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.     

Prenatal diagnosis of beta-thalassaemia by coelocentesis

Coelomic fluid and placental tissue were obtained from four women undergoing termination of pregnancy at 7-9 weeks gestation for psychological reasons. All four women and their partners were known carriers of beta-thalassaemia and DNA analysis in their blood identified the mutation carried by each of them. Allelespecific polymerase chain reaction and denaturing gradient gel electrophoresis techniques were used to detect and identify the mutations in the DNA extracted from the coelomic cells and placental tissue. Three fetuses were found to be carriers of either the paternal or maternal mutation, while one was found to be affected by beta-thalassaemia. There was concordance in the results obtained from the chorionic villi and coelomic cells. Amplification of the apolipoprotein B gene variable number tandem repeats (VNTR), in the DNA of the coelomic cells showed normal sagregation of alleles in the fetuses, thus excluding maternal contamination. The results of this study demonstrate that coelocentesis may be a reliable alternative technique for the diagnosis of beta-thalassaemia from as early as 7 weeks gestation.     

First-trimester nuchal translucency: a risk analysis on fetal chromosome abnormality

PURPOSE: To investigate the importance of nuchal translucencies in the first trimester of pregnancy as an ultrasonographic marker for fetal chromosome abnormalities. MATERIALS AND METHODS: One hundred two first-trimester fetuses with a nuchal translucency of 3 mm or more were karyotyped. Multiple logistic regression analysis was performed to estimate the risk of fetal chromosomal abnormalities related to nuchal translucencies. RESULTS: Fifty-five (54%) of the fetuses had a normal karyotype. Forty-seven (46%) had an abnormal karyotype. The risk of chromosome abnormality was strongly increased in fetuses with a septated nuchal translucency compared with fetuses with a nonseptated nuchal translucency. CONCLUSION: First-trimester nuchal translucency is an important ultrasonographic marker for chromosomal abnormalities in the fetus. The presence of a normal karyotype in a fetus is a strong indication that detailed ultrasonographic examination for associated anomalies should be undertaken.     

Pharmacological properties of traditional medicines. XXIV. Classification of antiasthmatics based on constitutional predispositions

A 13q isodisomy in a balanced karyotype: 45,XY,-13,-13, + i(13)(q10) was found in cultured amniocytes studied because of advanced maternal age. The isochromosome was monocentric and a new mutation as both parents had normal chromosomes. Fetal blood was studied to exclude 13-trisomy mosaicism. All (100) lymphocytes studied had the same karyotype with i(13)(q10) as the amniocytes. To determine the origin of the isochromosome, six microsatellite markers from 13q were analysed: D13S175, D13S166, D13S162, AC224, COLAC1 and D13S122. The results indicated that the i(13)(q10) was of paternal origin and isodisomic. The father had a risk of 1/20 for being a carrier for an autosomal recessive, progressive brain disorder, variant late infantile neuronal ceroid lipofuscinosis (CLN5). The risk for the fetus for this disorder of chromosome 13 was excluded by haplotype analysis. A healthy child was born at week 40 of pregnancy, supporting the idea that there are no paternally imprinted genes on chromosome 13q. Analysis of extra embryonal tissue (four samples studied) revealed the same balanced karyotype with the i(13)(q10)pat chromosome. According to the cytogenetic and molecular studies, the origin of the isochromosome 13 could be a transverse centromere cleavage at the paternal meiosis II or at an early mitosis.     

Who gets custody?

To elucidate the mechanisms that facilitate tolerance at the maternal-fetal interface, we are investigating the role of genes that are involved in peripheral self-tolerance in couples with idiopathic recurrent miscarriage. CTLA-4 is a negative regulator of T-cell proliferation and has been associated with human autoimmune disease. An AT(n) polymorphism in the 3'-untranslated region (UTR) of the human gene results in AT stretches that vary in length from 16 to 46 bp. We hypothesized that long stretches of AT repeats would result in mRNA instability, and reduced fetal survival in humans. We examined the transmission of AT(n) alleles in 60 couples with a history of > or = 3 unexplained spontaneous abortions to their 51liveborn children and 10 abortuses. The shorter allele was transmitted from heterozygous mothers to 26 of 35 liveborn children (chi2 = 8.3, P = 0.0040) and to three of nine aborted fetuses (chi2 = 1.0, P = 0.317). The shorter allele was transmitted from heterozygous fathers to 15 of 32 liveborn children (chi2 =0.12, P=0.726) and to five of eight aborted fetuses (chi2 = 0.5, P = 0.480). Furthermore, liveborn fetuses who inherited smaller alleles were more likely to represent the first successful pregnancy than liveborn fetuses who inherited larger maternal alleles (Pexact = 0.044) and fetuses of first pregnancies that inherited the smaller allele were significantly more likely to survive to term (Pexact = 0.0086). The preferential transmission of maternally-inherited shorter alleles to liveborn children, but random transmission of paternally-inherited alleles, suggests that CTLA-4 may be imprinted in humans and that this gene may play a role in inducing or maintaining tolerance at the maternal-fetal interface.     

