ABSTRACT
Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or potentially signifies a new phenotypic subtype. The databases of Wolfson Medical Center, Sourasky Medical Center, and EB's personal collection were reviewed. Records from an additional family were obtained from RG. The patients' medical records, prenatal ultrasounds, and magnetic resonance imaging were assessed. In addition, we reviewed the medical literature for the association of ventriculomegaly/hydrocephalus (VM/HC) in JBTS. Only seven cases (from five families) were found with prenatal onset of VM/HC, diagnosed during the second trimester; three pregnancies were terminated, one was stillborn and three were born, of which one died within a week, and another died at the age of 6 years. Additional central nervous system findings included dysgenesis of the corpus callosum, delayed sulcation, polymicrogyria, and pachygyria. We found 16 publications describing 54 patients with JBTS and VM/HC: only five were diagnosed at birth and three were diagnosed prenatally. Hydrocephalus is extremely rare in JBTS. The recurrence of this association, reported in several publications in multiple family members, suggests that it might represent a new phenotypic subtype of JBTS possibly associated with specific genes or variants. Further genetic studies are needed to confirm this hypothesis. WHAT THIS PAPER ADDS: The association of fetal hydrocephalus with Joubert-Boltshauser syndrome (JBTS) is very rare but not a chance association. This association represents a new phenotypic subtype of JBTS possibly linked to specific genes or variants.
Subject(s)
Abnormalities, Multiple , Cerebellum , Eye Abnormalities , Hydrocephalus , Kidney Diseases, Cystic , Retina , Humans , Hydrocephalus/diagnostic imaging , Hydrocephalus/complications , Cerebellum/abnormalities , Cerebellum/diagnostic imaging , Eye Abnormalities/complications , Eye Abnormalities/diagnostic imaging , Abnormalities, Multiple/diagnostic imaging , Female , Kidney Diseases, Cystic/complications , Kidney Diseases, Cystic/diagnostic imaging , Kidney Diseases, Cystic/genetics , Male , Retina/abnormalities , Retina/diagnostic imaging , Cerebellar Vermis/abnormalities , Cerebellar Vermis/diagnostic imaging , Magnetic Resonance Imaging , Phenotype , Cerebellar Diseases/diagnostic imaging , Cerebellar Diseases/complications , Child , Infant, NewbornABSTRACT
PURPOSE: The study aimed to evaluate the causes of death and associated factors in cases of stillbirth, using post-mortem examination and applying a rigorous, evidence-based holistic approach. METHODS: Our retrospective observational study included cases of autopsy following stillbirth that occurred at our tertiary medical center during a period of 8 years. Detailed up-to-date criteria that incorporate clinical reports, medical history, prenatal imaging, and histopathological findings were used to evaluate the cause of death and associated factors. RESULTS: After applying our proposed methodology, 138 cases of stillbirth were classified into eight categories based on the causes of death. A definitive cause of death was observed in 100 (72%) cases, while 38 (28%) cases were considered unexplained. The leading cause of death was placental lesions (n = 39, 28%) with maternal vascular malperfusion (MVM) lesions being the most common (54%). Ascending infection was the second most common cause of fetal death (n = 24, 17%) and was often seen in the setting of preterm labor and cervical insufficiency. CONCLUSION: The largest category of cause of death was attributed to placental pathology. Using rigorous detailed up-to-date criteria that incorporate pathological and clinical factors may help in objectively classifying the cause of death.
ABSTRACT
AIM: To assess whether microcephaly with pontine and cerebellar hypoplasia (MICPCH) could manifest in the prenatal period in patients with calcium/calmodulin-dependent serine protein kinase (CASK) gene disorders. METHOD: In this international multicentre retrospective study, we contacted a CASK parents' social media group and colleagues with expertise in cerebellar malformations and asked them to supply clinical and imaging information. Centiles and standard deviations (SD) were calculated according to age by nomograms. RESULTS: The study consisted of 49 patients (44 females and 5 males). Information regarding prenatal head circumference was available in 19 patients; 11 out of 19 had a fetal head circumference below -2SD (range -4.1SD to -2.02SD, mean gestational age at diagnosis 20 weeks). Progressive prenatal deceleration of head circumference growth rate was observed in 15 out of 19. At birth, 20 out of 42 had a head circumference below -2SD. A total of 6 out of 15 fetuses had a TCD z-score below -2 (range -5.88 to -2.02). INTERPRETATION: This study expands the natural history of CASK-related disorders to the prenatal period, showing evidence of progressive deceleration of head circumference growth rate, head circumference below -2SD, or small TCD. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements and genetic studies are advised in the presence of progressive deceleration of head circumference growth rates or small TCD. WHAT THIS PAPER ADDS: Progressive deceleration of fetal head circumference growth rate can be observed. A small transcerebellar diameter is an additional important manifestation. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements are advised when measurements are within the low range of norm.
