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Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

OBJECTIVE. Common fetal anomalies of the kidneys and urinary tract encompass a complex spectrum of abnormalities that can be detected prenatally by ultrasound. Common fetal anomalies of the kidneys and urinary tract can affect amniotic fluid volume production with the development of oligohydramnios or anhydramnios, resulting in fetal pulmonary hypoplasia and, potentially, abnormal development of other fetal structures. CONCLUSION. We provide an overview of common fetal anomalies of the kidneys and urinary tract with an emphasis on sonographic patterns as well as pathologic and postnatal correlation, along with brief recommendations for postnatal management. Of note, we render an updated classification of fetal abnormalities of the kidneys and urinary tract based on the presence or absence of associated urinary tract dilation. In addition, we review the 2014 classification of urinary tract dilation based on the Linthicum multidisciplinary consensus panel.

This article is the first portion of a two-part review that illustrates the normal appearance of the cerebellum and posterior fossa on prenatal ultrasound and MRI and on postnatal diagnostic imaging studies. Classification and terminology of posterior fossa abnormalities in the literature are confusing due to evolution of concepts and sometimes lack of consensus. Accurate classification of posterior fossa anomalies is important for predicting fetal outcome and for appropriate counseling. In Part 1 of this review, prenatal and postnatal imaging techniques for assessing the posterior fossa will be discussed, followed by a discussion of how cerebellar malformations may be classified.

Objectives Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort. Methods This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians. Results NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased. Conclusion We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations. © 2013 John Wiley & Sons, Ltd.

Prenatal obstruction of the lower urinary tract may result in megacystis, with subsequent development of hydroureter, hydronephrosis, and renal damage. Oligo- or anhydramnios, pulmonary hypoplasia, and prune belly syndrome are lethal consequences. Causes and mechanisms responsible for obstruction remain unclear but might be clarified by anatomic study at autopsy. To this end, we employed 2 methods of tomographic imaging—optical projection tomography and contrast-enhanced microCT scanning—to elucidate the anatomy of the intact urinary bladder and urethra in 10 male fetuses with lower urinary tract obstruction. Images were compared with those from 9 age-matched controls. Three-dimensional images, rotated and sectioned digitally in multiple planes, permitted thorough examination while preserving specimens for later study. Both external and internal features of the bladder and urethra were demonstrated; small structures (ie, urethral crest, verumontanum, prostatic utricle, ejaculatory ducts) were seen in detail. Types of obstruction consisted of urethral atresia ( n = 5), severe urethral stenosis ( n = 2), urethral diaphragm ( n = 2), or physical kinking ( n = 1); classic (Young type I) posterior urethral valves were not encountered. Traditional light microscopy was then used to verify tomographic findings. The prostate gland was hypoplastic or absent in all cases; in 1, prostatic tissue was displaced inferior to the verumontanum. Findings support previous views that dissection may produce valve-like artifacts (eg, bisection of an obstructing diaphragm) and that deformation of an otherwise normal urethra may result in megacystis. The designation “posterior urethral valves” should not be used as a generic expression of urethral obstruction unless actual valves are demonstrated.

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human. DOI: http://dx.doi.org/10.7554/eLife.20898.001

The placenta has a fundamental role in fetal health and functions as an important bridge to normal fetal development throughout pregnancy. A complete fetal ultrasound (US) survey should include full assessment of the placenta for any possible abnormalities. Placental diseases range from abnormal morphology, size, location, extent, and degree of placentation, to abruption and the presence of rare placental neoplasms of benign or malignant nature. Some of these conditions are associated with other diseases including aneuploidies, and their discovery should alert the radiologist to perform a very thorough fetal US examination. At times, a fetal karyotype may be needed to provide additional information. Timely detection of placental abnormalities can alert the clinician regarding the need to make important management decisions to reduce fetal and maternal morbidity and mortality. Familiarity with the normal and abnormal imaging appearance of the placenta is therefore necessary for the radiologist. Ultrasound with Doppler is the initial imaging modality of choice for placental assessment. Magnetic resonance imaging serves as a problem-solving examination in instances where the US findings are equivocal or where additional information is needed. Computed tomography has a limited role in the evaluation of placental disease because of its relatively limited tissue characterization and in particular because of the resultant direct radiation exposure of the fetus. However, in specific instances, particularly after trauma, computed tomography can provide invaluable information for patient management.

Context.—When autopsy reports are delayed, clinicians and families do not receive information in a timely fashion. Objective.—Using lean principles derived from the Toyota Production System, we set out to streamline our autopsy reporting process. Design.—In a formal workshop setting, we identified the steps involved in producing an autopsy report, then sought to eliminate, abbreviate, or reschedule them into a more efficient format. We established intermediate deadlines for each case, taking care to make them visible; we initiated a weekly quality assurance review, giving attention to both scientific issues and approaching deadlines. Results.—By adopting a more standardized approach, eliminating redundancy, and improving the visibility of tasks, we improved the mean completion time of autopsy reports from 53 days (N = 47 cases) to 25 days (N = 47 cases). Previously, 17% of reports were completed by 30 days and 71% by 60 days; in the 15 months following initiation of the program, 72% of reports were completed by 30 days and 100% by 60 days. A follow-up survey of attending physicians revealed continuing appreciation for the autopsy and timely communication, with no perceived diminution in the quality of reports. Conclusions.—This approach was of great benefit in our laboratory and may assist others in reducing the turnaround time of their autopsy reports. It may also benefit other areas of the laboratory.

