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Introduction Although fetal brain injury due to COL4A1 gene mutation is well documented, fetal central nervous system (CNS) and placental histopathology lack description. We report CNS and placental pathology in fetal cases with symptomatic COL4A1 mutation. Methods We retrieved four autopsy cases of COL4A1 related disease, confirmed by genetic sequencing after fetal brain injury was detected. Results One case was a midgestation fetus with residua of ventricular zone hemorrhage and normal placental villi. Three cases were 30-32 week gestation fetuses: two demonstrated CNS small vessel thrombosis, with CNS injury. Both demonstrated high grade placental fetal vascular malperfusion (FVM). One additionally showed villous dysmorphism, the other demonstrated mild villous immaturity. The fetus whose placenta demonstrated high grade FVM was growth restricted. A fourth fetus demonstrated schizencephaly with a CNS arteriopathy with smooth muscle cell degeneration and cerebral infarcts; the placenta demonstrated severe villous dysmorphism and low grade FVM. Discussion These cases confirm that small vessel disease is important in producing intracranial pathology in COL4A1mutation. We report an arteriopathy distinct from microvascular thrombosis and demonstrate that placental pathology is common in fetal COL4A1 related disease. This tentatively suggests that placental pathology may contribute to CNS abnormalities by affecting circulatory sufficiency.

Objectives Septo‐optic dysplasia (SOD) is a clinical syndrome characterized by varying combinations of optic nerve hypoplasia, pituitary gland hypoplasia and abnormal cavum septi pellucidi. It is suspected on prenatal imaging when there is non‐visualization or hypoplasia of the septal leaflets. Long‐term postnatal outcomes of fetuses with prenatally suspected SOD have been documented poorly. The aims of this study were to describe the natural history of deficient septal leaflets, to quantify the incidence of postnatally confirmed SOD and to document the visual, endocrine and long‐term neurodevelopmental outcomes of these infants. Methods This was an observational retrospective study of all fetuses with prenatal imaging showing isolated septal agenesis, assessed at a single tertiary center over an 11‐year period. Pregnancy, delivery and neonatal outcomes and pre‐ and postnatal imaging findings were reviewed. Neonatal evaluations or fetal autopsy reports were assessed for confirmation of SOD. Ophthalmologic, endocrine, genetic and long‐term developmental evaluations were assessed. Imaging findings and outcome were compared between infants with and those without postnatally confirmed SOD. Results Of 214 fetuses presenting with septal absence on prenatal ultrasound and magnetic resonance imaging (MRI), 18 (8.4%) were classified as having suspected isolated septal agenesis suspicious for SOD. Uniform prenatal MRI findings in cases with suspected SOD included remnants of the leaflets of the cavum septi pellucidi, fused forniceal columns, normal olfactory bulbs and tracts and a normal optic chiasm. Twelve fetuses were liveborn and five (27.8%) had postnatally confirmed SOD. Only two of these five fetuses had additional prenatal imaging features (pituitary cyst, microphthalmia and optic nerve hypoplasia) supporting a diagnosis of SOD. The other three confirmed SOD cases had no predictive prenatal or postnatal imaging findings that reliably differentiated them from cases without confirmed SOD. Visual and endocrine impairments were present in two (40%) and four (80%) cases with confirmed SOD, respectively. In those with visual and/or endocrine impairment, developmental delay (median age at follow‐up, 2.5 (interquartile range, 2.5–7.0) years) was common (80%) and mostly severe. Neonates with isolated septal agenesis and a lack of visual or endocrine abnormalities to confirm SOD had normal development. Conclusions Only a quarter of fetuses with isolated septal agenesis suggestive of SOD will have postnatal confirmation of the diagnosis. Clinical manifestations of SOD are variable, but neurodevelopmental delay may be more prevalent than thought formerly. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.

Objective Near term unexpected stillbirth is a common, complex diagnostic challenge. We review a large cohort of near term to term gestation unexpected fetal deaths to document the common patterns of pathology and evaluate the utility of various standard autopsy procedures. Methods A total of 123 perinatal autopsies consisting of 94 intrauterine fetal deaths (IUFDs) and 29 intrapartum deaths (IPDs) were reviewed. Deaths were classified according to the laboratory investigations establishing cause of death. Results Cause of death was attributable to placental pathology without autopsy in 55.3% of IUFD and 17% of IPD. Correlative findings at autopsy increased the ability to establish cause of death in 86.2% of IUFD and 62% of IPD. Histology was largely corroborative, with the brain, lungs, and heart demonstrating significant changes in 46%, 34.5%, and 13.8%, respectively. Microbiology was corroborative but demonstrated single organism growth in 6 of 29 cases of fatal acute chorioamnionitis. Newborn metabolic screening revealed only elevated thyroid-stimulating hormone levels in 3 cases, of questionable relevance. Aneuploidy was established by screening molecular studies in 5 IUFDs, all of which had external or visceral dysmorphism. Karyotype was established in 69 cases and was not contributory in any of the IPD: 3 IUFDs had changes of unknown significance. Cause of death was not established at autopsy in 9% of IUFD and 10% of IPD. Discussion This is the largest uniformly investigated cohort of late gestation unexpected fetal deaths studied. We confirm the importance of both placental and fetal autopsy in establishing cause of death. Autopsy histology, microbiology, and cytogenetics provide important but largely corroborative data.

Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

Objectives To delineate the etiology and outcome of prenatally diagnosed isolated bilateral hyperechogenic kidneys (IBHK). Study design Pregnancies with IBHK on prenatal ultrasound identified and followed by us between January 1, 2000 and January 1, 2015 were evaluated regarding the etiology and outcome by evaluation of family history, targeted AR-PKD and AD-PKD DNA analysis, and microarray analysis, according to renal size and amniotic fluid volume. Results Of the 52 identified cases, there were 34 cases with enlarged kidneys, 16 with normal size kidneys, and two with small kidneys. There were seven cases with AD-PKD, six inherited, and one with de novo causative variants in the PKD1 gene. Fifteen had AR-PKD, and microarray analysis showed two inherited findings: one with 17q12 deletion including the HNF1B/TCF2 gene inherited from asymptomatic mother and a duplication at 3p26.1 inherited from a healthy father. Of the remaining four cases, three cases had bilateral multicystic dysplastic kidneys, and one had unilateral renal agenesis. Conclusion Microarray analysis and mutation analysis for PKD1 and PKHD1 have an important contribution to the diagnostic investigation of IBHK and to the management of affected and future pregnancies. Poor outcome was associated with large hyperechoic kidneys with oligohydramnios.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.

Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.

Aims We delineate and review the central nervous system (CNS) pathology of amniotic rupture sequence (ARS) and its extraneural associations. Materials and methods We review a consecutive 15-year fetal/neonatal autopsy series for cases of ARS to document its morphology and correlates. Results We retrieved 15 cases of ARS with complete dissection of the CNS. Seven lacked craniofacial abnormalities; in these the brain and spinal cord were normal. Eight had acalvaria or encephalocele, with facial clefts. All 8 had abnormal brains. Two cases demonstrated normal cerebral lobation with aqueductal stenosis/atresia (AS) and secondary changes. Two cases demonstrated holoprosencephaly and AS. Four other cases had large encephaloceles covered by amnion and extensive secondary change, 3 of which had absent olfactory bulbs, folded and thinned cerebral cortex, reduced thalami, and irregular ventricular systems with superimposed gliosis and hemorrhage. In these, the aqueduct or rostral 4th ventricle was either atretic or occluded by heterotopic neuronal masses. Conclusion CNS pathology in ARS is strongly associated with craniofacial clefts. There is a non-random association between AS, holoprosencephaly, and ARS. Some of the anomalies may be due to abnormal induction events, vascular instability, and the mechanical effects of craniofacial maldevelopment. .

Financial assistance was received in support of the study by grants from the German Federal Ministry of Education and Research (BMBF) (GeNeRARe, FKZ: 01GM1519D) to M. Z. and from the Institute of Health Carlos III: Convenio ISCIII‐ASEREMAC, and Fundación 1000 sobre Defectos Congénitos, of Spain to E. B.‐S. and I. R. G., Abdelfattah, F., Kariminejad, A., Kahlert, A.-K., Morrison, P.J., Gumus, E., Mathews, K.D., Darbro, B.W., Amor, D.J., Walsh, M., Sznajer, Y., Weiß, L., Weidensee, S., Chitayat, D., Shannon, P., Bermejo-Sánchez, E., Riaño-Galán, I., Hayes, I., Poke, G., Rooryck, C., Pennamen, P., Khung-Savatovsky, S., Toutain, A., Vuillaume, M.-L., Ghaderi-Sohi, S., Kariminejad, M.H., Weinert, S., Sticht, H., Zenker, M., Schanze, D.

Objective To assess the cerebral and vascular development in fetuses with hypoplastic left heart syndrome (HLHS). Methods Pregnant women carrying fetuses diagnosed with HLHS who decided to interrupt their pregnancies were included in our study. Aortic size and blood flow were assessed based from fetal echocardiography. Immunohistochemical staining was performed in brain sections obtained from pathology in fetuses with HLHS and control fetuses without heart disease. Results Twenty‐seven midgestation fetal HLHS were included (gestational age, 23.3 ± 3.4 weeks). Head circumference z scores were lower in HLHS fetuses. Middle cerebral artery pulsatility index, a measure of cerebrovascular resistance, was inversely correlated with the ascending aortic z score (P, What's already known about this topic? Structural brain abnormalities and abnormalities in neurodevelopment have been reported in HLHS. What does this study add? Our study describes abnormal vascular development that may account for abnormal neuronal and white matter differentiation in the developing fetus with HLHS.

Objective Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. Method Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. Results Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. Conclusion Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10 −12 ). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5 , thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.

Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.

Objective To evaluate the performance of a laboratory protocol for direct genetic analysis performed on tissues obtained from miscarriages, stillbirth and postnatal death. Methods Samples were collected between July 1st, 2011 and June 30th, 2014. QF-PCR analysis was the initial test followed by aCGH analysis performed on the normal QF-PCR specimens. Results Of the 1195 submitted specimens, a total of 1071 samples were confirmed as true fetal. The failure rate was 1.4%. Of those, 30.8% yielded abnormal results. Of the latter, 57.6% had abnormal QF-PCR and 42.4% had abnormal microarray result. Autosomal trisomies were detected in 61.2%, triploidy in 7.6%, monosomy X in 9.1%, sex-chromosome aneuploidy (apart from monosomy X) in 1.5%, molar pregnancies in 5.8% and copy number variants in 14.2% including microdeletions/microduplications and cryptic unbalanced rearrangements. The highest diagnostic yield was observed in the 1st trimester specimens at 67.6%. We confirmed that maternal age correlates with the likelihood of autosomal trisomies but not with triploidy, sex chromosome aneuploidies, molar pregnancy, or CNVs. Conclusion An efficient laboratory protocol, based on QF-PCR and aCGH of uncultured cells has replaced standard cytogenetic analysis in testing of tissue from all pregnancy losses in our center and resulted in reduced test failure rate and increased diagnostic yield.

