Posterior Fossa Abnormalities Research Articles

Fetal MRI findings, etiology, and outcome in prenatally diagnosed schizencephaly.

Schizencephaly is a rare brain anomaly which is increasingly detected in utero. There are limited data on the etiology and outcomes in fetal schizencephaly to guide workup and counselling. We aim to determine the associated imaging findings, etiology, and outcomes in schizencephaly detected in utero. This retrospective cohort study included 22 fetuses with a total of 34 schizencephaly defects identified by keyword search of fetal MRI reports from 1996-2022 followed by image review. Follow-up fetal and postnatal imaging, when available, were reviewed. Data on demographics, etiology, and outcomes were extracted from the electronic medical record. The schizencephaly defect was open in 28/34, most common in the MCA territory (23/34), and commonly involved the frontal (16/34) lobe. Additional intracranial abnormalities were seen in all fetuses including other cortical malformations (CM, 13/22), abnormal posterior fossa (12/22), abnormal corpus callosum (10/20), and intraparenchymal hemorrhage (9/22).The cause of schizencephaly was classified as secondary (as evidenced by intraparenchymal hemorrhage at schizencephaly, monochorionic twin gestation, infection, or maternal/placental risk factor) in 64% (14/22), potentially genetic in 9% (2/22), and unknown in 27% (6/22). Among those liveborn (n=8), the following outcomes were observed: postnatal death (1/8), tube feeding (1/7), shunted hydrocephalus (1/7), epilepsy (4/7). Among those >1 year of age, cerebral palsy (4/5) and speech delay or intellectual disability (3/5) were common. CM remote from schizencephaly was associated with epilepsy (p=0.03). On postnatal imaging, open defects often involuted (8/11) and there were high rates of new/additional findings (4/6). In this cohort, fetal schizencephaly was always associated with additional intracranial abnormalities. In most cases, there was evidence that schizencephaly was likely secondary to prior injury. Imaging characteristics may provide clues regarding neurodevelopmental outcome. Postnatal imaging is crucial in assessing evolution as well as for detection of additional abnormalities. ICH = intracranial hemorrhage; CM = cortical malformation; VM = ventriculomegaly; DGN = deep grey nuclei; SP = septum pellucidum; IPH = intraparenchymal hemorrhage; CC = corpus callosum; PMG = polymicrogyria; PVNH = periventricular nodular heterotopia; TTTS = twin-twin transfusion syndrome; GA = gestational age; CP = cerebral palsy.

Anomalies of the Craniocervical Junction (Chiari Malformations)

AbstractArnold Chiari malformations include a combination of posterior fossa, hindbrain, and cervical occipital junction abnormalities, sometimes associated with spinal cord abnormalities such as spina bifida, syringomyelia, and syringobulbia. The most frequent form is Chiari I syndrome but two other variants, progressively more severe, have been described. Chiari malformations are the result of defective development of posterior fossa and can be due to genetic mutations, skeletal malformations, and intrautero factors. Clinical manifestations depend on the compression of the nerve structures within the foramen magnum and the spinal canal and mainly consist in headache or neck pain, gait disturbances, sensory or motor abnormalities, and autonomic signs. However, a high number of cases of Chiari I is asymptomatic and the diagnosis is occasional. Diagnosis is performed through nuclear magnetic resonance imaging of the brain and cervical tract, although other investigations may support the diagnosis. First-line treatment for candidate patients is a surgical procedure that involves decompression of the posterior cranial fossa and the craniocervical junction, as well as correction of associated malformations with techniques that depend on the severity of the case. Anyhow, some symptomatic patients benefit from conservative medical treatment with nonsteroidal anti-inflammatory drugs.

Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity

The 3q29 deletion (3q29Del) is a copy number variant (CNV) with one of the highest effect sizes for psychosis-risk (>40-fold). Systematic research offers avenues for elucidating mechanism; however, compared to CNVs like 22q11.2Del, 3q29Del remains understudied. Emerging findings indicate that posterior fossa abnormalities are common among carriers, but their clinical relevance is unclear. We report the first in-depth evaluation of psychotic symptoms in participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes, and compare this profile to 22q11.2Del (N=31) and healthy controls (N=279). We also explore correlations between psychotic symptoms and posterior fossa abnormalities. Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder or attenuated positive symptoms, with a subset meeting criteria for clinical high-risk. 3q29Del had more severe ratings than controls on all domains and only exhibited less severe ratings than 22q11.2Del in negative symptoms; ratings demonstrated select sex differences but no domain-wise correlations with IQ. An inverse relationship was identified between positive symptoms and cerebellar cortex volume in 3q29Del, documenting the first clinically-relevant neuroanatomical connection in this syndrome. Our findings characterize the profile of psychotic symptoms in the largest 3q29Del sample reported to date, contrast with another high-impact CNV, and highlight cerebellar involvement in psychosis-risk.

