal changes seen in a group of 303 Mexican patients with de novo Acute myeloblastic Leukemia (AML). Two hundred forty-two patients were diagnosed and treated at two hospitals affiliated with the Instituto Mexicano del Seguro Social (IMSS). These are the Centro Medico Nacional Siglo XXI and Centro Medico La Raza Hospitals; the remaining 61 patients were diagnosed and treated at the Hospital General de Mexico (HGM). Clonal abnormalities were detected in 75.6 percent of the patients; this result agrees with what has been reported in other large series of AML studies. The incidence of changes per hospital was similar in patients from the IMSS hospitals (72-75 percent), while an increase was seen in patients from the HGM (85.2 percent). The cromosomal changes seen in this study in order of frequency were: t(15;17)[18.8 percent], t(9;22)[9.2 percent], miscellaneous chromosomal changes (mainly rearrangementa of chromosomes 1,2,3,12 y 17) [8.2 percent], abnormalities of 16q22 [7.3 percent], t(8;21)[6.3 percent], -7/del(7q)[5.6 percent], t(6;9)[5.3 percent), and abnormalities of 11q23 [4.6 percent]. We reported an increase in the indicidence of certain types of chromosomal changes seen in cases of AML, in comparison with reports from other countries. These differences must not be disregarded. We support this finding when comparing distribution of changes in the population of patients seen in the IMSS hospitals with those from the HGM; the main difference lies in the socioeconomic level

Asunto(s)

Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 17/ultraestructura , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , México/epidemiología , Cromosoma Filadelfia

RESUMEN

Objetivo. Evaluar si el interferón-alfa humano recombinante (IFN), combinado con quimioterapia, suprime la clona portadora del cromosoma Filadelfia en pacientes con leucemia mieloide crónica (LMC). Material y métodos. Se estudiaron 53 pacientes con LMC en fase crónica de novo. Los pacientes recibieron uno de tres esquemas de tratamiento: a) inducción a la remisión con daunorrubicina, vincristina, arabinósido de citosina y prednisona (DOAP) y mantenimiento con IFN (n = 12); b) inducción con busulfán (BUS) o hidroxiurea (HIDX) siguiendo el mantenimiento con IFN (n = 26); c) inducción con DOAP y mantenimiento con BUS (n = 15). Resultados. La remisión hematológica se observó dos a seis meses después del inicio de tratamiento: 10 tuvieron remisión completa, seis parcial, 14 menor y 23 nula. Los 16 con respuesta completa o parcial recibieron IFN. Ninguno de los 15 casos mantenidos con BUS tuvo respuesta parcial o completa. La proporción de casos con respuesta citogenética completa (3/12) fue ligeramante menor en los tratados con quimioterapia intensiva (DOAP/IFN) que en aquéllos (7/26) de quimioterapia convencional (BUS/HIDX/IFN). Conclusiones. Nuestros resultados muestran que: a) el IFN en combinación con quimioterapia contribuyó a lograr respuesta citogenética parcial o completa en 30 por ciento de los casos; y b) la quimioterapia (DOAP) combinada con IFN no fue superior, en términos de respuesta citogenética, al tratamiento combinado de monodrogas (Bus/Hidx) con IFN

Asunto(s)

Humanos , Masculino , Femenino , Citogenética , Quimioterapia Combinada , Interferón Tipo I , Interferón Tipo I/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Cromosoma Filadelfia , Inducción de Remisión

Asunto(s)

Adulto , Factores de Edad , Aberraciones Cromosómicas/genética , Enfermedades Genéticas Congénitas/genética , Genética Médica/métodos , Mutación/genética , Trastornos del Desarrollo Sexual/genética

Asunto(s)

Diferenciación Sexual/genética , Trastornos del Desarrollo Sexual/genética , Síndrome de Turner/genética , Cromosoma Y/fisiología