Motivational asymmetry caused by differences in subjective resource value is a key component of strategic models of aggression. We study the role of motivational asymmetry in determining differential aggression and mating success of male house crickets, Acheta domesticus .W e also assess the extent to which mating differences associated with motivational asymmetry are due to direct male‐male fighting vs. male‐ female interactions. We manipulated male motivation to compete for a mating opportunity by providing males with either no access or nightly access to females for 4 d prior to the experiment. As predicted, when males from each treatment had to compete for the female, those with lower prior access were more aggressive and mated more often. In contrast, when males from each treatment were paired individually with females, there was no significant difference in the frequencies with which they pursued, courted or mated with females. We also found no evidence for female choice based on motivational asymmetry; the rate of successful courtship did not differ between treatments. We conclude that prior mate encounter rate can generate motivational asymmetry, leading to differential mating success mediated by direct male‐male aggression.

Cloacal anomalies exhibit a wide variety of morphologic types and accompanying clinical severity. The association of malformations of the cloaca with partial, complete, or conjoined twinning has been appreciated for some time, but, with the advent of prenatal ultrasound technology, appears to occur with a greater frequency than once thought. This observation has important implications for pathogenesis. We present 2 representative cases, a 19-week-old female fetus with duplication of several caudal structures and a 21-week-old male fetus with cloacal exstrophy variant and demised co-twin with lower abdominal wall defect, extruded intestinal tract, absent external genitalia, and imperforate anus. These findings and previously published theories suggest that certain models of monozygotic twinning may apply to the pathogenesis of cloacal anomalies. Specifically, the partial or complete duplication of the organizing center within a single embryonic disc may increase the risk of mesodermal insufficiency and thus account for the failure of complete development of the cloacal membrane and consequent exstrophy or other aberration.

Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.

Gross imaging serves a number of important functions in the surgical pathology laboratory: documentation, teaching, and research. The position of sections taken for histopathology must also be recorded, especially in those instances where location is a vital part of the workup. Such section keys are particularly useful in helping to quantify areas of renecrosis, assess margins, and pinpoint areas for further sectioning, steps that are of critical importance for accurate diagnosis and therapy. Five methods of imaging surgical specimens—hand drawing, photocopying, flatbed scanning conventional photography, and digital photography—are compared for quality of reproduction, ease of use, expense, and turnaround time. (The J Histotechnol 27:231, 2004)

Fetal and infant autopsy yields information regarding cause of death and the risk of recurrence, and it provides closure for parents. A significant number of perinatal evaluations are performed by general practice pathologists or trainees, who often find them time-consuming and/or intimidating. We sought to create a program that would enable pathologists to conduct these examinations with greater ease and to produce reliable, informative reports. We developed software that automatically generates a set of expected anthropometric and organ weight ranges by gestational age (GA)/postnatal age (PA) and a correlative table with the GA/PA that best matches the observed anthropometry. The program highlights measurement and organ weight discrepancies, enabling users to identify abnormalities. Furthermore, a Web page provides options for exporting and saving the data. Pathology residents utilized the program to determine ease of usage and benefits. The average time using conventional methods (ie, reference books and Internet sites) was compared to the average time using our Web page. Average time for novice and experienced residents using conventional methods was 26.7 minutes and 15 minutes, respectively. Using the Web page program, these times were reduced to an average of 3.2 minutes ( P < 0.046 and P < 0.02, respectively). Participants found our program simple to use and the corrective features beneficial. This novel application saves time and improves the quality of fetal and infant autopsy reports. The software allows data exportation to reports and data storage for future analysis. Finalization of our software to enable usage by both university and private practice groups is in progress.

