Expanding the natural history of CASK-related disorders to the prenatal period

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

Fetal Brain Development: Regulating Processes and Related Malformations

This paper describes the contemporary state of knowledge regarding processes that regulate normal development of the embryonic–fetal central nervous system (CNS). The processes are described according to the developmental timetable: dorsal induction, ventral induction, neurogenesis, neuronal migration, post-migration neuronal development, and cortical organization. We review the current literature on CNS malformations associated with these regulating processes. We specifically address neural tube defects, holoprosencephaly, malformations of cortical development (including microcephaly, megalencephaly, lissencephaly, cobblestone malformations, gray matter heterotopia, and polymicrogyria), disorders of the corpus callosum, and posterior fossa malformations. Fetal ventriculomegaly, which frequently accompanies these disorders, is also reviewed. Each malformation is described with reference to the etiology, genetic causes, prenatal sonographic imaging, associated anomalies, differential diagnosis, complimentary diagnostic studies, clinical interventions, neurodevelopmental outcome, and life quality

Bilateral Maternal Pelvic Kidneys Presenting as a Tumor Previa: Sonographic Diagnosis and Obstetric Management

Renal ectopia occurs when the kidney fails to ascend normally to the retroperitoneal renal fossa. Bilateral cases have also been reported but are very rare. Pregnancy and labor with maternal renal ectopia provides a unique challenge to the obstetricians attempting to prevent damage to the kidneys during labor and allow safe delivery. We describe a case of congenital bilateral pelvic kidneys assessed and diagnosed by 3D sonography as “tumor previa” and managed accordingly

Fetal weight estimation for prediction of fetal macrosomia: does additional clinical and demographic data using pattern recognition algorithm improve detection?

Objective. The aim of this study was to test whether pattern recognition classifiers with multiple clinical and sonographic variables could improve ultrasound prediction of fetal macrosomia over prediction which relies on the commonly used formulas for the sonographic estimation of fetal weight. Study design. The SVM algorithm was used for binary classification between two categories of weight estimation: >4000gr and <4000gr. Clinical and sononographic input variables of 100 pregnancies suspected of having LGA fetuses were tested. Results. Thirteen out of 38 features were selected as contributing variables that distinguish birth weights of below 4000gr and of 4000gr and above. Considering 4000gr. as a cutoff weight the pattern recognition algorithm predicted macrosomia with a sensitivity of 81%, specificity of 73%, positive predictive value of 81% and negative predictive value of 73%. The comparative figures according to the combined criteria based on two commonly used formulas generated from regression analysis were 88.1%, 34%, 65.8%, 66.7%. Conclusions. The SVM algorithm provides a comparable prediction of LGA fetuses as other commonly used formulas generated from regression analysis. The better specificity and better positive predictive value suggest potential value for this method and further accumulation of data may improve the reliability of this approach

Changes in Serum Creatinine May Cause Hypoglycemia among Non-Critically Ill Patients Admitted to Internal Medicine Units

Background: The association between changes in serum creatinine levels and hypoglycemia during hospitalization was investigated. Methods: This was a retrospective analysis of medical charts. Patients were categorized as having significant change in creatinine (SCIC) when serum creatinine levels rose or dropped &ge; 0.3 mg/dL from admission values at any time during their hospitalization. Patients were considered hypoglycemic if they had at least one documented glucose level &le; 70 mg/dL during the hospitalization. Multiple logistic, linear and Cox regression analyses were used to ascertain the association between incident SCIC, severity and timing with incident hypoglycemia. Results: Included were 25,400 (mean age 69.9 &plusmn; 18.0, 49.3% were males). The rate of SCIC was 22.2%, and 62.2% of them were diagnosed upon admission. Patients with SCIC had a higher incidence of hypoglycemia compared to patients without (13.1% vs. 4.1%, respectively, p &lt; 0.001). Patients with SCIC had an increased risk of hypoglycemia (OR 1.853, 95% CI 1.586&ndash;2.166, p &lt; 0.001). The magnitude of SCIC was associated with the incidence (OR 1.316, 95% CI 1.197&ndash;1.447, p &lt; 0.001) and the number of events (HR 0.054, 95% CI 0.021&ndash;0.087, p = 0.001). More than 60% of patients with hypoglycemia had their first event documented during days 0&ndash;6 after SCIC occurrence. Of those, the majority of events occurred on day 0&ndash;1, and the rate showed a gradual decrease throughout the first 5 days from SCIC occurrence. The results were similar for patients with and without DM. Conclusions: Changes in creatinine during hospitalization may cause hypoglycemia among patients admitted to internal medicine departments, regardless of DM status

Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly

Microcephaly is a sign, not a diagnosis. Its incidence varies widely due to the differences in the definition and the population being studied. It is strongly related to neurodevelopmental disorders. Differences in definitions and measurement techniques between fetuses and newborns pose a great challenge for the diagnosis and prognostication of fetal microcephaly. A false positive diagnosis can result (in countries where it is legal) in erroneous termination of pregnancy, where a false negative diagnosis might lead to the birth of a microcephalic newborn. Microcephaly in growth restricted fetuses deserves special attention and separate evaluation as it is an important prognostic factor, and not necessarily part of the general growth retardation. Several genetic syndromes incorporating microcephaly and intrauterine growth retardation (IUGR) are discussed. Deceleration of the head circumference (HC) growth rate even when the HC is still within normal limits might be the only clue for developing microcephaly and should be considered during fetal head growth follow up. Combining additional parameters such as a positive family history, associated anomalies, and new measurement parameters can improve prediction in about 50% of cases, and thus should be part of the prenatal workup. Advances in imaging modalities and in prenatal genetic investigation along with the emergence of new growth charts can also improve diagnostic accuracy. In this article, we review the different definitions and etiologies of fetal microcephaly, discuss difficulties in diagnosis, investigate the reasons for the low yield of prenatal diagnosis, and provide improvement suggestions. Finally, we suggest an updated algorithm that will aid in the diagnosis and management of fetal microcephaly

The 'brain shadowing sign': a novel marker of fetal craniosynostosis

Introduction: The prenatal diagnosis of fetal craniosynostosis is challenging, especially in single-suture cases. When sutures are obliterated, sound waves fail to penetrate the cortical bone, creating an evident acoustic shadow on the underlying brain. The objective of this study was to evaluate the yield of the 'brain shadowing sign' (BSS) as a novel sono-graphic marker for craniosynostosis. Subjects and Methods: Patients with an antenatal diagnosis of fetal craniosynostosis (cases) and healthy controls paired for gestational age were enrolled in this retrospective case-control study. Two-dimensional scans were assessed by three examiners for the presence of the BSS and additional fetal findings. Results: The BSS was clearly depicted in all 24 cases on the first anal- ysis and in 22 cases on the second analysis. No fetus from the control group (n = 48) presented the BSS in any of the analyses. Fifteen cases had isolated craniosynostosis and 9 were syndromic (Apert, Saethre-Chotzen and craniofrontonasal syndromes), which were diagnosed significantly earlier due to additional malformations. Discussion: The BSS is a novel sonographic marker of craniosynostosis which can be used to increase the diagnostic rate of this rare condition and does not require the use of high-definition three-dimensional transducers to be depicted. (C) 2016 S. Karger AG, BaselDivision of Prenatal Diagnosis, Department of Obstetrics and Gynecology, Wolfson Medical Center, HolonGenetics Institute, Wolfson Medical Center, HolonPediatric Neurology Unit, Wolfson Medical Center, HolonDepartment of Obstetrics and Gynecology, Bnai Zion Medical Center, HaifaObstetric-Gynecologic Ultrasound Unit, Department of Obstetrics and Gynecology, AsaHarofeh Medical Center, Beer YaakovGenetics Institute, Tel Aviv Sourasky Medical CenterObstetric-Gynecologic Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelDepartment of Gynecology and Obstetrics, Fetal Medicine Unit, Hospital Israelita Albert EinsteinDepartment of Obstetrics, Fetal Medicine Division, Federal University of São PauloCentro Paulista de Medicina Fetal, São Paulo, BrazilDepartment of Obstetrics, Fetal Medicine Division, Federal University of São Paulo, and jCentro Paulista de Medicina Fetal, São Paulo, BrazilWeb of Scienc

Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders

ObjectiveBCORL1, 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 resultsWe 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&gt;T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G&gt;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.ConclusionsWe 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