A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.

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.

Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study.

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.

3D printed temporal bones for preoperative simulation and planning.

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.

The spectrum of cochlear malformations in CHARGE syndrome and insights into the role of the CHD7 gene during embryogenesis of the inner ear.

PURPOSE: We reviewed the genotypes and the imaging appearances of cochleae in CHARGE patients from two large tertiary centres and analysed the observed cochlear anomalies, providing detailed anatomical description and a grading system. The goal was to gain insight into the spectrum of cochlear anomalies in CHARGE syndrome, and thus, in the role of the CHD7 gene in otic vesicle development. METHODS: We retrospectively reviewed CT and/or MR imaging of CHARGE patients referred to our institutions between 2005 and 2022. Cochlear morphology was analysed and, when abnormal, divided into 3 groups in order of progressive severity. Other radiological findings in the temporal bone were also recorded. Comparison with the existing classification system of cochlear malformation was also attempted. RESULTS: Cochlear morphology in our CHARGE cohort ranged from normal to extreme hypoplasia. The most common phenotype was cochlear hypoplasia in which the basal turn was relatively preserved, and the upper turns were underdeveloped. All patients in the cohort had absent or markedly hypoplastic semicircular canals and small, misshapen vestibules. Aside from a stenotic cochlear aperture (fossette) being associated with a hypoplastic or absent cochlear nerve, there was no consistent relationship between cochlear nerve status (normal, hypoplasia, or aplasia) and cochlear morphology. CONCLUSION: Cochlear morphology in CHARGE syndrome is variable. Whenever the cochlea was abnormal, it was almost invariably hypoplastic. This may shed light on the role of CHD7 in cochlear development. Accurate morphological description of the cochlea contributes to proper clinical diagnosis and is important for planning surgical treatment options.

Guidelines for magnetic resonance imaging in pediatric head and neck pathologies: a multicentre international consensus paper.

The use of standardized imaging protocols is paramount in order to facilitate comparable, reproducible images and, consequently, to optimize patient care. Standardized MR protocols are lacking when studying head and neck pathologies in the pediatric population. We propose an international, multicenter consensus paper focused on providing the best combination of acquisition time/technical requirements and image quality. Distinct protocols for different regions of the head and neck and, in some cases, for specific pathologies or clinical indications are recommended. This white paper is endorsed by several international scientific societies and it is the result of discussion, in consensus, among experts in pediatric head and neck imaging.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies.

MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs∗86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.

Neuroimaging in Kabuki syndrome and another KMT2D-related disorder.

Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.

Success of Nonsedated Neuroradiologic MRI in Children 1-7 Years Old.

BACKGROUND. MRI use and the need for monitored anesthesia care (MAC) in children have increased. However, MAC is associated with examination delays, increased cost, and safety concerns. OBJECTIVE. The purpose of this study was to evaluate the success rate of nonsedated neuroradiologic MRI studies in children 1-7 years old and to investigate factors associated with success. METHODS. We retrospectively reviewed data from our institutional nonsedated MRI program. Inclusion criteria were outpatient nonsedated MRI referral, age 1-7 years old, and neuroradiologic indication. Exclusion criteria were MRI examinations for ventricular checks and contrast material use. Success was determined by reviewing the clinical MRI report. We recorded patient age and sex, type of MRI examination (brain, spine, craniospinal, head and neck, and brain with MRA), protocol length, presence of child life specialist, video goggle use, and MRI appointment time (routine daytime appointment or evening appointment). We used descriptive statistics to summarize patient demographics and clinical data and logistic regression models to evaluate predictors of success in the entire sample. Subset analyses were performed for children from 1 to < 3 years old and 3 to 7 years old. RESULTS. We analyzed 217 patients who underwent nonsedated MRI examinations (median age, 5.1 years). Overall success rate was 82.0% (n = 178). The success rates were 81.4% (n = 127) for brain, 90.3% (n = 28) for spine, 71.4% (n = 10) for craniospinal, 66.7% (n = 6) for head and neck, and 100% (n = 7) for brain with MRA. Age was significantly associated with success (odds ratio [OR], 1.33; p = .009). In children 1 to < 3 years old, none of the factors analyzed were significant predictors of success (all, p > .48). In children 3-7 years old, protocol duration (OR, 0.96; 95% CI, 0.93-0.99; p = .02) and video goggle use (OR, 6.38; 95% CI, 2.16-18.84; p = .001) were significantly associated with success. CONCLUSION. A multidisciplinary approach with age-appropriate resources enables a high success rate for nonsedated neuroradiologic MRI in children 1-7 years old. CLINICAL IMPACT. Using age as the primary criterion to determine the need for MAC may lead to overuse of these services. Dissemination of information regarding nonsedated MRI practice could reduce the rate of sedated MRI in young children.

Magnetic resonance features and cranial nerve involvement in pediatric head and neck rhabdomyosarcomas.

PURPOSE: Rhabdomyosarcoma (RMS) is a malignant tumor frequent in children. The frequency and characteristics of cranial nerve involvement in pediatric head and neck (H&N) RMS have been scarcely reported. The aim of this study is to review a large cohort of pediatric head and neck RMS with an emphasis on cranial nerve involvement. METHODS: We retrospectively reviewed H&N RMS cases from 3 tertiary hospitals over a 10-year period. Cranial nerve involvement was defined as radiologically apparent tumor extension along a nerve and/or the presence of secondary signs. Scans were reviewed by two pediatric neuroradiologists, blinded to clinical data. RESULTS: A total of 52 patients met the inclusion criteria. Histologically, 39/52 were embryonal RMS, while 13/52 were alveolar RMS. Regional lymph nodes metastases were present in 19.2%. Cranial nerve involvement was present in 36.5%. Nerves were mainly involved as a direct extension of the mass through skull base foramina or after invasion of cavernous sinus, Meckel's cave, orbital apex, or stylomastoid foramen. CONCLUSION: Cranial nerve involvement is frequent in pediatric head and neck RMS and occurs secondary to "geographic" invasion due to direct extension through skull base foramina or cavernous sinus. These tumors never showed distant perineural metastatic disease as is seen in cases of adult head and neck carcinomas. This implies a different biological interaction between the nerves and these tumors in comparison to adult H&N tumors.

Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases.

Systemic therapy for pediatric desmoid tumors has been challenged by a lack of high-quality clinical evidence and potential adverse effects. The gamma-secretase inhibitor nirogacestat has shown promising efficacy in adults. We report four cases of pediatric and young adult desmoid tumor patients (three with familial adenomatous polyposis [FAP] syndrome) who received nirogacestat on compassionate use. After a median of 13.5 months (range 6-18), three had durable benefit: a complete response (Case 1); a partial response (Case 2); stable disease (Case 3). The fourth had disease progression after a partial response. No patient experienced grade 3 or 4 adverse events.

Altered White Matter Organization in the TUBB3 E410K Syndrome.

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.

Diagnostic equivalency of fast T2 and FLAIR sequences for pediatric brain MRI: a pilot study.

BACKGROUND: Faster and motion robust magnetic resonance imaging (MRI) sequences are desirable in pediatric brain MRI as they can help reduce the need for monitored anesthesia care, which is a costly and limited resource that carries medical risks. OBJECTIVE: To evaluate the diagnostic equivalency of commercially available accelerated motion robust MR sequences relative to standard sequences. MATERIALS AND METHODS: This was an institutional review board-approved prospective study. Subjects underwent a clinical brain MRI using conventional multiplanar images at 3 Tesla followed by fast axial T2 and FLAIR (fluid-attenuated inversion recovery) sequences optimized for an approximately 50% reduction in acquisition time. Conventional and fast images from each subject were reviewed by two blinded pediatric neuroradiologists. The readers evaluated the presence of 12 findings. Intra-observer agreement was estimated for fast versus conventional sequences. For each set of sequences, interobserver agreement calculations and chi-square tests were used to evaluate differences between fast and conventional acquisitions. An independent third reader reviewed the intra-observer discrepancies and adjudicated them as being more conspicuous on fast sequence, conventional sequence or the equivalent. The readers also were asked to rate motion artifacts with a previously validated score. RESULTS: Images from 77 children (mean age: 11.3 years) were analyzed. Intra-observer agreement (fast versus conventional) ranged between 89.2% and 92.3%. Interobserver agreement ranged between 86.1% and 88.4%. Interobserver agreement was significantly higher for conventional FLAIR relative to fast FLAIR for small (<5 mm) foci of T2 in the white matter. Otherwise, interobserver agreement was not different between the fast and conventional sequences. For awake subjects, fast sequences had significantly fewer artifacts (P<0.05). CONCLUSION: Conventional T2 and FLAIR sequences can be optimized to shorten acquisition while maintaining diagnostic equivalency. These faster sequences were also less susceptible to motion artifacts.

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

Neuroimaging of Children With Surgically Treated Hydrocephalus: A Practical Approach.

OBJECTIVE: Children with surgically treated hydrocephalus commonly undergo multiple neuroimaging studies. The purpose of this article is to share an experience with use of the as low as reasonably achievable (ALARA) principle to guide the imaging approach to these patients. CONCLUSION: A reasonably achievable strategy for minimizing ionizing radiation in patients with surgically treated hydrocephalus includes rapid-sequence MRI and judicious use of dose-optimized head CT. Rapid-sequence MRI is particularly useful in the care of patients who have undergone endoscopic third ventriculostomy.

Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features.

PURPOSE: Chronic nonbacterial osteomyelitis (CNO) is a focal sterile inflammatory osteitis in children that most commonly develops in the long bones, but can occur in any bone. The disease course is variable, ranging from acute and self-resolving isolated lesions to chronic recurrent multifocal osteomyelitis (CRMO), which is frequently associated with extraosseous inflammatory disease. The purpose of this study was to present our clinical experience with CNO of the mandible in children. The specific aims were to 1) document the clinical characteristics, radiographic findings, and histologic features of CNO and 2) determine the percentage of our sample with multifocal disease (CRMO). MATERIALS AND METHODS: This is a retrospective case series of patients with mandibular CNO. To be included, patients had to have a mandibular lesion radiographically consistent with osteomyelitis without infection, onset before aged 18 years, and complete records. Medical records were reviewed for history, clinical features, imaging, and pathology. Descriptive data were summarized. RESULTS: The sample included 22 patients (13 female and 9 male patients) with disease onset at a mean age of 9.05 ± 2.4 years. On presentation, all patients reported mandibular pain and swelling, and 45% had trismus. All had clinical and/or radiographic findings of multifocal intraosseous disease and/or extraosseous inflammatory lesions. Of the patients, 12 (54%) had a documented family history of autoimmune or autoinflammatory disease and 15 (68%) had elevated erythrocyte sedimentation rates during a flare. Computed tomography scans typically showed expansion of the affected mandible with sclerosis of the medullary space, small foci of poorly defined lytic destruction with a lamellated periosteal reaction, and swollen muscles of mastication. Four distinct histologic features were noted including parallel and interconnected osteoid seams, atypical osteoid, areas of woven bone and hypocellular fibroblastic stroma resembling fibrous dysplasia, and patchy nodular fibrosis. CONCLUSION: Pediatric CNO of the mandible has characteristic radiographic and pathologic features and is usually found as one of multiple disease foci in CRMO rather than as an isolated lesion.

Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.

Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.