Congenital absence of the midbrain and upper pons is a rare human malformation. We describe two unrelated infants with this anomaly and cerebellar hypoplasia who were born at term but died in early infancy from lack of central respiratory drive. MRI in both cases disclosed the lesions during life. Neuropathological examination, performed in one, included immunocytochemical studies of NeuN, synaptophysin, vimentin, and glial fibrillary acidic protein (GFAP). Autopsy revealed a thin midline cord passing through the clivus, in place of the mid-brain; it corresponded to hypoplastic and fused corticospinal tracts with ectopic neural tissue in the surrounding leptomeninges. Some ectopia were immunoreactive for synaptophysin and NeuN and others were nonreactive. The neural surfaces facing the subarachnoid fluid-filled space left by the absent midbrain and upper pons were lined by an abnormal villous ependyma. The architecture of the cerebellar cortex was imperfect but generally normal, and Bergmann glial cells had normal radial processes shown by vimentin and GFAP. Structures of the telencephalon, diencephalon, lower brainstem, and spinal cord were generally well formed, but inferior olivary and dentate nuclei were rudimentary and the spinal central canal was dilated at lumbar levels. The cerebral cortex was normally laminated, but pyramidal neurons of layer 5 were sparse in the frontal lobes. The hippocampus, olfactory system, and corpus callosum were formed. An ectopic lingual thyroid was found and had been associated with hypothyroidism during life. A murine model resembling this dysgenesis is demonstrated by homozygous mutations of the organizer genes Wnt1 or En1, also resulting in cerebellar aplasia, and En2, associated with cerebellar hypoplasia. These genes are essential to the formation of the mesencephalic neuromere and rhombomere 1 (metencephalon or upper pons and cerebellum). Pax8 has binding sites in the promoter for En2 and is essential for thyroid development. We speculate that in the human, the failure to form a mesencephalon and metencephalon, with cerebellar hypoplasia, results from a mutation or deletion in the EN2 ( Engrailed-2) gene.

This second portion of a two-part review illustrates examples of posterior fossa disorders detectable on prenatal ultrasound and MRI, with postnatal or pathology correlation where available. These disorders are discussed in the context of an anatomic classification scheme described in Part 1 of this posterior fossa anomaly review. Assessment of the size and formation of the cerebellar hemispheres and vermis is critical. Diagnoses discussed here include arachnoid cyst, Blake's pouch cyst, Dandy-Walker malformation, vermian agenesis, Joubert syndrome, rhombencephalosynapsis, Chiari II malformation, ischemia, and tumors.

We report a case of intestinal malrotation without any associated GI tract complications diagnosed antenatally by fetal MRI. Antenatal US revealed a midline stomach. Subsequent fetal MRI confirmed the midline stomach and, in addition, revealed all loops of small bowel to the right of the midline and all large bowel to the left. All these features were consistent with intestinal malrotation. There was no abnormal bowel wall thickening, bowel dilatation, ascites or polyhydramnios. To our knowledge, this is a unique case of intestinal malrotation without associated GI tract complications diagnosed antenatally on fetal MRI.

Acalvaria is a rare congenital defect characterized by complete absence of the membranous neurocranium, dura mater, and associated scalp muscles in the presence of a normal skull base, facial bones, and scalp.1‐3 Acalvaria is usually associated with a closed NTD (e.g., hydrocephalus, holoprosencephaly). We report a case of acalvaria and hydrocephalus initially identified by abdominal ultrasonography and later confirmed by transvaginal ultrasonography and fetal pathologic examination. The prenatal sonographic findings are distinctive but may resemble exencephaly, anencephaly, osteogenesis imperfecta type II, or perinatal lethal hypophosphatasia. The diagnostic features are compared with the three other reported cases, and the sonographic differential is discussed. An effort is made to clarify the nomenclature of neurocranial defects that may be confused with acalvaria.

The ultrasonographic diagnosis of cerebral ventriculomegaly carries grave implications, in that affected fetuses may suffer abnormal postnatal development or therapeutic abortion. It is important for pathologists to corroborate the clinical diagnosis, but because diagnostic methodologies and criteria differ so radically, this can be problematic. The clinical diagnosis is made primarily by serial ultrasound examinations of the cerebral ventricles, spaces that can be altered postmortem, particularly when the brain is autolysed or deformed artifactually We therefore sought to learn if examination of tissue, rather than spaces, can identify accurately those fetuses diagnosed with cerebral ventriculomegaly by prenatal ultrasound. The thickness of the cerebral mantle was obtained in 100 control fetuses aged 14 to 26 postmenstrual weeks. Statistical analysis revealed significant correlation of cerebral mantle thickness with crown–rump length, foot length, and head circumference. Twenty fetuses diagnosed with ventriculomegaly showed mantle thicknesses that were less than the control mean. In a few cases, mantle thickness fell between the mean and —1 SD; in several others, thickness was diminished by — 1 SD to —2 SD; in one-half of cases, mantle thickness was 2 SDs or more below the expected mean. Head circumference was within 2 SDs of the control mean in most cases, and increased beyond 2 SDs in only two cases. Head circumference is an unreliable indicator of ventriculomegaly in the midgestational fetus. By contrast, cerebral mantle thickness is a simple and useful way of corroborating ultrasonographic diagnoses at autopsy and may also prove useful in clinical settings.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Mice homozygous for the piebald lethal (sl) mutation, which have a complete deletion of endothelin receptor-B, fail to form ganglion cells in the distal large intestine and are nearly devoid of cutaneous melanocytes. These phenotypic features stem from incomplete colonization of the hindgut and skin by neural crest-derived neuroblasts and melanoblasts, respectively. We have used expression of a transgene, dopamine-beta-hydroxylase-nlacZ, to study colonization of the enteric nervous system in sl/sl embryos and sl/sl wild-type chimeric mice. Enteric neuroblasts derived from the vagal neural crest colonize the developing foregut, midgut and distal small intestine of sl/sl embryos in a cranial-to-caudal manner indistinguishable from sl/+ or +/+ embryos. However, colonization of the large intestine is retarded and the distal large intestine is never colonized, a developmental defect identical to that observed in lethal spotted (endothelin-3 deficient) embryos. The coat pigmentation and relative distributions of mutant and wild-type ganglion cells in sl/sl wild-type chimeras indicate that the defect associated with endothelin receptor-B gene deletion is not strictly neuroblast autonomous (independent of environmental factors). Instead, intercellular interactions downstream of the endothelin receptor-B mediate complete colonization of the skin and gut by neural crest cells.