Small pituitary volume and central nervous system anomalies in Fanconi Anemia.

Fanconi anemia (FA) is a genomic instability disorder associated with congenital abnormalities, including short stature and the presence of central nervous system anomalies, especially in the hypothalamic-pituitary area. Thus, differences in pituitary size could associate with the short stature observed in these patients. Our aim was to evaluate whether central nervous system abnormalities and pituitary gland volume correlate with height and hormone deficiencies in these patients. In this cross-sectional exploratory study 21 patients diagnosed with FA between 2017 and 2022 in a Spanish Reference Center were investigated. Magnetic resonance imaging (MRI) was performed and pituitary volume calculated and corelated with height and other endocrine parameters. The percentage of abnormalities in our series was 81%, with a small pituitary (pituitary volume less than 1 SD) being the most frequent, followed by Chiari malformation type 1. The median value of pituitary volume was -1.03 SD (IQR: -1.56, -0.36). Short stature was found in 66.7% [CI95% 43-85.4]. Total volume (mm3) increases significantly with age and in pubertal stages. There were no differences between volume SD and pubertal stage, or the presence of endocrine deficiencies. No correlations were found between pituitary volume and the presence of short stature. The intraclass correlation index (ICC) average for volume was 0.85 [CI95% 0.61-0.94] indicating a good-to-excellent correlation of measurements. Central nervous system anomalies are part of the FA phenotype, the most frequent after pituitary hypoplasia being posterior fossa abnormalities, which may have clinical repercussions in the patient. It is therefore necessary to identify those who could be candidates for neurosurgical intervention. The size of the pituitary gland is smaller in these patients, but this does not seem to be related to hormone deficiency and short stature or exposure to a low dose of total body irradiation.

FRI285 Evidence For ZIC1 As A Novel Gene For Isolated Hypogonadotropic Hypogonadism With Phenotypic Pleiotropic Intersection With Cerebellar Malformation

Abstract Disclosure: J. Cassin: None. D.L. Keefe: None. K.E. Sung: None. C.C. Bojo: None. G. Santiago: None. L. Plummer: None. K.B. Salnikov: None. S.B. Seminara: None. R. Balasubramania: None. P.L. Mellon: None. Isolated Hypogonadotropic Hypogonadism (IHH) is a condition marked by absent pubertal development and low sex steroids in the setting of low/normal gonadotropins. Mutations in known IHH genes only explain <50% of the genetic etiology suggesting significant missing heritability in IHH. To explore this missing IHH heritability, we examined whole exome sequencing data from approximately 1400 IHH probands for rare genetic variants in novel genes that are enriched in IHH patients. We identified four IHH probands with rare, novel heterozygous variants in ZIC1 (p.H134Rfs*21, p.Y287X, p.E299K, p.S413Y), a gene encoding C2H2-type zinc finger protein (rare variant enrichment p <0.0001 for both truncating and missense alleles). Prior literature review show that heterozygous deletions affecting the ZIC1 gene have been linked to Dandy Walker malformation [DWM], a cerebellar malformation, while gain-of-function ZIC1 single nucleotide variants have been linked to coronal craniosynostosis (premature cranial suture fusion). Notably, two IHH subjects with novel ZIC1 variants in our cohort exhibited posterior fossa abnormalities (DWM [p.H134Rfs*21] and ventriculomegaly [E299K]) but none had any cranial suture defects. Given the above genetic enrichment, phenotypic overlap between DWM and IHH, and ZIC1’s known high expression in the hypothalamus, we explored whether ZIC1 regulates the expression of hypothalamic releasing factors. We determined that ZIC1 overexpression increases GNRH1 luciferase expression in the immortalized GnRH cell line, GT1-7. We next explored whether the rare ZIC1 variants identified in the four IHH probands would affect this phenotype. We discovered that three of the four ZIC1 variants significantly reduced GNRH1-luciferase expression. Of those, one truncating mutation, p.H134Rfs*21, resulted in lower ZIC1 protein content in the cell and failure to localize to the nucleus, suggesting a hypomorphic mechanism of action. These findings implicate ZIC1 variants as putatively causal for IHH. Further studies will define the precise ZIC1 transcriptional targets that relate to ZIC1’s pleotropic effects on GnRH transcription, neuronal function, cerebellar development, and cranial suture fusion. Presentation: Friday, June 16, 2023

