Fatal intrauterine adenoviral endomyocarditis with aortic and pulmonary valve stenosis: diagnosis by polymerase chain reaction.

We report a case of fatal hydrops fetalis owing to adenoviral endomyocarditis with aortic and pulmonary valve stenosis. A 1850-g macerated male stillborn delivered 1 week after fetal ultrasonography showed hydrops, cardiomegaly, and possible aortic valve stenosis. Autopsy confirmed hydrops and showed thickened, fibrotic semilunar valves with stenosis. The myocardium was focally fibrotic with areas of calcification. Polymerase chain reaction study of myocardial and aortic valve tissue was positive for adenovirus. Intrauterine viral myocarditis has been reported only rarely, but cases owing to Coxsackie B virus, adenovirus, and parvovirus B19 have appeared in the literature. With the exception of rubella, viral causation of significant valvular lesions in humans has received scanty support in the literature. This report suggests a broader group of causative agents. HUM PATHOL 31:1433-1435.

In utero development of hypertensive necrotizing pulmonary arterial lesions: report of a case associated with premature closure of the ductus arteriosus and pulmonary hypoplasia.

Premature closure of the ductus arteriosus (PCDA) is an uncommon defect in which pulmonary hypertension (PH) has been documented by echocardiography in patients and by direct measurement after experimental PCDA in animals. The pulmonary vascular histology in human cases has received little attention but in the few recorded observations the vessels were either normal or showed increased muscularity. We report the case of a 31 week hydropic female stillborn monozygotic twin in whom postmortem examination disclosed PCDA and hypoplasia of the lungs. Atypical plexiform lesions with necrotizing pulmonary arteritis were present. These lesions represent vascular consequences of severe pulmonary hypertension produced by greatly enhanced blood flow through a restricted vascular bed resulting from the combined effects of these two abnormalities. The findings in this case of PCDA with presumed severe PH indicate that severe pulmonary vascular changes can develop in utero and that the interval of time needed for development of such chances in secondary PH is relatively short.

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.

Neonatal hemochromatosis, renal tubular dysgenesis, and hypocalvaria in a neonate.

We report a neonate with neonatal hemochromatosis (NH), renal tubular dysgenesis (RTD), and hypocalvaria. NH is a fatal condition of the newborn, characterized by severe idiopathic liver failure of intrauterine onset and siderosis, intra- and extrahepatic, with sparing of the reticuloendothelial system. RTD is characterized by short, abnormally developed cortical tubules that lack proximal tubule differentiation. Although both NH and RTD have been reported as entities with a genetic component, similar findings can be secondary to in utero insults. Hypocalvaria has been reported in association with fetal hypoxia including that secondary to angiotensin converting enzyme inhibitors. This 38-week-old infant died at 8.5 h. The small nodular liver weighed 44 g. Grossly, the kidneys were normal. Hypocalvaria was present. Microscopically, the hepatic parenchyma was distorted by fibrous tracts, proliferation of bile ducts, and abundant iron deposition in hepatocytes. Extrahepatic siderosis in the pancreas, myocardium, and other organs was consistent with NH. Proximal convoluted tubules were not seen on routine stains and markers for proximal tubules were negative. Previous reports have linked NH with RTD and RTD with hypocalvaria. This infant had all three of these rare conditions, which have been hypothesized or shown to be due to genetic factors, hypoxia, or drugs. The etiology in this case is unknown.

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.

Cleidocranial dysplasia with neonatal death due to central nervous system injury in utero: case report and literature review.

