[Analysis of clinical characteristics and molecular genetics in eighteen patients with 1q21.1 microdeletion syndrome].

OBJECTIVE: To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). METHODS: Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. RESULTS: Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). CONCLUSION: 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.

Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia-The Neonatal Type of Alexander Disease.

INTRODUCTION: Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by GFAP mutation. Symptoms usually occur in the infantile age with macrocephaly, developmental deterioration, progressive quadriparesis, and seizures as the most characteristic features. In this case report, we provide a detailed clinical description of the neonatal type of AxD. METHOD: Next-Generation Sequencing (NGS), including a panel of 49 genes related to Early Infantile Epileptic Encephalopathy (EIEE), was carried out, and then Whole Exome Sequencing (WES) was performed on the proband's DNA extracted from blood. CASE DESCRIPTION: In the first weeks of life, the child presented with signs of increased intracranial pressure, which led to ventriculoperitoneal shunt implementation. Recurrent focal-onset motor seizures with secondary generalization occurred despite phenobarbital treatment. Therapy was modified with multiple anti-seizure medications. In MRI contrast-enhanced lesions in basal ganglia, midbrain and cortico-spinal tracts were observed. During the diagnostic process, GLUT-1 deficiency, lysosomal storage disorders, organic acidurias, and fatty acid oxidation defects were excluded. The NGS panel of EIEE revealed no abnormalities. In WES analysis, GFAP missense heterozygous variant NM_002055.5: c.1187C>T, p.(Thr396Ile) was detected, confirming the diagnosis of AxD. CONCLUSION: AxD should be considered in the differential diagnosis in all neonates with progressive, intractable seizures accompanied by macrocephaly.

[Analysis of clinical features and genetic variant in a child with Cowden syndrome 1].

OBJECTIVE: To explore the genetic etiology of a child with Cowden syndrome 1 (CS1). METHODS: A child who had visited the Ningbo Women and Children's Hospital on August 26, 2022 was selected as the study subject. Clinical information of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 13-year-old boy, had manifested with severe mental retardation, hyperactivity, autistic behavior, sparse and prominent teeth, macrocephaly, and skin freckles on the penis. His mother had presented with multiple papules, hamartomatous polyps, thyroid adenoma and macrocephaly. WES results revealed that the child has harbored a nonsense c.781C>T (p.Q261*) variant of the PTEN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.781C>T variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.781C>T variant of the PTEN gene probably underlay the pathogenesis in the child and his mother. Above finding has facilitated genetic counseling for this family.

Correlation analysis of maternal condition during pregnancy with head circumference and autism spectrum disorder: A propensity score-matched study.

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.

Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene. METHODS: Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole-exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing. RESULTS: Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system. CONCLUSION: Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1-related MLC.

Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing.

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.

Review of published 467 achondroplasia patients: clinical and mutational spectrum.

AIM: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. METHODS: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". RESULTS: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31-53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. CONCLUSION: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.

Optimization by mixture design of chitosan/multi-phase calcium phosphate/BMP-2 biomimetic scaffolds for bone tissue engineering.

The modulation of cell behavior during culture is one of the most important aspects of bone tissue engineering because of the necessity for a complex mechanical and biochemical environment. This study aimed to improve the physicochemical properties of chitosan/multi-phase calcium phosphate (MCaP) scaffolds using an optimized mixture design experiment and evaluate the effect of biofunctionalization of the obtained scaffolds with the bone morphogenetic protein BMP-2 on stem cell behavior. The present study evaluated the compressive strength, elastic modulus, porosity, pore diameter, and degradation in simulated body fluids and integrated these responses using desirability. The properties of the scaffolds with the best desirability (18.4% of MCaP) were: compressive strength of 23 kPa, elastic modulus of 430 kPa, pore diameter of 163 µm, porosity of 92%, and degradation of 20% after 21 days. Proliferation and differentiation experiments were conducted using dental pulp stem cells after grafting BMP-2 onto scaffolds via the carbodiimide route. These experiments showed that MCaP promoted cell proliferation and increased alkaline phosphatase activity, whereas BMP-2 enhanced cell differentiation. This study demonstrates that optimizing the composition of a mixture of chitosan and MCaP improves the physicochemical and biological properties of scaffolds, indicating that this solution is viable for application in bone tissue engineering.

Subdural Hemorrhage as an Early Presentation in a Case of Sotos Syndrome.