OBJECTIVE Fetal myelomeningocele (fMMC) surgery improves infant outcomes when compared with postnatal surgery. Surgical selection criteria and the option of pregnancy termination, however, limit the number of cases that are eligible for prenatal surgery. We aimed to quantify what proportion of cases could ultimately benefit from fetal therapy. METHODS We retrospectively reviewed all cases of fMMC referred to a large tertiary care center over a 10-year period and assessed their eligibility for fetal surgery, pregnancy termination rates, and actual uptake of the surgery. RESULTS Of 158 cases, 67 (42%) were ineligible for fetal surgery based on surgical exclusion criteria. Eleven fetuses (7%) had chromosomal anomalies, 10 of which (91%) had other anomalies on ultrasound. Thirty-four patients had a combination of maternal and fetal contraindications. Of the remaining 91 eligible cases (58%), 45 (49%) pregnancies were terminated, leaving only 46 (29% of initial 158 cases) as potential candidates for fetal repair. Actual uptake of fetal surgery was 15% (n = 14 of 91), but this increased after a national program was started. CONCLUSION Only a minority of fMMC cases will ultimately undergo fetal surgery. These numbers support the centralization of care in expert centers.

Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain. Postmortem cortex samples from gestational age (GA) 20–26 wk, GA 36–40 wk, postnatal age (PNA) 0–3 mo, PNA 3–6 mo, and adults were immunostained for P-gp. The intensity of P-gp staining in adults was significantly higher compared to at GA 20–26 wk (P < 0.05), GA 36–40 wk (P < 0.05), and PNA 0–3 mo (P < 0.05). P-gp intensity at GA 20–26 wk (P < 0.05), GA 36–40 wk (P < 0.05), and PNA 0–3 mo (P < 0.05) was significantly lower compared to at PNA 3–6 mo. P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3–6 mo of age. Given the immaturity of blood–brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging can be used to characterize brain maturation. MR imaging of the fetus is used in cases of suspected Chiari II malformation when further evaluation of the posterior fossa is required. We sought to investigate whether there were any quantitative ADC abnormalities of the cerebellum in fetuses with this malformation. MATERIALS AND METHODS: Measurements from ROIs acquired in each cerebellar hemisphere and the pons were obtained from calculated ADC maps performed on our Avanto 1.5T imaging system. Values in groups of patients with Chiari II malformations were compared with those from fetuses with structurally normal brains, allowing for the dependent variable of GA by using linear regression analysis. RESULTS: There were 8 fetuses with Chiari II malformations and 23 healthy fetuses, ranging from 20 to 31 GW. There was a significant linear decline in the cerebellar ADC values with advancing gestation in our healthy fetus group, as expected. The ADC values of the cerebellum of fetuses with Chiari II malformation were higher [1820 (±100) × 10 −6 mm 2 /s] than ADC values in the healthy fetuses (1370 ± 70) × 10 −6 mm 2 /s. This was statistically significant, even when allowing for the dependent variable of GA ( P = .0126). There was no significant difference between the pons ADC values in these groups ( P = .645). CONCLUSIONS: While abnormal white matter organization or early cerebellar degeneration could potentially contribute to our findings, the most plausible explanation pertains to abnormalities of CSF drainage in the posterior fossa, with increased extracellular water possibly accounting for this phenomenon.

Background and Purpose— Cerebral microbleeds (petechial hemorrhages) are a well-known consequence of cerebral amyloid angiopathy and chronic hypertension among other causes. We report 12 patients with a clinically and radiologically distinct microbleed phenomenon in the cerebral white matter. Methods— These patients were assessed at the University Health Network (Toronto, Canada) between 2004 and 2014. Results— Median age was 40 years (range, 27–63 years), and 7 out of 12 patients were women. All patients had brain magnetic resonance imaging during or immediately after an intensive care unit admission. All patients had respiratory failure, 11 out of 12 received mechanical ventilation, and 3 out of 12 received extracorporeal life support. Magnetic resonance imaging in all 12 patients showed extensive microbleeds, diffusely involving the juxtacortical white matter and corpus callosum but sparing the cortex, deep and periventricular white matter, basal ganglia, and thalami. Several patients also had internal capsule or posterior fossa involvement. Conclusions— We have described a distinct microbleed phenomenon in the cerebral white matter of patients with critical illness. The specific cause of the microbleeds is unclear, but the pathogenesis may involve hypoxemia as the microbleeds are similar to those described with high-altitude exposure.

We studied a series of patients with fetal akinesia deformation sequence (FADS)/arthrogryposis multiplex congenita (AMC), with nemaline bodies on muscle specimens, which revealed mutations in the NEB gene.We pathologically assessed seven cases from three families, who presented with AMC/FADS. Targeted genetic analysis for Ashkenazi Jewish mutation (in relevant patients) was followed by next-generation sequencing and multiplex ligation-dependent probe amplification.All cases were detected on prenatal ultrasound. Characteristic nemaline bodies on muscle specimens were demonstrated in at least one case in each of the nuclear families. In the Ashkenazi Jewish family, the known founder mutation was compounded by one recurrent novel splice site. The other two families were of Chinese and Korean origins, and only one pathogenic heterozygous mutation was detected in each.Nemaline myopathy due to NEB mutation(s) leads to FADS/AMC. Currently, mutated NEB is under-recognized as a cause for AMC/FADS. Our study attempts to raise recognition of this gene as a cause, suggesting the NEB gene should be included in genetic panels used for FADS/AMC cases and be fully covered when EXOME sequencing is utilized. A heterozygous mutation may suggest either compounding undetected one or digenic interaction that requires further genetic analyses. © 2016 John WileySons, Ltd.