We have studied omphalopagus conjoined twins with a diamniotic monochorionic placenta. Although conjoined twins usually present in a single amniotic sac, one other example of diamniotic placenta has been reported in omphalopagus twins [Weston et al., 1990: Am J Med Genet 37:558-561]. Most theories concerning the pathogenesis of conjoined twinning exclude the possibility of diamniotic placentation. However, Spencer [1992: Teratology 45:591-602] recently elaborated a model for conjoined twinning based on duplication of organizing centers (primitive streaks) during gastrulation. We have considered the fate of embryonic membranes according to this model of omphalopagus twinning and show that diamniotic placentation is a predictable outcome.

This comprehensive study of organ weights in sudden infant death syndrome (SIDS) should be of use to those studying postmortem data in SIDS and may have application to issues of growth and development. Analysis of data from 500 autopsies, performed over 15 years by one individual, revealed mean body weights generally below the 50th percentile for living infants. The weights of the thymus, lungs, liver, and brain were significantly greater than published norms. Thymic weights in SIDS probably represent the normal state more closely than those reported in several other series; elevated lung weights are presumably due to the intense pulmonary congestion and edema commonly encountered in SIDS; the liver edge routinely extends below the costal margins at SIDS autopsies, but the reason for increased weight is unknown, although a hemodynamic alteration seems likely; elevated brain weight has been described previously in SIDS. Other organs showed trends differing from "normal"--heart weights showed a marginally significant increase above published norms; for the adrenal glands, a uniform decrease was apparent, but slopes of linear regressions were low, hampering statistical analysis. Organ weights correlated more closely with body weight than with age. When victims were classified as "possible SIDS," "probable SIDS," or "classic SIDS," differences in organ weights were rarely significant. Analysis of organ weights using Z scores and their standard deviations (sigma-Z, or "pattern variability index") revealed increased variability in SIDS victims. Explanations for these findings include the possibility that some weights previously published as normal are low due to confounding variables. Changes could also be genuine, resulting from disturbances in growth or physiology, or artifactual, possibly the result of agonal or postmortem changes. A database on carefully selected, previously healthy infants who died suddenly and unexpectedly of known causes (i.e., trauma) is much needed.

In previous clinical reports, we have documented the association of several morphologic changes with congenital diaphragmatic hernia or, perhaps more appropriately termed, congenital diaphragmatic defect (CDD). These anomalies include decreased cardiac mass with left ventricular hypoplasia in infants with left-sided CDDs (Siebert et al., '84), enlarged, asymmetric chests (Siebert and Benjamin, '87), and extrathoracic anomalies (Benjamin et al., '88), including urinary tract anomalies and elevated kidney weights in otherwise normal kidneys (Glick et al., '90; Siebert et al., '90). Hypoplastic lungs and hearts and enlarged chests are thought to result from the herniation of abdominal viscera into the thoracic cavity, but for the renal abnormalities, pathogenesis is unclear. The findings are intriguing, for they could mirror unrecognized developmental relationships between the diaphragm, lung, heart, and kidney. In order to further examine these issues and to test the applicability of experimentally produced CDDs to human disease, we administered nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether), an herbicide known to produce diaphragmatic defects in rodents, to time-mated CD1 mice by gavage feeding on gestational days 8 and 9. Dosages were 200 (low dose) or 500 (high dose) mg/kg body weight, and fetuses were studied on gestational day 18. Diaphragmatic defects occurred in a dose-response fashion: 0% (0/48) control or sham-fed, 5% (5/104) in the low-dose group, and 25% (19/75) in the high-dose group. Several fetuses with cleft palate, renal agenesis, exencephaly/encephalocele, and/or Di-George sequence were noted at the high dose, the latter a previously undescribed finding. Diaphragmatic defects were primarily right sided and only associated with herniation of abdominal viscera in animals exposed to 500 mg/kg. Body weight was uniformly decreased and crown-rump length variably so by nitrofen exposure, while chest diameters were increased. Reduced heart and lung weights and elevated kidney weights were identified in animals exposed to low- or high-dose nitrofen, but this occurred regardless of the presence of a diaphragmatic defect, suggesting that growth of the lung, heart, and kidney is directly affected by nitrofen. Because the effects of nitrofen could not be differentiated from those associated with CDDs or visceral herniation, it is impossible to resolve questions regarding the interrelationships of diaphragmatic defects and pulmonary, renal, and cardiac changes. Morphogenetic, anatomic, and other differences between laboratory rodents and humans reaffirm the need for careful extrapolation between experimental, teratogenic models and human disease. © 1993 Wiley-Liss, Inc.

The risk of sudden infant death syndrome (SIDS) is said to be enhanced by factors such as prematurity, low birth weight, and perinatal distress. The significance of risk factors for SIDS research was questioned because the majority of SIDS victims seem to lack them. Therefore, postmortem records of 1144 infants who died suddenly and unexpectedly in King County, Washington, over a 25-year period were studied. Deaths were classified as "explained" if a cause was apparent, "classic" SIDS if the history and autopsy were unrevealing or, where the diagnosis of SIDS was doubtful, as "probable" or "possible" SIDS. The infants' birth certificates were compared with those of 3647 infants born during a similar period. Seventy-nine deaths (7%) were explained. The 1065 previously certified as SIDS were reclassified classic SIDS (82%), probable SIDS (13%), and possible SIDS (5%). Low birth weight, small size for gestational age, prematurity, and low 5-minute Apgar scores each form a "continuum"; the possible-SIDS group had the highest proportion of such infants, followed by the probable- and classic-SIDS groups, which exhibit extensive overlap with the control population. A 5-minute Apgar score of less than 7 and delayed postnatal growth rate are not risk factors for classic SIDS. Risk factors are more prevalent in SIDS infants where the diagnosis may be doubtful. The great majority of SIDS victims possess fewer risk factors. To avoid the bias of confounding variables, SIDS research should focus on as "pure" a SIDS population as is possible.

von Brunn's nests have long been recognized as precursors of benign lesions of the urinary bladder mucosa. We report here that von Brunn's nests are especially prevalent in the exstrophic bladder, a birth defect that predisposes the patient to formation of bladder cancer. Cells of von Brunn's nest were found to coalesce into a stratified, polarized epithelium which surrounds itself with a capsule-like structure rich in types I, III, and IV collagen. Histocytochemical analysis and keratin profiling demonstrated that nested cells exhibited a phenotype similar, but not identical, to that of urothelial cells of transitional epithelium. Immunostaining and in situ hybridization analysis of exstrophic tissue demonstrated that the FGF-10 receptor is synthesized and retained by cells of von Brunn's nest. In contrast, FGF-10 is synthesized and secreted by mesenchymal fibroblasts via a paracrine pathway that targets basal epithelial cells of von Brunn's nests. Small clusters of 10pRp cells, positive for both FGF-10 and its receptor, were observed both proximal to and inside blood vessels in the lamina propria. The collective evidence points to a mechanism where von Brunn's nests develop under the control of the FGF-10 signal transduction system and suggests that 10pRp cells may be the original source of nested cells.

BACKGROUND: We report the familial recurrence of urethral stenosis/atresia in two sibling fetuses with bladder outlet obstruction, severe oligohydramnios, and pulmonary hypoplasia. Urethral obstruction in the fetus, when severe, results in a dilated urinary bladder (megacystis) and associated urinary anomalies (hydroureter, hydronephrosis, renal dysplasia). Distention of the fetal abdomen, the result of megacystis or urinary ascites, leads to stretching and eventually hypoplasia or even absence of abdominal muscles. CASES: This constellation of findings, known by a variety of terms including “prune belly” syndrome, is associated with a variety of urethral changes, including posterior urethral valves and urethral stenosis/atresia. One fetus manifested unilateral postaxial polydactyly of the left hand. CONCLUSIONS: A microdeletion of 6p25.3, identified in mother and one fetus, is not associated with a gene known to be involved in urethral development and therefore of unknown significance. Birth Defects Research (Part A), 2009. © 2009 Wiley-Liss, Inc.

BACKGROUND: Evaluation of the cerebellar vermis is an important component of fetal autopsy, but lack of an established approach, inadequate normal anatomic data, and the subtle nature of some cerebellar malformations negatively affect concordance between prenatal ultrasound and autopsy diagnoses. METHODS: Gross anatomy and sagittal histologic sections of vermis from 26 midgestation fetuses with no posterior fossa anomalies detected by prenatal ultrasound or autopsy were examined to establish stage-specific norms. These were compared to data from three fetuses with prenatal ultrasound diagnoses of hypoplasia or absence of the cerebellar vermis, each of which had no or equivocal gross cerebellar malformation at autopsy. RESULTS: Two findings segregated cases from controls: (1) The ratio of the rostro-caudal length of the vermis to that of the cerebellar hemispheres was shorter for cases (

