BACKGROUND AND PURPOSE:Although the otic capsule is fully formed at birth, the vestibular aqueduct (VA) continues to mature postnatally. Failure of this maturation-VA hypoplasia-identifies a subgroup of patients with Menière disease and can be detected on CT by measuring the angular trajectory of the VA (ATVA). However, the age at which the ATVA stabilizes and hypoplasia can be reliably diagnosed remains unclear. We, therefore, defined the normal timeline of ATVA development to establish age-specific CT norms for distinguishing physiologic VA development from fetal/hypoplastic arrest. MATERIALS AND METHODS:We retrospectively reviewed temporal bone and head CTs in 159 children (318 ears) 0-16 years of age without an otologic abnormality. Two head and neck radiologists measured the ATVA and retrolabyrinthine bone (RL) thickness-previously established surrogates of VA hypoplasia-on axial reformatted images. Interreader reliability was assessed by the intraclass correlation coefficient. We modeled the ATVA versus age by using generalized additive mixed models. First-derivative analysis of the age spline identified when ATVA change plateaued. Eighty percent and 95% prediction intervals determined the ages at which the ATVA reliably fell below clinical thresholds (140°, 130°, 120°). RESULTS:Interreader agreement was excellent (intraclass correlation coefficient = 0.92 ATVA; 0.88, RL thickness). The mean ATVA declined from 135° (SD, 7.5°) in infants to 98° (SD, 6.0°) in adolescents. At the 80% prediction interval, the ATVA upper limit fell below 140° by ∼1.8 years; 130° by ∼3.1 years; and 120° by ∼10.4 years. The 95% interval excluded ATVA ≥140° by ∼3.0 years and ≥130° by ∼10.3 years, but not >120° before 16 years of age. No ears older than 8 years of age fell in the fetal category (≥140°), and none older than 12 years of age fell in the intermediate category (121°-139°). First-derivative analysis showed that ATVA change plateaued at ∼5.0 years. RL thickness of ≥1.2 mm universally corresponded to a mature ATVA (≤120°). CONCLUSIONS:ATVA transitions from a fetal (≥140°) to mature (≤120°) trajectory across the first decade, stabilizing by ∼5 years. ATVA >120° before ∼10 years reflects normal development; after ∼12 years, it indicates adult-persistent hypoplasia. RL thickness of ≥1.2 mm serves as a practical surrogate for mature VA orientation. These benchmarks empower radiologists to differentiate normal maturation from Menière disease associated VA hypoplasia, enabling early risk-stratification and management.

Abstract From 1990 to 2024, women neuroradiologists in North America have made tremendous progress in the areas of leadership, clinical innovation, research, education, diversity, equity and inclusion, and global outreach. This chapter begins with summaries of their key accomplishments in four broad domains, followed by short biographical sketches of numerous luminaries organized by leadership roles and areas of expertise, and ending with conclusions and future directions.

Purpose:To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction. Methods:We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 unaffected family members. Results:All 149 individuals had sporadic MBS, with no recurrence within or across generations. Common co-occurring phenotypes included tongue hypoplasia (81.9%), micrognathia (66.4%), congenital talipes equinovarus (42.3%), major limb anomalies (31.5%), intellectual disability (30.9%), sleep difficulties (22.8%), and Poland anomaly (14.1%). Filtering for rare de novo or autosomal recessive single-nucleotide, insertion/deletion, and structural variants in the sequenced cohort yielded 173 single-nucleotide variant/indels in 113 genes. Although we prioritized 7 candidate genes with de novo variants and 5 with biallelic variants, no compelling recurrently mutated genes were identified. Similarly, we found no convincing variants in 2 putative genes previously implicated in MBS: PLXND1 (HGNC:9107) and REV3L (HGNC:9968). Conclusion:We did not identify a strong or unifying germline genetic etiology for MBS. Future studies may explore alternative causes, including environmental exposures, somatic variants, and/or complex inheritance patterns affecting brainstem and organ embryogenesis.

An 11-year-old boy with a history of cleft palate repair, placement of multiple sets of pressure-equalizing tubes, and suspected ectodermal dysplasia was referred from a general ear, nose, and throat physician after a 1-year history of hearing loss. What is your diagnosis?

