Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism

OBJECTIVES: This study explores reactions to low-level chemical challenge, aiming at the development of test procedures for assessing individual sensitivity to smells and chemicals. METHODS: Subjects with symptoms and neuropsychological test results compatible with toxic encephalopathy type 2A (TE-2A) and 2B (TE-2B) and unexposed referents (N=12 in each group) were challenged in an exposure chamber. Toluene exposure was started at 11 mg/m3, and it followed a geometric progression scale with a ratio of 2, until reaching 180 mg/m3. In a counterbalanced design, the subjects were similarly exposed to n-butyl acetate starting at a concentration of 14 mg/m3 and increasing to 228 mg/m3. At each exposure level, smell intensity was measured on a 7-step category scale. Mucous membrane irritation and annoyance reactions were rated on visual analogue scales. RESULTS: Both TE groups showed high sensitivity to the low-level solvent challenge, which provoked immediate annoyance and fatigue reactions. In particular the TE-2B group related smell intensity to various annoyance dimensions during exposure to n-butyl acetate, a pattern not observed during toluene exposure. The reference group clearly separated smell intensity and annoyance reactions in both exposure conditions. CONCLUSIONS: The reaction of the TE cases suggests that chemical sensitivity can be distinguished from normal annoyance reactions by the inability to differentiate between smell intensity and an experience of irritation from mucous membranes in air concentrations well below the trigeminal irritation threshold level. Fatigue coreactivity in challenges to single substances below the neurotoxic level may also be important.     

Labyrinthine anomalies in trisomy 13 mosaicism

The temporal bone histopathology of a 2-month-old male with a bilateral cleft palate, cleft lip and polydactylia due to trisomy 13 mosaicism was studied. Anomalies in the ear involved a partial absence of the superior semicircular canal, an abnormally wide lateral semicircular canal, underdeveloped cochlear coils, an abnormally broad modiolus, an undeveloped organ of Corti and an underdeveloped basilar membrane in the basal turn of the cochlea, an unusually wide cochlear aqueduct, and deformed stapedial crura.     

Confined placental mosaicism for trisomy 8 and intra-uterine growth retardation

This report describes a case of apparent confined placental mosaicism for trisomy 8 in a pregnancy which produced a male infant with intra-uterine growth retardation. Postnatal cytogenetic and molecular studies were consistent with biparental disomy 8. Postnatally, the infant experienced a period of rapid catch-up growth and exhibited no clinical features of trisomy 8 mosaicism. His development was age appropriate.     

Prenatal diagnosis of triploidy and trisomy 21 through fetal erythroblasts isolated from maternal blood

BACKGROUND: A long-sought goal of medical genetics has been the development of prenatal diagnostic procedures that do not endanger the conceptus. The safety of noninvasive methods for prenatal diagnosis would be especially attractive because they could be extended to all pregnant women, regardless of their ages or histories. Noninvasive prenatal diagnosis for the entire population might be possible recovering fetal cells from maternal blood. For this purpose, we have studied fetal erythroblasts. MATERIALS AND METHODS: To evaluate the potential of the method for clinical use, we studied maternal blood samples from 11 women referred to us for prenatal diagnosis between 15 and 20 weeks of gestation. For simple and effective enrichment of fetal nucleated erythrocytes from peripheral maternal blood, we combined a triple density gradient and magnetic-activated cell sorting (MACS) of anti-CD71 transferrin receptor antibody labeled cells. The isolated cells were analysed by using dual-colour interphase fluorescent in situ hybridization (FISH) with X-, Y-, 18- and 21-specific DNA probes. RESULTS: Chromosomal abnormalities detected on enriched fetal cells include trisomy 21 and triploidy. CONCLUSIONS: Based on the current results it is suggested that the technique described here is a simple, fast, efficient and reliable method for non invasive prenatal diagnosis.     

Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment

In a pilot study to establish fetal nucleated red blood cell (NRBC) detection in maternal blood, trisomy 13 was diagnosed by FISH analysis at 11 weeks' gestation. The NRBCs were detected after a single-step ficoll density gradient enrichment. In blood samples taken both before and after CVS, 52 and 80 NRBCs, respectively, were found to be positive for fetal haemoglobin. In 47 per cent of these cells, FISH analysis for X and Y chromosomes confirmed the fetal sex. Moreover, 48 per cent of these NRBCs showed three fluorescent signals for a chromosome 13 probe, which confirmed the diagnosis of trisomy 13, previously detected at CVS karyotyping. This is the first report of non-invasive prenatal diagnosis of trisomy 13, i.e., pre-CVS, in the first trimester. The high number of fetal NRBCs detected indicates a connection with aneuploidy, probably due to early impairment of the feto-maternal barrier.     

