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Warsaw Breakage Syndrome (WABS) is a rare autosomal recessive cohesinopathy characterized by growth retardation and congenital anomalies. This report aims to highlight the prenatal diagnosis of WABS through ultrasound findings and genetic testing. We report a case of prenatal diagnosis of WABS in a 24-week gestation fetus exhibiting microcephaly, delayed sulcation, short corpus callosum, cerebellar vermis hypoplasia and intrahepatic portal-systemic shunts. The couple had a history of a prior pregnancy termination due to severe intrauterine growth restriction and cerebral malformations. Whole exome sequencing revealed compound heterozygous pathogenic variants [NM_030653.4:c.1403dupT, p.(Ser469Valfs*32) and c.1672C>T, p.(Arg558*)] in the DDX11 gene, consistent with WABS. The same pathogenic variants were identified in the prior terminated fetus upon subsequent analysis. Postmortem examination of the proband confirmed the prenatal ultrasound findings. This case expands the understanding of the prenatal phenotypic spectrum of WABS by identifying specific cerebral and extracerebral anomalies associated with pathogenic variants in the DDX11 gene. Incorporating advanced genetic diagnostics like whole exome sequencing into prenatal care provides valuable information for genetic counseling and management of rare genetic disorders., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Congenital Zika syndrome (CZS) has been identified a constellation of congenital anomalies caused by Zika Virus (ZKV) infection during pregnancy. The infection with ZKV could lead to microcephaly of the fetus due to a severe decrease in brain volume and reduced brain growth. The preliminary screening of CZS is based on measuring head circumference; the diagnosis is made if this measurement is below two standard deviations below the mean. The analyses of the 3D head features of infected infants are limited. This study analyzed 3D head images of 35 ZKV-positive cases with an average age of 16.8 ± 2 months and 35 controls with an average age of 14.4 ± 5 months. This study focused on identifying potential diagnostic characteristics of CZS. The 3D head images were captured using a 3D imaging system. The averaged images of the two groups were aligned to illustrate the size and shape differences. There were significant differences in centroid size, head circumference (HC), head height (HH), and chin height (CH) between the two groups. We also identified significant differences in the indices of chin height/total facial height (CH/TFH) and head height/head circumference ratio (HH/HC) between the CZS and control cases. An HH/HC of 0.49 showed a sensitivity of 0.86 and a specificity of 0.74 in diagnosing CZS, which is more sensitive than the routinely used HC measurement. The index of HH/HC has potential to be used as the gold standard for the early screening for the detection of CZS cases.

Purpose: This study aimed to identify continuous epileptiform discharges (CEDs) on electroencephalograms (EEG) and to determine their clinical significance in children with congenital Zika syndrome (CZS)., Methods: This prospective cohort study included 75 children diagnosed with CZS born from March 2015 and followed up until September 2018 (age up to 36 months). EEG was performed to detect CEDs up to 24 months old. Data on obstetric, demographic, and clinical signs; cranial computed tomography (CT); ophthalmology examination; anti-seizure medication; growth; and motor development were collected. Fisher's exact test was used to verify the associations between categorical variables, and the T- test was used to compare the mean z-scores of anthropometric measurements between the groups with and without CED., Results: CEDs were identified in 41 (54.67 %) children. The mean age of CEDs identification was 12.24 ± 6.86 months. Bilateral CEDs were shown in 62.89 % of EEGs. CEDs were associated with severe congenital microcephaly, defined by z-score >3 standard deviation of head circumference (HC) below the mean for sex and age (p = 0.025), and worse outcomes, including first seizure before 6 months (p = 0.004), drug-resistant epilepsy (p < 0.001), chorioretinal scarring or mottling (p = 0.002), and severe CT findings (p = 0.002). The CED group had lower mean z-scores of HC up to 24 months of age., Conclusion: This is the first description of the prevalence and significance of CEDs that also remains during wakefulness in patients with CZS. New investigations may suggest that it is more appropriate to classify the EEG not as a CED, but as a periodic pattern. Anyway, CEDs may be a marker of neurological severity in children with CSZ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To comprehensively evaluate the contributions of numerical chromosomal abnormality, copy number variant (CNV), and sequence variant (SV) to fetuses with small head circumference in a Chinese cohort using chromosome microarray analysis and whole exome sequencing., Methods: A total of 157 fetuses with small heads defined as head circumference < - 2 standard deviation (SD) were recruited between October 2014 and March 2023. We used the ultrasonic measurement parameter Z-score to define small head as possible microcephaly (3 < Z ≤ -2), microcephaly (-5 < Z ≤ -3), or pathologic microcephaly (Z ≤ -5). Ultrasound findings and genetic results were analyzed., Results: The overall diagnostic yield of chromosomal abnormalities by microarray analysis was 13 %. Whole exome sequencing revealed eight novel variants and two interesting candidate genes and provided a 25.4 % incremental yield compared with microarray analysis. Of the detected SVs, 56 % were de novo and the most common inheritance pattern was autosomal dominant inheritance presented in 11/16 fetuses. Compared with isolated small heads, non-isolated small heads had a significantly higher detection rate of chromosomal abnormalities (16 % vs. 3.0 %, P = 0.049) but not SVs (24 % vs. 5.5 %, P = 0.126). Subgroup analysis showed that intracranial anomalies had a similar high detection rate of SVs in fetuses with all small heads subgroups while no chromosomal abnormalities and causative SVs were found in fetuses with isolated possible microcephaly., Conclusions: Ultrasound findings of small fetal head circumference < 3 SD below the mean, especially those with intracranial structural abnormalities, indicate the need for genetic counseling. Genetic variants, mainly copy number variants and SV, may be responsible for the substantial proportion of small fetal head circumference, while most are de novo. Whole exome sequencing and microarray analysis are effective diagnostic approaches for this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Background: Idiopathic basal ganglia calcification, also known as Fahr's disease, it is a neurological disease characterized by intracranial calcification caused by heterozygous SLC20A2 mutations. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, tremor, dystonia, ataxia, and seizures., Objectives: The aim of this study was to investigating the clinical implications of the SLCA20A2 gene and identifying a new phenotype through a family., Methods: Two siblings with growth retardation, bilateral cataracts, microcephaly, and convulsion were included in the study. The MRI showed cerebral atrophy, corpus callosum hypoplasia, microcalcifications. Chromosomal microarray analysis was performed to identify the existence of copy number variation. The whole exome sequencing analysis of the individual IV-I was performed, and Sanger sequencing was performed for segregation., Results: Whole exome sequencing revealed a homozygous NM&#95;006749.5:c.1794 + 1G > A of the SLC20A2 gene. The Sanger sequencing confirmed the affected siblings were homozygous and the parents were heterozygous., Conclusions: SLC20A2 gene heterozygous mutations were associated with the adult-onset phenotype, while homozygous SLC20A2 mutations in the two affected siblings we reported in our study resulted in a severe clinic including growth retardation, bilateral cataracts, microcephaly, and convulsion. We showed that biallelic mutations in the SLC20A2 gene that cause the Fahr's disease lead to more severe phenotypes contrary to what is known. The two siblings, showing similar phonotypic and genotypic characteristics, would be the youngest cases in the pediatric age group published in the literature., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Biallelic variants in PPIL1 have been recently found to cause a very rare type of pontocerebellar hypoplasia and congenital microcephaly in which simplified gyral pattern was not observed in all of the patients. Here, we describe a series of nine patients from eight unrelated Egyptian families in whom whole exome sequencing detected a previously reported homozygous missense variant (c.295G>A, p.Ala99Thr) in PPIL1. Haplotype analysis confirmed that this variant has a founder effect in our population. All our patients displayed early onset drug-resistant epilepsy, profound developmental delay, and visual impairment. Remarkably, they presented with recognizable imaging findings showing profound microcephaly, hypoplastic frontal lobe and posteriorly predominant pachygyria, agenesis of corpus callosum with colpocephaly, and pontocerebellar hypoplasia. In addition, Dandy-Walker malformation was evident in three patients. Interestingly, four of our patients exhibited hematopoietic disorder (44% of cases). We compared the phenotype of our patients with other previously reported PPIL1 patients. Our results reinforce the hypothesis that the alterative splicing of PPIL1 causes a heterogeneous phenotype. Further, we affirm that hematopoietic disorder is a common feature of the condition and underscore the role of major spliceosomes in brain development., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess the longitudinal evolution of EEG findings in children with Zika related-microcephaly (ZRM) and to evaluate the associations of these patterns with the children's clinical and neuroimaging characteristics., Methods: As part of the follow-up of the Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC) in Recife, Brazil, we performed serial EEG recordings in a subgroup of children with ZRM to evaluate changes in background rhythms and epileptiform activity (EA). Latent class analysis was used to identify patterns in the evolution of EA over time; clinical and neuroimaging findings were compared across the identified groups., Results: Out of the 72 children with ZRM who were evaluated during 190 EEGs/videoEEGs, all participants presented with abnormal background activity, 37.5% presented with an alpha-theta rhythmic activity, and 25% presented with sleep spindles, which were less commonly observed in children with epilepsy. EA changed over time in 79.2% of children, and three distinct trajectories were identified: (i) multifocal EA over time, (ii) no discharges/focal EA evolving to focal/multifocal EA, and (iii) focal/multifocal EA evolving to epileptic encephalopathy patterns (e.g., hypsarrhythmia or continuous EA in sleep). The multifocal EA over time trajectory was associated with periventricular and thalamus/basal ganglia calcifications, brainstem and corpus callosum atrophy and had less focal epilepsy, whereas the children in the trajectory which evolved to epileptic encephalopathy patterns had more frequently focal epilepsy., Significance: These findings suggest that, in most children with ZRM, trajectories of changes in EA can be identified and associated with neuroimaging and clinical features., Competing Interests: Declaration of Competing Interest None of the authors has any conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To explore the application value of voxel-based morphometric (VBM) in prenatal diagnosis of microcephaly., Methods: A retrospective study of magnetic resonance imaging of fetuses with microcephaly was performed using a single-shot fast spin echo sequence; semiautomatic segmentation of grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF); calculation of their volumes; and VBM analysis of their GM. Two independent samples t-test was used to statistically analyse the fetal GM volume in the microcephaly and normal control groups. Total intracranial volume (TIV), GM volume, WM volume, and CSF volume were linearly regressed against gestational age and compared between the two groups., Results: In the fetus with microcephaly, GM volume of frontal lobe, temporal lobe, cuneus, anterior central gyrus, and posterior central gyrus decreased significantly (P < 0.001, corrected by family-wise error at mass level). The GM volume of microcephaly was significantly lower than that of the control group (except for 28 weeks of gestation) (P < 0.05). TIV, GM volume, WM volume, and CSF volume were all positively correlated with gestational age, and the curves in the microcephaly group were all lower than those in the control group., Conclusion: Compared with the normal control group, the GM volume of microcephaly fetuses decreased, and there were significant differences in many brain regions through VBM analysis., (© 2023 International Society for Developmental Neuroscience.)

Pontocerebellar hypoplasia (PCH) is currently classified into 16 subgroups. Using mostly next-generation sequencing, pathogenic variants have been identified in as many as 24 PCH-associated genes. PCH type 8 (PCH8) is a rare heterogeneous disorder. Its clinical presentation includes severe development delay, increased muscle tone, microcephaly, and magnetic resonance imaging (MRI) abnormalities such as reduced cerebral white matter, a thin corpus callosum, and brainstem and cerebellar hypoplasia. To date, only two variants in the CHMP1A gene (MIM: 164010), NM&#95;002768.5: c.88 C > T (p.Glu30*) and c.28-13 G > A, have been identified homozygously in seven patients with PCH8 from four families (MIM: 614961). CHMP1A is a subunit of the endosomal sorting complex required for transport III (ESCRT-III), which regulates the formation and release of extracellular vesicles. Biallelic CHMP1A loss of function impairs the ESCRT-III-mediated release of extracellular vesicles, which causes impaired progenitor proliferation in the developing brain. Herein, we report a patient with PCH8 who had a homozygous CHMP1A variant, c.122delA (p.Asn41Metfs*2), which arose from segmental uniparental disomy. Although our patient had similar MRI findings to those of previously reported patients, with no progression, we report some novel neurological and developmental findings that expand our knowledge of the clinical consequences associated with CHMP1A variants., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Introduction: Zika virus (ZIKV) is an arbovirus (arthropod-borne virus) in the genus Flavivirus and Flaviviridae family. In November 2015, several cases of microcephaly in Northeastern of Brazil suggested ZIKV involvement. Case Report: A 33-year-old primigravida developed fever and cutaneous rash at 7th week of gestation (WGA). The ultrasound and MRI examination showed head circumference < 5th centile and enlargement of lateral ventricles. The infant was delivered at 39th WGA with microcephaly. Microscopy of the placenta showed chronic villitis and intervillitis, nodular stromal fibrosis in the stem villi, and vascular thickening. Postnatal CT showed collapsed cranium due to growth impairment of the suprathalamic brain, multiple cerebral calcifications, parenchymal atrophy, and ventricular dilatation. Now, at 6 years old, the child suffers from severe neurologic symptoms, including seizures. Conclusion: This case gathers images of prenatal and postnatal period, and placental histopathology. The long-term follow-up highlights the dramatic neurological sequelae induced by ZIKV.

We report a case of fetal microcephaly found during the second trimester ultrasound and confirmed by further ultrasound scans and fetal MRI. The array comparative genomic hybridisation analysis of the fetus and the male parent showed a 1.5 Mb deletion overlapping the Feingold syndrome region, an autosomal dominant syndrome that can cause microcephaly, facial/hand abnormalities, mild neurodevelopmental delay and others. This case illustrates the need for a detailed investigation by a multidisciplinary team to provide prenatal counselling regarding a postnatal outcome to the parents and orient their decision towards the continuation or termination of pregnancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

SMPD4 loss is a rare neurodevelopmental disorder that leads to severe mental and physical disability and early death in infancy. Most cases of this genetic condition have been diagnosed postnatally. This article focuses on the prenatal findings of affected fetuses. The phenotypes can include growth restriction, arthrogryposis (clenched hands, foot deformity), as well as cerebral abnormalities (simplified gyral pattern/lissencephaly, cerebellar hypoplasia, corpus callosum deformity). SMPD4 loss is detectable via exome sequencing. Here, two fetuses displayed a homozygotic pathogen variant in the SMPD4 gene, encoding for the enzyme Sphingomyelinase-4. Both parents were heterozygous carriers of the pathogenic variant. On detection of the above mentioned signs exome sequencing is indicated, with focus on the SMPD4 gene., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Phosphoglycerate dehydrogenase (PHGDH) deficiency is a rare autosomal recessive genetic disease of serine biosynthesis. Its typical features are congenital microcephaly, epileptic seizures, and psychomotor developmental delay. Here, we reported the first Chinese familial cases with genetically confirmed PHGDH deficiency and reviewed several previous reports. Two siblings in this family presented with microcephaly, psychomotor retardation, and epilepsy in early juvenile. Brain magnetic resonance imaging (MRI) showed only a slight change of enlarged ventricle. Biochemical investigations revealed low serum serine and glycine concentrations. The whole-exome sequencing (WES) results identified a missense variant in the PHGDH gene (NM&#95;006623.4: exon11: c.1211T>A, p. Val404Asp). Although two patients in this Chinese family carried the same pathogenic mutation in the PHGDH, their symptoms and responses to treatment were not exactly the same. We found a novel variant in the PHGDH gene and expanded the genotypic and phenotypic spectrum of serine biosynthesis disorders., (© 2022 The Authors. International Journal of Developmental Neuroscience published by John Wiley & Sons Ltd on behalf of International Society for Developmental Neuroscience.)

With its sensitivity to soft tissue, MRI is a powerful tool for the study of the neuroanatomical manifestations of a variety of conditions, such as microcephaly-related morbidities that are not easily visualized by other imaging techniques, such as CT. In addition to structural imaging, more recently, researchers have found changes in brain function in a wide range of neurological conditions-highlighting the utility of MRI for the study of microcephaly.In this methods chapter, basic mouse preparation and the acquisition of data for in vivo anatomical MRI will be discussed. Additionally, we will provide our protocol for the perfusion and fixation of brain tissue with gadolinium contrast agent. Following that, the process of optimization of system parameters will be shown for anatomical imaging of in vivo and ex vivo brain tissue. Lastly, the chapter will detail a protocol for fcMRI along with a discussion of considerations specific to functional imaging., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS)., Methods: This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected., Results: Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months., Conclusions: The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Microcephaly is a prominent feature of patients with primary autosomal recessive microcephaly 2 (MCPH2) caused by mutations in the WD Repeat Domain 62 (WDR62; OMIM: 613,583)., Aim: The study aimed to identify the underlying genetic factor(s) causing microcephaly in two patients in a consanguineous Iranian family., Methods: Two male patients (11 and 27 years old) were noticed due to microcephaly, neurodevelopmental delay, and occasional seizures. The younger patient (the proband) was subjected to paired-end whole-exome sequencing followed by Sanger sequencing to detect any underlying genetic factor., Results: Upon examination, both patients showed microcephaly as a prominent manifestation; they were under-weighted as well. The patients had a moderate gross motor impairment, severe cognitive disability and speech delay, increased deep tendon reflexes, flexible joint contractures, sensorineural hearing loss, and vertical nystagmus as a new ocular finding. The proband had more severe neurodevelopmental delay symptoms. The brain magnetic resonance imaging series revealed severe structural and cortical brain abnormalities in addition to hemiatrophy. Using Whole-exome Sequencing, a novel homozygous missense variant-NM&#95;001083961.2; c.1598A > G: p.(His533Arg)-was identified in the WDR62. Subsequently, in silico analyses determined the possible impacts of the novel variant on the structure and function of WDR62 protein., Conclusions: Herein, we identified a novel homozygous missense variant in the WDR62 in two patients with MCPH2. Vertical nystagmus and sensorineural hearing loss were detected as novel neurological findings. The present study expands the phenotype and genotype spectrum of MCPH2., (© 2021. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Zika virus (ZIKV) is a widespread flavivirus transmitted to humans through the bite of Aedes mosquitoes. The number of ZIKV cases increased significantly between 2015 and 2016, and Brazil was the first to report autochthonous transmission of infection. The main neurological disorder related to ZIKV infection is microcephaly. Fetal magnetic resonance imaging (MRI) is the gold standard examination for the analysis of fetal brain infection, followed by obstetric ultrasonography. Cerebral atrophy, intracranial calcifications, ventriculomegaly, cerebellar, and brain gyrus abnormalities are some of the most common findings. Postnatal MRI shows high sensitivity and specificity. Corpus callosum abnormalities, cerebellar hypoplasia, and choroid plexus dilation can be also observed. We present a review of congenital ZIKV infection with emphasis on pre and postnatal brain findings using ultrasonography, MRI, computed tomography, and three-dimensional reconstruction models.

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients., (© 2022. The Author(s).)

One of the most common definitions of microcephaly cited is that of an occipitofrontal circumference (OFC) of the head that is less than two standard deviations below the average for age (or gestational age, if identified prenatally) and sex. Similarly, severe microcephaly is defined as an OFC that is less than three standard deviations below the average. Microcephaly is not a diagnosis, but rather, a finding that is secondary to a multitude of etiologies that can be categorized as prenatal versus postnatal, genetic versus environmental, and congenital versus acquired., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Describing the urodynamic parameters of children aged 3 to 5 years with microcephaly related to congenital Zika syndrome and verifying the association with clinical, imaging and neurological characteristics., Methods: From October 2018 to March 2020, children with Zika-related microcephaly underwent urological, ultrasonographic and urodynamic evaluation. In selected cases, complementary exams such as urethrocystography and scintigraphy were performed. The children also underwent a complete neurological evaluation. To compare frequency between groups, we used Pearson's chi-squared test or Fisher's exact test., Results: This study evaluated 40 children, of whom 85% were 4 years old, and all had abnormalities on the urodynamic study, with low bladder capacity (92.5%) and detrusor overactivity (77.5%) as the most frequent findings. Only three children had ultrasound abnormalities, but no child had cystographic or scintigraphic abnormalities, and the postvoid residual volume was normal in 80% of cases. In spite of a frequency of 67.5% of intestinal constipation, there was no record of febrile urinary tract infection after the first year of life. All children presented severe microcephaly and at least one neurological abnormality in addition to microcephaly. The homogeneity of the children in relation to microcephaly severity and neurological abnormalities limited the study of the association with the urodynamic parameters., Conclusions: Urodynamic abnormalities in children aged 3 to 5 years with Zika-related microcephaly do not seem to characterize a neurogenic bladder with immediate risks for the upper urinary tract. The satisfactory bladder emptying suggests that the voiding pattern is reflex.

L-serine is an important amino acid that ensures neuronal differentiation and development. The SLC1A4 gene encodes proteins that transport amino acids such as serine, alanine, threonine and glutamate into neurons. Pathogenic variants in SLC1A4 gene interneuron transport of L-serine impaired and a severe global developmental delay occurs, characterized by microcephaly and refractory seizures. In this article, we would like to describe the demographic, clinical, electroencephalography (EEG) and magnetic resonance imaging (MRI) features of a patient with a novel pathogenic variant in the 6th exon of the SLC1A4 gene (p.Gly374Arg) detected by whole-exome sequencing, which is extremely rare (there have been twenty patients reported in the literature). It is emphasized that SLC1A4 gene variants should be kept in mind if the patients have microcephaly, global developmental delay, refractory seizures, and there are no abnormalities in basal metabolic investigations, and the thin corpus callosum and myelination delay is seen on the MRI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Zika virus infection during pregnancy is linked to birth defects, most notably microcephaly, which is associated with neurodevelopmental delays., Objective: The goals of the study were to propose a method for severity classification of congenital microcephaly based on neuroradiologic findings of MRI scans, and to investigate the association of severity with neuropsychomotor developmental scores. We also propose a semi-automated method for MRI-based severity classification of microcephaly., Materials and Methods: We conducted a cross-sectional investigation of 42 infants born with congenital Zika infection. Bayley Scales of Infant and Toddler Development III (Bayley-III) developmental evaluations and MRI scans were carried out at ages 13-39 months (mean: 24.8 months; standard deviation [SD]: 5.8 months). The severity score was generated based on neuroradiologist evaluations of brain malformations. Next, we established a distribution of Zika virus-microcephaly severity score including mild, moderate and severe and investigated the association of severity with neuropsychomotor developmental scores. Finally, we propose a simplified semi-automated procedure for estimating the severity score based only on volumetric measures., Results: The results showed a correlation of r=0.89 (P<0.001) between the Zika virus-microcephaly severity score and the semi-automated method. The trimester of infection did not correlate with the semi-automated method. Neuropsychomotor development correlated with the severity classification based on the radiologic readings and semi-automated method; the more severe the imaging scores, the lower the neuropsychomotor developmental scores., Conclusion: These severity classification methods can be used to evaluate severity of microcephaly and possible association with developmental consequences. The semi-automated methods thus provide an alternative for predicting severity of microcephaly based on only one MRI sequence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

This is a case report of Methenyl Tetrahydrofolate synthetase deficiency (MTHFS deficiency) characterized by global developmental delay, cerebral hypomyelination, severe spastic tonicity in extremities, and microcephaly. Mutation in the MTHFS gene was reported in the Whole Exome Sequencing (WES) and confirmed with Sanger sequencing of parents. It is of great significance to report since it would be the first case of MTHFS mutation reported from Iran and the fourth throughout the world with novel mutation and brain imaging., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: In October 2015, an epidemic of Zika began in Colombia's geographic areas with a high population of mosquitoes of the genus Aedes. We aimed to describe the fetal brain ultrasound findings in pregnant women with active symptoms or a history of symptoms suggestive of Zika virus (ZIKV) infection., Material and Methods: Eligible pregnant women were tested with reverse transcriptase-polymerase chain reaction (RT-PCR) for ZIKV and followed prospectively using detailed anatomic ultrasound and transvaginal neurosonography to detect structural anomalies of the fetal central nervous system (CNS)., Results: A total of 115 symptomatic women with a positive ZIKV RT-PCR and 55 with a negative ZIKV RT-PCR were enrolled in the study; CNS compromise of the fetus occurred in 22% and 17%, respectively (p = 0.255). Callosal dysgenesis (14.5%) was the most frequent anomaly of the CNS, followed by microcephaly (13.6%) and neuronal migration disorders (8.3%). When symptomatic ZIKV RT-PCR-positive women were categorized by trimester of infection, CNS anomalies were present in 40% of first-trimester infections, compared with 21% and 7% in second- and third-trimester infections (p = 0.002). CNS anomalies were also more severe in first-trimester-infected fetuses than in second- and third-trimester-infected fetuses. The high prevalence of CNS anomalies in fetuses of symptomatic ZIKV RT-PCR negative women suggests a high rate of false-negative cases and an even higher prevalence of CNS anomalies than observed in this study., Conclusions: The prevalence of fetal CNS anomalies was higher than previously reported in the literature for both symptomatic RT-PCR-positive and -negative pregnant women. Corpus callosum anomalies, microcephaly, neuronal migration disorders, and brain parenchymal hyperechogenicities were the most frequent CNS anomalies detected. In addition, CNS anomalies were more frequent and severe in infected fetuses during the first trimester of pregnancy than during the second or third trimester., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Abstract: FOXG1, located at chromosome 14q12, is critical for brain development, and patients with FOXG1 mutation exhibit developmental encephalopathy with high phenotypic variability, known as FOXG1 syndrome. Here, we report 3 cases of FOXG1 syndrome that presented with infantile hypotonia and microcephaly.A total of 145 children with developmental delay and/or hypotonia were evaluated by whole-exome sequencing (WES) in the pediatric neurology clinic and medical genetics center at Asan Medical Center Children's Hospital, from 2017 to 2019. Each FOXG1 mutation was confirmed by Sanger sequencing. The clinical findings of each patient with FOXG1 mutation were reviewed.WES identified de-novo, pathogenic, and heterozygous FOXG1 mutations in 3 of 145 patients in our patient cohort with developmental delay and/or hypotonia. The characteristics of brain magnetic resonance imaging (MRI) were reported as callosal anomaly, decrease in frontal volume, fornix thickening, and hypoplastic olfactory bulbs. A phenotype-genotype correlation was demonstrated as a patient with a novel missense mutation, c.761A > C (p.Tyr254Ser), in the forkhead domain had better outcome and milder brain abnormalities than the other 2 patients with truncating mutation in the Groucho binding domain site, c.958delC (p.Arg320Alafs), or N-terminal domain, c.506dup (p.Lys170GlnfsThe). Importantly, all 3 patients had hypoplastic olfactory bulbs on their brain MRI, which is a distinct and previously unrecognized feature of FOXG1 syndrome.This is the first report of FOXG1 syndrome in a Korean population; this condition accounts for 2% (3 of 145 patients) of our patient cohort with developmental delays and/or hypotonia. Our report contributes to understanding this extremely rare genetic condition in the clinical and genetic perspectives., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aimed to compare the anthropometric measurements and body proportionalities of neonates born before the Zika virus epidemic with those born during this period. We compared 958 neonates born during the pre-Zika epidemic with 264 neonates born during the epidemic period. The newborns had their head circumference, weight, and length classified according to the Fenton & Kim growth chart. We considered disproportionate those individuals that presented microcephaly and adequate weight or length for sex and gestational age, and those whose head circumferences were lower than the ratio ((length / 2) + 9.5) - 2.5cm. We estimated the frequencies of Zika positivity and brain imaging findings among neonates with microcephaly born during the epidemic period, concerning the anthropometric and body proportionality parameters. Low weight and proportionate microcephaly were similar among newborns from both periods. However, the frequencies of newborns with microcephaly with a very low length and disproportionate microcephaly were higher among the neonates of the epidemic period with brain abnormalities and positive for Zika virus. We conclude that, at birth, the disproportion between head circumference and length can be an indicator of the severity of microcephaly caused by congenital Zika.

Background and Purpose: Definitions of fetal microcephaly and macrocephaly are debatable. A better understanding of their long-term prognoses would help guide parental education and counseling. This study aimed to explore the correlation between 2D and 3D fetal brain MR imaging biometry results and the long-term neurodevelopmental outcomes., Materials and Methods: This analysis is a historical cohort study. Fetal brain biometry was measured on 2D and 3D MR imaging using a volumetric MR imaging semiautomated algorithm. We measured and assessed the following brain structures: the supratentorial brain volume and cerebellar volume and cerebellar volume/supratentorial brain volume ratio, in addition to commonly used 2D brain MR imaging biometric variables, including occipitofrontal diameter, biparietal diameter, and transcerebellar diameter. Microcephaly was defined as ≤ 3rd percentile; and macrocephaly, as ≥ 97th percentile, corresponding to -2 SDs and +2 SDs. The neurodevelopmental outcome of this study cohort was evaluated using the Vineland-II Adaptive Behavior Scales, and the measurements were correlated to the Vineland standard scores., Results: A total of 70 fetuses were included. No significant correlation was observed between the Vineland scores and either the supratentorial brain volume, cerebellar volume, or supratentorial brain volume/cerebellar volume ratio in 3D or 2D MR imaging measurements, after correction for multiple comparisons. No differences were found among fetuses with macrocephaly, normocephaly, or microcephaly regarding the median Vineland standard scores., Conclusions: Provided there is normal brain structure on MR imaging, the developmental milestone achievements in early years are unrelated to 2D and 3D fetal brain MR imaging biometry, in the range of measurements depicted in this study., (© 2021 by American Journal of Neuroradiology.)

Introduction: Children with Congenital Zika Syndrome (CZS) present structural cortical changes that may compromise the integrity of their connections with urinary and digestive systems, causing bowel and bladder dysfunctions., Objective: To evaluate bladder and bowel dysfunction (BBD) in children with CZS., Study Design: This is an observational cross-sectional study of a series of CZS cases. Urinary tracts were investigated using a bladder function protocol consisting of clinical history, detailed physical examination, laboratory tests, ultrasound of the lower and upper urinary tracts, and urodynamic evaluation. The bowel function protocol expanded anamnesis with questions related to signs and symptoms of functional disorders, Bristol scale, and ultrasound of the rectal ampoule., Results: Forty children with CZS, aged between one and five years were included. The majority (80%) had bladder and bowel dysfunction (BBD), 12.5% had bladder dysfunction only, and 7.5% only bowel dysfunction. A reduced bladder capacity was confirmed in 36 patients (90%), while 15 (40%) presented postvoid residual greater than 20% of their cystometric capacity. Thirty-five patients (87.5%) presented four signs/symptoms of functional bowel disorders and the rectal ampoule ultrasound was >2.9 cm in 21 (52.5%). Moreover, 19 (47.5%) presented urinary tract infection, while 5 (12.5%) developed pyelonephritis and required hospitalization. Renal ultrasound showed nephrolithiasis in three (7.5%), one (2.5%) presented horseshoe kidney, and a duplicated collecting system was found in three patients. Cryptorchidism was presented in eight (34%)., Discussion: Our study confirmed the presence of BBD in 80% of the children with CZS studied in this series. This is the first time that bowel dysfunction is confirmed in the settings of CZS. This recognition will facilitate early identification and appropriate therapies in an attempt to reduce complications. One limitation of the study is the absence of a control group. Due to the new aspects of CZS, it has been difficult to find a suitable group of patients with neurological disorders to compare and performing urodynamic studies in children without neurological or non-neurological voiding dysfunction is unethical. Appropriate control groups for future studies may be children with microcephaly due to other causes or older children with CZS who were not yet investigated or treated. Another limitation is the lack of a standard quantitative evaluation of bowel dysfunction in children with neurological disorders., Conclusion: Bladder and bowel dysfunction was confirmed in 80% of the children with CZS. This is a new Zika virus-associated neuromuscular disorder that needs to be further investigated., Competing Interests: Conflict of interest The authors have no conflicts of interest, and the sponsors contributed only with financial support., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency., (© 2021. The Author(s).)

Objective: MCPH (microcephaly primary hereditary) is a group of autosomal recessive developmental disorders with microcephaly present at birth and intellectual disability. Since a second trimester ultrasound is not able to detect subtypes with minimal prenatal presentations, only prenatal diagnosis by genetic testing can confirm these cases and allow for effective genetic counseling, especially a family with a previously affected child., Case Report: A 37-year-old women was pregnant for the third time and had two prior children with profound microcephaly and mental retardation. Targeted panel sequencing identified novel compound heterozygous ASPM pathogenic variants: c.1615&#95;1616del (p. Glu539ArgfsTer15); c.∗293T > A (p. Leu98Ter), which confirmed the diagnosis of MCPH5 (#OMIM 608716). Genetic testing was conducted for family members and applied on prenatal diagnosis., Conclusion: This is the first cases of MCPH5 to be reported in Vietnam and the genetic result aided in prenatal diagnosis of a high-risk pregnancy. The study highlights the importance of genetic testing in defining definitive diagnosis which allowed for timely prenatal diagnosis and genetic counseling for the family., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To compare ultrasound growth measurements of fetuses with and without microcephaly in suspected Zika virus infection., Methods: A retrospective cohort study included pregnant women with suspected Zika virus infection to evaluate 110 fetuses with and without microcephaly. The women had been admitted to the fetal medicine unit between October 2015 and August 2016. Cases of fetal microcephaly resulting from other causes were excluded. Variables evaluated were the ultrasound measurements taken at fetal biometry. The relation between each fetal biometry measurement and gestational age was analyzed using fractional polynomials in random-effects regression models. To evaluate fetal growth, curves of the mean fetal biometric parameters were constructed as a function of gestational age., Results: Mean biparietal diameter and mean head circumference increased in both groups as a function of gestational age. In the group with fetal microcephaly, mean head circumference was significantly larger in the 13th and 14th weeks of pregnancy, becoming smaller compared with the group without microcephaly from the 20th week onwards, with the difference increasing with gestational age., Conclusion: Fetal head circumference continues to increase until birth, even after a diagnosis of microcephaly, with a reduction only in the pace of growth. Growth decelerates as the pregnancy approaches term., (© 2021 International Federation of Gynecology and Obstetrics.)

Background: The Zika virus (ZIKV) epidemic had devastating consequences in Brazil. We investigated whether a radiologic finding (ie, infratentorial abnormalities) was associated with sight-threatening defects in children born with congenital Zika syndrome (CZS). We also investigated whether ophthalmic abnormalities correlated with head circumference (HC) and gestational age of infection., Methods: Cross-sectional evaluation based upon a previous cohort from March 2016 to December 2018, in Paraíba, Brazil. The study population was comprised of children born to mothers with laboratory-confirmed ZIKV infection during pregnancy (ZIKV reverse transcriptase polymerase chain reaction [RT-PCR]+) and children born with clinical and radiologic features of CZS., Results: A total of 75 infants had complete data. All 75 had brain calcifications. Microcephaly was present in 53 (71%) of them. Infratentorial abnormalities were present in 17 infants (22.7%). Ophthalmic abnormalities were seen in 16 of the 17 children (94%) with infratentorial abnormalities, while 28% of children without infratentorial abnormalities had ophthalmic findings (odds ratio [OR]: 42.0; 95% confidence interval [CI]: 5.1-342.9). Similar associations were observed when macular chorioretinal atrophy and optic nerve abnormalities were analyzed individually (OR: 23.7; 95% CI: 6.0-93.3 and OR: 11.5; 95% CI: 3.3-40.0, respectively). Infratentorial abnormalities were more frequently associated with ophthalmic abnormalities (94%) than microcephaly (43.4%) (P < .001). Mean HC was statistically different between groups with and without ophthalmic abnormalities (P = .01). A statistically significant difference in gestational age between both groups was not noted (P = .12)., Conclusions: In children with CZS, the presence of infratentorial abnormalities is a significant predictor of ophthalmic abnormalities. All neonates whose mothers had ZIKV exposure during pregnancy should have an ophthalmologic examination., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Different fetal ultrasound (US) nomograms of the head circumference (HC) have been established; however, comparisons between the detection rates of microcephaly among US nomograms are few and inconsistent. We aimed to compare the prenatal diagnostic rate of fetal microcephaly (FM) among four widely used US nomograms of the fetal HC, when applied to the same group of fetuses., Methods: We retrospectively identified singleton pregnancies complicated by fetal HC < 5th percentile for gestational age (GA) by US, without other risk factors for FM and with normal fetal brain MRI. Raw values of HC by US were converted to z-scores using four nomograms (Chervenak = A , Hadlock = B , Gelber = C , Papageorghiou = D ). Z-scores value of the HC were classified as normal, possible normal, or microcephaly if values were >-2, ≤ -2 and >-3, or ≤ -3, respectively and compared among the four nomograms., Results: Fifty one fetuses at a mean (±SD) GA of 28 (±4) weeks were included. The four nomograms resulted in different z-score values of the fetal HC for the same subject ( p  < .001) and none of them showed 100% agreement. Reference C and D showed the highest agreement in classifying subjects as normal, possible normal, or with microcephaly (simple Kappa = 0.8915, % agreement = 94.1%), while A and B had the lowest agreement (simple Kappa = 0.0977, % agreement = 51.0%)., Conclusions: Despite the use of similar prenatal cutoff z-score values of the fetal HC, the four nomograms led to different diagnostic rates of FM. More consistent diagnostic criteria are therefore needed to define FM, especially in the absence of other risk factors for FM and normal fetal brain MRI, since the prenatal diagnosis can affect pregnancy management.

Primary microcephaly (MCPH) is a rare neurogenic disorder with most cases being inherited in an autosomal recessive pattern. The present report is of a case of second gravid patient with recurrent fetal microcephaly with agenesis of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Maternal TORCH profile and amniotic fluid chromosomal microarray were normal. Following the termination of pregnancy, the autopsy evaluation has shown additional findings of evolving craniosynostosis, and semilobar holoprosencephaly. Whole exome sequencing done on fetal DNA from amniotic fluid, revealed a pathogenic compound heterozygous variant (NM&#95;025009.5) c.2863C>T (p.Arg955Ter) in exon 22 and c.1372&#95;1375del (p.Lys459SerfsTer2) in exon 11 of CEP135 gene: known to cause primary microcephaly-8; and both partners in the couple are heterozygous carriers for the same. With the identification of MCPH genes and with the availability of next-generation sequencing (NGS) based exome sequencing, a definitive prenatal diagnosis of primary microcephaly and also appropriate genetic counselling for the couple has become possible., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM&#95;005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM&#95;005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.

Importance: The Zika virus infects progenitor neuron cells, disrupts cerebral development, and, in mice, drives hypothalamic defects. Patients with microcephaly caused by congenital Zika infection present with midline cerebral defects, which may result in hypopituitarism., Objective: To analyze postnatal growth and the presence of clinical and biochemical features associated with hypopituitarism in children with congenital Zika infections., Design, Setting, and Participants: In this prospective cohort study at 2 public referral hospitals in Bahia, Brazil, specializing in the treatment of congenital Zika infection, clinical data and growth parameters of 65 patients with the infection were evaluated. Data were analyzed from April 2017 through July 2018., Exposure: Congenital Zika infection., Main Outcomes and Measures: Length, weight, and head circumference were measured at birth and during follow up (ie, at 27 months of life) for each patient. Basal levels of free thyroxine, thyrotropin, cortisol, corticotropin, prolactin, insulin-like growth factor 1, insulin-like growth factor binding protein 3, urine and plasma osmolality, electrolytes, glucose, and insulin were evaluated at the age of 26 months to 28 months. All patients underwent central nervous system computed tomography scans and ophthalmic and otoacoustic evaluations at the time of this investigation or had done so previously., Results: Among 65 patients (38 [58.4%] male; median [interquartile range] age at enrollment, 27 [26-28] months), 61 patients presented with severe brain defects (93.8%), including corpus callosum agenesis or hypoplasia (ie, midline brain defects; 25 patients [38.5%]) and optic nerve atrophy (38 patients [58.5%]). Most patients presented with severe neurodevelopmental delay (62 of 64 patients [96.9%]). Past or present clinical signs of hypopituitarism were rare, occurring in 3 patients (4.6%). Severe microcephaly, compared with mild or moderate microcephaly, was associated with a shorter length by median (interquartile range) z score at birth (-1.9 [-2.5 to -1.0] vs -0.3 [-1.0 to 0]; P < .001), but this difference did not persist at 27 months (-1.6 [-2.3 to -0.3] vs -2.9 [-4.0 to -1.2]; P = .06). Growth hormone deficiency or hypothyroidism were not observed in any patients, and glucose and insulin levels were within reference ranges for all patients. Low cortisol levels (ie, below 3.9 µg/dL) were observed in 4 patients (6.2%). These 4 patients presented with low (ie, below 7.2 pg/mL) or inappropriately low (ie, below 30 pg/mL) corticotropin levels. Low corticotropin levels (ie, below 7.2 pg/mL) were observed in 6 patients (9.2%). Diabetes insipidus was evaluated in 21 patients; it was confirmed in 1 patient (4.8%) and suggested in 3 patients (14.3%)., Conclusions and Relevance: This study found that congenital Zika infection with microcephaly was associated with midline brain defects and optic nerve atrophy. Children with congenital Zika infections presented with prenatal growth impairments with a lack of postnatal catch-up, as shown by persistent short length from birth until 27 months; these impairments were not associated with growth hormone deficiency. Patients also presented with severe developmental delay that was not associated with hypothyroidism, while central adrenal insufficiency and diabetes insipidus occurred in some patients.

Microcephaly, disproportionate pontine and cerebellar hypoplasia (MICPCH) syndrome is a rare and genetic disorder, which is mainly caused by mutations in the CASK gene. We described four variations in the CASK gene in Chinese female patients with MICPCH, who presented with microcephaly, developmental delay, and motor disorder. The CASK mutations were identified using NGS (the next-generation sequencing), copy number variation sequencing. Two novel variations in the CASK gene were revealed including a frameshift mutation c.1000&#95;1001insG (p.Asp334GlyfsTer32) and a nonsense mutation c.2110A > T (p.Lys704Ter). Two other aberrations were c.316C > T (p.Arg106Ter) and Xp11.4-p11.3 (41,700,001-44,660,000) × 1 loss. We provided clinical manifestations and neuroimaging findings of the four patients. The genetic variation spectrum of MICPCH caused by CASK was updated. Furthermore, we expounded on the molecular mechanism of the disease and noticed that it was not possible to relate the magnitude of the genetic alteration to a particular phenotype., (© 2021 International Society for Developmental Neuroscience.)

Numerous studies have reported abnormalities in the development of oral structures in congenital infections that also involve microcephaly. In this context, it is necessary to identify possible dental anomalies of shape and/or number in patients with Zika virus syndrome using radiography. The study population consisted of 35 children born with congenital ZIKV who underwent intraoral radiographic examinations for 24 consecutive months. A modified periapical technique was performed in an occlusal position for the maxilla and mandible. Categorical data were expressed as absolute and percentage frequencies and compared using Pearson's Chi-square test, with a 95% confidence interval. Of the entire sample, eight children (22.8%) had dental anomalies of shape and/or number, and four children (11.4%) presented with both anomalies, with agenesis of the upper and lower deciduous/permanent incisors and dental form modifications, such as microdontia and anomalous cusps. When we considered age and sex, there was no statistically significant difference between patients who presented with agenesis and those who presented with modifications. Children with congenital Zika virus syndrome were more likely to have dental modifications in the number and shape of their teeth, and it is essential to implement medium- to long-term monitoring to diagnose other possible alterations throughout the development of the mixed and permanent dentition, favoring their treatment.

The objective of the study was to describe the complexity of diagnosis and evaluation of Zika-exposed pregnant women/fetuses and infants in a U.S. Congenital Zika Program. Pregnant women/fetuses and/or infants referred for clinical evaluation to the Congenital Zika Program at Children's National (Washington, DC) from January 2016 to June 2018 were included. We recorded the timing of maternal Zika-virus (ZIKV) exposure and ZIKV laboratory testing results. Based on laboratory testing, cases were either confirmed, possible, or unlikely ZIKV infection. Prenatal and postnatal imaging by ultrasound and/or magnetic resonance imaging (MRI) were categorized as normal, nonspecific, or as findings of congenital Zika syndrome (CZS). Of 81 women-fetus/infant pairs evaluated, 72 (89%) had confirmed ZIKV exposure; 18% of women were symptomatic; only a minority presented for evaluation within the time frame for laboratory detection. Zika virus could only be confirmed in 29 (40%) cases, was possible in 26 (36%) cases, and was excluded in 17 (24%) cases. Five cases (7%) had prenatal ultrasound and MRI findings of CZS, but in only three was ZIKV confirmed by laboratory testing. Because of timing of exposure to presentation, ZIKV infection could not be excluded in many cases. Neuroimaging found CZS in 7% of cases, and in many patients, there were nonspecific imaging findings that warrant long-term follow-up. Overall, adherence to postnatal recommended follow-up evaluations was modest, representing a barrier to care. These challenges may be instructive to future pediatric multidisciplinary clinics for congenital infectious/noninfectious threats to pregnant women and their infants.