Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia.

BACKGROUND: SUMOylation involves the attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues on thousands of substrates with target-specific effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and deconjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein 1α (HP1α). METHODS: We performed exome sequencing and segregation studies in a family with several infants presenting with an unidentified syndrome. RNA and protein expression studies were performed in fibroblasts available from one subject. RESULTS: We identified a kindred with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, no achievement of developmental milestones, early respiratory failure, neutropenia and recurrent infections. All died within four months after birth. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable aetiology. The proband's fibroblasts demonstrated decreased mRNA expression. Protein expression studies showed significant protein dysregulation in total cell lysates and in the chromatin fraction. We found that HP1α levels as well as different histones and H3K9me3 were reduced in patient fibroblasts. These results support previous studies showing interaction between SENP7 and HP1α, and suggest loss of SENP7 leads to reduced heterochromatin condensation and subsequent aberrant gene expression. CONCLUSION: Our results suggest a critical role for SENP7 in nervous system development, haematopoiesis and immune function in humans.

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance.

A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss-of-function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.

Diagnosis of fetal cortical abnormalities by new reference charts for assessment of sylvian fissure biometry.

OBJECTIVE: To develop novel fetal reference ranges for the characterization of the normal appearance of the Sylvian fissures (SF) along gestation and to apply them to fetuses with cortical abnormalities affecting the SF. METHODS: In this cross-sectional study, we used three-dimensional sonographic multiplanar reformatting (3D-MPR) to examine the fetal SF. Normal development was assessed in the second and third trimesters. SF parameters were evaluated in predefined axial and coronal planes: insular height and length, SF depth, and the extent of the coverage of the insula by the frontal and temporal lobes. Intra-observer variability and inter-rater reliability for the studied parameters were evaluated. The new reference charts were applied to 19 fetuses with cortical abnormalities involving the SF who had appropriate sonographic volumes for 3D-MPR analysis. Their diagnoses were confirmed by autopsy, fetal or postnatal MRI, genetic findings related to cortical malformations, or an abnormal cortical imaging pattern with similar MRI findings in an affected sibling. We applied the two previously published references for the evaluation of fetal SF development to these cases and compared the ability of the references to correctly detect SF abnormalities. RESULTS: The study included 189 fetuses of low-risk singleton pregnancies between 24 and 34 gestational weeks. The insular length or height increased with gestational age in the axial and coronal planes with adjusted R2  = 0.621, p < 0.0001 and R2  = 0.384, p < 0.0001, respectively. The SF depth also increased with gestational age in the axial and coronal planes with adjusted R2  = 0.695, p < 0.0001 and R2  = 0.219, p = 0.008, respectively. The extent of the coverage of the insula by the frontal and temporal lobes in the coronal plane increased with gestational age (adjusted R2  = 0.627, p < 0.0001 and R2  = 0.589, p < 0.0001, respectively). The interclass correlation coefficients of the intra- and inter-rater reliability of the studied parameters ranged between 0.71 and 0.97. The cortical anomalies in the 19 fetuses were polymicrogyria (7), simplified gyral pattern (3), dysgyria (3), lissencephaly (2), cortical malformation related to tubulinopathy (1), brain atrophy (1), cortical dysplasia (1), and cobblestone malformation (1). Three of the fetuses had multiple cortical anomalies. In 17 of 19 (89%) cases, at least one of our 6 SF parameters was found to be out of the normal range. In the coronal plane, SF height and depth were measured below 2SD in 9 (47%) and 4 (21%) cases, respectively. In the axial plane, SF length and depth were out of the normal ranges in six (31.5%) and four (21%), correspondingly. In the coronal plane, the opercular coverage by the frontal and temporal lobes was below 2 SD in 10 (52%) and 11 (57%), respectively. The scoring of the SF operculization by Quarello et al. was abnormal in 8 cases (42%). The measurement of the SF angle according to Poon et al. was abnormal in 14 cases (74%). CONCLUSIONS: The fetal SF is a complex developing structure that can be reliably characterized by sonographic parameters. One abnormal parameter is sufficient to raise the suspicion of SF malformation. Our new SF parameters might facilitate the detection of prenatal cortical abnormalities affecting the SF.

Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder.

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient's fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient's cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.

LMOD3-Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings.