Sertoli-Leydig cell tumour complicated by X chromosomal mosaicism

We describe a case of well-differentiated Sertoli-Leydig cell tumour (SLCT) of the ovary. A 48-year-old Japanese woman had had symptoms of virilization, i.e. alopecia and facial hair, for 8 years. Although the patient had given birth to three normal children, laboratory investigations revealed an elevated serum level of free testosterone and tripartite mosaicism (45X/46XX/47XXX). Computed tomography and magnetic resonance imaging revealed a tumour of the left ovary. After oophorectomy, the serum level of free testosterone returned to the normal range and symptoms of virilization resolved. To our knowledge, this is the first reported case of a patient with SLCT who had tripartite mosaicism and had given birth to normal children. Although the aetiology of SLCT is not known, we believe that SLCT is associated with sex chromosomal abnormalities at least in some cases.     

Prenatal diagnosis of mosaic trisomy 8 with investigations of the extent and origin of trisomic cells

Even though some treatments have been shown to be efficacious in clinical trials, there is no guarantee that they are effective with a specific patient. This article outlines some of the methods clinicians can use to evaluate the effectiveness of therapy with individual patients. These methods include 1) the before-after design, 2) the reversal design, 3) interrupted time series, and 4) multiple baselines. This paper recommends that patients who are being treated, whether privately or in hospital, be seen as experiments with a sample size of 1 and that their progress be monitored using 1 of these methods.     

The oro-facial manifestations of trisomy 8 mosaicism: a case report

The malformations commonly found in fetuses of diabetic mothers occur before the 7th week of pregnancy, when fetal nutritional needs are met largely by the yolk sac. The diabetic milieu has been hypothesized to cause a disruption in the metabolism of arachidonic acid and phosphatidylinositol turnover, leading to a reduction in prostaglandin levels. In this study we evaluated how the diabetic milieu affects yolk-sac prostaglandin levels. We used ultrasound to characterize and guide aspiration of the yolk sacs of eight diabetic and 12 healthy women prior to elective abortion. In addition, we studied the yolk sacs of two healthy women in whom pregnancy termination was carried out by hysterectomy. All fetuses were between 8 and 10 weeks gestational age at the time of pregnancy termination. The yolk-sac prostaglandin E2 levels were measured using radioimmunoassay. We found that the yolk-sac diameters of diabetic women were 1.2 mm larger than those of normal women. Furthermore, the mean prostaglandin E2 level in healthy women was 3605 pg/ml, whereas prostaglandin was undetected in all the yolk sacs of diabetic women (p < 0.001). While this study suggests that defective yolk-sac metabolism of prostaglandins is one of the mechanisms responsible for diabetic embryopathy, further research is necessary to place yolk-sac enlargement and the role of prostaglandins in perspective.     

Normal outcome of a pregnancy with mosaicism for double trisomy in amniotic fluid cells

True chromosomal mosaicism of double trisomy (48,XX, +7, +20) was detected in amniotic fluid cell cultures at 16 and 20 weeks of gestation. No aneuploid cells were found in chorionic villus samples (CVS) by semidirect preparation and long-term culture. High-level ultrasound did not indicate any structural abnormality of the fetus. At 38 weeks of gestation, a phenotypically normal girl was born. She is now 22 months old and normally developed. At birth, various samples were investigated by routine cytogenetic methods or by fluorescence in situ hybridization with the probe p7t1 (umbilical cord blood, placental tissue, umbilical cord fibroblasts, urine sediment) and no abnormal cells could be detected in any of those tissues.     

Prenatal diagnosis

The enormous progress witnessed in the field of prenatal diagnosis during the past two decades is likely to continue into the future. Improved imaging techniques are likely to enhance the resolution of noninvasively obtained fetal images considerably over their current excellent quality. Although this undoubtedly will be true for ultrasonography, the increased speed of magnetic resonance equipment may offer a new realm of imaging possibilities. Computerized image processing, analysis, and three-dimensional reconstructions all should make interpretation of fetal images easier and more understandable to the nonspecialist. Advances in molecular genetics will continue to accelerate, greatly expanding the range and accuracy of prenatal diagnosis. The alert pediatrician who is sensitive to genetic issues may, by early detection of pediatric disorders and careful family history assessment, be in a position to identify families at risk for serious genetic conditions and provide the opportunity to make informed decisions on reproductive options that avert a major tragedy. The pediatrician, working with obstetric colleagues, should be part of a team effort to support families going through prenatal testing. Familiarity with these rapidly changing technologies will make it far easier to support the family needing additional explanation about prenatal diagnosis issues.     

Prenatal diagnosis of diastematomyelia

The long-term follow-up (from age 6 to 20 years) of a girl with Gitelman's syndrome, who had four hypomagnesaemic-tetanic episodes associated with normal plasma calcium, hypokalemia and hypocalciuria, is presented. During and after puberty, hypomagnesaemia was of the order of 0.41-0.49 mmol/l and plasma potassium was at the lower reference limit. The long-term clinical course and growth of this patient appeared good, but, magnesium supplementation reduces the risk of tetanic crises.     