The synthesis of both ontogenetic and phylogenetic data should provide the ideal explanation of morphologic variation, but for the primate dentition, this has not yet occurred. Information concerning growth and development of primate teeth is lacking, in part because of the paucity of specimens. We have therefore examined the deciduous second molars (dm2) and tooth buds of the permanent first molar (M1) of 12 chimpanzees (Pan troglodytes), aged 6.5 months of gestation to 4 postnatal months. The ordering of cusp calcification was identical to that of other primates. By regression analysis, correlations of mesial and distal widths with buccal, lingual, and mesiodistal lengths were low, most probably because of decreased rates of change (slopes) and the relatively small sample size. Correlations were, however, greater for mandibular than for maxillary dentition and higher for age than for body weight; for both the dm2 and M1, distal moieties increased faster and were more highly correlated with other dental variables and age than were mesial ones. Comparison with data from humans revealed both differences and similarities in the absolute size and growth rate of dental moieties during the perinatal period. As the reasons for ontogenetic variation become understood for individuals, species, and higher taxa, the phylogenetic implications of differential growth should become clearer as well.

Previous studies in rodents have indicated that the facial changes of fetal alcohol syndrome (FAS) closely resemble those of a mild form of holoprosencephaly. In order to examine this relationship in non-human primates, we evaluated a 133-day gestation macaque (Macaca nemestrina) with holoprosencephaly, median cleft lip and palate, and encephalocele. The mother had been given ethanol once per week (1.8 g/kg body weight) from weeks 2 to 19 postconception. Diagnosis of holoprosencephaly was made following ultrasound evaluation for polyhydramnios and delivery of the female fetus by caesarean section. Another fetus of identical age was delivered by caesarean section for use as a control. Both fetuses were studied by anthropometric, gross, radiographic, and histologic techniques. In the fetus exposed to alcohol, no extracranial anomalies were identified and the karyotype was normal. The brain was micrencephalic, with absent olfactory bulbs, tracts, optic nerves and chiasma, fused frontal lobes, and a single, dilated lateral ventricle; a parietooccipital encephalocele consisted of thin, dysplastic cortex bordering the ventricle; the cerebellum was dysplastic and superiorly displaced. Within the craniofacial complex, anophthalmia was bilateral; premaxillary components were absent, palatal shelves separate, the maxillae closeset, and the ethmoid bone small and deformed. Most of these defects are similar to those encountered in humans with holoprosencephaly and support the hypothesis of shared etiologic and pathogenetic relations between the facial anomalies of fetal alcohol syndrome and holoprosencephaly.

Anatomic details of the infantile oropharynx and relationships to possible airway obstruction in sudden infant death syndrome (SIDS) are understood incompletely. Tonkin recognized this in 1975, suggesting that enlargement of the tongue might be important in SIDS, within the context of other anatomic and physiologic factors unique to early life. We therefore conducted a morphometric study of the tongue in 100 victims of SIDS and 36 control infants; the latter group consisted of infants with the same range in age and body size who had grown normally and died acutely. Highly significant differences in tongue weight, width, and thickness were demonstrated between the two groups by linear regression and analysis of covariance. Two multivariate techniques, stepwise discriminant analysis and factor analysis, identified marked discordance between somatic and lingual size in SIDS and a statistical uniqueness in tongue thickness. Certain explanations for lingual enlargement in SIDS were ruled out: redistribution of fluid and other effects of death, postmortem interval, duration and mode of feeding, and smallness of control tongues. At present, the functional significance of these observations is unclear. The effects of both normal and increased tongue size on airway patency are, however, widely recognized. Further studies of the enlarged tongue, addressing such topics as in situ anatomy and developmental mechanisms, are necessary to establish the potential for pathophysiologic consequences in SIDS.

While there is evidence that human perinatal exposure to environmental tobacco smoke (ETS) can result in an increased risk of respiratory disorders and sudden infant death syndrome, evidence linking ETS exposure to neurodevelopmental handicaps is suggestive but less compelling. We previously noted that postnatal ETS exposure, rather than prenatal exposure, resulted in reduced concentration of hindbrain DNA and increased protein/DNA ratio when rat brain tissue was studied at 9 weeks postnatal age. We have now evaluated the effects of ETS exposure during pregnancy on brain development by assaying brain tissue at term. ETS exposure had no detectable effects on regional brain concentrations of DNA, protein and cholesterol or on protein/DNA and cholesterol/DNA ratios. While ETS exposure during pregnancy also had no detectable effects on the weights of the individual fetuses or on the weights of various organs, certain regions of the fetal skeleton demonstrated accelerated ossification. The findings of this study are contrasted to the developmental effects of both nicotine and ETS in Rhesus macaques. Additional studies designed specifically to assess the risk of prenatal ETS exposure on brain development in non-human primates and other precocial species are warranted.

Of 144 patients with the CHARGE association (literature 136, new patients 8), 47 (33%) had either a postmortem examination (30) or computerized axial tomography scan (17) of the head. Twenty-six of 47 (55%) had definite central nervous system (CNS) malformations; arhinencephaly, with or without other defects (11), holoprosencephaly (2), holoprosencephaly with arhinencephaly (1), other forebrain defects (3), hindbrain defects (3), or other defects (6). The presence of CNS malformation was most strongly associated with choanal atresia. This review demonstrates a predominance of forebrain anomalies, particularly arhinencephaly and holoprosencephaly, which may provide a clue to the mechanism of abnormal morphogenesis involved in CHARGE association.