To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron-dense protein inclusions in skeletal myofibers. Although clinically, nemaline myopathy can be viewed as a common pathway phenotype, its molecular basis is heterogeneous, with mutations in 11 identified genes implicated in its pathogenesis so far. Whole-exome sequencing revealed that the affected fetuses were compound heterozygous for 2 newly reported pathogenic variants in the LMOD3 gene, which encodes leiomodin 3. To our knowledge, this article is the first report of LMOD3-related nemaline myopathy since the original reported cohort. We provide a detailed description of the prenatal imaging of these affected fetuses, which we hope, in combination with next-generation sequencing, may contribute to further diagnosis in additional families.

Unique Imaging Features Enabling the Prenatal Diagnosis of Developmental Venous Anomalies: A Persistent Echogenic Brain Lesion Drained by a Collecting Vein in Contrast with Normal Brain Parenchyma on MRI.

OBJECTIVE: To describe the prenatal imaging features enabling diagnosis of developmental venous anomalies (DVA). METHODS: Four fetuses with unexplained persistent echogenic parenchymal brain lesions were studied. The evaluation included dedicated neurosonography, fetal MRI, serology for intrauterine infection, screening for coagulation abnormalities, and chromosomal microarray. Postnatal neurodevelopmental follow-up or autopsy results were assessed. RESULTS: DVA presented as very slowly growing echogenic brain lesions without cystic components, calcifications, or structural changes on otherwise normal neurosonographic scans performed at 2- to 3-week intervals. A specific Doppler feature was a collecting vein draining the echogenic parenchyma. Fetal brain MRI depicted normal anatomy on half-Fourier acquisition single-shot turbo spin-echo and diffusion-weighted imaging. The rest of the evaluation was normal. CONCLUSIONS: In cases with a persistent, parenchymal echogenic lesion without clastic or structural changes, DVA should be considered. Demonstration of a collecting vein draining the lesion and normal brain anatomy on MRI confirm the diagnosis.

Characteristics of orbital lymphoma: a clinicopathological study of 26 cases.

OBJECTIVE: Evaluation of the medical data of patients with orbital and adnexal lymphoma. DESIGN: Cohort study of all cases diagnosed with orbital or adnexal lymphoma at Meir Medical Center between 1993 and 2007. PARTICIPANTS: Twenty-six patients, with intraorbital or subconjunctival masses with orbital involvement, were examined and followed up between 1 and 8 years. MATERIALS AND METHODS: Examined data included: clinical presentation, age, gender, imaging, tumor location, surgical management, and pathological diagnosis. RESULTS: Presenting signs and symptoms included proptosis, eyelid lesions, tearing, chemosis, decreased visual acuity, ptosis, pain, squint, and optic nerve compression. In five cases, lymphoma was misdiagnosed on neuroimaging. Bone changes were seen in four patients. All cases were B cell lymphomas; with the majority (22 cases) of small B cell type; consisting of primary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and two cases of small cell lymphoma. One small cell lymphomas was of follicular type on a background of CLL, and the other was CLL/SLL type. Fourteen cases were primary orbital disease, and 12 cases were systemic disease. Macroscopic appearance of lymphoma at open biopsy was characteristic in most cases. Flow cytometry phenotyping gave rapid reliable diagnosis of the disease. CONCLUSIONS: Epiphora or chemosis in the presence of an orbital mass should alert the ophthalmologist to suspect lymphoma. Lymphoma may be easily misinterpreted on neuroimaging for other diseases. Bone changes seen on CT are more common than is generally perceived. Macroscopic appearance at open biopsy was characteristic.

Familial Brain Periventricular Pseudocysts.

INTRODUCTION: We report the rare finding of recurrent periventricular pseudocysts (PVPC) in consecutive pregnancies in 4 families and their postnatal outcome. MATERIALS AND METHODS: We reviewed the databases of 3 large ultrasound units searching for the diagnosis of PVPC in 2 pregnancies of the same patient. RESULTS: The first case of recurrent PVPC was diagnosed in 2011 and since then 3 additional families were diagnosed (8 cases of PVPC all in all). All fetuses underwent fetal MRI that confirmed the presence of frontal or frontocaudal PVPC. Amniocentesis, when performed, demonstrated a normal karyotype. Termination of pregnancy was carried out in 2 pregnancies in 2 of 4 families. The remaining 6 pregnancies ended with a term delivery, and to date all babies are developing normally. CONCLUSION: The rare finding of recurrent brain PVPC in consecutive pregnancies raises the possibility of a hereditary etiology as opposed to a sporadic event. As in isolated PVPC, frontocaudal 'familial PVPC' appears to carry a favorable prognosis.