Subject(s)
Microcephaly , Nervous System Malformations , Female , Humans , Infant , Infant, Newborn , Male , Pregnancy , Fetus , Gestational Age , Microcephaly/diagnosis , Nervous System Malformations/genetics , Retrospective StudiesABSTRACT
PURPOSE: Fetal growth assessment is a key component of prenatal care. Sex-specific fetal brain nomograms on ultrasound are available and are clinically used. In recent years, the use of fetal MRI has been increasing; however, there are no sex-specific fetal CNS nomograms on MRI. The study aimed to assess the differences in fetal brain biometry and growth trajectories and to create population-based standards of the fetal brain on MRI. METHODS: In this cross-sectional study, brain structures of singleton fetuses with normal brain MRI scans were analyzed: biparietal diameter, occipitofrontal diameter, trans-cerebellar diameter, and the corpus callosum were measured and converted into centiles. Sex-specific nomograms were created. RESULTS: A total of 3848 MRI scans were performed in one tertiary medical center between 2011 and 2019; of them, 598 fetuses met the inclusion criteria, 300 males and 298 females between 28- and 37-weeks' gestation. Males had significantly larger occipitofrontal diameter than females (median 75%, IQR 54-88%; median 61%, IQR 40-77%) and biparietal diameter (median 63%, IQR 42-82%; median 50%, IQR 25-73%), respectively (p < 0.001). The cerebellum had the greatest growth rate, with a 1.5-fold increase in diameter between 28 and 37 weeks' gestation, with no measurement difference between the sexes (p = 0.239). No significant difference was found in the corpus callosum (p = 0.074). CONCLUSION: Measuring both sexes on the same nomograms may result in over-estimation of male fetuses and under-estimation of females. We provide fetal sex-specific nomograms on two-dimensional MRI.
Subject(s)
Sex Characteristics , Ultrasonography, Prenatal , Pregnancy , Female , Male , Humans , Ultrasonography, Prenatal/methods , Cross-Sectional Studies , Brain/diagnostic imaging , Biometry/methods , Gestational Age , Magnetic Resonance Imaging/methodsABSTRACT
INTRODUCTION: The subarachnoid space (SAS) is a potential space surrounding the brain where the cerebrospinal fluid (CSF) flows. Previous work demonstrated how the SAS width changes during pregnancy and measured the normal values per gestational week. OBJECTIVES: Studying the ratio between the fetal brain volume (STV) and the SAS width (SS ratio), as measured via fetal magnetic resonance imaging (MRI) in different fetal pathologies - macrocephaly and microcephaly, and studying the correlation between this ratio and the gestational week. METHODS: A retrospective study was conducted on 77 fetuses that underwent fetal MRI scans during gestational weeks 29-37, in three groups: 23 normocephaly, 27 macrocephaly, and 27 microcephaly. SAS width was measured in 10 points via fetal MRI scans, and a ratio was calculated between the width and STV. RESULTS: The SS ratio is largest in microcephaly group and smallest in normocephaly group, with the macrocephaly group between them. All comparisons were statistically significant except between the macrocephaly and normocephaly groups. There was a strong positive correlation between SS ratio and week of gestation. CONCLUSIONS: The SS ratio is statistically different between normocephalic fetuses and fetuses with macrocephaly or microcephaly. From week 29 this ratio enlarges with gestational age. DISCUSSION: The SAS affects the fetal head circumference, an important parameter of fetal growth, thus we decided to study the SS ratio in pathologies of the head circumference. Previous work demonstrated how the STV and the SAS width expand starting at a specific gestational age, thus the gestational week also affects the SS ratio. Summary: The SS ratio is affected by pathologies of the fetal head circumference and by gestational age.
Subject(s)
Megalencephaly , Microcephaly , Pregnancy , Female , Humans , Microcephaly/diagnostic imaging , Retrospective Studies , Fetus/diagnostic imaging , Magnetic Resonance Imaging/methods , Gestational Age , Subarachnoid Space/diagnostic imaging , Megalencephaly/diagnostic imaging , Ultrasonography, Prenatal/methodsABSTRACT
OBJECTIVE: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations. METHODS AND RESULTS: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development. CONCLUSIONS: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.