OBJECTIVES:Oval window atresia (OWA) is a rare otologic condition often associated with a maximal conductive hearing loss, and variable ossicular and facial nerve canal (FNC) anomalies, which have contributed to suboptimal middle ear surgical outcomes. No grading scheme exists to detail the spectrum of associated temporal bone anomalies in OWA; therefore, our objectives were to complete an audiometric and radiographic review to characterize audiometric patterns of hearing loss, and refine the classification system for OWA to determine suitability for middle ear surgery. METHODS:A retrospective audiometric and radiographic review was conducted at a pediatric tertiary care institution. Patients with OWA identified on temporal bone computerized tomography (CT) scans obtained from 01/2010 to 06/2024 were included. Audiological, radiological, and patient factors were analyzed. RESULTS:Thirty-one patients (48 ears) with OWA were identified. Across frequencies, the air-bone gap decreased significantly as frequency increased (ANOVA with pairwise comparisons, p < 0.001) due to a worsening of bone conduction thresholds and improvement in air conduction thresholds. The FNC was abnormal in 43/48 ears and was determined to overlay the oval window in 6 ears. Additional anomalies included inferiorly displaced, dehiscent, and duplicated canals. Ossicular anomalies were reported in 46/48 ears, and stapedial anomalies were most common. CONCLUSIONS:Our findings indicate OWA may manifest audiometrically with consistent and specific hearing loss characterized by a 60-80 dB ABG at lower frequencies that decreases above 2 kHz. CT findings of OWA show considerable variability. We propose a new classification system for OWA based on facial nerve position as this directly influences middle ear surgical feasibility. LEVEL OF EVIDENCE: 4:

Diseases involving the pediatric masticator space often vary from those encountered in adults, with congenital abnormalities encountered more commonly and the assortment of benign and malignant neoplasms encountered differing in type and frequency. Familiarity with the imaging findings for these diseases is important for timely and accurate diagnosis and management. This article briefly reviews masticator space anatomy and provides detailed description of the imaging findings associated with benign and malignant diseases that may be encountered in the pediatric masticator space.

PURPOSE. To functionally evaluate novel human sequence-derived candidate genes and variants for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). METHODS. Through exome and genome sequencing of a genetically unsolved human oCCDD cohort, we previously reported the identification of variants in many candidate genes. Here, we describe a parallel study that prioritized a subset of these genes (43 human genes, 57 zebrafish genes) using a G0 CRISPR/Cas9-based knockout assay in zebrafish and generated F2 germline mutants for 17. We tested the functionality of variants of uncertain significance in known and novel candidate transcription factor-encoding genes through protein binding microarrays. RESULTS. We first demonstrated the feasibility of the G0 screen by targeting known oCCDD genes phox2a and mafba. Approximately 70% to 90% of gene-targeted G0 zebrafish embryos recapitulated germline homozygous null-equivalent phenotypes. Using this approach, we then identified three novel candidate oCCDD genes (SEMA3F, OLIG2, and FRMD4B) with putative contributions to human and zebrafish cranial motor development. In addition, protein binding microarrays demonstrated reduced or abolished DNA binding of human variants of uncertain significance in known and novel sequence-derived transcription factors PHOX2A (p.(Trp137Cys)), MAFB (p.(Glu223Lys)), and OLIG2 (p.(Arg156Leu)). CONCLUSIONS. This study nominates three strong novel candidate oCCDD genes (SEMA3F, OLIG2, and FRMD4B) and supports the functionality and putative pathogenicity of transcription factor candidate variants PHOX2A p.(Trp137Cys), MAFB p.(Glu223Lys), and OLIG2 p.(Arg156Leu). Our findings support that G0 loss-of-function screening in zebrafish can be coupled with human sequence analysis and protein binding microarrays to aid in prioritizing oCCDD candidate genes/variants.

The spectrum of congenital and infantile masses of the head and neck is broad, including developmental and neoplastic entities. The diseases encountered in this vulnerable patient population differ substantially from those in older children and adults. Familiarity with the types of encountered masses, typical imaging characteristics, and expected clinical course is critical for radiologists who care for pregnant women (fetuses) and infants. This knowledge allows radiologists to provide a timely diagnosis and appropriate follow-up imaging recommendations and, in some fetal imaging cases, inform delivery planning. This article uses a location-based approach to highlight imaging features of numerous common and rare congenital and infantile masses of the head and neck.