Cleidocranial dysplasia (CCD), an uncommon disorder involving membranous bones, is rarely lethal in early life. The calvaria is defective and wormian bones are present. Abnormalities of the clavicles vary in severity from a minor unilateral defect to bilateral absence. This report concerns pre- and postmortem anatomical and radiological findings in a 15-day-old female neonate with CCD. Her postnatal course was characterized by seizures and recognition of hydrocephalus during the first day of life. The calvaria was hypoplastic with numerous wormian bones. A pseudofracture of the right clavicle was present. Hydrocephalus was present in the brachycephalic brain which had a severely thinned cerebral cortex. Hemosiderin in the ventricular lining and marked subependymal gliosis were interpreted as evidence of old intraventricular hemorrhage that had occurred in utero. A CCD-related condition, Yunis-Varon syndrome (YVS), is noted for early lethality and for developmental and secondary abnormalities of the central nervous system. The present case only partially matches the phenotype of YVS and might represent a part of a spectrum of phenotypic variants ranging from viable CCD to lethal YVS.

Ischemia-reperfusion injury in the intestines of newborn pigs.

Although the pathogenesis of necrotizing enterocolitis remains uncertain, ischemia appears to be an important contributing factor to the development of this disorder. Reperfusion plays a major role in ischemia-related injury, and oxygen free radicals produced during reperfusion most likely contribute to the injury. These oxidants can be generated during prostanoid metabolism, which increases during reperfusion of ischemic gut in adult subjects. The present study was designed to: 1) examine the effects of superior mesenteric artery occlusion, e.g. ischemia and reperfusion in vivo on the development of histopathologic intestinal injury; 2) determine whether products of arachidonic acid metabolism, e.g. prostanoids are increased during reperfusion of ischemic gut; and 3) determine whether oxygen free radical scavengers attenuate the injury in newborn pigs. Chronically catheterized placebo-pretreated newborn pigs exposed to ischemia-reperfusion, placebo-pretreated nonischemic control pigs, and polyethylene glycol-superoxide dismutase (SOD) plus polyethylene glycol-catalase (CAT)-pretreated, ischemic pigs were studied by examining changes in intestinal circulation, oxygenation, prostanoids, and tissue injury. In the placebo-pretreated pigs, intestinal blood flow decreased to very low levels during superior mesenteric artery occlusion. During reperfusion, blood flow increased, but remained below baseline. After ischemia, oxygen uptake returned to values that were similar to baseline. Intestinal efflux of the vasodilator 6-keto-prostaglandin F1alpha was evident (p < 0.05 versus no or zero efflux) during early reperfusion. Histopathologic scoring of terminal ileal samples showed significant mucosal necrosis, surface epithelial disruption, lamina propria congestion and hemorrhage, submucosal hemorrhage, edema, and increases in cells compared with the placebo-pretreated nonischemic pigs. In the SOD plus CAT-pretreated ischemic pigs, changes in intestinal blood flow, oxygen uptake, 6-keto-prostaglandin F1alpha efflux, and the pattern of the ileal tissue injury did not differ significantly from the placebo-pretreated ischemic pigs. In summary, superior mesenteric artery occlusion for 1 h and reperfusion for 2 h resulted in severe intestinal ischemia, early postocclusive limited increases in intestinal perfusion and oxygen uptake, efflux of vasodilating prostanoids during early reperfusion, and signs of ischemic tissue injury in the placebo- and SOD plus CAT-pretreated pigs. This study demonstrates that, after superior mesenteric artery occlusion and reperfusion, severe intestinal tissue injury is detected in vivo, prostanoid efflux increases, and SOD plus CAT given just before occlusion does not attenuate the extent of injury in newborn pigs.

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.

The lethal hemolytic mutation in beta I sigma 2 spectrin Providence yields a null phenotype in neonatal skeletal muscle.