Prenatal diagnosis of fucosidosis

A pregnancy from a family at risk for fucosidosis was monitored. Determinations of fucosidase and mannosidase were performed on the serum and white blood cells of several members of the family, om amniotic fluid and amniotic fluid cells of the fetus at several passages, and on fibroblast cell lines from index cases. The fetus was diagnosed as being free from the disease. This conclusion was confirmed after birth by fucosidase determination in plasma and white cells from cord blood, and in the placenta. Fluctuations in fucosidase activity were observed in extracts from cultured amniotic cells at various passages. The possible causes of this variability are discussed.     

Prenatal diagnosis of 45,X/46,XY mosaicism with postnatal confirmation in a phenotypically normal male infant

Prenatal detection of chromosome mosaicism has always been a diagnostic dilemma. In 21 reported cases of chromosomal mosaicism in cultured amniotic fluid cells, only two cases had cytogenetic confirmation of the mosaicism. All 21 pregnancies resulted in either phenotypically normal liveborns or grossly normal abortuses. We report a case of XO/XY mosaicism detected prenatally and confirmed postnatally in a grossly normal male infant. The indication for prenatal cytogenetic diagnosis was advanced maternal age (38 years). A diagnosis of XO/XY mosaicism was made from two separate culture flasks of amniotic fluid cells, with 45,X cells predominating (86.4%). The Y chromosome was of normal size but carried no fluorescent band. The parents were counseled and were advised that the phenotype of XO/XY mosaicism can range from relative normality to sexual maldevelopment. They decided to continue this pregnancy. The infant was born at term and was a grossly normal male with normal penis and descended, normal-sized testes. Leukocyte culture from the cord blood and a skin fibroblast culture confirmed the mosaicism of XO/XY. The father's Y chromosome was of identical size and carried a small fluorescent band. It appears that an altered Y chromosome may be predisposed to anaphase lag leading to mosaicism.     

Low-level mosaicism for both trisomy 15 and monosomy-X in amniotic fluid cells confirmed in fetal tissues

We report here a case of true fetal mosaicism for both trisomy 15 and monosomy-X; the aberrant cell lines were initially detected at amniocentesis as low-level mosaicism (trisomy 15) and multiple-cell pseudo-mosaicism (monosomy-X). In the fetal lymphocytes, only metaphases with a normal chromosome complement were observed. After termination of the pregnancy, various fetal biopsies revealed both trisomy 15 and monosomy-X mosaicism, whereas, at autopsy, no external or internal abnormalities could be detected in the fetus. The karyotype can be described as 45,X[15]/47,XY,+15[3]/46,XY[27]. Our results implicate that an additional amniocentesis could be more helpful than fetal blood sampling in predicting the fetal karyotype after diagnosis of chromosome mosaicism at amniocentesis.     

Cytogenetic and molecular genetic characterization of trisomy 20 mosaicism in fetal blood and tissues

We report a case of mosaic trisomy 20, the most common autosomal mosaicism identified in amniocytes, ascertained in a woman referred for amniocentesis because of abnormal ultrasound at 18.1 weeks' gestation which revealed short femurs and nuchal thickening. Metaphase analysis of 98 clones revealed 47,XY, +20 in 96 cells (98 per cent). Trisomy 20 was demonstrated in 6 cells (12 per cent) in a total of 50 cells from two fetal blood cultures obtained after pregnancy termination. Fluorescence in situ hybridization (FISH) analysis of interphase nuclei utilizing a chromosome 20 alpha-satellite centromeric DNA probe revealed three signals in 57/546 nuclei (10 per cent) in fetal blood. Metaphase analysis of 167 cells from seven different fetal tissue sources revealed trisomy 20 in 32 cells (19.2 per cent). The percentage of trisomy 20 cells varied with tissue type, with the highest percentage (13/25 cells, 52 per cent) identified in the small intestine and lymph nodes and the lowest percentage (1/34 cells, 2.9 per cent) identified in a specimen of chorionic villi. Molecular genetic analyses utilizing polymerase chain reaction (PCR)-formated dinucleotide repeat polymorphisms demonstrated that the non-disjunctional event most likely occurred post-zygotically and that the origin of the extra chromosome 20 was maternal. This study is the first to demonstrate trisomy 20 cells in fetal blood, suggesting that mosaic trisomy 20 can be embryonic in origin. In cases of prenatally detected mosaic trisomy 20, examination of fetal blood should be considered, as well as study of placental membranes, skin, and urine sediment to confirm the karyotype and determine its significance.     

Prenatal diagnosis: methods--indications--risks

The demands made on prenatal care in terms of fetal anomaly recognition and full and early counseling have become more and more sophisticated over the last few years. Today, a range of non-invasive and invasive procedures are now available for the detection of fetal anomalies, genetic disorders and e.g. infection. The most important of the former are ultrasound and triple test (determination of alpha feto-protein, HCG and unconjugated estriol), while amniocentesis remains the major invasive measure. The indications, the information they provide, and possible risks of these procedures are discussed.