EP06.01: Open fourth ventricle at 15–18 weeks: a transient finding of uncertain significance or a marker for posterior fossa abnormality

EP06.01: Open fourth ventricle at 15–18 weeks: a transient finding of uncertain significance or a marker for posterior fossa abnormality

Enlarged Intracranial Translucency, as a Potential Marker for Diagnosis of Joubert Syndrome during First-Trimester Screening: A Case Report

AbstractJoubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder that is usually diagnosed late in pregnancy or postnatally based on a pathognomonic midbrain–hindbrain malformation seen on magnetic resonance imaging brain, which consists of the hypoplasia of the cerebellar vermis, thickened superior cerebellar peduncles, and a deepened interpeduncular fossa described as molar tooth sign. The recurrence rate of JS in the same family is high (25%). In the era of first-trimester anomaly scan, early diagnosis of fetal anomaly is of utmost importance. First-trimester screening or first-trimester scan that is performed from 11 to 13 weeks, 6 days plays an important role in early diagnosis of posterior fossa abnormalities like Blake's pouch cyst, Vermian hypoplasia, Dandy-Walker malformation, and JS and related disorders based on increased intracranial translucency thickness. Our case also shows that early diagnosis of JS can be done by an enlarged intracranial translucency.

Long Term Outcomes of Fetal Posterior Fossa Abnormalities Diagnosed with Fetal MRI.

The diagnosis of posterior fossa abnormalities (PFA) in the intrauterine period; and pregnancy outcomes are still controversial. PFA is generally referred to as maternal-fetal medicine specialists. The primary purpose of PFA diagnosis is to screen for other accompanying abnormalities, provide prognostic information to families, and discuss the termination option. This retrospective study was conducted with patients diagnosed with PFA between January 2013 and September 2020 in the tertiary Perinatology Clinic. All patients were routinely performed second-trimester ultrasound screening, and the definitive diagnosis was made by fetal MRI in the presence of a suspected anomaly. Between 2013 and 2020, 164 fetal MRIs were performed for fetal abnormalities, and 22 fetuses were diagnosed with a PFA on fetal MRI. Considering the fetal MRI indications of the cases, four patients (18%) were diagnosed with Mega Cisterna Magna (MSM), Two patients were diagnosed with rhomboencephalosynapsis, thirteen patients were diagnosed with Vermian Hypoplasia-Dandy-Walker variant. In the remaining two patients, those with neural tube defects and lumbosacral NTD are still alive. However, iniencephaly was detected in the other patient and died in the postnatal period. Diagnosis of PFA abnormalities is complex, and it is a condition that cannot be predicted clearly which patients will have a good prognosis and which will have a bad prognosis. The prognosis is not affected by maternal and fetal factors and allows the recognition of additional accompanying abnormalities. Fetal MRI is an imaging method that can provide retrospective examination and research, especially in pregnancies with poor prognoses.

Institutional Evaluation of Fetal Neurology Consults and Postnatal Outcomes: A 10-Year Retrospective Cohort Review.

An increasing number of centers are offering fetal neurology consultation services; however, there is limited information available in overall institutional experiences. Data are lacking on the fetal characteristics, pregnancy course, and the influence of fetal consultation on perinatal outcomes. The aim of this study is to provide insight on the institutional fetal neurology consult process and areas of strengths and weaknesses. We performed a retrospective electronic chart review of fetal consults from April 2, 2009, to August 8, 2019, at Nationwide Children's Hospital. The objectives were to summarize clinical characteristics, agreement of prenatal and postnatal diagnoses based on best available imaging, and postnatal outcomes. Of the 174 maternal-fetal neurology consults placed, 130 qualified for inclusion based on data available for review. Of the 131 anticipated fetuses, 5 experienced fetal demise, 7 underwent elective termination, and 10 died in the postnatal period. The majority were admitted to the neonatal intensive care unit; 34 (31%) required supportive intervention for feeding, breathing, or hydrocephalus, and 10 (8%) experienced seizures during their neonatal intensive care unit (NICU) stay. Imaging results from 113 babies who had prenatal and postnatal imaging of the brain were analyzed based on the primary diagnosis. The most common malformations were as follows (prenatal % vs postnatal %): midline anomalies (37% vs 29%), posterior fossa abnormalities (26% vs 18%), and ventriculomegaly (14% vs 8%). Additional disorders of neuronal migration were not seen on fetal imaging but were present in 9% of the postnatal studies. Analysis of agreement between prenatal and postnatal diagnostic imaging for the 95 babies who had MRIs at both time points found moderate concordance (Cohen kappa: 0.62, 95% CI 0.5-0.73; percent agreement: 69%, 95% CI 60%-78%). Consult recommendations for neonatal blood tests affected postnatal care in 64 of 73 cases in which the infant survived and data were available. Establishing a multidisciplinary fetal clinic can provide timely counseling and create rapport with families to have continuity of care for birth planning and postnatal management. Prognosis based on radiographic prenatal diagnosis requires caution as some neonatal outcomes may vary considerably.

Relative prevalence and outcome of fetal posterior fossa abnormality.

To find out the relative incidence and outcome of posterior fossa abnormality (PFA) in terms of survival at birth until 2 years of age. We conducted a prospective study; all fetuses diagnosed with posterior fossa abnormality were followed-up. The outcome was observed with respect to survival, the presence of associated anomalies, the existence of developmental delay after a telephonic interview. Out of 2703 children with congenital anomalies, 921 (34.1%) had a central nervous system defect;76 cases of PFA were fully followed. Dandy-Walker malformation (DWM) was present in 50% (38/76), mega cisterna magna 18.4% (14/76), Blake pouch cyst 13.2% (10/76), vermian hypoplasia (VH) 13.2% (10/76) and arachnoid cyst 5.2% (4/76). The diagnosis was possible before 20 weeks in only 12 (15.8%) cases.The mean gestational age at delivery was 34.7 ± 6.7 weeks. Associated anomalies were seen in 35/76 (46.1%) cases. A total of 35/76 (46.1%) survived after 2 years; there was developmental delay in 9.2% of cases. There is a large variation in the outcome of PFA depending upon the type of anomaly. Associated anomalies are common in VH and DWM, making their prognosis worse.

Reference ranges of fetal cisterna magna volume measurements by three-dimensional ultrasonography in the late second trimester considering sonographic experience.

Volume measurements of fetal cisterna magna (CM) by three-dimensional (3D) ultrasonography may have a role in the diagnosis of various posterior fossa abnormalities. To evaluate reference intervals and reliability of fetal CM volume values by virtual organ computer-aided analysis (VOCAL) in structurally normal fetuses, considering experience of evaluators. Three operators with different 3D sonography experience levels measured CM volumes of 100 structurally normal fetuses at 18-27 weeks of gestation. Reference intervals for CM volumes were generated. Intraclass correlation coefficients (ICC) were calculated. Mean fetal CM volume measurements by the three operators did not significantly (P = 0.49, P = 0.22, and P = 0.17, respectively) change through 20-23 weeks of gestation. Moderate degrees of inter-observer reliability were found with an ICC of 0.69 between novice and intermediate-level, ICC of 0.74 between experienced and intermediate-level, and ICC of 0.78 between experienced and novice observer, respectively. The novice sonographer generally overestimated CM measurements. Intra-observer reliability was good (ICC=0.85). A reference chart for fetal CM volume by VOCAL was formed, revealing uniform mean values of 20-23 weeks of gestation. The inter-observer reliability is moderate, and biases seem relatively common for all experience categories.

Identifying Posterior Fossa Abnormality in Pediatric Aerodigestive Patients, a Case Series.

Multidisciplinary clinics like Aerodigestive programs focus on issues associated with airway, pulmonary, and gastrointestinal issues. Rarely, significant neurological issues like posterior fossa abnormality are identified as the primary etiology. We describe 3 such patients and compare their clinical presentation to the other patients seen in Aerodigestive clinic. A retrospective chart review was conducted to review the 3 posterior fossa patients and the remainder of children that were referred to the Aerodigestive Clinic at Children's Hospital Los Angeles from June 2016 to August 2018. Clinical characteristics including triple endoscopies and sleep studies were recorded. Of the 110 patients included for review, 3 patients (3%) had an underlying posterior fossa abnormality; all of whom had symptoms of sleep disordered breathing along with dysphagia compared with 30% incidence of this symptom profile in the remaining Aerodigestive population. Presence of sleep disordered breathing and dysphagia, with underlying vomiting history, warrants considering evaluation for posterior fossa abnormalities in addition to traditional workup for aerodigestive disorders. Due to the rarity of this presentation and small sample size, future studies with multicenter collaboration may help better describe identifiers to delineate this population with similar aerodigestive symptoms and clarify diagnostic algorithms.

OP03.12: Egyptian key, jumping frog and open wings: sonographic pattern recognition for cranial posterior fossa abnormalities in the first trimester

OP03.12: Egyptian key, jumping frog and open wings: sonographic pattern recognition for cranial posterior fossa abnormalities in the first trimester

Facing PHACE Twenty-five Years Later

Objectives: To review the key features of PHACE syndrome over the past 25 years, highlighting evaluation, management, current gaps in knowledge, and potential next steps in research and patient-centered care. Methods: Literature review and synthesis of expert opinion. Results: PHACE is a congenital neurocutaneous syndrome in which affected patients have posterior fossa abnormalities, hemangiomas, arterial anomalies, cardiac anomalies, and/or eye anomalies. Since its discovery 25 years ago, the scientific and medical communities have made strides in understanding and developing best practice approaches to diagnosis, outcomes, and surveillance. More research will be needed to fully elucidate the pathogenesis of this condition as well as long-term outcomes. We offer suggestions for healthcare maintenance to coordinate and streamline multidisciplinary patient care. Conclusions: Our understanding of PHACE syndrome has grown immensely since its discovery. As we continue to learn about long-term outcomes and the importance of surveillance into adulthood, a multidisciplinary and patient-centered approach is critical to optimize care for individuals with this disease.

Posterior cranial fossa and cervical spine morphometric abnormalities in symptomatic Chiari type 0 and Chiari type 1 malformation patients with and without syringomyelia

To better understand how anatomical features of Chiari malformation type 0 (CM0) result in the manifestation of Chiari malformation type 1 (CM1) signs and symptoms, we conducted a morphometric study of the posterior cranial fossa (PCF) and cervical canal in patients with CM1 and CM0. This retrospective study had a STROBE design and included 120 adult patients with MRI evidence of a small PCF (SPCF), typical clinical symptoms of CM1, and a diagnosis of CM1, CM0, or SPCF-TH0-only (SPCF with cerebellar ectopia less than 2mm and without syringomyelia). Patients were divided by MRI findings into 4 groups: SPCF-TH0-only, SPCF-TH0-syr (CM0 with SPCF and syringomyelia), SPCF-CM1-only (SPCF with cerebellar ectopia 5mm or more without syringomyelia), and SPCF-CM1-syr (CM1 with syringomyelia). Neurological examination data and MRI parameters were analyzed. All patient cohorts had morphometric evidence of a small, flattened, and overcrowded PCF. The PCF phenotype of the SPCF-TH0-only group differed from that of other CM cohorts in that the length of clivus and supraocciput and the height of the PF were longer, the upper CSF spaces of PCF were taller, and the area of the foramen magnum was smaller. The SPCF-TH0 groups had a more significant narrowing of the superior cervical canal and a smaller decrease in PCF height than the SPCF-CM1 groups. Patients with SPCF-TH0 with and without syringomyelia developed Chiari 1 symptoms and signs. Patients with SPCF-TH0-syr (Chiari 0) had more constriction of their CSF pathways in and around the foramen magnum than patients with SPCF-TH0-only.

The importance of first trimester screening of cranial posterior fossa in predicting posterior fossa malformations which may be identified in the following weeks of gestation.

