Frecuencia de la mutación 185delAG en el gen BRCA1 en mujeres chilenas sanas con antecedentes familiares de cáncer de mama / Frequency of the 185delAG mutation in the BRCA1 gene in chilean healthy women with family history of breast cancer

Background: Breast cancer is the most common malignancy among women, and is the second cause of cancer mortality among Chilean women. Female mortality due to breast cancer in Chile has shown a steady increase from 9.5 deaths per 100.000 women in 1985 to 12.8 deaths per 100.000 in 1995. A family history of breast cancer is one of the main risk factors for the development of the disease. BRCA1 and BRCA2 are two major hereditary breast cancer susceptibility genes. Mutations in these genes are associated to inherited breast cancer; 664 predisposing mutations have been described, but in specific populations only some of them, such as 185delAG have been found to be associated with susceptibility to breast cancer. Aim: To establish the frequency of the 185delAG mutation in the BRCA1 gene in Chilean healthy women with a family history of breast cancer. Patients and Methods: The 185delAG mutation was studied by mismatch polymerase chain (PCR) reaction in 382 Chilean healthy women with at least two relatives affected with breast cancer. The PCR products were digested with the restriction enzyme HinfI. Digestion of the normal allele (170 pb fragment) produces a 150 pb fragment; the PCR product for the mutant allele does not contain a site for HinfI and therefore remains as a 170 bp fragment after digestion. Results: One of the 382 healthy women presented the fragment of 170 pb after digestion with HinfI suggesting that she was heterozygous carrier for this mutation. The mutant patient had a mammography without suspicion of cancer. Conclusions: The frequency of the 185delAG mutation in BRCA1 was 0.26 percent (1/382) in Chilean healthy women with a family history of breast cancer

Síndrome de X frágil: análisis clínico en 300 pacientes con retardo mental inespecífico en la población chilena / Fragile X syndrome: clinical analysis of 300 Chilean patients with unspecific mental retardation

Background: Fragile X syndrome is the most important cause of sex linked mental retardation and the second of chromosomal origin, after Down syndrome. Aim: To apply the modified Hagerman score to patients with mental retardation and to relate clinical findings with cytogenetic and molecular diagnosis. Patients and methods: The modified Hagerman score was applied to 214 male and 86 female patients with mental retardation. The clinical variables in non fragile X and fragile X cases, determined by molecular and cytogenetic methods, were compared. Results: The score in 210 non fragile X males was 10.5 + 3.7 (range 3 23), compared to 21.4 + 2.1 (range 19 to 23) in the four fragile X patients. All fragile X patients had mental retardation, attention deficits, hyperactivity disorders, hand biting and poor visual contact. Hand biting, flapping and persevering speech were observed in a significantly higher number of fragile X males. Only one of 86 females had fragile X syndrome. Her most relevant findings were a long face and high forehead, an attention deficit, hyperactivity and poor visual contact. No clinical differences with other mentally retarded females were found. Condusions: Approximately 5 percent of institutionalized males with mental retardation have a fragile X syndrome

Pesquisa molecular y clínica del síndrome de X-frágil en 300 pacientes con retardo mental inespecífico / Clinical and metabolic screening for fragile X syndrome in 300 patients with unspecific mental retardation

Background: Fragile X syndrome is the most freqent cause of mental retardation linked to the X chromosome. In the majority of cases, the mutation responsible for the syndrome is an expansion of the trinucleotide repeat (CGG)n, present in the 5' region of exon 1 of the gene for mental retardation associated with fragile X syndrome (FMR-1). Aim: To report the results of a fragile X screening in patients with mental retardation. Patients and methods: Fragile X screening using polymerase chain reaction methods was done in 386 X chromosomes from 300 patients (214 male), aged 4 to 26 years old. The modified Hagerman test was applied to male patients. Hybridization techniques were applied in a subgroup of 51 patients. Results: (CGG)n 30 was the allele found with the highest frequency in 50.2percent of patients. (CGG)n 29 was found in 29percent of patients. One subject had an allele with 46 CGG repeats, which corresponds to the gray zone. Hybridization studies were highly concordant with PCR, detecting four males with fragile X syndrome and a carrier female. The average clinical score of mental retardation not due to fragile X syndrome was 10.3 ñ 3.4 (range 3 to 23), and 97percent of males had a score below 19. The concordance between scores over 20 and molecular genotype was 98percent. Conclusions: The distribution of (CGG)n repeats, observed in this study, was significantly different to that previously reported for a normal Chilean population. The dispersion of molecular status and clinical score was lower than previously described using cytogenetic techniques