Point mutations in beta I sigma 1 spectrin that impair the self-association of spectrin alpha beta heterodimers cause mild to severe hemolytic disease and erythrocyte shape abnormalities. Most such mutations act in a dominant negative fashion. One mutation that is particularly devastating is found in beta spectrin Providence. The Providence mutation replaces serine2019 with proline. Heterozygotes display microcytic and fragile erythrocytes; homozygotes die in the neonatal period. It has recently been determined that an alternative transcript of the same beta I sigma 1 spectrin gene expressed in erythroid lineage cells is the major spectrin in skeletal and cardiac muscle and in some neurons. Because the site of the Providence mutation is common to both beta I sigma 1 and beta I sigma 2 spectrin, defective protein must also be expressed in these tissues. Yet the impact of this or any other beta I spectrin mutation outside of the red cell is unexplored. To address this question with respect to skeletal muscle, we have examined the effects of the Providence mutation in cultured muscle cells, after adoptive gene transfer to adult mice, and in two infants homozygous for spectrin Providence. Transfection of the FLAG epitope tagged wild-type beta I sigma 2 or Providence beta I sigma 2 cDNA constructs into C2C12 myoblasts demonstrated by sedimentation velocity analysis that spectrin beta I sigma 2 Providence formed alpha II/-beta I sigma 2 heterodimers in muscle cells but not heterotetramers. Correspondingly, wild-type beta I sigma 2 spectrin formed both alpha II/beta I sigma 1 dimers and heterotetramers, although the proportion of dimers was surprisingly high, which suggested some limitation on self-association in the muscle environment. After adoptive gene transfer into adult mouse skeletal muscle in vivo, both the wild-type and mutant beta I sigma 2 spectrins assembled into a subsarcolemmal complex in a pattern indistinguishable from the native spectrin skeleton. Skeletal muscle taken at autopsy from two infants homozygous for spectrin Providence was normal histologically, as was the intracellular distribution of beta I sigma 2 spectrin as measured by immunoperoxidase staining. These patients also revealed no clinical evidence of myopathy or muscle wasting. It is unknown if they would have experienced dystrophic or myopathic changes if they had lived longer, although we believe that this is unlikely based on the absence of clinical myopathies in patients with other (albeit less severe) beta I spectrin self-association defects. Collectively, these observations indicate that the spectrin mutations that impact tetramer and oligomer formation, even those with a severe hemolytic phenotype, do not impact skeletal muscle function primarily because skeletal muscle does not use the oligomerizing feature of the spectrin skeleton to the same degree as erythrocytes.

The detection of non-immune hydrops through second-trimester maternal serum screening.

The objective was to investigate whether non-immune hydrops in euploid pregnancies is associated with alterations in the second-trimester levels of maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Ten singleton cases of fetal non-immune hydrops were identified. The aetiology and timing of onset of the earliest signs of non-immune hydrops, including polyhydramnios, in relation to maternal serum screening for Down syndrome were assessed. There was no clear relationship between the aetiology of non-immune hydrops and the analyte levels, as aetiologies varied widely. AFP levels were elevated overall (median = 1.78 MOM) and uE3 levels were unremarkable (median = 0.82 MOM). hCG levels were elevated (median = 3.53 MOM) when non-immune hydrops was present at the time of screening, but were unremarkable (median = 0.82 MOM) when the non-immune hydrops presented later. It is concluded that second-trimester non-immune hydrops is associated with elevated hCG levels.

Liver and brain iron deficiency in newborn infants with bilateral renal agenesis (Potter's syndrome).

Significant changes in fetal iron status potentially occur in pregnancies in which reduced fetal nutrient delivery is severe enough to result in intrauterine growth retardation (IUGR), particularly if chronic fetal hypoxia is also present and increases fetal iron demand for hemoglobin synthesis. Neonates rarely die following IUGR secondary to maternal preeclampsia, but bilateral renal agenesis, which is also characterized by reduced maternal-fetal blood flow, late gestation placental failure, and IUGR, is uniformly fatal. We measured neonatal liver iron concentration, as an assessment of fetal storage iron status, and heart and brain iron concentrations, as assessments of nonheme tissue iron status, in 11 infants who died in the neonatal period of bilateral renal agenesis, and compared them with values for gestational age-matched control infants whose gestation was not complicated by fetal growth retardation or hypoxia. Stainable nonheme iron in the hepatocytes was significantly reduced in all and completely absent in 8 of the 11 cases of renal agenesis (P < .001 compared with control). The mean +/- SEM liver iron concentration of the bilateral renal agenesis group (999 +/- 218 micrograms/g dry tissue weight) was 26% of the control value (3894 +/- 548 micrograms/g dry tissue weight; P < .001). Brain iron concentration was also lower in the group with bilateral renal agenesis (109 +/- 17 vs. 161 +/- 19; P = .015) and was correlated with liver iron concentration (r = .47; P = .03). Heart iron concentrations were similar in the two groups. Nine of the subjects with bilateral renal agenesis had placental weights below the fifth percentile for gestational age. The bilateral renal agenesis group had a lower mean birth weight (P < .001) and had a higher prevalence of fetal growth retardation (55% vs. 0%; P < .001). We conclude that infants with bilateral renal agenesis are at risk for severe iron deficiency of storage and nonstorage tissues. Liveborn infants with nonfatal fetal conditions characterized by significant restriction of maternal-fetal blood flow may also be at significant risk for postnatal iron deficiency.