Dysmorphogenesis of the central nervous system (CNS) can be broadly classified within a pathogenetic frame-work. Natural deformations result from aberrant mechanical forces, such as intrauterine constraint, and may result in craniosynostosis and abnormally shaped calvaria and brains. Dysplasia is reflected in altered gyral patterns and heterotopias, while disruptions in morphogenesis produce more serious consequences. Examples are early amnion rupture sequence, porencephaly, and atelencephaly/aproscencephaly. Malformations are diagnosed prenatally with increasing frequency and include such recognized entities as neural tube defects (anencephaly, encephalocele, myelomeningocele), holoprosencephaly, agenesis of the corpus callosum, and Dandy-Walker and Arnold-Chiari malformations. By maintaining a pathogenetic view of congenital anomalies of the CNS, the variability of anatomic features and role of etiologic factors may be better comprehended.

In a recent case of monochorionic diamniotic twinning we observed one twin with acardia, cyclopia, and aprosencephaly, an association not reported previously. In most cases of acardia, the development of tissues in superior regions of the body is disrupted severely, while inferior structures develop more normally. A common explanation for this disruption is hypoxia-ischemia due to twin reversed arterial perfusion (TRAP). In this condition, arterial-arterial and venous-venous anastomoses in the placenta permit twin-twin transfusion and reversal of blood flow in the umbilical vessels and aorta of the recipient twin. The heart is absent or severely deficient, either by secondary atrophy or possibly a more primary, though currently unknown, mechanism. As a result, cranial tissues are less likely to be perfused with oxygenated blood than caudal tissues. A host of craniocerebral anomalies are observed in acardia, including total absence of the head and brain, rudimentary brain, anencephaly, holoprosencephaly, neuronal migration defects, and near-normal brain. Hypoxia-ischemia could be an important factor in the disruption of tissues in the present case, although a more generalized process affecting heart, head, and brain cannot be excluded. The findings suggest that hypoxia-ischemia may play a role in the pathogenesis of some cases of holoprosencephaly and aprosencephaly. This mechanism has been underreported and requires additional investigation.

Sirenomelia and caudal regression have sparked centuries of interest and recent debate regarding their classification and pathogenetic relationship. Specific anomalies are common to both conditions, but aside from fusion of the lower extremities, an aberrant abdominal umbilical artery ("persistent vitelline artery") has been invoked as the chief anatomic finding that distinguishes sirenomelia from caudal regression. This observation is important from a pathogenetic viewpoint, in that diversion of blood away from the caudal portion of the embryo through the abdominal umbilical artery ("vascular steal") has been proposed as the primary mechanism leading to sirenomelia. In contrast, caudal regression is hypothesized to arise from primary deficiency of caudal mesoderm. We present five cases of caudal regression that exhibit an aberrant abdominal umbilical artery similar to that typically associated with sirenomelia. Review of the literature identified four similar cases. Collectively, the series lends support for a caudal regression-sirenomelia spectrum with a common pathogenetic basis and suggests that abnormal umbilical arterial anatomy may be the consequence, rather than the cause, of deficient caudal mesoderm.

BACKGROUND: Previous published reports on the number of non-growing follicles (NGFs) in the human ovary have employed model-based methods for number estimates. These methods are time-intensive, and require correction factors and assumptions that ultimately limit their accuracy. Here, we describe the modification, application and validation of a modern fractionator/optical disector technique for the estimation of human ovarian NGF number. METHODS: Forty-eight pairs of normal human ovaries were collected from women (age 8-51 years) undergoing elective bilateral oophorectomy, organ donation, or from autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. The precision of individual NGF counts was determined by calculating the observed coefficient of error (OCE). Intra-observer variability and variation in NGF number between ovaries within a pair were also determined. RESULTS: The mean OCE was 16.6% with larger variations observed at lower follicle counts. In recount experiments of the same ovary, NGF number estimates varied by 15-29%, except at very low follicle counts where variation was greater, but absolute differences were small. There was no significant difference in NGF number between ovaries within a pair (Wilcoxon signed rank test, P = 0.81). CONCLUSIONS: Modern stereology methods provide an unbiased, efficient method for estimating NGF number in the human ovary. Both ovaries within a pair contain similar numbers of NGFs.

Publisher Summary Malformations in oral–facial–digital syndrome (OFDS) commonly involve the oral, facial, and digital regions. The association of specific anomalies and inheritance patterns forms the basis for recognizing at least 12 variants. A variety of terms has been used to describe the cluster of syndromes known as “OFDS,” including dysplasia linguofacialis, Mohr syndrome, Mohr–Majewski syndrome, orodigitofacial dysostosis, orofaciodigital syndrome, oro–facio–digital syndrome, Thurston syndrome, and Varadi syndrome. Phenotypic changes in OFDS are widely variable and account for many of the diagnostic and taxonomic uncertainties over this group of disorders. A variety of anomalies are recognized for the oral region. Frenula are broad and short and may involve maxillary, mandibular, or lingual tissues. Among facial changes, cleft lip and palate are common findings in OFDS. Clefts may be “true” clefts, but more often a midline notch or “pseudocleft” involves the vermilion border of the upper lip and gives a feline appearance. Digital anomalies vary in severity and include brachydactyly, polydactyly, and syndactyly, which can involve any of the digits of one or more extremity.