STUDY DESIGN:A retrospective chart review.OBJECTIVE:The aims of this study were to review pathophysiology, workup, and treatment for Hirayama disease (HD); and to assess outcomes from a single institution.SUMMARY OF BACKGROUND DATA:HD is a rare, painless, cervical myelopathy with distal upper extremity weakness, muscle wasting, and spinal cord atrophy. Disease progression-a consequence of repeat flexion injury-occurs up to 5 years from the initial diagnosis.METHODS:Single-institution review of pediatric HD patients from 2010 to 2020.RESULTS:Patients (n=10 male, n=2 female) presented in the second decade (14-20 y) with painless progressive distal upper extremity weakness and atrophy without sensory loss. Electromyography (n=12) demonstrated denervation in C7-T1 myotomes and flexion/extension magnetic resonance imaging showed focal cord atrophy and anterior displacement of the posterior dura with epidural enhancement in flexion. Treatment included observation and external orthoses (n=9) and anterior cervical discectomy with fusion (n=3). One of the 9 patients managed conservatively experienced further deterioration; no patient who underwent anterior cervical discectomy with fusion progressed.CONCLUSIONS:Patients with HD require a multidisciplinary approach to diagnosis and treatment to preserve function. Treatment is preventive and aims to minimize flexion injury by inhibiting motion across involved joints. First-line management is avoidance of neck flexion and use of rigid orthosis; in cases of failed conservative management and/or rapid clinical deterioration, surgical fixation can be offered.

BACKGROUND:Otitic hydrocephalus is increased intracranial pressure without ventricular dilation secondary to mastoiditis and cerebral venous sinus thrombosis (CVST). It is associated with significant visual morbidity, though more detailed data on visual outcomes is lacking. We sought to better characterize the management of increased intracranial pressure and visual outcomes in this population. METHODS:Retrospective chart review at a quaternary Children's Hospital of patients <18 years of age who were diagnosed with otitic hydrocephalus from January 2009 to July 2023. Data were collected on patient demographics, clinical course, imaging, and treatment outcomes. RESULTS:Fifteen patients were identified with mastoiditis complicated by otitic hydrocephalus. The average age was 5.7 years (range 2-15). Eight patients were male (53%). Six patients (40%) had cranial nerve VI palsy and 14 (93%) developed papilloedema. Eleven patients (73%) developed progressively worsening papilloedema despite improving infection, clot burden, and acetazolamide; of these, three required ventriculostomy catheters. Eight were started on corticosteroids. Six had resolution of papilloedema without the need for shunt placement. Two patients had evidence of optic atrophy from increased ICP and visual loss prior to corticosteroid initiation. Both had stabilization of their condition without further visual loss. CONCLUSION:This study highlights the importance of systemic corticosteroids as part of the treatment paradigm for otitic hydrocephalus to prevent vision loss in patients otherwise unresponsive to medical management. It also identifies the risk of papilloedema progression and visual morbidity even after the initiation of appropriate medical therapy. Visual outcomes were significantly improved and invasive neurosurgical procedures were avoided with use of corticosteroids.

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.

Objective: Demonstrate the utility of 3D printed temporal bone models in individual patient preoperative planning and simulation. Methods: 3D models of the temporal bone were made from 5 pediatric and adult patients at a tertiary academic hospital with challenging surgical anatomy planned for cochlear implantation or exteriorization of cholesteatoma with complex labyrinthine fistula. The 3D models were created from CT scan used for preoperative planning, simulation and intraoperative reference. The utility of models was assessed for ease of segmentation and production and impact on surgery in regard to reducing intraoperative time and costs, improving safety and efficacy. Results: Three patients received cochlear implants, two exteriorization of advanced cholesteatoma with fistulas (1 internal auditory canal/cochlea, 1 all three semicircular canals). Surgical planning and intraoperative referencing to the simulations by the attending surgeon and trainees significantly altered original surgical plans. In a case of X -linked hereditary deafness, optimal angles and rotation maneuvers for cochlear implant insertion reduced operating time by 93 min compared to the previous contralateral side surgery. Two cochlear implant cases planned for subtotal petrosectomy approach due to aberrant anatomy were successfully approached through routine mastoidectomy. The cholesteatoma cases were successfully exteriorized without necessitating partial labyrinthectomy or labyrinthine injury. There were no complications. Conclusion: 3D printed models for simulation training, surgical planning and use intraoperatively in temporal bone surgery demonstrated significant benefits in designing approaches, development of patient -specific techniques, avoidance of potential or actual complications encountered in previous or current surgery, and reduced surgical time and costs.

Prenatal MRI plays an essential role in the evaluation of the head and neck. This article overviews technical considerations and both isolated and syndromic anomalies of the fetal calvarium, globes and orbits, ears, maxilla, mandible, and neck.