Background Congenital giant neck teratomas are rare tumours associated with high perinatal mortality. Recent advances in prenatal diagnosis and delivery by ex utero intrapartum treatment (EXIT) have improved perinatal outcome. Case An otherwise healthy 32-year-old woman, gravida 3, para 2, was referred to our institution at 25 weeks' gestation with a diagnosis of a fetal giant cervical teratoma. Ultrasound and magnetic resonance imaging (MRI) findings suggested airway obstruction in the fetus. An EXIT procedure was attempted but did not result in survival of the baby, despite extensive preoperative planning and the best efforts of a multidisciplinary team. Conclusion Despite prenatal detection and diagnosis of airway compromise in a fetus with a giant neck teratoma, securing the fetal airway can be challenging. This is because massive teratomas can completely distort normal tissue and anatomy.

Background:Dural sinus malformation (DSM) is a term used to describe congenital vascular malformations characterized by massive dilation of one or more dural sinuses: these dilatations are typically associated with arteriovenous shunts. Such malformations can present antenatally but their early natural history and anatomy is poorly defined.Methods:We reviewed five years of autopsy experience and retrieved three primary vascular malformations of the fetal dural sinuses with ultrasound, magnetic resonance imaging (MRI) and post-mortem correlation.Results:Fetal ultrasound and MRI obtained between 19 and 23 weeks gestational age demonstrated in all cases dilation of the dural sinuses. In two cases vascular thromboses were present in either the dilated dural sinus (one of three) or the associated arteriovenous fistula (one of three). All cases were autopsied at 22-23 weeks gestational age. In one there was imaging and autopsy evidence of remodeling of the dural sinuses associated with a pial arteriovenous fistula. In two cases, no arteriovenous malformation was identified on initial imaging, but only became evident at autopsy. One case showed morphological overlap with vein of Galen aneurysmal malformation, with a midline arteriovenous shunt and vein of Galen ectasia. The other demonstrated a perisylvian dural arteriovenous fistula.Conclusion:In utero thrombosis of feeding vascular malformations or of the dural sinus malformation may be prominent. The early in utero developmental trajectory of dural sinus malformation (DSM) is poorly defined and deserves further study.

Objectives Rhombencephalosynapsis is a rare, but increasingly recognized, brain malformation characterized by congenital fusion of the cerebellar hemispheres and absence of the vermis. Rhombencephalosynapsis is associated with significant developmental delay, seizures and involuntary head movements. We report four cases, with correlation of prenatal and postnatal imaging and autopsy findings. Methods Over a 2-year period, four cases of rhombencephalosynapsis were diagnosed in the perinatal period, three in one center and one in another center. The clinical cases were reviewed, and correlation was made between the prenatal and postnatal imaging and autopsy findings where available. Results All cases presented initially with ventriculomegaly on prenatal ultrasound examination. Subsequent magnetic resonance imaging (MRI) established the diagnosis in two cases and postnatal MRI established the diagnosis in a further two cases. Autopsy was available and confirmed the diagnosis in two cases. In one case the pregnancy was terminated, two infants died in the neonatal period and one died in infancy. Conclusions The cases in this perinatal series of rhombencephalosynapsis showed a very poor prognosis. The presence of ventriculomegaly on prenatal ultrasound imaging should alert the physician to consider rhombencephalosynapsis in the differential diagnosis. MRI appears to be the imaging modality of choice in establishing the diagnosis. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Misoprostol is a synthetic prostaglandin analog administered vaginally to induce labor for intrauterine death or termination of pregnancy for congenital abnormalities. We encountered a case of misoprostol induction of labor at 14 weeks of gestation for fetal acrania associated with amniotic bands. Histology demonstrated abundant deposits of refractile material appearing to be of vegetable fiber origin on the maternal surface of the fetal membranes. Misoprostol tablet scrapings had a similar microscopic appearance. Ten additional placentas from cases of misoprostol induction of labor between 16 and 18 weeks of gestation were examined and half were found to contain such deposits. No deposits were seen in cases between 15 and 18 weeks of gestation where misoprostol was not used. We attribute the refractile material to a nonmedicinal ingredient, microcrystalline cellulose, in the misoprostol tablet preparation. This study demonstrates that vaginal administration of misoprostol tablets can be detected microscopically in at least half of cases and may have a florid appearance simulating a potential causative factor of fetal malformation. Despite the large amounts of microcrystalline cellulose and its apparent embedding in placental tissue, the misoprostol in our index case was unlikely to have caused the amniotic bands and the resulting cranial abnormality.

Background:Survivors of acute respiratory distress syndrome (ARDS) report generalized weakness and reduced exercise tolerance up to two years following discharge from the intensive care unit (ICU). Persistent neuromuscular complications of ARDS may contribute to the functional disability observed in these patients.Methods:Sixteen ARDS survivors underwent comprehensive neurological evaluation and standardized electrodiagnostic testing 6 to 24 months after ICU discharge. Four of these patients agreed to open muscle biopsy.Results:Seven of sixteen patients had clinically significant focal compressive mononeuropathies. Electrodiagnostic testing failed to reveal any changes attributable to critical illness polyneuropathy or myopathy. All four muscle biopsies were abnormal, and although the pathological features were structurally non-specific, the presence of an acquired myopathy remains possible. Four patients had persistent mixed sensory complaints but had normal electrodiagnostic evaluation.Conclusions:The high frequency of mononeuropathies highlights the need for vigilance in daily ICU care. The findings also suggest that complaints of weakness and reduced exercise capacity in ARDS survivors may be related to combined effects of compressive neuropathies and generalized longstanding structural changes in muscle and may support an organic basis for longterm functional disability.