Agonist and antagonist actions of (-)pindolol at recombinant, human serotonin1A (5-HT1A) receptors

Prenatal diagnosis and clinical follow up of a patient with mosaicism for anomalies of chromosome 18 are reported. The fetus appeared on ultrasound to have multiple anomalies, including clubbed feet, abnormal hand positioning, edema of the scalp, cleft palate, and polyhydramnios. The karyotype on amniocytes was 47,XY,+i(18p). Postnatally, the peripheral blood karyotype was 46,XY,+i(18q), whereas the skin fibroblast karyotype was 47,XY,+i(18p). The infant had many features consistent with those previously described in cases of tetrasomy 18p and some that were consistent with trisomy 18q.     

Prenatal diagnosis of ring chromosome 6 in a fetus with hydrocephalus

A patient with ring chromosome 6/monosomy 6 mosaicism is presented. At 25 weeks' gestation, ultrasound examination demonstrated fetal hydrocephalus. Amniocentesis was performed. The fetal karyotype was 45,XY,-6/ 45,XY,-6,+f/46,XY,r(6)(p25q27). Delivery of this male infant was by Caesarean section at 37 weeks' gestation. The karyotype in peripheral blood lymphocytes was 46,XY,r(6)(p25q27) with no indications of mosaicism. The infant had hydrocephalus which required treatment with a ventriculoperitoneal shunt at 22 days of age. He had no other obvious serious congenital anomalies. By 17 months he had developed microcephaly, seizures, severe bilateral hearing loss, and global development delay. This patient provides information regarding phenotypic variability of ring chromosome 6 and also reinforces the importance of offering amniocentesis if fetal hydrocephalus is detected as an isolated anomaly.     

Receptor-activated Ca2+ influx via human Trp3 stably expressed in human embryonic kidney (HEK)293 cells. Evidence for a non-capacitative Ca2+ entry

Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.     

Hyperkalaemia with renal tubular dysfunction by sulfamethoxazole-trimethoprim for Pneumocystis carinii pneumonia in patients with lymphoid malignancy

The prenatal diagnosis of an 11q;22q translocation in a triplet pregnancy detected at the time of chorionic villus sampling (CVS) because of advanced maternal age is reported. Karyotypes obtained from two apparently different CV samples showed the balanced form of translocation, while the one obtained from a third empty sac showed the unbalanced form: 46,XX,-22,+der(22)t(11;22). Second-trimester amniocentesis confirmed the balanced translocation in one of the two viable fetuses and a normal karyotype in the other. The detected karyotypes derived from two different types of meiotic segregation, alternate and adjacent 1. To our knowledge, this is the first reported case of an unbalanced karyotype not due to a 3:1 meiotic segregation of this specific translocation.     

Cytogenetic abnormalities in mesoblastic nephroma: a link to Wilms' tumour?

Cytogenetic analysis of tumour material from a congenital mesoblastic nephroma is reported. Two cell lines were found, one with a normal 46,XY karyotype and the other with a hyperdiploid 51,XY karyotype, including a rearrangement of chromosome 11 at 11p15. This finding is of interest since loss of allelic heterozygosity at polymorphic 11p15 loci has been described in sporadic Wilms' tumour [1], and both cytogenetic [2] and molecular [3] changes of 11p15 are found in the Wiedemann-Beckwith syndrome, a condition with a predisposition to embryonal tumours, particularly Wilms' tumour. Our results lead us to speculate on the implications relating to the pathogenesis of this relatively benign tumour variant with respect to the current understanding of the genetics of Wilms' tumour.     

