Hsal 1 is related to kidney and gonad development and is expressed in Wilms tumor.

Townes-Brocks syndrome (TBS) is a human genetic disorder with features including urogenital, limb, anal and cardiac malformations associated with mutations of the TBS gene, Hsal 1. To begin to understand the role of the Hsal 1 protein (p140) in both normal development and disease pathogenesis, both message and protein expression were evaluated in specific tissues associated with TBS. DNA sequence information for Hsal 1 predicts that this homeotic, Drosophila homologue (Sal) encodes a zinc-finger protein consistent with a transcription factor. mRNA for Hsal 1 was highly expressed in fetal kidney and brain, with detectable production in thymus and heart. p140 was found in fetal ureteric bud, fetal and postnatal renal tubular epithelium, and renal blastema. In the 14-week fetal testis, the Hsal 1 protein was specifically expressed in the testosterone producing Leydig cells while in adult gonads Hsal 1 was also found in both Leydig and Sertoli cells, spermatogonia of the testis, and granulosa cells of the ovary. Evaluation of Wilms tumor revealed consistently high expression of the gene product in the epithelial and blastemal components. These spatial and temporal patterns of expression for Hsal 1, and the phenotypic effects associated with TBS, suggest that Hsal 1 plays an important role in the development and functional maintenance of the kidney and gonads. Furthermore, the Hsal 1 gene product may play a part in the pathogenesis of specific neoplasms occurring in these organs in addition to its specific role in Townes-Brocks syndrome.

The placenta in pseudoxanthoma elasticum: clinical, structural and immunochemical study.

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder clinically characterized by skin, cardiovascular and eye manifestations, mainly due to calcification and fragmentation of elastic fibres. Although infrequent, complications during pregnancy in women affected by PXE have been reported. The aim of the present study was to compare structural features of placentae at term from 14 control and 15 PXE-affected women, in order to better understand if and how abnormal mineral and/or matrix accumulation might affect placental function in PXE. In all cases, pregnancy, fetus growth and delivery were normal. Both gross and light microscopy examination did not reveal dramatic differences between placentae of PXE patients and controls, with regard to weight, dimensions, infarcts, thrombi, inflammatory lesions or vessels. However, necrotic changes and mineralization appeared statistically more pronounced in PXE. By electron microscopy the most remarkable differences between PXE and control placentae were observed in the localization and morphology of mineral precipitates; a significant higher deposition of mineral precipitates was observed associated with the "matrix"-type fibrinoid and among collagen fibrils, especially on the maternal side. Immunocytochemistry revealed the presence of vitronectin and fibronectin associated with the PXE-specific mineralizations and the absence of mineralization on the small and scarce elastic fibres in either controls or in PXE.

Atypical squamous metaplastic cells: reproducibility, outcome, and diagnostic features on ThinPrep Pap test.

BACKGROUND: Atypical squamous metaplastic (ASM) cells are associated with high-grade squamous intraepithelial lesions (HGSIL) in many cases. The reproducibility of the diagnosis and biopsy follow-up results of cases designated as ASM were studied at Women and Infants' Hospital of Rhode Island. METHODS: Of 180 patients with ASM who the authors examined from January 1, 1998 to September 30, 1998, 147 (81.7%) had subsequent biopsies. Results of the biopsies were tallied. Twenty cases were rescreened in a blinded fashion to determine intra- and interobserver agreement and to identify diagnostic features. RESULTS: Sixty-five (44.2%) cases of ASM had HGSIL on biopsy, 26 (17.7%) had low-grade squamous intraepithelial lesion, and 56 cases (38.1%) were benign. Overall individual consistency is 8 of 16 (50%), and overall agreement is 13 of 64 (20%). CONCLUSIONS: Sixty-two percent of cases designated as ASM cytologically were associated with SIL, primarily HGSIL, at biopsies. The findings underscore the importance of this subcategory of atypical squamous cells. However, poor reproducibility suggests the need for refined criteria and/or continuing education, and obtaining second opinion. Cancer (Cancer Cytopathol)

Asplenic-hyposplenic overwhelming sepsis: postsplenectomy sepsis revisited.