Gangliogliomas are generally benign tumors, composed of transformed neuronal and glial elements, with rare malignant progression of the glial component. The current study of a rare case of a woman harboring a ganglioglioma with areas of malignant transformation addresses two fundamental questions: (1) Are the ganglioglioma and its malignant component clonal in origin? (2) What are the genetic alterations associated with the initiation and subsequent malignant progression of ganglioglioma? By using the human androgen receptor gene (HUMARA) assay, we found the ganglioglioma and the malignant component to be clonal in origin, suggestive of initial transformation of a single neuroglial precursor cell with subsequent malignant progression. Conventional and array comparative genomic hybridization (approximately 2.5-Mb resolution) analyses found chromosomal losses to be predominant in the benign areas of the ganglioglioma, with gains more prevalent in the malignant component. Regions of chromosomal loss, postulated to harbor genes involved in the initiation of ganglioglioma, included 1p35-36, 2p16-15, 3q13.1-13.3, 3q24-25.3, 6p21.3-21.2, 6q24-25.2, 9p12, Xp11.3-11.22, and Xq22.1-22.3. Direct analysis demonstrated loss of p19 expression and p53 mutation in the malignant areas, highly suggestive of these alterations being involved in the malignant progression of the ganglioglioma. Additional chromosomal alterations specific to the malignancy involved gains on 1p35-34.2, 2q24.1-32.3, 3q13.1-13.3, 6q13-16.2, 7q11.2-31.3, 8q21.1-23, 11q12-31, and 12q13.2-21.3. This molecular-pathological study has provided insight into the pathogenesis of gangliogliomas and associated rare malignant progression. Deciphering the specific genes residing in these chromosomal regions may further our understanding of not only these rare tumors but also the more common gliomas.

Radiation induced peripheral nerve tumors (PNT) are a rare but known complication of radiotherapy. The clinical and pathologic features of six cases of post-radiation PNT’s are reported here, more than doubling the number of known cases reported in the literature. We reviewed six cases of radiation induced PNT and performed a review of the current literature on radiation induced neurofibromas. Patient’s ranged in age from 18 months to 49 years at the time of their original diagnosis, with radiation doses to the primary tumor ranging from 24 to 40 Gy with post radiation intervals from 10 to 50 years. The majority of PNT’s identified were neurofibromas (3) and schwannomas (3). Nuclear atypia, S100 positive staining and mild—moderate cellularity were common pathologic findings. There are only a handful of neurofibromas in the 60 cases of PNT’s thus far reported. This case series broadens the post-radiation neurofibroma literature. While the pathology of PNT induced transformation is still poorly understood, experiments and pathology are congruent on the possibility of malignant transformation, especially for the “atypical neurofibroma”. On the clinical level, this case series lends its support to some, but not all, of the risk factors thought to predispose to the formation of radiation induced neurofibromas. Though rare, the complication of radiation-induced neurofibroma cannot be ignored, especially with the increasing use of focused radiosurgical techniques.

The etiology of idiopathic dilated cardiomyopathy (iDCM) remains unknown. Immune therapies have improved outcome in fetuses with DCM born to mothers with autoimmune disease (aDCM). The purpose of this retrospective study was to compare the myocardial B and T cell profiles in fetuses and neonates with idiopathic DCM (iDCM) versus autoimmune-mediated DCM (aDCM) and to describe the normal cell maturation within the human fetal myocardium. Of 60 fetal autopsy cases identified from institutional databases, 10 had aDCM (18–38 weeks), 12 iDCM (19–37 weeks) and 38 had normal hearts (11–40 weeks). Paraffin-embedded myocardium sections were stained for all lymphocyte (CD45), B cells (CD20, CD79a), T cells (CD3, CD4, CD7, CD8) and monocyte (CD68) surface markers. Two independent, blinded cell counts were performed. Normal hearts expressed all B and T cell markers in a bimodal fashion, with peaks at 22 and 37 weeks of gestation. The aDCM cohort was most distinct from normal hearts, with less overall T cell markers [EST −9.1 (2.6) cells/mm2, p = 0.001], CD4 [EST −2.0 (0.6), p = 0.001], CD3 [EST −3.9 (1.0), p

Objectives/Hypothesis: Middle and external ear anomalies are well recognized in Down syndrome (DS, trisomy 21). Inner ear anomalies are much less frequently described. This study reviews inner ear morphology on imaging to determine the prevalence of cochlear and vestibular anomalies in children with DS. Study Design: The authors conducted a retrospective review of imaging features of (DS) inner ear structures. Methods: Fifty-nine sequential patients with DS with imaging of the inner ear were identified by a radiology report text search program. Quantitative biometric assessment of the inner ear was performed on patients with high-resolution computed tomography or magnetic resonance images of the petrous bone. Petrous imaging was performed for evaluation of inflammatory disease or hearing loss. Spinal imaging, which included petrous views, was performed in most cases to exclude C1 to 2 dislocation, a potential complication of DS. Measurements were compared with normative data. Results: Inner ear dysplasia is much more common in DS than previously reported. Inner ear structures are universally hypoplastic. Vestibular malformations are particularly common and a small bony island of the lateral semicircular canal (

