Congenital diabetes in an infant with trisomy 21

A newborn infant with trisomy 21 was found to have congenital diabetes which appears to be permanent. Congenital diabetes is extremely rare and differs from type I or type II diabetes. It has never been reported previously in Down's syndrome and it seems to be due to a selective beta cell defect with undetectable C-peptide but normal alpha-cell function.     

FISH studies of the sperm of fathers of paternally derived cases of trisomy 21: no evidence for an increase in aneuploidy

The introduction of transmyocardial laser revascularization for ischaemic heart disease has brought with it new challenges for anaesthetists. These include acute deterioration of cardiac function, the need for emergency cardiopulmonary bypass and difficulty weaning from haemodynamic support. Recurrent arrhythmias can occur despite amiodarone prophylaxis. We describe our initial experience and the problems we encountered.     

2q21-qter trisomy in hepatoblastoma

Cytogenetic findings and fluorescens in situ hybridization results of a hepatoblastoma of a boy of two and half years of age are presented. Cytogenetic analysis and fluorescens in situ hybridization technique were performed using tumor tissue obtained by biopsy. The direct culture was harvested after 16 hour colcemid treatment. The results of G-banding were as follows: 47,XY,add(4) (q26),-9,+20. There were considerable variation in the degree of condensation and hence in the number of visible G-bands both between metaphases and between homologous chromosomes in the same metaphases. Fluorescens in situ hybridisation were carried out by whole chromosome painting probes: 2,3,4, and 20. The karyotype of the malignant cells was adjusted accordingly: 47,XY,der(4)(q35),dir ins(9;2)(p22;q?21q?25),+20. The results confirm the most common primary chromosome abnormalities in hepatoblastoma are the following: trisomy 2, trisomy 20 and 4q structural rearrangement. Fluorescens in situ hybridization confirms the importance of trisomy 2q21-qter in hepatoblastoma. Authors recommend the use of fluorescens in situ hybridization to correct any tumor karyotype with difficult or ambiguous chromosome morphology.     

Analysis of false-negative and underreported smears in the Florence district screening program for cervical carcinoma

AIMS AND BACKGROUND: To review false-negative or underreported (reactive changes, squamous or glandular atypia) smears performed in women developing histologically proven CIN2 or more severe lesions within 24 months and evaluate error causes. The study setting was the Florence District cervical cancer population-based screening: about 60,000 women age 25-60 years screened per year. METHODS: 118 false-negative or underreported cases were identified at screening files-cancer Registry matching, and the original smears were reviewed by six independent readers to judge smear adequacy and error type. RESULTS: Sampling errors (reported as inadequate, negative or less severe than CIN1 at review) accounted for 74% and screening/interpretation errors (reported as CIN1 or more severe at review) accounted for 26% of studied cases. Screening/interpretation errors were more likely ascribed to misinterpretation and underreporting than to misperception of cellular abnormalities. CONCLUSIONS: Quality control should above all address the problem of sampling adequacy. Due to the rarity of misperceived abnormalities (true screening errors), manual or automated rescreening of negative smears would not be an effective procedure for quality control.     

Echogenic fetal bowel and calcified meconium in a fetus with trisomy 21

A case of acute cholecystitis in an immunosuppressed patient with hepatocellular dysfunction is reported. The diagnostic dilemmas posed by the lack of specific sonographic findings, the possibility of acute gallbladder disease without early cystic duct obstruction, and the absence of clear guidelines for the interpretation of delayed appearance of the gallbladder on hepatobiliary scintigraphy in this subgroup of patients are discussed.     

Maternal serum screening for trisomy 18 in the first trimester of pregnancy

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or non-parenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.     

The lower cervical spine in trauma: a study of false-negative and false-positive findings

Evaluation of roentgenographic studies of the lower cervical spine may be complicated by posttraumatic immobility, certain body types, and technical factors which produce equivocal findings. False-positive and false-negative findings are reported, with suggestions for additional views and more diagnostic evaluation.     