We aimed to investigate the value of posterior fossa ultrasonography measurements in predicting fetal posterior fossa anomaly at 11-14 weeks of gestation. The study was performed at Zeynep Kamil Women and Children's Diseases Training and Research Hospital. Measurements were made in two groups: the control group consisted of 328 fetuses with normal postnatal outcome and the study group consisted of 22 fetuses with enlarged 4th ventricle. In the study group, we questioned the value of intracranial translucency (IT) and brainstem (BS) measurements and the BS/brainstem-to-occipital bone (BSOB) ratio in order to predict possible posterior fossa anomalies that may be identified in advanced gestational weeks. The differences of ultrasonographic measurements between groups with p < 0.05 were considered statistically significant. IT value, BSOB value, and BS/BSOB ratio were determined as ultrasonographic variables in predicting normal development of the fetal posterior fossa, with cutoff values of 2.7, 5.1, and 0.3. Negative predictive values of these three measurements for posterior fossa abnormalities were 100%. There was no statistically significant difference between the three variables for other diagnostic accuracy values (specifities and positive predictive values) (p > 0.05). IT, BSOB, and BS/BSOB ratio can be used as ultrasonographic markers to predict the normal development of the fetal posterior fossa.

The impact of adding fetal MRI to sonographically diagnosed intrauterine ventriculomegaly: a prospective cohort study

Objective: Intrauterine fetal ventriculomegaly (IVM) is one of the most commonly detected fetal anomalies. Prenatal diagnosis in IVM is considered a challenge with a significant impact on management. The current study aims to evaluate the added value of performing fetal MRI to sonographically diagnosed IVM. Methods: A prospective cohort study was conducted at a tertiary University Hospital in the period between January 2017 and March 2019. We included pregnant women with a single fetus sonographically diagnosed IVM (symmetrical or asymmetrical). First, a basic obstetric sonographic examination was done, followed by a detailed (2D/3D) fetal CNS anomaly scan for the detection of other associated anomalies. A fetal MRI brain scan was performed for all cases. Results: Sixty women were included in the study. Of the 60 fetuses with IVM, additional findings were seen on MRI in 14 cases (23%), and most of these findings were identified in fetuses with severe IVM (about 50%). No additional abnormalities were identified in fetuses of less than 24 weeks gestation. Callosal and septum pellucidum lesions (29%), along with posterior fossa abnormalities (28%) and cortical malformations (21%) accounted for the most common additional significant fetal MRI findings. Fetal MRI sensitivity, specificity, and positive and negative predictive values in correlation with those of prenatal ultrasound turned out to be notably higher, approaching nearly 100 %. Conclusions: Fetal MRI for sonographically diagnosed moderate or severe IVM is recommended to guide clinical management.

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

White-Sutton syndrome with hot water epilepsy and coexistence of SHOX gene variations.

The purpose of this study is to reveal the effect on the clinical phenotype of variants detected at family examination of a case of combined pogo transposable element derived with zinc finger domain (POGZ) gene, tubulin folding cofactor E (TBCE) gene, and short stature homeobox (SHOX) gene variation. A Turkish non-consanguineous family consisting of five members was investigated. Whole exome sequence analysis and chromosomal microarray analysis (CMA) were performed for a 2-year-old male patient (the proband) with global developmental delay, hypotonia, dysmorphia, and hot water epilepsy. Targeted sequence and chromosomal microarray analyses were performed for each family member. A heterozygous c.3908_3911delTCTG/p.V1303fs*6 variant was detected in the POGZ gene and a heterozygous c.626T > G(p.L209X) variant in the TBCE gene in the proband. In addition, a gain of 0.1MB was detected in the Xp22.33(602488-733497) × 3/Yp11.32(552488-683497) × 3 region at CMA. The SHOX (312865) gene defined in Online Mendelian Inheritance in Man is located in this region. While the proband's father and brother had heterozygous variations only in the TBCE gene, neither TBCE nor POGZ mutations were detected in the mother or sister. A gain in Xp22.33(419224-883640) × 3 was detected in the mother at CMA. Except for short stature and Madelung deformity, no phenotypical findings were detected in the mother. Other family members were also phenotypically normal. The family screening confirmed that dysmorphic findings and global developmental delay in the proband resulted from the variation in the POGZ gene, while short stature was caused by the gain in the Xp22.33(602488-733497) × 3/Yp11.32(552488-683497) × 3 region. In addition, the pathogenic POGZ gene variation in our patient may be a possible cause of hot water epilepsy. Heterozygous variation in the TBCE gene was clinically insignificant. Hot water epilepsy has not previously been reported in the rare patients with POGZ gene mutation. Additionally, in contrast to the previous literature, the proband exhibited no features of autism. It should also be remembered that posterior fossa abnormalities are frequently seen in these patients. We think that this case and family review involving POGZ and SHOX gene mutations will make a useful contribution to the existing literature.