Recent evidence suggests that immune-mediated gastric epithelial cell apoptosis through Fas-Fas ligand interactions participates inHelicobacter pyloridisease pathogenesis. To define the role of Fas signaling in vivo,H. pyloristrain SS1 infection in C57BL/6 mice was compared to that in mice deficient in the Fas ligand (gld).gldmice had a degree of gastritis similar to that of C57BL/6 mice after 6 weeks (gastritis score, 5.2 ± 0.6 [mean ± standard error] versus 3.5 ± 0.8) and 12 weeks (4.0 ± 0.7 versus 3.4 ± 0.5) of infection. Bacterial colonization was comparable in each group of mice at 12 weeks of infection (2.1 ± 0.3 versus 1.6 ± 0.3 forgldand C57BL/6, respectively; the difference is not significant). Sixty-seven percent ofH. pylori-infectedgldmice displayed atrophic changes in the gastric mucosa, compared with 37% of infected C57BL/6 mice, at 12 weeks. In addition, atrophic changes were more severe inH. pylori-infectedgldmice (P< 0.05). Splenocytes isolated fromH. pylori-infected C57BL/6 mice had a twofold increase in production of the Th1 cytokine gamma interferon (IFN-γ) in response toH. pyloriantigens at both 6 and 12 weeks compared to controls (143 ± 65 versus 69 ±26 pg/ml and 336 ± 73 versus 172 ± 60, respectively). In contrast, there was a lack of detectable IFN-γ ingldmice infected with the bacterium.H. pylori-infected C57BL/6 mice had increased epithelial cell apoptosis compared with sham-infected C57BL/6 mice (35.0 ± 8.9 versus 12.3 ± 6.9;P< 0.05). Epithelial cell apoptosis did not differ betweenH. pylori-infected and controlgldmice (5.2 ± 1.6 versus 6.5 ± 2.9 [not significant]). These data demonstrate that mice with mutations in the Fas ligand develop more severe premalignant mucosal changes in response to infection withH. pyloriin association with both an impaired gastric epithelial cell apoptotic response and IFN-γ production. The Fas death pathway modulates disease pathophysiology following murine infection withH. pylori. Deregulation of the Fas pathway could be involved in the transition from gastritis to gastric cancers duringH. pyloriinfection.

Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Opsoclonus is a dyskinesia consisting of involuntary, arrhythmic, chaotic, multidirectional saccades, without intersaccadic intervals. We used a magnetic scleral search coil technique to study opsoclonus in two patients with paraneoplastic complications of lung carcinoma. Eye movement recordings provided evidence that opsoclonus is a three-dimensional oscillation, consisting of torsional, horizontal, and vertical components. Torsional nystagmus was also present in one patient. Antineuronal antibody study revealed the presence of anti-Ta (Ma2 onco-neuronal antigen) antibodies in one patient, which had previously been associated only with paraneoplastic limbic encephalitis and brainstem dysfunction, but not opsoclonus, and only in patients with testicular or breast cancer. Neuropathologic examination revealed mild paraneoplastic encephalitis. Normal neurons identified in the nucleus raphe interpositus (rip) do not support postulated dysfunction of omnipause cells in the pathogenesis of opsoclonus. Computer simulation of a model of the saccadic system indicated that disinhibition of the oculomotor region of the fastigial nucleus (FOR) in the cerebellum can generate opsoclonus. Histopathological examination revealed inflammation and gliosis in the fastigial nucleus. This morphological finding is consistent with, but not necessary to confirm, damage to afferent projections to the FOR, as determined by the model. Malfunction of Purkinje cells in the dorsal vermis, which inhibit the FOR, may cause opsoclonus by disinhibiting it.

Objective To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral center. Methods An 11-year retrospective review of perinatal autopsies from 2002 to 2013 was performed to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were examined for the presence of TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the features of TLD to determine whether they could be identified. Results Thirty-one cases of TD underwent perinatal autopsy, and prenatal ultrasound imaging was available for review in 24 (77%). Mean gestational age at diagnosis of TD was 21.3 (range, 18-36) weeks. TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends showed that TLD features were present in 50% (5/10) of all TD cases between 2002 and 2006 and in 79% (11/14) of those detected between 2007 and 2013. Conclusions At present, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal counseling and guide molecular investigations to confirm the specific diagnosis of TD.

Background:Fabry’s disease is an X-linked disorder, caused by a deficiency of the lysosomal enzyme α-galactosidase A which results in the accumulation of the glycosphingolipid, ceramide trihexose in the vascular endothelium and can lead to cerebral infarction. Male hemizygotes are generally more severely affected than heterozygote females. Clinical disease in females is thought to be due to unequal X chromosome inactivation.Case:A 19-year-old woman, who was previously well, presented with neurological deficits secondary to basal ganglia and pontine infarction. Extensive cardiac, arterial and hematologic investigations did not identify the etiology of her stroke. Muscle biopsy revealed endothelial lysosomal aggregates most consistent with a diagnosis of Fabry’s disease. The diagnosis was confirmed on the basis of molecular genotype analysis.Discussion:Inherited causes of stroke such as Fabry’s disease should be considered in young patients with stroke if an etiologic diagnosis is not reached after complete investigations. Muscle biopsy can assist with the diagnosis and guide further investigations. This report summarizes the biochemical and histological features of Fabry’s disease and the associated genetic abnormalities.

Nephronophthisis associated ciliopathies (NPHP-AC) are a group of phenotypically related conditions that include Joubert syndrome, Meckel syndrome, nephronophthisis (NPHP), and Senior-Loken syndrome. We report on a male fetus with prenatal ultrasound findings at 24 weeks of gestation of anhydramnios, large and echogenic kidneys and situs inversus totalis. Histopathology revealed nephronophthisis and tracheal mucosa electron microscopy revealed ciliary dysgenesis. DNA analysis of the NPHP genes showed a previously unreported homozygous mutation, p.Arg603* (c.1078+1G>A), in the INVS/NPHP2 gene. This mutation is thought to abolish the splice donor site for exon 8, which likely disrupts the normal splicing of the INVS/NPHP2 gene.