Subdural hemorrhages (SDHs) in the pediatric population are associated with a high mortality and morbidity and may present in the context of abusive head trauma. Diagnostic investigations for such cases often include evaluation for rare genetic and metabolic disorders that can have associated SDH. Sotos syndrome is an overgrowth syndrome associated with macrocephaly and increased subarachnoid spaces and rarely with neurovascular complications. Here, we report two cases of Sotos syndrome, one with SDH during infancy who underwent repeated evaluation for suspected child abuse prior to the Sotos syndrome diagnosis and the other with enlarged extra-axial cerebrospinal fluid spaces, demonstrating a possible mechanism for SDH development in this setting. These cases suggest that some individuals with Sotos syndrome may be at elevated risk of developing SDH in infancy and that Sotos syndrome should be on the differential diagnosis during a medical genetics evaluation in cases of unexplained SDH, especially in the setting of macrocephaly.

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.

New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant.

Thauvin-Robinet-Faivre syndrome (#617107) is a rare autosomal recessive overgrowth syndrome characterized by intellectual disability, facial dysmorphism, macrocephaly, and variable congenital malformations. It is caused by homozygous or compound heterozygous FIBP gene mutations. The FIBP gene is located on the 11q13.1 region and codes the acidic fibroblast growth factor intracellular binding protein, which is involved in the fibroblast growth factor (FGF) signaling pathway. FGF signaling is required for neurogenesis and neuronal precursor proliferation. The FGF controls cell proliferation, differentiation, and migration in embryonic development and in adult life. Overgrowth syndromes consist of a wide spectrum disorders characterized by prenatal and postnatal excess growth in weight and length, often associated malformations, intellectual disability, and neoplastic predisposition. Embryonic tumors are especially common in these syndromes. Thauvin-Robinet-Faivre syndrome is a recently described overgrowth syndrome with typical facial dysmorphic and clinical features. To date, only four patients have been reported with this disorder. Herein, two new cases of Thauvin-Robinet-Faivre syndrome are reported with overgrowth, intellectual disability, typical dysmorphic signs in one dysplastic kidney, and a novel homozygous FIBP gene variant. Exome sequencing analysis showed that both affected siblings share the same homozygous c. 412-3_415dupCAGTTTG FIBP gene variant. Reporting two new cases with this rare autosomal recessive overgrowth syndrome with a novel FIBP gene variant will support and expand the clinical spectrum of Thauvin-Robinet-Faivre syndrome. Also discussed will be the function of FIBP in tumorigenesis and the possible renal tumor susceptibility in heterozygous carriers will be emphasized.

Syndrome of megalencephaly, mega corpus callosum, and complete lack of motor development: an unusual case and a literature review.

The syndrome of megalencephaly, mega corpus callosum (MEG-MegaCC) accompanied by complete lack of motor development is a rare condition with only few sporadic cases having been reported in the literature. In this paper, we describe a child from non-consanguineous parents presenting with MegaCC, psychomotor retardation, and language impairment linked to MEG-MegaCC syndrome. Genetic analysis, radiological findings, and detailed neurological phenotype of MEG-MegaCC syndrome with its overlapping syndromes would allow for a better classification of the disease spectrum.

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Megalencephalic leukoencephalopathy with subcortical cysts protein-1: A new calcium-sensitive protein functionally activated by endoplasmic reticulum calcium release and calmodulin binding in astrocytes.