Subject(s)
Agenesis of Corpus Callosum/genetics , Brain/metabolism , Nervous System Malformations/genetics , Polymicrogyria/genetics , Repressor Proteins/genetics , Septum Pellucidum/metabolism , Brain/abnormalities , Brain/diagnostic imaging , Child , Child, Preschool , Family Health , Humans , Infant , Magnetic Resonance Imaging/methods , Male , Mutation , Septum Pellucidum/abnormalities , Exome Sequencing/methodsABSTRACT
Interstitial deletions of 16q24.1-q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema-Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1-q24.2. This report extends the phenotype of both 16q24.1-q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3'-UTR part of FOXC2.
Subject(s)
Eyelashes , Lymphedema , Neurodevelopmental Disorders , Eyelashes/abnormalities , Forkhead Transcription Factors/genetics , Humans , Lymphedema/complications , Lymphedema/diagnosis , Lymphedema/genetics , Neurodevelopmental Disorders/complications , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/geneticsABSTRACT
OBJECTIVE: The representation of women among authors of peer reviewed scientific papers is gradually increasing. The aims of this study were to examine the trend of the proportion of women among authors in the field of rheumatology during the last two decades. METHODS: Articles published in journals ranked in the top quartile of the field of rheumatology in the years 2002-2019 were analysed. The authorship positions of all authors, country of the article's source and manuscript type were retrieved by specifically designed software. RESULTS: Overall, 153 856 author names were included in the final analysis. Of them, 55 608 (36.1%) were women. There was a significant rise in the percentage of women authors over time (r = 0.979, P <0.001) from 30.9% in 2002 to 41.2% in 2018, with a slight decline to 39.8% in 2019. There were significantly fewer women in the senior author positions compared with the first author positions (24.3% in senior position vs 40.9% as first author, P <0.001). CONCLUSION: The proportion of women among authors of rheumatology articles has increased over the years, both in general and as a first or senior author; however, their proportion is still <50% and there is still a gap between the proportion of women among first authors and the proportion of women among senior authors.
Subject(s)
Authorship , Periodicals as Topic/trends , Rheumatology/statistics & numerical data , Women , Humans , Periodicals as Topic/statistics & numerical dataABSTRACT
PURPOSE: To characterize the population of women who underwent mid-trimester preterm premature rupture of membrane (PPROM) in a country where mid-trimester abortions are legal and available. METHODS: A retrospective cross-sectional cohort study was conducted at a tertiary referral hospital, during 2013-2016. Mid-trimester defined as gestational age 13 + 0 to 23 + 6 weeks. Rupture of membrane was defined by documentation of fluid passing through the cervix on sterile speculum examination, and a positive Nitrazine (Bristol-Myers Squibb, Princeton, NJ) or erning test. All records were evaluated for medical history, laboratory data, postnatal examination, and autopsy findings, and a database was constructed. RESULTS: A total of 61 women were hospitalized for mid-trimester PPROM during the study period. Mean maternal age was 32 ± 5.98, range 20-45 years old. The majority (50, 82%) of patients decided to terminate their pregnancy before reaching the limit of viability at 24 weeks gestation. The overall prognosis of pregnancies reaching term was better than expected, with six (9.8%) patients delivering live babies and four of them born at term (36 ± 5 to 40 ± 6 weeks gestation), all after PPROM following amniocentesis or selective fetal reduction. A total of 60% of women with hypothyroidism had unbalanced TSH levels above 4.0 mIU/L prior to their pregnancy. A notable number of women (15, 24.6%) had PPROM following a pregnancy achieved by assisted reproductive technology (ART). CONCLUSIONS: Most women with diagnosed mid-trimester PPROM opted for pregnancy termination before the limit of viability when granted the choice. Possible risk factors for early PPROM are unbalanced hypothyroidism and ART. PPROM following amniocentesis can in some cases reseal and reach term, suggesting conservative treatment is a reasonable management for those cases.