Absence of the spleen or splenic function predisposes individuals to risk of overwhelming infection. These infections are most often due to encapsulated organisms, especially pneumococcus, Haemophilus influenzae type b, and meningococcus, but any bacterial agent may cause the rapid onset of septicemia, meningitis, pneumonia, and shock characteristic of the asplenic-hyposplenic condition. The risk is greatest in infants and young children, but asplenic-hyposplenic adults also have an increased risk of infection. Prophylactic antibiotics and immunization with polyvalent pneumococcal, H. influenzae type b, and meningococcal vaccines have reduced the incidence of infections in asplenic-hyposplenic individuals, but even these measures have not eliminated the risk. Surgeons have adopted techniques to save as much splenic tissue as possible and some splenic functions, such as pitting red cells, have been preserved, but conservative surgery has not provided total protection against overwhelming infection. Therapies designed to interrupt the cascade of overwhelming sepsis have not yet been successful. In those cases in which the spleen is surgically removed, the underlying disease or condition leading to splenectomy influences the risk of sepsis. Splenectomy incidental to other operations, such as gastrectomy, results in the lowest risk for overwhelming infection, but this is still some 35-fold greater than the risk for overwhelming infections in the general population. In increasing order of risk, the other main indications for surgical removal of the spleen are idiopathic thrombocytopenia purpura, trauma, transplantation procedures, hereditary spherocytosis, staging Hodgkin's disease, portal hypertension with hypersplenism, and thalassemia. Pathologists should comment on the risk of overwhelming sepsis when spleens are processed as surgical specimens, and should carefully weigh all splenic tissue, including accessory spleens and splenic implants (splenosis), in autopsy cases with and without overwhelming sepsis.

Beta-cell hyperplasia in macrosomic infants and fetuses of nondiabetic mothers.

The objective of this study was to test the hypothesis that macrosomic infants of nondiabetic mothers have beta-cell hyperplasia in their pancreases. Pancreatic tissues were examined from 10 macrosomic fetuses and liveborn infants and from 10 comparison cases matched for gestational age and gender. None of the mothers had a history of diabetes and all had normal glucose screening during pregnancy. Tissues were stained with hematoxylin and eosin and a monoclonal antibody against beta cells and were analyzed using an image analysis program to evaluate the size and surface area of beta-cell clusters. Brain/liver weight ratios were calculated and compared. The total surface area and cluster size of beta cells in the pancreases of macrosomic subjects were significantly larger than in the comparison pancreases. The study subjects lacked macroscopic and histopathologic findings expected in infants of diabetic mothers. We conclude that some macrosomic fetuses and infants of nondiabetic mothers manifest beta-cell hyperplasia. This corresponds to the higher insulin levels in macrosomic infants of nondiabetic mothers described in previous clinical studies. In macrosomic fetuses the stimulus for beta-cell hyperplasia may not involve aberrant maternal glucose levels.

Hepatic subcapsular hematomas in fetuses and neonatal infants.

In fetuses and neonates hepatic subcapsular hematomas are relatively common lesions and may be life-threatening. Conditions previously associated with these hematomas include trauma, coagulopathies, hypoxia, sepsis, pneumothorax, maternal diseases, and placental lesions. In this study of 755 perinatal autopsies, hepatic subcapsular hematomas were found in 52 (6.9%) cases, including 31 stillborn fetuses and 21 liveborn infants. The average body weight was 690 g. A comparison group consisted of 52 temporally proximal autopsies of fetuses and neonates without hematomas. Body weights, gender, maternal age, and stillbirth or postnatal survival were matched as closely as possible while evaluating the presence or absence of sepsis, pneumothorax, cerebral germinal matrix hemorrhage, trauma, coagulopathy, placental lesions, and maternal diseases. Sepsis was associated with 62% of the cases with hepatic subcapsular hematomas and with 25% of the comparison group (P =.0001). Group B streptococcus infection was the most common cause of sepsis, but many different organisms were isolated. Cerebral germinal matrix hemorrhages were present in 35% of the cases with hematomas and in 14% of the comparison group (P =.0001). No other lesions or conditions were statistically different in the study group versus the comparison group. The delicacy of the hepatic capsule and its connections to the collagen along the sinusoids provide insight for the pathogenesis of hematomas in premature fetuses and neonates. We conclude that sepsis is present in most perinatal cases of hepatic subcapsular hematomas and that such patients also frequently have cerebral germinal matrix hemorrhages. Each of these lesions is a greater hazard among very small premature fetuses or neonates than among older fetuses and neonates.