Cardiac morphology at late fetal stages in the mouse with trisomy 16: consequences for different formation of the atrioventricular junction when compared to humans with trisomy 21

OBJECTIVE: The mouse with trisomy 16 (Ts16) is held to be a genetic model for humans with Down's syndrome (Ts21). Both trisomies are associated with atrioventricular septal defects, but the precise morphology in the mouse remains unclear. We have therefore characterised cardiac morphology in the mouse with Ts16. METHODS: Ts16 fetuses, from a Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross, were collected on gestational days 17 or 18 (full term = 19 days) and studied using scanning electron microscopy and serial sections. RESULTS: The hearts showed a spectrum of deficient atrioventricular septation which we categorised into two types. In one, a common atrioventricular junction was separated into right and left orifices by a tongue of tissue joining two valvar leaflets that bridged the ventricular septum to varying extent. In the other, a common atrioventricular junction was connected exclusively to the left ventricle. All hearts had ostium primum atrial and ventricular septal defects, together with abnormal ventriculo-arterial connections. No heart had the typical morphology seen in the human with Down's syndrome, namely a balanced common atrioventricular junction, guarded by a common valve, with the aorta connected exclusively to the left ventricle. CONCLUSIONS: The cardiac defects seen in Ts16 mice show marked differences from the typical anatomy in human Ts21, suggesting more complex mechanisms of cardiac dysmorphogenesis in Ts16. The mouse model will prove valuable in elucidating the mechanism of normal expansion of the atrioventricular junctions, and help in charting the precise steps involved in atrial and ventricular septation.     

Effects of lead time, length bias, and false-negative assurance on screening for breast cancer

This article presents a model of breast cancer screening programs. The model shows the effects of the screening threshold, screen sensitivity, and false-negative assurance on the cumulative mortality rate in the screened population. It shows that factors of screen design and a penalty associated with false-negative assurance can result in excess mortality rates in screened populations--especially in those age classes in which the incidence of rapidly growing tumors is high. Factors related to the magnitude of this effect are described.     

Physical findings in 21q22 deletion suggest critical region for 21q- phenotype in q22

Human beta-amyloid precursor protein immunoreactivity was demonstrated in axonal swellings (spheroids) around periventricular leukomalacia (PVL) of neonates. Immunoreactive axons were found at the early, but not late stage of PVL. beta-Amyloid precursor protein immunoreactivity was homogeneous in damaged axons at the early stage of PVL manifesting microglial activation, concentrated at the center of axonal swellings at the subsequent stage manifesting astrogliosis, and undetectable at the terminal stage of cavitation or neovasculation. Immunostaining for beta-amyloid precursor protein was useful in localizing PVL lesions at their early stages.     

Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21

Although some of the susceptibility to Graves' disease is conferred by genes in the human leucocyte antigen (HLA) region on the short arm of chromosome 6, other genetic factors must also predispose. Among the cytokines involved in thyroid autoimmunity interferon-gamma (IFN-gamma) plays a key role in the pathogenesis of Graves' disease. We therefore analyzed the first intron of the IFN-gamma gene for a dinucleotide (CA) repeat polymorphism on chromosome 12q. Two hundred two Caucasian patients with Graves' disease and 214 Caucasian controls were analyzed by polymerase chain reaction (PCR) and subsequent polyacrylamide gel electrophoresis technique: eight different alleles designated as IFN-gamma*1 to IFN-gamma*8 could be differentiated. Among Graves' disease patients IFN-gamma*5 (12.9% vs. 6.8%, p < 0.04) was significantly more frequent whereas IFN-gamma*2 (2.5% vs. 9.8%, p < 0.002) was significantly less frequent. Patients positive for the genetic susceptibility marker HLA DQA1*0501 had significantly more IFN-gamma*3 alleles (13.6% vs. 2.6%, p < 0.009) and IFN-gamma*5 alleles (22.1% vs. 7.6%, p < 0.03) compared with DQA1*0501 positive controls. Also, among patients with endocrine ophthalmopathy IFN-gamma*3 (17.9% vs. 4.2%, p < 8 x 10(-6)) and IFN-gamma*5 (18.9% vs. 7.0%, p < 0.003) were significantly more frequent compared with controls. Although a significant association of IFN-gamma microsatellite polymorphism was observed, only a small proportion of Graves' disease patients have these markers. Thus, it is likely that the detected microsatellite polymorphisms play only a minor role in the susceptibility to Graves' disease.     

Rapid screening method for detecting mutations in the 21-hydroxylase gene

Impaired synthesis of adrenal steroid hormones because of steroid 21-hydroxylase deficiency is one of the most common inborn errors of metabolism. To expedite molecular diagnosis in families with 21-hydroxylase deficiency, we have designed a rapid strategy to determine nine of the most common mutations in the 21-hydroxylase gene. According to the mutation to be detected, we apply either of two simple strategies: digestion with adequate restriction enzyme or use of the amplification-created restriction site (ACRS) approach and subsequent restriction analysis. Both procedures are rapid and, being nonradioactive, are safer to perform; moreover determination of zygosity in the analyzed mutations requires only one tube per mutation.     