BACKGROUND AND PURPOSE: Morning glory disc anomaly (MGDA) is a congenital malformation characterized by a funnel-shaped optic disc excavation with radiating vessels and a central glial tuft. Imaging is essential to evaluate associated cephalocele and steno-occlusive vasculopathy. The goal of this study was to assess optic nerve, chiasmatic, and sphenoid bone morphology in MGDA. MATERIALS AND METHODS: This retrospective study examined all subjects with funduscopically confirmed MGDA diagnosed and imaged with brain MR imaging between 2008 and 2023. RESULTS: Thirty-two children met inclusion criteria. Ocular involvement was unilateral in 29 subjects and bilateral in 3. Segmental optic nerve enlargement ipsilateral to the MGDA was seen in 21 subjects, with 3 also demonstrating a segmental reduction in the size of the ipsilateral optic nerve. Segmental reduction in the size of the ipsilateral optic nerve was present in 3 additional subjects, one with bilateral MGDA. The optic chiasm appeared asymmetrically thickened in 21 subjects, often with deformity. The optic nerves appeared normal in signal intensity in all subjects, with faint peripheral chiasmatic enhancement in 4 of 20 patients who received contrast. Optic nerve findings were stable in 15 subjects with multiple examinations. A persistent craniopharyngeal canal was identified in 17 subjects with sphenoid cephalocele in 1 and mild inferior pituitary gland displacement in 4. Tubular or nodular nasopharyngeal lesions were seen in 10 subjects. One subject had an off-midline sphenoid bone cleft, midbrain deformity, and abnormal thickening of and enhancement around the left oculomotor nerve; the oculomotor nerve finding was present in 1 additional patient. CONCLUSIONS: MGDA often manifests with ipsilateral optic nerve thickening, leading to a potential misdiagnosis as optic glioma. MGDA is also commonly associated with a persistent craniopharyngeal canal with variable pituitary gland and infundibular deformity, cephalocele, and tubular or nodular nasopharyngeal lesions.

ObjectiveAtraumatic cerebrospinal fluid (CSF) rhinorrhea is uncommon in children and necessitates a multi-disciplinary evaluation for an etiology. Underlying osseous abnormality due to extensive or multifocal low flow vascular anomaly should be considered as a potential cause of spontaneous CSF leak. Treatment of multifocal low flow vascular anomalies may include medical and surgical approaches. In this series, we seek to determine the presenting signs and symptoms and medical and surgical treatment options for multifocal or extensive low flow vascular anomalies.MethodsA retrospective case series at a quaternary care children’s hospital was compiled. All children with CSF rhinorrhea diagnosed and treated for multifocal low flow vascular anomalies at our institution were included. A total of four patients were identified.ResultsAll four patients had delay in initial diagnosis of underlying cause of meningitis and CSF rhinorrhea. Average age at diagnosis of multifocal low flow vascular anomaly was 7 years. This was on average 4 years after initial presentation for medical attention. Treatment approach was multidisciplinary and included medical management with sirolimus and bisphosphonates as well as surgical approaches to the skull base (lateral and anterior) to prevent CSF egress.ConclusionConsideration of multifocal low flow vascular anomaly should be included in any pediatric patient presenting with CSF rhinorrhea.

PURPOSE:Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome. This study aimed to explore the prevalence of isolated IP-II, IP-II with EVA, and cases with a genetic or syndromic basis in our cohort. METHODS:From a large, multicentre database of dysplastic cochleae (446 patients, 892 temporal bones), those with imaging features of IP-II were examined in detail, including whether there was a genetic or syndromic association. RESULTS:A total of 78 patients with IP-II were identified. Among these, 55 patients had bilateral IP-II and EVA (only 12 with typical Mondini triad), 8 with bilateral IP-II and normal VA, 2 with bilateral IP-II and unilateral EVA, and 13 with unilateral IP-II (9 with unilateral EVA). Among the group with bilateral IP-II and bilateral EVA in whom genetic analysis was available, 14 out of 29 (48%) had SLC26A4 mutations and a diagnosis of Pendred syndrome, 1 had a FOXI1 mutation, and a few other genetic abnormalities; none had KCNJ10 pathogenic variants. CONCLUSION:Bilateral IP-II-bilateral EVA may be seen in the context of Pendred syndrome (SLC26A4 or FOXI1 mutations) but, in the majority of our cohort, no genetic abnormalities were found, suggesting the possibility of unknown genetic associations. IP-II in isolation (without EVA) is favored to be genetic when bilateral, although the cause is often unknown.

Purpose: Fem1 homolog B (FEM1B) acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CULLIN 2-based E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. Methods: To understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in utero electroporation assays, as well as experiments on patient's cells. Results: Five individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1BR126Q). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells. In addition, the individuals' cells exhibited signs of oxidative stress and induction of type I interferon signaling. Conclusion: Overall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation, resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.