A case of distal 9q trisomy syndrome associated with an unusual inheritance of ABO blood type

A male infant with distal 9q trisomy syndrome associated with an unusual inheritance of ABO blood type is reported. His clinical features were concordant with those of distal 9q trisomy syndrome. His karyotype was 46,XY, -10, +der (10) t(9;10) (q22.3;q24.3) confirmed by G-banding and high resolution methods. His father had the balanced translocation t(9;10) (q22.3;924.3). He had a blood type of AB, despite his father's blood type of AB and his mother's blood type of O. The gene of ABO blood type is located at 9q34.1-q34.2. Therefore, he would have received A and B type alleles from his father. 9q trisomy syndrome should be carefully investigated with ABO blood type.     

Is serum thyroglobulin a useful marker for thyroid cancer in patients who have not had ablation of residual thyroid tissue?

Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.     

Genetic localization of Cd63, a member of the transmembrane 4 superfamily, reveals two distinct loci in the mouse genome

We describe a patient with Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukaemia (ALL) who developed it 2.5 years after being diagnosed with myelodysplastic syndrome (MDS). The patient initially had refractory anaemia (RA), but progressed to refractory anaemia with excess blasts (RAEB) 2 years later, that terminated in ALL. An immunophenotypic analysis of the lymphoblasts revealed CD10 and CD19 positive cells. The karyotype was normal 46,XY in RA phase, 46,XY,20q-during the RAEB phase, and 46,XY,t(9;22)(q34;q11),20q-during the ALL phase. Furthermore, p190 BCR-ABL mRNA was detected in the ALL blasts. These findings indicate that this ALL arose from the MDS clone through multiple cytogenetic evolutions, the final event of which was the acquisition of p190 BCR-ABL type Ph1.     

Barriers to effective psychiatric emergency services for elderly persons

OBJECTIVE: To evaluate the etiology and outcome of fetal hydrops of nonimmune origin diagnosed in utero during the first half of pregnancy. METHODS: We reviewed 45 cases of nonimmune fetal hydrops presenting between 11 and 17 weeks' gestation over a 4-year period. RESULTS: The median gestational age at diagnosis of fetal hydrops was 14 weeks. Placental edema was most commonly associated with generalized skin edema. Ascites was also observed in four cases, but no case presented with pleural or pericardial effusion. The fetal karyotype was abnormal in 35 cases (77.8%). Of the ten fetuses with a normal karyotype, four were classified as idiopathic, three had isolated atrioventricular septal defect, two were associated with maternal infection, and one had multiple pterygium. Fetal heart rate anomalies were found in both chromosomally normal and abnormal fetuses. All but one of the karyotypically abnormal pregnancies and five of ten euploid pregnancies were terminated. In all six pregnancies that continued, resolution occurred before mid-gestation. Three continuing euploid pregnancies resulted in fetal death, and only two had a normal outcome. CONCLUSION: Nonimmune fetal hydrops diagnosed before 18 weeks' gestation is associated with a higher incidence of aneuploidy than hydrops diagnosed during the second half of pregnancy. In most affected fetuses with a normal karyotype, spontaneous resolution occurred before 24 weeks' gestation, although the outcome was generally unfavorable.     

Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results

OBJECTIVE: Our purpose was to determine whether nuchal thickness measurement can identify the euploid fetuses in midtrimester pregnancies at increased risk for Down syndrome on the basis of maternal age and serum screening. STUDY DESIGN: Nuchal thickness was obtained prospectively in 651 consecutive fetuses at 14 to 21 weeks' gestation and at > or = 1:270 risk for Down syndrome on the basis of unconjugated estriol, alpha-fetoprotein, and human chorionic gonadotropin levels. The risk of Down syndrome with a normal nuchal thickness was determined. A receiver-operator characteristic curve was used to determine a serum-based risk threshold below which the risk for Down syndrome was low. The prevalence of Down syndrome in fetuses with both a normal nuchal thickness and a below-serum-risk threshold was compared with prevalence in either those above threshold risk or with an abnormal nuchal thickness. RESULTS: There were eight cases of trisomy 21 and one case each of 46,XX/47,XXX, 46,XY/47,XY, +7, and 46,XX, 11q-. The sensitivity of an abnormal nuchal thickness (> or = 6 mm) for detecting Down syndrome was four in eight (50%) (95%) confidence interval 15.3% to 84.6%). The risk of Down syndrome was significantly increased with an abnormal compared with a normal nuchal thickness, four in 13 (30.8%) versus four in 638 (0.6%), p < 0.0001. A risk threshold was defined at > or = 1:100 on the basis of the receiver-operator characteristic plot. Of 390 cases with a normal nuchal thickness and a serum risk estimate < 1:100, there were no cases of Down syndrome (0/390 vs 8/253, p = 0.002). CONCLUSION: Normal nuchal thickness significantly reduces the risk of Down syndrome and may help reduce the number of amniocenteses done for abnormal triple screen results.     