BACKGROUND: MLC1 is a membrane protein highly expressed in brain perivascular astrocytes and whose mutations account for the rare leukodystrophy (LD) megalencephalic leukoencephalopathy with subcortical cysts disease (MLC). MLC is characterized by macrocephaly, brain edema and cysts, myelin vacuolation and astrocyte swelling which cause cognitive and motor dysfunctions and epilepsy. In cultured astrocytes, lack of functional MLC1 disturbs cell volume regulation by affecting anion channel (VRAC) currents and the consequent regulatory volume decrease (RVD) occurring in response to osmotic changes. Moreover, MLC1 represses intracellular signaling molecules (EGFR, ERK1/2, NF-kB) inducing astrocyte activation and swelling following brain insults. Nevertheless, to date, MLC1 proper function and MLC molecular pathogenesis are still elusive. We recently reported that in astrocytes MLC1 phosphorylation by the Ca2+/Calmodulin-dependent kinase II (CaMKII) in response to intracellular Ca2+ release potentiates MLC1 activation of VRAC. These results highlighted the importance of Ca2+ signaling in the regulation of MLC1 functions, prompting us to further investigate the relationships between intracellular Ca2+ and MLC1 properties. METHODS: We used U251 astrocytoma cells stably expressing wild-type (WT) or mutated MLC1, primary mouse astrocytes and mouse brain tissue, and applied biochemistry, molecular biology, video imaging and electrophysiology techniques. RESULTS: We revealed that WT but not mutant MLC1 oligomerization and trafficking to the astrocyte plasma membrane is favored by Ca2+ release from endoplasmic reticulum (ER) but not by capacitive Ca2+ entry in response to ER depletion. We also clarified the molecular events underlining MLC1 response to cytoplasmic Ca2+ increase, demonstrating that, following Ca2+ release, MLC1 binds the Ca2+ effector protein calmodulin (CaM) at the carboxyl terminal where a CaM binding sequence was identified. Using a CaM inhibitor and generating U251 cells expressing MLC1 with CaM binding site mutations, we found that CaM regulates MLC1 assembly, trafficking and function, being RVD and MLC-linked signaling molecules abnormally regulated in these latter cells. CONCLUSION: Overall, we qualified MLC1 as a Ca2+ sensitive protein involved in the control of volume changes in response to ER Ca2+ release and astrocyte activation. These findings provide new insights for the comprehension of the molecular mechanisms responsible for the myelin degeneration occurring in MLC and other LD where astrocytes have a primary role in the pathological process.

[EXAMINING THE ASSOCIATION BETWEEN THE FETAL SUPRATENTORIAL BRAIN VOLUME AND THE SUBARACHNOID SPACE IN VARIOUS FETAL PATHOLOGIES USING MAGNETIC RESONANCE IMAGING].

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.

Fetal macrocephaly: Pathophysiology, prenatal diagnosis and management.

Macrocephaly means a large head and is defined as a head circumference (HC) above the 98th percentile or greater than +2SD above the mean for gestational age. Macrocephaly can be primary and due to increased brain tissue (megalocephaly), which in most cases is familial and benign or secondary. The latter may be due to various causes, including but not limited to communicating or non-communicating hydrocephalus, cerebral edema, focal and pericerebral increased fluid collections, thickened calvarium and brain tumors. Megalocephaly can be syndromic or non-syndromic. In the former, gyral and structural CNS anomalies are common. It is important to exercise caution when considering a diagnosis of megalocephaly due to limitations in the accuracy of HC measurement, lack of nomograms for specific populations, inconsistencies between prenatal and postnatal HC growth curves and progression over time. The degree of macrocephaly is important, with mild macrocephaly ≤2.5SD carrying a good prognosis, especially when one of the parents has macrocephaly and normal development. Cases in which the patient history and/or physical exam are positive or when parental HC are normal are more worrisome and warrant a neurosonogram, fetal MRI and genetic testing to better delineate the underlying etiology and provide appropriate counseling.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.

Clinical factors associated with need for neurosurgical care in young children with imaging for macrocephaly: a case control study.

BACKGROUND: Macrocephaly is present in 2.3% of children with important neurosurgical conditions in the differential diagnosis. The objective of this study was to identify clinical associations with actionable imaging findings among children with head imaging for macrocephaly. METHODS: We conducted a case-control study of head imaging studies ordered for macrocephaly among children 24 months and younger in a multistate children's health system. Four neurosurgeons reviewed the images, determining cases to be a 'concern' if neurosurgical follow-up or intervention was indicated. Electronic health records were reviewed to collect patient-level data and to determine if surgery was performed. Controls were matched 3:1 to cases of 'concern' in a multivariate model using conditional logistic regression. RESULTS: In the study sample (n = 1293), 46 (4%) were concern cases, with 15 (1%) requiring surgery. Significant clinical factors associated with neurosurgical concern were bulging fontanel [aOR 7.47, (95% CI: 2.28-24.44), P < 0.001], prematurity [aOR 21.26, (95% CI: 3.76-120.21), P < 0.001], any delay [aOR 2.67, (95% CI: 1.13-6.27), P = 0.03], and head-weight Z-score difference (W_diff, defined as the difference between the Z-scores of head circumference and weight) [aOR 1.70, (95% CI: 1.22-2.37), P = 0.002]. CONCLUSIONS: Head imaging for macrocephaly identified few patients with findings of concern and fewer requiring surgery. A greater head-weight Z-score difference appears to represent a novel risk factor for neurosurgical follow-up or intervention.