BACKGROUND: Both clinical and postmortem diagnoses of posterior fossa anomalies remain difficult to make and to corroborate. This is particularly true for Dandy-Walker malformation and variant. Difficulties arise for a variety of reasons, including technical and methodological ones, but also because the conditions may overlap anatomically with others, most notably mega cisterna magna, Blake's pouch cyst, and posterior fossa (arachnoid) cysts. Family counseling is difficult and complicated not only by diagnostic uncertainties but by the highly variable prognosis. METHODS: In this study, a systematic pathologic approach to study of the posterior fossa is put forth. The benefits of postmortem imaging and in situ and ex situ examination of posterior fossa contents are demonstrated. RESULTS: Normative data for cerebellar width (transverse cerebellar diameter) and height and vermian width and height are derived for the fetal period. These data will help workers recognize changes in these structures, particularly hypoplasia. CONCLUSIONS: Basic morphologic definitions of posterior fossa anomalies are advanced, in the hopes that better agreement can be reached between clinical and pathologic diagnoses and that better patient and family care will result. Birth Defects Research (Part A) 76:674–684, 2006. © 2006 Wiley-Liss, Inc.

This autopsy-based study was designed to evaluate sonographic and neuropathologic findings of fetuses diagnosed prenatally with Dandy-Walker malformation complex.The retrospective study encompassed a series of 44 autopsy cases from 2 tertiary referral centers with a prenatal ultrasound diagnosis of Dandy-Walker malformation complex between 1995 and 2003. Ultrasound and pathology data from the cases and from age-matched controls were reviewed in a blinded manner. An unequivocal diagnosis of Dandy-Walker malformation complex from ultrasonography or pathology archival images required significant hypoplasia or aplasia of the cerebellar vermis.Neuropathologic examination failed to confirm the prenatal diagnosis of Dandy-Walker malformation complex in 59% (26/44, 95% confidence interval [CI] 44-72) of the cases. After standardized reevaluation of high quality archival sonograms and pathology images, concordance remained poor at 55% (6/11 cases, 95% CI 28-79). Sonographic features that favored concordance included marked enlargement of the cisterna magna (or = 10 mm), complete aplasia of the vermis, and a trapezoid-shaped gap between the cerebellar hemispheres. This latter finding contrasted with a keyhole-shaped gap in fetuses with no cerebellar neuropathology.Correlation between a prenatal ultrasound diagnosis of Dandy-Walker malformation complex and autopsy neuropathology findings is poor. Unequivocal prenatal sonographic diagnosis of Dandy-Walker malformation complex should be reserved for cases with the classic findings of Dandy-Walker malformation, including enlargement of the cisterna magna, aplasia of the vermis, and a trapezoid-shaped, rather than keyhole-shaped, interhemispheric gap.III.

Objectives To describe the prenatal imaging findings in fetuses at risk for Joubert syndrome (JS), review the literature and propose a protocol for prenatal diagnosis of JS using ultrasound and MRI. Methods We reviewed prenatal ultrasound and fetal MRI studies in two pregnancies at 25% recurrence risk for JS and correlated these findings with gross neuropathology in one affected fetus. Results While abnormalities such as occipital encephalocele or enlarged cisterna magna have been identified before mid-trimester, the definitive diagnosis of JS, based on core cerebellar findings, has only been possible after 17 weeks' gestation. Conclusions With longitudinal monitoring, it is possible to diagnose JS in at-risk pregnancies before 24 weeks' gestation. On the basis of our data and review of the literature, we propose a protocol for monitoring pregnancies at risk for JS, utilizing serial ultrasounds combined with fetal MRI at 20–22 weeks' gestation to maximize the accuracy of prenatal diagnosis. Copyright © 2005 John Wiley & Sons, Ltd.

Individuals with holoprosencephaly (HPE) and limb reduction defects have been ascribed historically to a variety of syndromes with overlapping phenotypic features. As such, these patients are challenges for clinicians and researchers alike. In an effort to better understand this association, we reviewed our autopsy records and identified five cases of HPE with reduction defects of the limbs and other anomalies. One case appears to be the third reported instance of Steinfeld syndrome, while others represent microgastria-limb reduction sequence, VATER/VACTERL association, and an additional unique condition characterized by HPE, rhombencephalosynapsis, absent left radius, first metacarpal, and thumb, and congenital heart disease. The phenotypic heterogeneity inherent in these patients continues to complicate diagnosis, which will hopefully be simplified by continuing delineation at morphologic and especially genetic levels.