Gentamicin dosage intervals in neonates: longer dosage interval--less toxicity

Our objective was to construct a nomogram of the fetal lingual size early pregnancy and to assess the size of the tongue in abnormal fetuses. The lingual width was measured by using transvaginal ultrasonography in 80 normal fetuses at 13 and 18 weeks' gestation. In addition the tongue was measured in 22 fetuses at these gestational ages who had an abnormal karyotype or oro-facial malformations. A linear relationship was found between the lingual width and gestational age in normal fetuses. The lingual size was within the normal range in cases of trisomy 13, trisomy 21 and Turner syndrome. A small tongue was observed in fetuses with micrognathia. Correlation between lingual width and gestational age was observed in early pregnancy. The relationship between the size of the tongue and oro-facial malformation needs further evaluation.     

True hermaphroditism with XX/XY sex chromosome mosaicism: report of a case

A case of true hermaphroditism with 46, XX/46, XY karyotype is reported. The propositus, reared as a male, showed ambiguous external genitalia with perineoscrotal hypospadias, and internal genitalia represented by bilateral ovotestes, normal uterus and tubes. Periodic menstrual bleedings appeared at puberty. The endocrinologic data demonstrated the secretory activity of both the ovarian and the testicular tissue. The analysis of red cell, lymphocyte and serum markers, done on the propositus and on his parents, failed to show any evidence of double fertilization. On this basis, the origin of the XX/XY condition (mosaicism versus chimerism) and its developmental consequences are discussed.     

Of abscission and other breakthroughs

Plexiform fibrohistiocytic tumors are rare lesions of proposed myofibroblastic origin occurring primarily in infants and children. There is a characteristic biphasic histology comprised of both fibroblastic and histiocyte-like components. These tumors tend to be locally aggressive with prognosis dependent on completeness of resection. A previous cytogenetic case report of this tumor described a stemline clone with a karyotype of 46,XY,-6,-8, del(4)(q25q31),del(20)(q11.2),+der(8)t(8;?) (p22;?),+mar. We report a different cytogenetic finding in another plexiform fibrohistiocytic tumor which demonstrated a simpler karyotype of 46,XY,t(4;15)(q21;q15). The implications of cytogenetic heterogeneity in fibroblastic tumors is briefly discussed.     

Are duodenal ulcer seasonal fluctuations paralleled by seasonal changes in 24-hour gastric acidity and Helicobacter pylori infection?

Short-term cultures from two histologically benign chemodectomas, one from the carotid body and one from the vagal nerve, were analyzed cytogenetically. The former had a small abnormal clone with the karyotype 46,XX,t(3;19)(q21;q13),t(12;15) (p13;q12-14), whereas the majority of the cells from the latter tumor displayed two related abnormal clones: 46,XY,i(I)(q10)/ 46,iderm,add(2)(q37). The findings add to the evidence that chemodectomas are heterogeneous neoplasms and suggest that the heterogeneity may possibly be associated with the site of origin.     

A cytogenetic survey of 200 unclassifiable mentally retarded children with congenital anomalies and 200 normal controls

A cytogenetic survey was carried out on 200 patients with mental retardation and multiple congenital anomalies, and on 200 normal adult controls. Patients with a known syndrome were excluded from the survey. Chromosome analyses were carried out on 'blind-coded' slides using the ASG banding technique as the routine stain. After the initial analyses (at least 15 cells per person) the slides were decoded, destained and reused for C and Q band polymorphism studies. Five major chromosome abnormalities were detected in the patient group during the survey. They included three patients with de novo, apparently balanced, reciprocal translocations, karyotypes 46,XY,rcp(3;16)(q21;p12); 46,XX,rcp(5;8)(p15;q22); and 46,XX,rcp(5;12)(p11;q24); one with karyotype 47,XX,+mar and one with karyotype 46,XX,der(13),t(13;?)(q34;?). One additional patient whose karyotype in lymphocytes was 46,XX,inv(9)(p11;q13) was found to have a mosaic karyotype 46,XX,inv(9)(p11;q13)/46,XX,inv(9) (p11;q13), der(12),t(12;?)p13;?) in cultured skin fibroblasts. None of the 200 controls had a major chromosome abnormality. From the combined results of this and previous surveys it is now apparent that about 6.2% of the unclassifiable mentally retarded patients with three or more congenital anomalies and about 0.7% of the controls reveal major chromosome abnormalities.