First trimester pregnancy loss associated with varicella zoster virus infection: histological definition of a case.

Pathological demonstration of varicella infection in first trimester aborted tissue is reported. A 24-year-old primigravida manifested chickenpox infection about 38 days after her last menstrual period or at 24 days age of the embryo. The conceptus survived another 4 to 5 weeks. The macerated embryo and placental tissue revealed nuclear changes consistent with varicella infection. Immunohistochemical stains and electron microscopy were confirmatory.

Central nervous system malformations in a perinatal/neonatal autopsy series.

Congenital malformations of the central nervous system (CNS) are among the most common anomalies, but data on the incidence of CNS malformations in autopsy populations are scant. We examined 4122 autopsies between the years 1958 and 1995. There were 363 cases (8.8%) with CNS malformations; 235 were neonates and 128 stillborns. The overall gender ratio was 1:1, although more male neonates and more female stillborns had malformations. The body weights ranged from 24 to 6440 g. Neural tube defects were the most common types of malformations (45.5%) and included anencephaly, meningoencephalocele, meningocele/meningomyelocele, craniospinal rachischisis, and spina bifida occulta. The incidences of other malformations were: congenital hydrocephalus (12.4%), neuronal/glial proliferation disorders such as micro- and macrocephaly (8.8%), neuronal migration disorders (8.8%), prosencephalon growth disorders such as holoprosencephaly and arhinencephaly (8.5%), abnormalities of the midline structures such as agenesis of corpus callosum (4.1%), developmental cysts (3.3%), cerebellar malformations (3%), and vascular malformations (2%). Miscellaneous malformations (3%) consisted of acephalia in four cases with twin reversed arterial perfusion (TRAP), two cases of hydranencephaly, and four cases of rare degenerative and metabolic encephalopathies.

Reference values for singleton and twin placental weights.

The largest series of normal singleton placental weights was collected in the Collaborative Perinatal Study between the years 1959 and 1966 but values for normal twin placental weights were not published. In our study we examined 787 singleton and 514 twin normal placentas. Placentas with associated conditions known to affect the weights of placentas were excluded. After establishing the normal values for singleton and twin placental weights, we concluded that weight gain of twin placentas appears to accelerate between 24 and 36 weeks but reaches a plateau after 37 weeks, whereas singleton placentas appear to gain weight more uniformly throughout gestation. The mean values of twin placental weights for each gestational age are less than double those of singleton placental weights for the same duration of gestation. Our singleton and twin placentas are heavier than those from previously published data and may reflect a generational or nutritional change over the 30 years since the original numbers were compiled.

Pathology of the lung in surfactant-treated neonates.

Respiratory distress syndrome (RDS) is associated with prematurity-related deficiency of surfactant. Surfactant replacement therapy has been used in premature infants to prevent RDS or reduce its severity. In this study we describe the pathology of the lungs after surfactant replacement therapy. All the neonatal autopsies during the years 1989 and 1990 (n = 235) were examined. Infants > or = 31 weeks gestation, with congenital anomalies or who lived more than 2 weeks were excluded from the study. Infants who had received intratracheal Survanta, a modified surfactant extracted from cow lung (n = 14), were compared with infants who did not receive exogenous surfactant (n = 20). The two groups were statistically comparable in terms of weight, gestational and postnatal age, gender, and clinical management. H&E-stained lung sections were examined independently by two pathologists without knowledge of surfactant treatment status; any discrepancies in histological evaluation were resolved by joint review. Nine histological features were evaluated including hyaline membranes, necrosis of the epithelium, hemorrhage, edema, inflammation, metaplasia, arteriolar muscular hyperplasia, interstitial fibrosis, and pulmonary interstitial emphysema (PIE). Histological changes were graded from 0 to 3+. When it was present, cerebral periventricular-intraventricular hemorrhage (PVH-IVH) was graded 1-4. The presence or absence of sepsis and necrotizing enterocolitis (NEC) were also determined. Comparisons between patient groups were performed using the Mann-Whitney U, Student's t and chi 2 tests. The severity of hyaline membrane disease, PIE, and epithelial necrosis was less severe in the surfactant-treated group than in the untreated group. There were no differences between the two groups in the degree of pulmonary hemorrhage or in the incidence of PVH-IVH, sepsis, or NEC.