Objective To review the anomaly spectrum of prenatally detected absent pulmonary valve syndrome (APVS) and the outcome after diagnosis. Previous fetal studies reported survival rates of ≤ 25% for patients with intended postnatal care. Methods Clinical data and echocardiograms of 12 cases with a fetal diagnosis of APVS between 2000 and 2010 were analyzed in this retrospective single-center study. Collected parameters included: gestational age at referral, associated fetal abnormalities, cardiothoracic ratio, maximum diameters of pulmonary annulus and main and branch pulmonary arteries, ventricular dimensions and function as well as ventricular Doppler flows. Karyotyping included fluorescence in-situ hybridization (FISH) analysis for microdeletion 22q11.2. Results Median gestational age at diagnosis was 24 weeks. Three subtypes of APVS were observed: (1) with tetralogy of Fallot (TOF) and no arterial duct (n = 10; 83%); (2) isolated, with a large arterial duct (n = 1; 8%); and (3) with tricuspid atresia, right ventricular dysplasia and a restricted duct (n = 1; 8%). The cardiothoracic ratio and pulmonary artery dimensions were increased in all cases. The karyotype was abnormal in 70% of fetuses with TOF and their mortality rate was significantly higher due to pregnancy termination (n = 3) or perinatal demise (n = 2) (hazard ratio, 5; 95% CI, 0.87−28.9; P = 0.015). Of seven live births with active postnatal care, six children (86%) were alive without residual respiratory symptoms at a median follow-up of 4.7 (range, 2.1−10.6) years. Conclusion Outcome after fetal diagnosis of APVS was significantly better in this study compared with those of previous fetal series, with a low mortality rate for actively managed patients.

Few articles report on youth's perceptions about health-related issues and needs and even fewer have given voice to youth with disabilities, chronic health conditions, or youth in therapeutic foster care. The purpose of this study was to explore perceptions of health issues from the perspectives of youth placed in therapeutic foster care, youth with chronic medical conditions, and youth with disabilities. Twelve focus groups with 67 youth aged 13-20 were conducted in rural, suburban, and urban communities in the Commonwealth of Virginia. Data analysis revealed both within unique group themes and themes that cut across unique groups. Youth in therapeutic foster care with chronic health conditions or with disabilities perceive themselves as being different from their peers. Participants in each group expressed concerns about the unique issues that they confront daily and how these challenges differentiate them from youth who do not share their life experiences. They expressed the desire for other youth to understand them better and to not treat them differently. Discussion and implications focus on the need to create programs to support the unique needs of these youth.

Within the placenta, most centrally placed intervillous thrombi are thought to form at sites of foetomaternal haemorrhage, while parabasally located intervillous thombi have been linked to maternal vascular disease. To determine whether parabasally located haemorrhagic lesions were morphologically heterogeneous, the authors performed a retrospective review of 25 placentas with thrombohaematomas occurring in the vicinity of the basal plate. Using morphological criteria, two lesions were distinguished: (1) the parabasally located intervillous thrombus, which had all the morphological features of more centrally located intervillous thrombi; and (2) the rounded intraplacental haematoma. Rounded intraplacental haematomas form as a result of disruption of vasculopathic decidual arterioles in a setting of maternal vascular underperfusion and are thus aetiologically distinct from classically described intervillous thrombi.

Although in recent years placental pathology has been the subject of a wealth of detailed descriptions and diagnostic categorization, systematic correlation of these conditions with the pathology of stillbirth has not been attempted. We examine the relationship between specific inflammatory, maternal, and fetal vascular pathologies and the central nervous system pathology and histological indicators of fetal compromise. Our design was a retrospective case series of 37 3rd-trimester intrauterine fetal deaths. In general, mixed placental pathologies were the rule, with three quarters of the placentas demonstrating combinations of maternal vascular pathology, fetal vascular pathologies, umbilical cord abnormalities, or inflammatory lesions. The range of brain pathology was limited to acute, severe congestion, white matter edema, and neuronal karyorrhexis (pontosubicular necrosis with or without neuronal karyorrhexis at other sites). Established periventricular leukomalacia was present in only 2 cases. The presence of neuronal karyorrhexis or white matter gliosis was correlated with the presence of a high-grade inflammatory lesion and with fetal thymic involution. Neuronal karyorrhexis, but not white matter gliosis, correlated as well with histologically established fetal vascular lesions in the placenta, even once the effect of inflammation was accounted for. Gliosis also correlated with inflammation, meconium staining, and thymic involution. Central nervous system injury may be the end result of complex placental pathologies, and neuronal injury may be a consequence of the fetal inflammatory response. The correspondence between the time courses of histological features of chorioamnionitis, neuronal karyorrhexis, and thymic involution points to irreversible central nervous system injury being common 12–48 hours prior to in utero demise.

In contrast to thrombi and haematomas at other body sites, thrombi in the placental intervillous space are not traditionally known to undergo organisation. This report presents 11 examples of a form of organising thrombotic process that develops as a plaque on the foetal aspect of the basal plate. Originally identified in the placenta of a foetus showing severe intrauterine growth restriction, further examples of this lesion, which we term a 'basal plate plaque', show a spectrum of placental involvement. Small lesions appear to occur at points of localised stasis at the basal plate (eg, at edges of anchoring villi or in small basal plate depressions). Large areas of involvement, as seen in the original case, may be pathological markers of more generalised disturbances in placental circulation or of hypercoagulability in the intervillous space. Large basal plate plaques may therefore prove to be diagnostically significant and should be reported.

Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Pathological descriptions of fetal stage Seckel syndrome are rare and pre-date the evolving understanding of the genetic and molecular mechanisms involved. The autopsy findings in a case of fetal Seckel syndrome at 30 weeks gestation are presented, with detailed description of the neuropathological findings. Severe neurological abnormalities in a male fetus were observed that included microencephaly, cortical neuronal migration disorder, white matter tract hypoplasia/aplasia, premature depletion of the germinal matrix with cystic transformation and patchy absence of the external granular cell layer of the cerebellum. The striking neuropathological finding in this case was evidence of failure of the developing brain’s germinal elements, providing rare morphological insight into the abnormal development of the Seckel syndrome fetal brain. The selective failure of this proliferating cell population correlates with the emerging molecular evidence that Seckel syndrome is caused by defects in ATR-dependent DNA damage signaling with resultant premature death of proliferating cells.