Telomere homeostasis in trophoblasts and in cord blood cells from pregnancies complicated with preeclampsia.

BACKGROUND: Telomeres are nucleoprotein structures, essential for chromosome stability and cell survival. Telomeres are progressively shortened with each cell division and by environmental factors. Telomere loss has been linked to age and stress-induced premature senescence. Dysfunctional telomeres tend to form aggregates, which consist of the end-to-end fusion of telomeres. Telomere elongation is carried out by telomerase, which is a specific reverse transcriptase capable of adding telomeric repeats to chromosome termini. The TERC gene encodes the RNA template of the telomerase. Another compensatory mechanism that is enhanced in response to telomere shortening and senescence is the telomere capture (TC). Telomere shortening and elevated aggregate formation have been observed in trophoblasts from pregnancies complicated with preeclampsia (PE). OBJECTIVE: We opted to study mechanisms of telomere shortening in trophoblasts from pregnancies complicated with PE and to assess telomere length and homeostasis in fetal cord blood cells from PE pregnancies. STUDY DESIGN: Placental specimens and cord blood samples from uncomplicated pregnancies and from pregnancies complicated with PE were collected. Staining with 4',6-diamidino-2-phenylindole was used to assess nuclear fragmentation: senescence-associated heterochromatin foci (SAHF). Fluorescence in situ hybridization was used to evaluate TERC gene copy number and TC. Telomere length and aggregate formation were assessed in cord blood using quantitative fluorescence in situ hybridization. Nonparametric Kruskal-Wallis and Mann-Whitney U tests were applied to test the differences between the study groups. RESULTS: Nine samples from pregnant patients with PE without intrauterine growth restriction and 14 samples from uncomplicated pregnancies that served as controls were collected. In cord blood cells, no differences were observed in telomere length, aggregate formation, TERC copy number, TC, or SAHF between PE and controls. In PE trophoblasts the percentage of cells with SAHF was higher in PE trophoblasts compared to controls (56.8 SD = 10.5% vs 35.2 SD = 10.7%, P = .028). The percentage of cells with abnormal TERC copy number was increased in PE trophoblasts compared to controls (31 ± 3.6% vs 12.97 SD = 5%, P = .004) as well as the percentage of cells with TC (27.4 SD = 9.4% vs 16 SD = 4.67%, P = .028). CONCLUSION: We suggest that telomere shortening in PE trophoblasts is linked to cellular increased senescence. Alterations in telomere homeostasis mechanisms are present in such cases. These findings support the role of telomeres in the pathogenesis of trophoblastic dysfunction in PE. The lack of telomere shortening, modified telomere homeostasis mechanisms, and increased senescence in cord blood from pregnancies complicated with PE suggests that these processes are probably restricted primarily to the placenta.

T cell-derived microvesicles induce mast cell production of IL-24: relevance to inflammatory skin diseases.

BACKGROUND: It has recently been shown that microvesicles derived from activated T cells can stimulate human mast cells (MCs) to degranulate and release several cytokines. OBJECTIVE: The aim of this study was to characterize microvesicle-induced MC expression patterns. Through identification of unique cytokine and chemokine expression, we attempted to reveal pathogenetic roles for this pathway of MC activation. METHODS: T cell-derived microvesicles were labeled with PKH67 to allow visualization of their interaction with human MCs. Consequent gene expression profiling was studied by using a whole-genome microarray and analyzed for identification of cellular pathway clusters. Expression of 3 selected genes, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 7 (CCL7), and IL24, was validated by means of quantitative RT-PCR and specific ELISA. IL24, which has not been recognized heretofore in MCs, was also tested for its effect on keratinocyte signal transducer and activator of transcription 3 phosphorylation and for its presence in MCs in psoriatic skin lesions. RESULTS: Uptake and internalization of activated T cell-derived microvesicles into human MCs occurred within 24 hours. Microvesicles induced the upregulation of several clusters of genes, notably those that are cytokine related. Among these, IL24 appeared to be a hallmark of microvesicle-induced activation. MC-derived IL-24, in turn, activates keratinocytes in vitro, as manifested by signal transducer and activator of transcription 3 (STAT3) phosphorylation, and is produced in MCs within psoriatic lesions. CONCLUSION: Production of IL-24 is a unique feature of microvesicle-induced MC activation because its production by these cells has not been recognized thus far. We propose that this MC-derived cytokine might contribute to the pathologic findings in T cell-mediated skin inflammation.

Waterhouse Friderichsen syndrome complicating fulminant Enterobacter cloacae sepsis in a preterm infant: the unresolved issue of corticosteroids.

Bilateral adrenal hemorrhage can complicate severe sepsis in the neonate and is most commonly attributed to meningococcal disease; however, it can be caused by other etiologic agents as well. We report herein a fatal case of Enterobacter cloacae sepsis in a preterm infant, resulting in massive adrenal hemorrhages. This is the first documented case of adrenal hemorrhage following infection with this pathogen.

Does normal fetal brain ultrasound predict normal neurodevelopmental outcome in congenital cytomegalovirus infection?

OBJECTIVE: We evaluated the neuropsychological outcome of children with proven congenital cytomegalovirus (CMV) infection and normal consecutive fetal neurosonographic examinations. METHODS: We retrospectively reviewed laboratory and imaging findings of children with congenital CMV infection. The study group consisted of children with a positive polymerase chain reaction (PCR) in amniotic fluid and virus isolation in urine in the first week of life, and normal fetal ultrasonographic (US) examination findings, including a normal multiplanar neurosonographic evaluation. Patients with abnormal magnetic resonance (MR) findings were not excluded. The study and control groups were evaluated for cognitive, language, and motor development at one follow-up examination conducted at 11-81 months of age. RESULTS: Children with congenital CMV infection and normal fetal brain findings in the US examination did not differ from the control group in terms of cognitive, language, motor, emotional-behavioral, and executive functioning. There were no differences between congenitally infected children who had a normal fetal brain MR examination and children whose fetal brain MR examination raised suspicion of a possible brain insult. CONCLUSIONS: Normal neurosonographic examinations during pregnancy appear to predict a normal early neuropsychological outcome in fetuses with congenital CMV infection. Outcome did not correlate with suspected abnormal white matter on fetal MR imaging.

αvß3 Integrin Expression and Mitogenic Effects by Thyroid Hormones in Chronic Lymphocytic Leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The thyroid hormones, T3 and T4, bind the αvß3 integrin and activate phosphorylates ERK (pERK). These tumor-promoting actions were reported in a number of malignancies, but not in CLL. METHODS: Primary cells from 22 CLL patients were verified for disease markers (CD5/CD19/CD23) and analyzed for αvß3 by flow cytometry (FC), ImageStream, Western blots (WB), and immunohistochemistry (IHC) in archival bone marrow (BM, n = 6) and lymph node (LN, n = 5) tissues. Selected samples (n = 8) were incubated with T3 (1-100 nM) or T4 (0.1-10 µM) for 30 min, and the expression levels of αvß3, pERK and PCNA (cell proliferation marker) were determined (WB). RESULTS: αvß3 was detected on the membrane of circulating CLL cells and in the BM but not in the LN. T3 and T4 enhanced αvß3 protein levels in primary CLL cells. Similarly, pERK and PCNA were rapidly induced in response to T3 and T4 exposure. CONCLUSIONS: αvß3 integrin is expressed on primary CLL cells and is induced by thyroid hormones. We further suggest that the hormones are mitogenic in these cells, presumably via αvß3-mediated signaling.

Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.

OBJECTIVE: Telomeres shorten and aggregate with cellular senescence and oxidative stress. Telomerase and its catalytic component human telomerase reverse-transcriptase regulate telomere length. The pathogenesis of preeclampsia and intrauterine growth restriction involves hypoxic stress. We aimed to assess telomere length in trophoblasts from pregnancies with those complications. STUDY DESIGN: Placental specimens from 4 groups of patients were studied: severe preeclampsia, intrauterine growth restriction, preeclampsia combined with intrauterine growth restriction, and uncomplicated (control). Telomere length and human telomerase reverse-transcriptase expression were assessed by using quantitative fluorescence-in-situ protocol and immunohistochemistry. RESULTS: Telomere length was significantly lower in preeclampsia, intrauterine growth restriction, and preeclampsia plus intrauterine growth restriction placentas. More aggregates were found in preeclampsia, but not in intrauterine growth restriction placentas. Human telomerase reverse-transcriptase was significantly higher in the controls compared with the other groups. CONCLUSION: Telomeres are shorter in placentas from preeclampsia and intrauterine growth restriction pregnancies. Increased telomere aggregate formation in preeclampsia but not in intrauterine growth restriction pregnancies, implies different placental stress-related mechanisms in preeclampsia with or without intrauterine growth restriction.

BRCA1/2 germline mutations in Jewish patients with uterine serous carcinoma.

INTRODUCTION: Whether and to what extent germline mutations in the BRCA1 and BRCA2 genes increase the risk for developing uterine serous carcinoma (USC) remain controversial. We assessed the rate of the 3 predominant BRCA1/2 mutations in Jewish patients with USC and the relevance of carrier status to clinicopathological features and survival. METHODS: Jewish patients with histologically confirmed USC diagnosed between April 1997 and December 2007 were genotyped for the 3 predominant BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method and log-rank tests were used for survival analyses. RESULTS: Overall, 8 (25.8%) of 31 Jewish patients with USC who participated in the study were mutation carriers: 4 were BRCA2 (6174delT) carriers and 2 each carried the BRCA1 mutations (185delAG and 5382insC). The median ages of the carriers and the noncarriers were 66 and 74 years, respectively (P = 0.124). Four (50%) of the mutation carriers and 2 (8%) of the noncarriers had a family history of breast-ovarian cancer (P = 0.026). With a median follow-up of 76 months, the overall median survival time was 25 months. No significant differences in the median survival time, 2-year survival, or progression-free survival were noted between the mutation carriers and the noncarriers. CONCLUSIONS: The high rate of the predominant BRCA1/2 mutations in unselected Jewish USC patients, if confirmed by future studies, suggests that USC could be considered an expression of the hereditary breast-ovarian cancer syndrome.

Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

OBJECTIVE: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome. METHODS: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses. RESULTS: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal. CONCLUSIONS: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.

Prenatal diagnosis of oral cyst caused by foregut duplication.

Prenatal diagnosis of oral cystic lesions is rare but is reported more frequently. The diagnosis of sublingual cyst is important because of the potential for airway obstruction. A rare case of a foregut duplication cyst associated with unilateral sclerocorneal microphthalmia is reported. The differential diagnosis and the limitations of the prenatal ultrasound and the postnatal MRI are discussed.

Monitoring of chemotherapy-induced cell death in melanoma tumors by N,N'-Didansyl-L-cystine.

Early assessment of the efficacy of anticancer agents is a highly desirable and an unmet need in clinical oncology. Clinical imaging of cell-death may be useful in addressing this need, as induction of tumor cell-death is the primary mechanism of action of most anticancer drugs. In this study, we examined the performance of N,N'-Didansyl-L-cystine (DDC), a member of the ApoSense family of novel small molecule detectors of cell-death, as a potential tool for monitoring cell-death in cancer models. Detection of cell-death by DDC was examined in fluorescent studies on B16 melanoma cells both in vitro and ex vivo following its in vivo administration. In vitro, DDC manifested selective uptake and accumulation within apoptotic cells that was highly correlated with Annexin-V binding, changes in mitochondrial membrane potential, and caspase activation. Uptake was not ATP-dependent, and was inducible by calcium mobilization. In vivo, DDC selectively targeted cells undergoing cell-death in melanoma tumors, while not binding to viable tumor cells. Chemotherapy caused marked tumor cell-death, evidenced by increased DDC uptake, which occurred before a detectable change in tumor size and was associated with increased animal survival. These data confirm the usefulness of imaging of cell-death by DDC as a tool for early monitoring of tumor response to anti-cancer therapy.

Fatal outcome following foetal cerebellar haemorrhage associated with placental thrombosis.

Cerebellar haemorrhage is a rare prenatal event. Possible aetiologies for foetal intracranial haemorrhage include: trauma, asphyxia, infection, vascular defects, blood dyscrasias, ingestion of drugs and alloimmune and isoimmune thrombocytopenia. We report the ultrasonographic diagnosis of a cerebellar haematoma at 21 weeks of gestation. The foetus succumbed at 33 weeks of gestation following rupture of a subcapsular liver haematoma. An autopsy demonstrated a placental foetal thrombotic vasculopathy and thrombi in the chorionic vessels. We assume that hypercoagulability was responsible for the multiple infarcts in the foetus with haemorrhagic transformation in the cerebellum and liver. The differential diagnosis of foetal cerebellar haemorrhage includes maternal hypercoagulability; in this case multiple haemorrhagic/ischaemic events may be encountered during the pregnancy. A thorough investigation to elucidate the aetiology is pertinent in every case of foetal cerebellar haemorrhage in order to enable accurate counselling and correct management.