Subject(s)
Aborted Fetus , Fetal Membranes, Premature Rupture/mortality , Pregnancy Outcome/epidemiology , Premature Birth/mortality , Adult , Amniocentesis , Cross-Sectional Studies , Female , Fetal Membranes, Premature Rupture/etiology , Gestational Age , Humans , Infant, Newborn , Infant, Premature , Live Birth/epidemiology , Maternal Age , Middle Aged , Obstetric Labor Complications/etiology , Perinatal Mortality , Pregnancy , Pregnancy Trimester, Second , Premature Birth/etiology , Retrospective Studies , Risk Factors , Stillbirth/epidemiology , Young AdultABSTRACT
Epilepsy and intracranial pressure (ICP) can be interrelated. While shunt malfunction is recognized as a cause of seizures, shunt over-drainage is seldom reported as such. We report a child who had undergone ventriculoperitoneal shunt insertion at the age of 6 months following an excision of a left ventricle choroid plexus papilloma, who developed refractory epilepsy since the age of 3 years. An MRI showed small ventricles. The child presented with acute hydrocephalus due to proximal shunt malfunction at the age of 11 years and was treated with an endoscopic third ventriculostomy. Following the procedure, the seizures abated. Our case suggests that intractable epilepsy may be related to intracranial hypotension. Potential treatments for shunt over-drainage may be indicated even in the absence of classic over-drainage symptoms, in the presence of refractory epilepsy.
Subject(s)
Drug Resistant Epilepsy/etiology , Ventriculoperitoneal Shunt/adverse effects , Ventriculostomy/methods , Child , Drug Resistant Epilepsy/surgery , Humans , MaleABSTRACT
OBJECTIVE: To characterize the biometric parameters in ultrasound and brain MRI of fetuses with isolated mega cisterna magna (MCM). METHODS: Cross-sectional historical cohort study conducted at a single tertiary medical center between 2011 and 2018. All fetuses underwent US and brain MRI scans. Matching analysis was performed according to gender and gestational age. RESULTS: The study included a total of 103 fetuses; 44 fetuses with isolated MCM in the study group, and a control group of 59 fetuses with normal CNS. The study group had larger biparietal diameter (BPD) (86 vs. 79.8 mm, p = .001) and head circumference (HC) (318 vs. 292 mm, p < .001) on ultrasound. On MRI, study group had larger occipitofrontal diameter (OFD) (99 vs. 92 mm, p < .001) and BPD (77 vs. 72 mm, p < .001). Male fetuses' prevalence was higher in the study group (77.3% vs. 47.5%). After matching 20 fetuses from each group, the study group had larger HC (310.1 versus 300.7 mm, p = .029) and OFD (113.4 versus 108.3 mm, p = .009) on ultrasound, and larger OFD (97.4 versus 94.6, p = .013) on brain MRI. CONCLUSIONS: Isolated MCM may be related to other large fetal CNS biometric measurements in both ultrasound and MRI and might be influenced by fetal gender.
Subject(s)
Cisterna Magna , Ultrasonography, Prenatal , Biometry , Brain , Cohort Studies , Cross-Sectional Studies , Female , Gestational Age , Humans , Magnetic Resonance Imaging , Male , PregnancyABSTRACT
OBJECTIVE: It is common knowledge among clinicians who treat PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) patients that emotional stress can trigger PFAPA attacks similarly to other autoinflammatory diseases. However, it has never been proved scientifically. Our aim was to examine whether emotional stress serves as a trigger for PFAPA attacks. METHODS: Patients aged 3-12 years, with active PFAPA, from two Israeli medical centers were enrolled to this study. Patient's parents were reached via phone calls in two occasions: a stressful period related to the COVID-19 pandemic restrictions and a less stressful period. In both times they were asked to report occurrence of PFAPA attacks in the preceding 2 weeks. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. The significance level was set at 0.05. RESULTS: Mean age was 7.28 ± 2.7 for the 99 paediatric patients enrolled in the study. Scores for the mean emotional distress questionnaire were statistically significant higher in the stressful period compared to the less stressful period (35.6 ± 8.1 vs. 32.1 ±7.7, respectively, P = 0.047). In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the less stressful period (p = 0.017). CONCLUSION: PFAPA flares during COVID-19 outbreak are described. This study is the first to suggest that emotional stress is associated with PFAPA attacks.
Subject(s)
COVID-19 , Disease Outbreaks , Emotions , Fever , COVID-19/epidemiology , Child , Child, Preschool , Female , Fever/etiology , Humans , Israel , Male , Stress, PhysiologicalABSTRACT
Annual influenza epidemics are associated with high morbidity and mortality worldwide, with vaccinations being the main preventive intervention; however, the compliance rate of health care employees remains low. Study aims were to examine vaccination rates among physicians and nurses in surgical and medicine wards, compare between medium and large tertiary hospitals, and identify factors associated with increased vaccination rates. Structured questionnaires were distributed. A total of 238/339 (70.2%) were vaccinated. In multivariate analysis, respiratory illness during precedent winter (odds ratio [OR] 3.146, P = .007), working in a medium hospital (OR 2.4, P = .003), and an attending resident with an infectious diseases subspecialty (OR 20.473, P = .007) were associated with a higher vaccination rate. Institutional email or portal messages were associated with decreased vaccination rates (OR = 0.259, P = .007). The leading reason for vaccination was "to stay healthy" (73.5%). Recruiting experts in the field, providing up-to-date information, and increasing management's involvement could encourage vaccination among health care employees.
Subject(s)
Influenza Vaccines , Influenza, Human , Attitude of Health Personnel , Health Personnel , Humans , Influenza, Human/prevention & control , Tertiary Care Centers , VaccinationABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted mainly via respiratory droplets. A key question in the coronavirus disease 2019 pandemic is whether SARS-CoV-2 could be transmitted via the airborne route as well. We report for the first time SARS-CoV-2 nosocomial infections despite using surgical masks and physical distancing. This report may provide possible evidence for airborne transmission of SARS-CoV-2.
ABSTRACT
Pontocerebellar hypoplasia (PCH) encompasses a group of neurodegenerative disorders. There are ten known subtypes with common characteristics of pontine and cerebellar hypoplasia or atrophy, neocortical atrophy, and microcephaly. PCH is associated with anterior horn cell degeneration in PCH1a and PCH1b due to mutations in the VRK1 and EXOSC3 genes. Late onset PCH1 has been described in single case reports. The molecular etiology remains mostly unknown. We describe two siblings from a consanguineous Moslem Arabic family with a unique combination of progressive cerebellar atrophy and a SMA-like anterior horn cell degeneration due to a homozygous mutation in the PLA2G6 gene (NM_003560.2). The PLA2G6 gene encodes phospholipase A2 beta, which is involved in the remodeling of membrane phospholipids, signal transduction and calcium signaling, cell proliferation and apoptosis. Mutations in PLA2G6 are known to cause Neurodegeneration with brain iron accumulation 2 (NBIA2): Our patients have some similarities with NBIA2; both are characterized by rapidly progressive psychomotor regression and cerebellar atrophy. However, NBIA2 is not known to exhibit anterior horn cell degeneration. Our patients' phenotype is more consistent with late onset PCH1; thus, indicating that the spectrum of clinical and radiological presentations of PLA2G6 mutations should be extended and that this gene should be included in the molecular evaluation of patients with late onset PCH1.
Subject(s)
Anterior Horn Cells/pathology , Atrophy/pathology , Cerebellar Diseases/pathology , Group VI Phospholipases A2/genetics , Mutation , Spinocerebellar Degenerations/pathology , Adolescent , Age of Onset , Anterior Horn Cells/metabolism , Atrophy/genetics , Cerebellar Diseases/genetics , Child , Female , Humans , Infant, Newborn , Male , Phenotype , Prognosis , Spinocerebellar Degenerations/geneticsABSTRACT
PURPOSE: Measurement of the fetal brain can be achieved by different modalities, we aimed to assess the agreement between these methods and the head circumference at birth. METHODS: A retrospective study conducted between 2011-2018 at a tertiary referral medical center. Sonographic head circumference (HC), 2D MRI bi-parietal diameter (BPD) and occipito-frontal diameter (OFD), 3D MRI supra-tentorial volume (STV), and head circumference (HC) at birth were measured and converted into centiles according to gestational age. Spearman's rank correlation coefficient was used to assess the correlation between the modalities. RESULTS: A total of 88 fetuses were included. Mean gestational age at the time of fetal US and brain MRI acquisition were 34.4⯱â¯2.8 and 34.6⯱â¯2.6 weeks, respectively. A correlation was found between prenatal sonographic HC and the 3D MRI STV centiles (Rsâ¯=â¯0.859, pâ¯<â¯0.001), the BPD in 2D MRI (Rsâ¯=â¯0.813, pâ¯<â¯0.001), and the OFD in 2D MRI (Rsâ¯=â¯0.840, pâ¯<â¯0.001). Sonographic HC, OFD on 2D MRI, and STV on 3D MRI were all found to be correlated with the HC at birth (Rsâ¯=â¯0.865, pâ¯<â¯0.001; Rs 0.816, pâ¯<â¯0.001; Rsâ¯=â¯0.825, pâ¯<â¯0.001, respectively). CONCLUSIONS: There is a statistically significant agreement among the different prenatal clinically used modalities for measuring fetal brain and the head circumference at birth, however, this correlation is not perfect. Further study is needed to investigate the long-term prognosis of these fetuses.