Indications for the use of radiotherapy in the management of a variety of benign intracranial neoplastic and nonneoplastic pathologies are increasing. Although the short-term risks are minimal, the long-term risks of radiation-induced de novo secondary neoplasms or malignant progression of the primary benign tumor need to be considered. There are currently 19 reported cases of tumors linked with stereotactic radiotherapy/radiosurgery, to which we add our second institutional experience of a patient who succumbed to a glioblastoma multiforme (GBM) after stereotactic radiotherapy for an acoustic neuroma (AN). Review of these 20 cases revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of the cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (NF2; 8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of the primary benign AN, some 2 to 6 years after focused radiotherapy, was found in six of eight NF2 patients, with pathological verification of a malignant nerve sheath tumor documented in most. The exact carcinogenic risk after radiotherapy is unknown but likely extremely low. However, the risk is not zero and requires discussion with the patient, with specific consideration in young patients and those with a cancer predisposition.

Abnormal cortical development will lead to abnormal axons in white matter. The purpose was to investigate (1) the microstructural changes in subcortical white matter adjacent to malformations of cortical development (MCD) and (2) the deep white matter tracts using diffusion tensor imaging (DTI).Thirteen children with a variety of MCD were recruited. The fractional anisotropy (FA), trace, and eigenvalues (lambdamajor, lambdamedium, lambdaminor) of subcortical white matter of MCD were compared with contralateral normal side. The deep white matter tracts were graded based on the size, color hues and displacement of the tracts as visualized on color vector maps and tractography; grade 1 was normal tract size and color hue, grade 2 was reduced tract size but preserved color hue and grade 3 was loss of color hue or failure of tracking on tractography.The subcortical white matter adjacent to abnormal cortex demonstrated reduced FA (p0.05) and tendency to increase trace (p = 0.06). There was a significant elevation in lambdamedium and lambdaminor (p0.05), but no significant change in lambdamajor (p0.05). Twelve cases demonstrated alteration in white matter tracts. Seven cases of focal cortical dysplasia and two cases of transmantle MCD demonstrated grade 3 pattern of white matter tract.Reduced FA is a sensitive but nonspecific marker of alteration in microstructure of white matter. The elevated lambdamedium and lambdaminor may reflect a dominant effect of abnormal myelin. Alteration in white matter tracts was observed in most cases of MCD.

Although pyomyositis is uncommon in North America, it may be difficult to distinguish clinically from inflammatory myositis. We describe 2 cases of infectious myositis that were initially diagnosed as inflammatory myositis. As illustrated by these cases, infectious myositis is often a challenging diagnosis and requires a high degree of suspicion.

Cardiovascular dysfunction is common after cervical spinal cord injury (SCI) in humans. At least three spinal cord elements involved in cardiovascular control have been identified: descending vasomotor pathways (DVPs), sympathetic preganglionic neurons, and spinal afferents. However, little is known about the localization of the DVPs within the human spinal cord, which limits our understanding of the mechanisms of cardiovascular dysfunction after SCI. This study was undertaken to examine the association of cardiovascular abnormalities after SCI in humans with the severity of degeneration and axonal loss within the DVPs. A detailed chart review and histopathological examination of postmortem spinal cord tissue was conducted in individuals with cervical SCI (n = 7) and control individuals with an intact central nervous system (n = 5). Individuals with SCI were divided into group 1 (severe cardiovascular abnormalities) and group 2 (no/minor cardiovascular disturbances). The area of degeneration and the number of preserved axons within different areas of the spinal cord were quantitated using EMPIX imaging software. Two areas of possible localization of DVPs were investigated: area I, within the dorsal aspects of the lateral funiculus; and area II, within the white matter adjacent to the dorsolateral aspect of the lateral horn. Comparison of the extent of axonal degeneration in both SCI groups demonstrated that individuals in group 1 had more extensive axonal degeneration than those in group 2. The number of intact axons within areas I and II in individuals from group 1 was significantly lower than those from group 2 or control cases (p = 0.029; p = 0.028). The most dramatic axonal loss was observed within area I in individuals with cardiovascular dysfunction. We conclude that loss and degeneration of DVPs, which are localized within the dorsolateral aspects of the human spinal cord, contributes to abnormal cardiovascular control after SCI. This information adds to our knowledge of pathobiology of cardiovascular dysfunction after human SCI and may ultimately suggest novel therapeutic strategies as regenerative and reparative approaches become translated to the clinic.

Calcifications associated with both benign and neoplastic intra-axial lesions of the central nervous system (CNS) are well recognized. Bony metaplasia in the CNS, where there is formation of mature trabecular bone, is a much more rare entity and has not been reported in the spinal cord. We present a case of bony metaplasia in the conus medullaris associated with a low grade astrocytoma. Radiological, pathological and clinical features of this unique case are discussed.

Wolfram syndrome, characterised by diabetes insipidus, diabetes mellitus, optic atrophy sensorineural deafness and acquired urinary tract abnormalities, is an hereditary neurodegenerative syndrome, the pathogenesis of which is unknown. We report the post-mortem findings on a patient with well-documented Wolfram syndrome. The brain showed severe degeneration of the optic nerves, chiasm and tracts as well as severe loss of neurons from the lateral geniculate nuclei, basis pontis, and the hypothalamic paraventricular and supraoptic nuclei. In addition, there was a widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices and the deep cerebral white matter. This widespread axonal pathology parallels the pattern of neurodegeneration and in many areas is more striking than neuronal loss.

Objective Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality. Case report The first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch. Conclusion Complete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy.