Views of BRCA gene mutation carriers on preimplantation genetic diagnosis as a reproductive option for hereditary breast and ovarian cancer

BACKGROUND: In May 2006, the UK Human Fertilization and Embryology Authority (HFEA) approved use of preimplantation genetic diagnosis (PGD) for lower penetrance, late onset cancer susceptibility syndromes such as hereditary breast and ovarian cancer (HBOC). This is the first report on views of BRCA gene mutation carriers on use of PGD for HBOC. METHODS: Between December 2005 and February 2006, a postal survey of BRCA mutation carriers attending a Familial Cancer Clinic was undertaken. RESULTS: Of 102 women sent questionnaires, 52 (51%) responded. Thirty-nine (75%) felt it was acceptable to offer PGD for HBOC. Fifteen (37.5%) of 40 who had completed their families would personally have considered PGD if it had been available. Only one of seven (14%) contemplating a future pregnancy would consider PGD. Eighteen (35%) wrote extensively about their concerns including increasing availability of effective treatment and good quality of life. CONCLUSIONS: The majority of BRCA gene mutation carriers are supportive of offering PGD to others, thus endorsing the HFEA decision. However, most women would not consider it personally. Concerns raised highlight the need for regular HFEA reviews of the licensing criteria, as HBOC may cease to be a "serious life threatening illness" in the future.     

Fetal macrocytosis in association with chromosomal abnormalities

Mean red cell volume (MCV) was determined in 264 fetuses between 15-41 weeks. After exclusion of anemic, hypoxic, and chromosomally abnormal fetuses, the MCV in 208 umbilical venous samples was shown to decrease with gestation (r = 0.64; P less than .001), and a normal range was constructed by linear regression analysis. An elevated MCV was found in both fetuses with triploidy, in four of five with monosomy X, and in four of ten with trisomies 18 or 21. The MCV was similarly raised in four of five fetuses with gross anomalies in whom cytogenetic cultures had failed. Significant correlations were found in chromosomally abnormal fetuses between the elevation in MCV and both the nucleated red cell (r = 0.69; P less than .01) and reticulocyte counts (r = 0.57; P less than .05). There was a similar correlation with nucleated red cells in 16 severely anemic fetuses with Rh disease, 12 of whom had a raised MCV. Elevation in MCV was unrelated to hypoxia. Macrocytosis had a sensitivity of 71% and a specificity of 95% in the second trimester for predicting an abnormal karyotype in nonanemic fetuses (kappa index 0.60). Fetal MCV may provide clinically useful information while one awaits culture results. We suggest that karyotyping be considered in fetuses undergoing blood sampling for other indications in whom the MCV is raised.     

Amniotic pressure in disorders of amniotic fluid volume

Amniotic pressure was measured in 49 pregnancies with abnormal quantities of amniotic fluid. Among 17 with polyhydramnios, the pressure was always above the normal mean for gestation and exceeded the upper limit of normal in nine. In polyhydramnios, amniotic pressure correlated positively with the depth of the deepest pool (r = 0.65, P = .04) and negatively with fetal PO2 (r = -0.57, P = .03) and pH (r = -0.56, P = .04). Amniotic pressure was raised in all those with a deepest pool of greater than 15 cm, and was normal in all with a deepest pool less than 15 cm. Amniotic pressure fell significantly with drainage of amniotic fluid in those with raised pressure (mean 12.7 mmHg, 95% confidence interval 7.0-18.3; P = .002) but not in those with normal pressure (mean 0.3, 95% confidence interval -3.2 to +3.9; P = .82). Restoration of normal amniotic pressure in one pregnancy was accompanied by marked improvement in fetal acid-base status. Among 24 pregnancies with severe oligohydramnios, amniotic pressure was always below the normal mean, falling below the lower limit of normal in eight; whereas in another eight pregnancies with mild/moderate oligohydramnios, amniotic pressure was scattered evenly within the normal range. Amnioinfusion of 55-500 mL of normal saline in cases of severe oligohydramnios led to a significant rise in pressure (4.7 mmHg, 95% confidence interval 3.5-5.9; P less than .0001). We conclude that amniotic pressure is high in polyhydramnios and low in oligohydramnios. Pressure monitoring may be beneficial during amnioinfusion and therapeutic amniocentesis.     

Anti-neutrophil cytoplasmic antibodies in Japanese children with ulcerative colitis

Objective: To investigate the diagnostic value of anti-neutrophil cytoplasmic antibodies (ANCA) in the diagnosis of ulcerative colitis (UC) in Japanese children.
Methodology Serum samples from 23 children with UC (17 Japanese, 6 non-Japanese), 27 children with Crohn's disease (CD) (10 Japanese, 17 non-Japanese), 10 children with other diarrhoeal diseases, and 33 normal, healthy adult volunteers were assayed for ANCA using an indirect immunofluorescence technique.
Results ANCA were detected in 6/17 (35%) UC patients and 0/10 (0%) CD patients in Japanese children, and in 3/6 (50%) UC patients and 3/17 (18%) CD patients in non-Japanese children. The difference in prevalence between Japanese and non-Japanese children with UC was not statistically significant ( P >0.05). ANCA were not found in other diarrhoeal patients and volunteers.
Conclusions Although ANCA have been reported to be useful in the diagnosis of UC in adults, they may be of limited use in Japanese children. This might reflect the heterogeneity of UC.     

Erythroblastosis and reticulocytosis in anemic fetuses

The fetal blood erythroblast and reticulocyte counts were determined in umbilical cord samples obtained at 17 to 36 weeks' gestation from 127 pregnancies complicated by red blood cell isoimmunization. The reticulocyte count increased linearly with fetal anemia, and the erythroblast count increased exponentially. Significant erythroblastosis was observed only when the hemoglobin concentration deficit was greater than 7 gm/dl. Of the 52 fetuses with a hemoglobin concentration deficit greater than 7 gm/dl, 35 had ultrasonographic evidence of hydrops. These data suggest that medullary hematopoiesis is stimulated by mild anemia and that recruitment of extramedullary sites occurs when anemia is severe. Extensive hepatic erythropoiesis may be the cause of fetal hydrops in red blood cell isoimmunization.     

Multiple sulphatase deficiency: prenatal diagnosis using chorionic villi

Multiple sulphatase deficiency was diagnosed in the first trimester of pregnancy by demonstrating markedly reduced activities of arylsulphatases and heparin sulphamidase by direct assays on chorionic villi (CV). The diagnosis was confirmed by assays on cell cultures of villi and fetal skin fibroblasts. Two further pregnancies of this mother were monitored similarly and predicted to be unaffected; one produced a normal healthy infant, the other miscarried shortly after CV sampling.     

Plasma amino acids of the mid-trimester human fetus

The amino acid concentrations in umbilical cord plasma taken at fetoscopy were measured from 12 fetuses between 18 and 29 weeks gestation. Concurrent maternal plasma levels were measured. Fetal plasma showed consistently higher concentrations of plasma amino acids with the ratios varying between 1.1:1 and 3:1 and the difference always reached statistical significance. It is suggested that these results reflect the in vivo situation of the mid-trimester human fetus.     

Fetoscopy and fetal blood sampling in the management of a twin pregnancy with 45,X/46,XX amniotic fluid cell mosaicism and a suspected fluid sampling error

A 37 year-old woman with a twin pregnancy underwent amniocentesis to exclude fetal chromosome abnormality. The results indicated that both fetuses were mosaics, with 45,X and 46,XX, cell lines. Since it was suspected from the ultrasound scan that the twins were dizygotic, the result was questioned. Fetoscopy and fetal blood sampling were performed and karyotyping the fetal lymphocytes confirmed that one twin was indeed a mosaic, 45,X/46,XX, but the other had a normal male chromosome complement. The pregnancy resulted in the birth of a phenotypically normal girl, in whom the 45,X/46,XX mosaicism was confirmed, and a normal boy.