Fryns syndrome: a new definition.

Fryns syndrome is a lethal, autosomal recessive syndrome of multiple congenital anomalies described by Fitch et al. in 1978 and Fryns et al. in 1979. As originally described, the major diagnostic criteria included abnormal facies; small thorax with widely spaced, hypoplastic nipples; distal limb and nail hypoplasia; and diaphragmatic hernia with pulmonary hypoplasia. Malformations involving other systems occurred irregularly in published reports. We reviewed 41 published cases of Fryns syndrome and added 4 cases of our own. The major diagnostic criteria described by Fryns were consistent in all cases with the exception of two criteria. Narrow thorax with hypoplastic nipples and gastrointestinal anomalies were present in less than 50% of the cases. Although for 16 of the 41 published cases there was no information on central nervous system findings, 21 of the 29 remaining cases (72%) had CNS malformations. These lesions were absence of corpus callosum, arhinencephaly, and heterotopia of cerebral and cerebellar tissue. Similarly, for 12 of the 41 published cases there was no information on cardiovascular findings but 29 of the 33 remaining cases (88%) had congenital heart disease. These lesions were ventricular septal defects, arterial septal defects, and persistent left superior vena cava. We conclude that central nervous system anomalies and congenital heart disease should be added to the major diagnostic criteria of Fryns syndrome.

Detection of human parvovirus B19 in early spontaneous abortuses using serology, histology, electron microscopy, in situ hybridization, and the polymerase chain reaction.

OBJECTIVE: To determine whether there is an association between parvovirus B19 infection and early spontaneous abortion at less than 20 weeks' gestation. METHODS: Eighty samples of early spontaneous abortions were analyzed. Each sample was examined histologically for the presence of viral inclusions, and selected cases were analyzed for parvovirus using electron microscopy and in situ hybridization. Polymerase chain reaction DNA amplification for the virus was done in each case. Maternal sera were analyzed for immunoglobulin (Ig) M and IgG parvovirus antibodies and compared with temporally matched controls. RESULTS: Five cases in the study group had evidence of seroconversion for parvovirus, compared with two controls. Products of conception from two of these five cases were positive for virus by polymerase chain reaction amplification, and only one of these two had a characteristic inclusion of parvovirus histologically. Conversely, five chorionic vesicles from mothers who had not seroconverted had histologic changes suggesting parvovirus infection, but all of these cases were negative for parvovirus using in situ hybridization, polymerase chain reaction, and electron microscopy. CONCLUSIONS: Parvovirus B19 DNA was found in two of 80 early spontaneous abortuses. Although viral DNA was detected in two cases, there was no clear evidence that the infections caused fetal death. Neither case showed erythroblastosis with large numbers of inclusions, as is seen in hydropic fetuses with parvovirus infection. In addition, in five cases in which parvovirus infection was not documented serologically or by the polymerase chain reaction, there was erythroid nuclear clearing suggestive of parvovirus B19 inclusions. This indicates that histologic evaluation for parvoviral inclusions is not always reliable in early spontaneous abortuses.

Estimating the time of death in stillborn fetuses: III. External fetal examination; a study of 86 stillborns.