Screening for trisomy 21 by measuring nuchal translucency during the first trimester of pregnancy

The purpose of the present literature review is to assess the screening value of trisomy 21 by measurement of fetal nuchal translucency (NT) thickness in the first trimester. NT is a subcutaneous translucency between the skin and the soft tissues overlying the cervical spine, which disappears in the second trimester. Ultrasound examination was used to image a sagittal section of the fetus to measure the maximum thickness of the subcutaneous translucency. NT is physiological for a measurement < 3 mm but the incidence of chromosomal abnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 mm. Differential diagnoses include cystic hygroma and fetal hydrops. For screening purposes, a cut-off threshold value of > or = 3 mm, with a standardized technique, gave a sensitivity > or = 50%, a false positive rate < 5% and a positive predictive value > 1%. In the chromosomally normal group, prognosis was good, but incidence of structural defects and fetal loss increased, with a sharp rise in these complications for fetal translucency thickness > or = 5 mm.     

Collagen type VI gene expression in the skin of trisomy 21 fetuses

Using site-directed mutagenesis, changes of Tyr221 in plasminogen activator inhibitor-1 (PAI-1) have provided mutants with normal activity, but with increased stability. At physiological conditions, the transition of the PAI-1 mutants Tyr221His and Tyr221Ser to the latent form was significantly prolonged (half-lives 14.8 and 4.1 h, respectively) as compared to wild-type PAI-1 (2.0 h). Their half-lives, especially for the Tyr221Ser mutant, were even more prolonged in the presence of vitronectin (23.8 and 53.7 h, respectively). While wild-type PAI-1 was more stable at lower pH, the PAI-1 mutants Tyr221His and Tyr221Ser had stability optima at about pH 6.5, but displayed shorter half-lives at pH 5.5.     

Ophthalmic findings with partial trisomy (duplication) of the long arm of chromosome 7

BACKGROUND: The sensitivity of diagnostic imaging of processes in the parotid gland has been increased by improved spatial resolution, yet specificity remains unchanged. The purpose of this study was to determine whether the low-flow color duplex technique alters the specificity of B-mode ultrasonography. PATIENTS AND METHODS: Forty-one patients with tumors of the parotid gland were examined by color duplex echography as well as histologically. Twenty-eight of the 41 patients had benign tumors and 13 had malignant disease. In 17 of 41 patients, color duplex ultrasonography failed to detect any vascularization within the tumor. Histopathological examination showed that 3 of these 17 tumors were malignant and 14 of 17 were benign. Intranodal vascularization was detected in 24 cases. Ten of these patients were found to have malignant tumors of the parotid gland; 14 had benign parotid tumors. RESULTS: Our present findings show that marked intratumoral vascularization especially appears in malignant tumors. In contrast to lymph nodes, the location and texture of intranodal blood vessels do not provide information about the nature of the neoplasm. CONCLUSIONS: Low flow duplex ultrasonography does not increase the specificity of preoperative examination in tumors of the parotid gland.     

HELLP syndrome in the 21st week of pregnancy in mosaic trisomy 9

We report for the first time the case of postabortional HELLP-syndrome in the 21st week of gestation. In this case mosaic trisomy 9 was confirmed by amniocentesis prior to induction. Pertinent history, clinical course and pathoanatomical morphology are described. We emphasize the early onset of the HELLP-syndrome in association with trisomy 9 after abortion. The possibility of interconnections between trisomy 9 and the occurrence of HELLP-syndrome (sparse blood, vessels in the villi, circulatory deficit on the fetal side of the placenta, increased production of e.g. vasopressive substances) is discussed.     

Natural history of false-negative papanicolaou smears: a prospective study using screening colposcopy in addition to cytology

The regular Papanicolaou (Pap) smear is cornerstone of women's preventive healthcare. The introduction of the regular Pap smear as a screening tool for cervical cancer has markedly decreased the number of deaths from cervical cancer. During the past decade, however, the rate of death from cervical cancer has remained relatively static. This screening method is known to have a high rate of false-negative results; therefore, serial examinations are necessary for optimal sensitivity. The sensitivity of the routine pelvic examination is further increased with the addition of colposcopy to cytologic screening. Patients identified as having disease by colposcopy and biopsy but not by Pap smear (false-negative), are followed up, and the progression of their disease is documented until the Pap smear reflects the known change. A total of 276 patients whose Pap tests showed "no abnormal cells" and mild dysplasia (CIN-1 [cervical intraepithelial neoplasia]) by colposcopy and biopsy, who opted not to be treated, were followed up as a function of time. The results of the Pap test on the 276 patients progressed to a low-grade squamous intraepithelial lesion (LGSIL) or higher within 42 months. In this study, false-negative Pap tests that were identified by simultaneously performed colposcopy became positive within 42 months; therefore, careful repetitive screening is necessary. The author argues that a definitive, prospective study on the addition of colposcopy or similar adjunct procedure to the routine pelvic examination, in selected cases, is needed.     