A normative study of obstetric complications associated with fetal trisomy 18.

Our objective was to determine whether the cesarean section rate and amniotic fluid lecithin-sphingomyelin ratio (L/S ratio) associated with fetal trisomy 18 are different from those associated with euploid pregnancies. Forty-nine trisomy 18 pregnancies were identified and their records were reviewed. Of the 22 live-born infants, 15 (68%) were delivered by cesarean section. The overall cesarean section rate for the institution ranged from 19.1% to 22.6%. In five patients with gestational ages between 35 and 38 weeks who had amniocentesis as part of the evaluation of intrauterine growth retardation, the L/S ratios were < or = 1.8. These data confirm that undiagnosed trisomy 18 pregnancies are associated with an increased cesarean section rate. Further, trisomy 18 fetuses appear to have delayed maturation of the L/S ratio. These results reinforce the importance of a karyotypic evaluation of selected pregnancies complicated by intrauterine growth retardation, even in the third trimester, and suggest that the prenatal diagnosis of trisomy 18 is of obstetric importance.

Cerebrohepatorenal (Zellweger) syndrome: clinical, neuropathological, and biochemical findings.

An infant with Zellweger syndrome is reported. A detailed description of the clinical findings is provided. In particular, the neuropathological aspects are highlighted and the underlying biochemical derangements discussed. In addition, some of the known pathogenetic mechanisms that are involved in producing the phenotype of Zellweger syndrome are analyzed.

Cardiac malformation in two infants with hypochondrogenesis.

Autopsy records from the Women and Infants' Hospital from January 1974 through January 1994 were reviewed to identify cardiac malformations in the presence of skeletal dysplasia. Of 24 cases of lethal fetal or neonatal osteochondrodysplasias, 4 were given diagnoses in which disorders of type II collagen are regarded as causative. These 4 were categorized in the spondyloepiphyseal dysplasia (SED) spectrum of disorders; specifically two patients with hypochondrogenesis and two with spondyloepiphyseal dysplasia congenita were identified. Defects in cardiac septation were noted in the 2 patients with hypochondrogenesis. No cardiovascular abnormalities were present in the remaining cases, which included thanatophoric dysplasia, osteogenesis imperfecta, and asphyxiating thoracic dystrophy. Although cardiovascular malformations have been described in other types of osteochondrodysplasias, e.g., short rib polydactyly syndrome type II and chondroectodermal (Ellis-van Creveld) dysplasia, congenital heart disease has not been described in hypochondrogenesis. Type II collagen, which has been found to be abnormal in some patients with hypochondrogenesis, is considered to have a limited tissue distribution, and has not been detected as yet in human myocardium. The findings presented here suggest that type II collagen may function in human cardiogenesis.

Unusual combination of congenital heart defects in an infant with Noonan syndrome.

Congenital heart disease occurs in 35-50% of patients diagnosed with Noonan syndrome. We present an infant with an unusual combination of congenital heart defects not previously reported, including partial atrioventricular septal defect, polyvalvular dysplasia, and progressive hypertrophic cardiomyopathy. We discuss the possible interaction between these lesions that may have led to the patient's rapid demise.