OBJECTIVE: To determine how accurately the time of fetal death can be predicted from the extent of external maceration in a stillborn fetus. METHODS: Autopsy photographs of 86 stillborns with well-timed deaths were studied retrospectively. Sixty randomly chosen fetuses (learning set) were assessed unblinded to develop proposed gross criteria for timing fetal death; 26 fetuses (test set) were then randomly and blindly assessed to test the accuracy of the proposed criteria. RESULTS: The two earliest changes in the learning cases were areas of desquamation measuring at least 1 cm in diameter and brown-red discoloration of the umbilical cord stump. Both changes occurred primarily in fetuses with death-to-delivery intervals of 6 or more hours. Other early changes included desquamation involving the face, abdomen, or back (12 or more hours); desquamation involving 5% or more of the body surface (18 or more hours); brown skin discoloration (24 or more hours); and a moderate or severe extent of desquamation (24 or more hours). The only late change that correlated with a specific duration of intrauterine retention was mummification (2 or more weeks). When the 26 test fetuses were randomly and blindly assessed using these gross criteria, 18 (69%) were classified correctly with respect to the approximate time of fetal death. CONCLUSION: External fetal examination is useful for estimating the time of death in many stillborns; this information may be helpful when a complete autopsy cannot be performed.

Undifferentiated small cell hepatoblastoma with a unique chromosomal translocation: a case report.

Cytogenetic studies of pediatric tumors have revealed a number of reproducible karyotypic abnormalities, including del(p13) found in aniridia-Wilms' tumor association, t(8;14) in Burkitt's lymphoma, and t(11;22) in Ewing's sarcoma. To date, no consistent cytogenetic abnormality has been reported in association with hepatoblastoma. We report the case of a 7-month-old male infant with the undifferentiated small cell variant of hepatoblastoma. Immunohistochemistry revealed reactivity with antibodies to cytokeratin and vimentin throughout the tumor. Alpha-fetoprotein, neuron-specific enolase, and S100 stains were negative. Chromosomal analysis of metaphase cells from a culture of tumor tissue revealed a translocation of most of the long arm of chromosome 22 to the distal long arm of chromosome 10.

The urinary system in Down syndrome: a study of 124 autopsy cases.

We examined 124 autopsy cases of Down syndrome for the presence of renal and urinary tract abnormalities. The cases were divided into three groups: (I) fetuses of 16-22 weeks gestation (n = 18), (II) stillborns or newborns who died on the first day of life (n = 9), and (III) Down patients 1 day to 25 years of age (n = 97). Kidney weight was reduced by a mean of 14.4% compared with expected values. Renal hypoplasia, defined as kidney weight less than two-thirds expected, was found in 18 cases. Glomerular microcysts were found in 23 of 97 cases in group III. Focal dilatation of tubules was found in 10, simple cysts in 7, and immature glomeruli deep in the renal cortex in 18 cases. Obstructive uropathy occurred in 2 of 18 (11.1%) in group I, 2 of 9 (22.2%) in group II, and 4 of 97 (4.1%) in group III. Obstructive uropathy with bilateral cystic dysplastic kidneys resulted in Potter's sequence. We suggest that obstructive uropathy is associated with Down syndrome. When severe, it results in Potter's sequence and an early perinatal death. A chromosomal analysis is recommended in any case of obstructive uropathy in the fetal or neonatal period.

Streptococcus viridans infections in midgestation.

During a 14-year period Streptococcus viridans was isolated at autopsy from 18 neonates or stillborn fetuses delivered in midgestation (18-28 weeks) at Women & Infants' Hospital in Providence, Rhode Island. Evidence of swallowed and/or aspirated, infected amniotic fluid by the fetus was found in 16 of 18 cases along with chorioamnionitis and funisitis. Of the 18 cases, maternal infection was documented in 6 cases; delivery was preceded by spontaneous rupture of membranes in 9 cases and vaginal bleeding in 7 cases. Poor maternal obstetric history was indicated by only 12 living children from 42 total pregnancies in the 12 multigravidas in the study. It is concluded that S. viridans may have a significant role in the pathogenesis of second trimester amniotic fluid infections with abortions and fetal and neonatal sepsis.

Infections, preterm delivery, and perinatal death in midgestation.

Amniotic fluid infection results in considerable pregnancy wastage in the second and early third trimesters. In our study of 1119 perinatal autopsies amniotic sac infection was associated with death in 133 fetuses and neonates in midgestation. These cases accounted for almost 12% of all perinatal autopsies and for 20% of all perinatal autopsies in midgestation at Women and Infants Hospital during the past decade. Gram-positive organisms, especially coagulase negative staphylococcus, group B streptococcus and Streptococcus viridans, were the most common pathogens isolated.