La variación genética de MSX1 presenta un dimorfismo sexual en la fisura labiopalatina no sindrómica en la población chilena / Genetic variation of MSX1 has a sexual dimorphism in non syndromic cleft palate in the Chilean population

Background: Recent studies in mice have demonstrated that the Msx-1 homebox gene is implicated in cleft palate. Thus, it has been suggested that its human homologue, MSX1 (HOX-7), located in chromosome 4 could be involved in the etiology of non syndromic cleft lip palate. Aim: To study the linkage between non syndromic cleft palate and variations of MSX1 gene. Patients and methods: Seventy three patients with non syndromic cleft lip palate (34 simplex and 37 multiplex), 127 unaffected relatives of the cases (61 relatives of simplex cases and 66 relatives of multiplex cases) and 77 controls were studied. DNA was extracted from leukocytes and the intragenic microsatellite sequence was amplified by PCR. Results: A polymorphism of four alleles was observed, 1 (175 bp), 2 (173 bp), 3 (171 bp) and 4 (169 bp). Alleles 2 and 4 showed a joint variation in males with multiplex cleft lip palate and in their respective unaffected male relatives, that was significant when compared with male controls. Instead, the joint variation of alleles 1 and 4 of unaffected female relatives had significant differences with female controls. Females with multiplex cleft lip palate differed from female controls only in allele 1. Conclusions: These results support the hypothesis of a genetic heterogeneity in the etiology of non syndromic cleft lip palate

Asociación entre la variación genética de MSX1 (Hox-7) y la fisura labiopalatina no sindrómica en población chilena / Association between the genetic variation of MSX1 (Hox-7) and non syndromic cleft lip palate in chilean subjects

Background: Homeotic genes have regulatory functions during development. It has been postulated that the human Msx-1 homeotic gene can be involved in the etiology of non syndromic cleft lip palate, since its homologous Msx-1 is involved in cleft palate of mice. Aim: To perform an association analysis between the genetic variation of Msx-1 and non syndromic cleft lip palate in Chilean subjects. Patients and methods: Seventy patients with non syndromic cleft lip palate, 136 healthy relatives of these patients and 69 non related normal individuals were studied. CA microsatellite in Msx- gene, that was amplified with PCR, was studied. Results: No differences in the genetic frequencies of Msx-1 alleles, were observed in the three groups studied. Allelic heterogeneity for allele 2 seems to be related to cases of non syndromic cleft lip palate from multiplex families and heterogeneity for allele 3 is related with simplex families cases. Conclusions: These results seem to support the hypothesis of genetic heterogeneity in the etiology of non syndromic cleft lip palate

Aspectos genético moleculares del síndrome de X-frágil / Molecular and genetic features of fragile X syndrome

The fragile X syndrome is the most frequent cause of sexlinked mental retardation. In the majority of the cases the mutation responsible for the Martin Bell syndrome is produced when an expansion of the (CGG)n repetition is present in the region 5' of the exón 1 of the gene for X-fragile mental retardation 1 (FMR1), together with a hipermethylation in the CpG promoter region of the gene. The result of this situation is the absence of the FMRP protein coded by the gene. The correlation between length of the (CGG)n sequences and the X-fragile phenotype has permitted a more precise diagnosis of affected and carrier individuals by means of direct DNA analysis. Neverthless the molecular genetic basis of the instability and expansion of the (CGG)n sequences represents a problem not yet resolved. Two morphologic microsatellite (AC)n repetitions, FRAXAC1 and FRAXAC2 that flanck the FMR-1 gene have been recently described. It has been suggested that some haplotypes of FRAXAC1 and FRAXAC2 could be associated to long (CGG)n repetitions and thet these haplotypes would confer more instability to the repeated fragment thus increasing the probability of expansion. It has also been described that the (CGG)n repetition of the FMR-1 gene is interrupted by AGG trinucleotides and that the loss of one AGG would be an important mutational event in the generation of predisposing unstable alleles of the X-fragile syndrome

Tiempos de la erupción dentaria temporal en pacientes con síndrome de Down / Time of temporal dental eruption in patients with Down's syndrome