The clinical utility of the perinatal autopsy.

OBJECTIVE: To evaluate the clinical utility of the perinatal autopsy in determining the cause of a perinatal death. DESIGN: Retrospective observational survey. SETTING: University-affiliated, private, tertiary care hospital, limited to obstetrics, gynecology, and neonatology. SUBJECTS: All fetal deaths and neonatal deaths from 1990 and 1991 at Women and Infants Hospital, Providence, RI, were reviewed. Fetal deaths with a gestational age of less than 20 weeks and neonatal deaths occurring more than 48 hours after birth were excluded. MAIN OUTCOME MEASURES: A clinical medical record review assessed the clinical diagnosis. Pathology records were reviewed independently. The clinical and autopsy diagnoses were compared and categorized as follows: (1) confirm (clinical and autopsy diagnoses concordant); (2) change (clinical and autopsy diagnoses discordant); (3) add (significant unexpected findings noted on the autopsy although the clinical diagnosis was not altered); (4) autopsy inconclusive; (5) autopsy not done or not available. RESULTS: Of 168 perinatal deaths, an autopsy was not obtained in 26.2% and was inconclusive in 24.2% of cases with an autopsy. Of 94 patients with conclusive autopsies, in 55.3%, the pathologic diagnosis confirmed the clinical diagnosis, and in 44.7%, it changed or significantly added to the clinical diagnosis. CONCLUSIONS: These findings support the clinical relevance of the perinatal autopsy. As few published reports directly address the specific yield of the autopsy among fetal and neonatal deaths, these results may be useful in counseling patients who are considering a perinatal autopsy.

46,XX gonadal agenesis in a neonate with multiple congenital anomalies: case report and review of the literature.

We report a neonate with 46,XX gonadal agenesis, a rare disorder, confirmed by autopsy, karyotype determination, and fluorescent in situ hybridization examination of intact cells. Multiple other anomalies, including diaphragmatic hernia, a doomed bicuspid aortic valve, and müllerian derivative defects, were present. There was no sexual ambiguity. The age of this patient and the presence of anatomically dispersed congenital anomalies are unique among reported examples of 46,XX gonadal agenesis. Review of the literature reveals that all five previously reported cytogenetically confirmed patients with 46,XX gonadal agenesis were 17 to 25 years of age, none were diagnosed before their teens, all had female phenotype with sexual infantilism, three had müllerian derivative anomalies, and none had nongenitourinary anomalies. The abnormalities in this case may represent a polytopic field defect due to unknown insults occurring at approximately 6 weeks of developmental age.

Relaxation of imprinting in trophoblastic disease.

Genomic imprinting--the uniparental-dependent transmittance of a genetic trait--has been accepted in recent years as a major mechanism in mammalian genetics. We studied the expression of the H19 gene, a parentally imprinted (maternally expressed) gene, by in situ hybridization in human placenta and trophoblastic disease. Expression was found to be abundant, in a decreasing order, in the intermediate trophoblast (villous and interstitial), the cytotrophoblast, and the syncytiotrophoblast. The villous stroma was also prominently labeled. Partial hydatidiform mole showed a similar pattern of expression as normal placenta. As expected, complete hydatidiform mole, whose genome consists of two haploid sets of paternal origin, was not labeled in the villous stroma and surrounding trophoblastic layer. However, some of the large mononuclear cells in the proliferating groups sprouting from the villous surface were strongly labeled. Prominent expression of H19 was found in placental site trophoblastic tumor and gestational choriocarcinoma. The phenomenon of emergence of expression of alleles subject to repression according to their gamete of origin is termed relaxation of imprinting, and is considered to be relevant to tumorigenesis. We suggest that the expression of the maternally expressed H19 gene in the androgenetic tissue of complete hydatidiform mole represents relaxation of imprinting and may be associated with its malignant potential.