Cross-hybridization of the chromosome 13/21 alpha satellite DNA probe to chromosome 22 in the prenatal screening of common chromosomal aneuploidies by FISH

In a routine application of commercially available centromeric DNA probes for the prenatal screening of common trisomies involving the autosomes 13, 18, and 21, and sex chromosomes, four cases of discrepancy between fluorescence in situ hybridization (FISH) results and follow-up cytogenetic analysis were observed from a total of 516 cases of amniocentesis. In three of these cases, the results were false negative, and in one false positive. In this case, amniocentesis was performed because of a positive triple test in a 34-year-old woman with previous infertility treatment. The alpha satellite DNA probe for chromosomes 13/21 revealed five signals in 50 per cent of uncultured amniocytes, while standard cytogenetic analysis showed a normal karyotype. FISH analysis on metaphase chromosomes demonstrated the location of the additional signal in the centromeric region of chromosome 22. This additional signal was also present in the centromeric region of chromosome 22 of the mother, providing evidence for a possible inherited polymorphism in chromosome 22 responsible for unspecific hybridization with the alpha satellite probe for chromosomes 13/21 in this case. The observed polymorphism in centromeric regions may contribute to unreliability of the use of the 13/21 alpha satellite probe for prenatal screening by FISH.     

Morphological classification of nuchal skin in human fetuses with trisomy 21, 18, and 13 at 12-18 weeks and in a trisomy 16 mouse

An increase in the nuchal translucency that can be detected at 10-14 weeks of gestation by ultrasound forms the basis for a screening test for chromosomal abnormality. Several mechanisms leading to this increase in skin thickness have been proposed, including changes of the extracellular matrix, cardiac defects and abnormalities of the large vessels. This study examines the composition of the extracellular matrix of the skin in gestational age-matched fetuses with trisomy 21, 18 and 13 from 12-18 weeks. Immunohistochemistry was applied with monoclonal and polyclonal antibodies against collagen type I, III, IV, V and VI and against laminin and fibronectin. Collagen type VI gene expression was further studied by in situ hybridization to detect differences in expression patterns of COL6A1, COL6A3 and COL1A1 between normal fetuses and those with trisomy 21. The ultrastructure of tissue samples was studied by transmission electron microscopy (TEM) and additionally by immunogold TEM. Further, we examined the morphology of the skin in an animal model for Down's syndrome, the murine trisomy 16, by light and TEM. The dermis of trisomy 21 fetuses was richer in collagen type VI than that of normal fetuses and other trisomies, and COL6A1, located on chromosome 21, was expressed in a wider area than COL6A3, which is located on chromosome 2. Collagen type I was less abundant in the skin of trisomy 18 fetuses, while the skin of all three trisomies contained a dense network of collagen type III and V in comparison with normal fetuses. Collagen type IV, of which two genes are located on chromosome 13, was expressed in the basement membranes of the skin in all fetuses and additionally in the dermal fibroblasts only of trisomy 13 fetuses. Likewise, laminin was present in all basement membranes of normal and trisomic fetuses as well as in dermal fibroblasts of fetuses with trisomy 18. LAMA1 and LAMA3 genes are located on chromosome 18. Dermal cysts were found in the skin of trisomy 18 and 13, but not in trisomy 21 and normal fetuses. Ultrastructural findings showed that an extracellular precipitate containing glycosaminoglycans was regularly present in the skin of trisomy 21 fetuses and murine trisomy 16 embryos. In conclusion, this study suggests that the skin edema in fetal trisomies is characterized by specific alterations of the extracellular matrix that may be attributed to gene dosage effects as a result of a genetic imbalance due to the condition of fetal trisomy.     

An analysis of meiotic pairing in trisomy 21 oocytes using fluorescent in situ hybridization

We report the use of chromosome 21-specific painting probes to analyze early stages of oogenesis in nine trisomy 21 fetuses. The proportion of cells in zygotene and pachytene in the trisomic ovaries ranged from 8 to 70% with a mean of 42% +/- 19 while the comparable values of euploid specimens ranged from 34 to 90% with a mean of 65% +/- 19. The low proportion of pairing cells may be the basis for the ovarian dysgenesis observed in some trisomy infants. Five percent of trisomic pachytene cells exhibited complete asynapsis which is an order of magnitude higher than that observed in euploid cells. A large fraction of the asynaptic cells were atretic which is consistent with the hypothesis of meiotic pairing as a signal for atresia. In addition, the asynaptic cells exhibited asynapsis of chromosomes other than 21, which we interpret as an interchromosomal effect of trisomy 21.