Se examinaron 255 pacientes con síndrome de Down que asisten a escuelas especiales de Santiago, Chile, con el propósito de describir los tiempos de erupción para la dentición decidual y compararlos con los de la población normal. En los niños con síndrome de Down se observa retraso significativo en la erupción de los siguientes dientes: el incisivo central derecho (15,27 ñ 5,515 meses) y los incisivos laterales derecho e izquierdo (18,44 ñ 9,652 y 18,15 ñ 11,82 meses) y los caninos derecho e izquierdo (25,87 ñ 7,667 y 26,65 ñ 7,431 meses, respectivamente) en el maxilar inferior. Las niñas con síndrome de Down presentan retraso significativo en la erupción de los incisivos laterales derecho e izquierdo (17,31 ñ 14,42 y 17,31 ñ 14,42 meses, respectivamente), los caninos derecho e izquierdo (30,70 ñ 6,454 y 30,60 ñ 7,249 meses, respectivamente, y el primer molar izquierdo 25,87 ñ 14,34 meses) en el maxilar superior; el incisivo central izquierdo (12,02 ñ 7,286 meses), los incisivos laterales derecho e izquierdo (27,59 ñ 10,01 y 24,66 ñ 23,86 meses, respectivamente), los caninos derecho e izquierdo (27,83 ñ 11,25 y 28,80 ñ 10,60 meses, respectivamente) y el segundo molar derecho (28,83 ñ 3,454 meses) en el maxilar inferior. La secuencia de erupción en los niños con s. de Down fue similar a la observada en los normales. Las edades de erupción mostraron una distribución gaussiana y las varianzas existentes en el grupo con s. de Down fueron significativamente superiores a las de los normales

Síndrome X frágil: estudio clínico citogenético y molecular en una familia chilena / Fragile X syndrome: cytogenetical clinic and molecular study in a chilean family

El síndrome del cromosoma X-frágil es la causa más frecuente de retardo mental hereditario en el varón y se asocia a un marcador citogenético ubicado en la banda Xq 27.3 (FRAXA) del cromosoma X. Durante muchos años el diagnostico estuvo basado en la identificación citogenética del marcador; sin embargo, este método no ha resultado confiable para el diagnóstico prenatal y la detección de portadores masculinos o femeninos clínicamente normales. El descubrimiento de las bases moleculares de este síndrome ha permitido desarrollar sondas que posibilitan la identificación confiable de los afectados y los portadores por análisis directo del ADN. Se describen los resultados de un estudio clínico, citogenético y molecular en la familia de una probando X frágil. En el afectado un varón de 2 años 4 meses con retraso mental y dismorfias se comprobó un sitio X frágil, pero su madre y una tía no tenían signos clínicos y sitio frágil. El análisis molecular mostró, en el paciente, una banda de 6,5 Kb, que indicaba la presencia de la mutación causal, mientras la madre exhibía dos bandas, una de 5,2 y otra de 6,0 Kb, que la identifican como heterocigota. En contraste, la tía presentó una sola banda de 5,2 Kb característica de los individuos normales

Cronología de la erupción dentaria permanente en pacientes con síndrome de Down / Chronology of the eruption of the permanent dentition in patients with Down's syndrome

Se examinaron 240 pacientes con síndrome de Down, que asisten a escuelas especiales de Santiago de Chile, con el propósito de determinar la cronología de erupción de la dentición de definitiva y compararla con el patrón de erupción de la población chilena normal. Los niños con síndrome de Down presentan en el maxilar superior e inferior un retraso significativo de la erupción de algunos dientes; éstos son los siguientes: en el maxilar superior, el primer molar derecho (85,35 ñ 20,03 meses) e izquierdo (87,41 ñ 22,37 meses), primer y segundo premolar izquierdo (161,60 ñ 60,43 y 172,10 ñ 79,57 meses, respectivamente) y canino izquierdo (163,72 ñ 81,55 meses). En el maxilar inferior, el primer molar derecho (90,98 ñ 24,52 meses), el incisivo central derecho e izquierdo (84,26 ñ 21,38 y 84,59 ñ 17,72 meses, respectivamente), el incisivo lateral derecho e izquierdo (101,89 ñ 23,79 y 117,53 ñ 83,02 meses, respectivamente) y el canino izquierdo (147,57 ñ 41,54 meses). Las niñas con síndrome de Down presentan en el maxilar superior e inferior retraso significativo en la erupción de los siguientes dientes: en el maxilar superior, los segundos molares derecho e izquierdo (172,71 ñ 83,02 y 191,88 ñ 55,90 meses, respectivamente) y el primer molar izquierdo (84,48 ñ 19,65 meses). En el maxilar inferior, segundo molar y primer premolar derechos (163,30 ñ 59,31 y 131,07 ñ 21,94 meses, respectivamente) y ambos incisivos laterales derecho e izquierdo (102,27 ñ 52,86 y 112,87 ñ 73,47 meses, respectivamente). La secuencia de la erupción dentaria superior e inferior en niños con síndrome de Down comparada con la de la población normal presenta una gran asincronía que afecta a veinte dientes (71,4%). En las niñas con síndrome de Down esta secuencia asincrónica afecta sólo a 15 dientes (53,6%). Una de las principales diferencias entre los individuos Down y normales se debe a la mayor varianza observada en la muestra Down