Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

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.

Single-institution Series of Hirayama Disease in North America.

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.

Non-Syndromic Sensorineural Hearing Loss in Children.

Pediatric hearing loss is common with significant consequences in terms of language, communication, social and emotional development, and academic advancement. Radiological imaging provides useful information regarding hearing loss etiology, prognosis, therapeutic options, and potential surgical pitfalls. This review provides an overview of temporal bone imaging protocols, an outline of the classification of inner ear anomalies associated with sensorineural hearing loss and illustrates some of the more frequently encountered and/or important causes of non-syndromic hearing loss.

Conductive Hearing Loss in Children.

A variety of congenital and acquired disorders result in pediatric conductive hearing loss. Malformations of the external auditory canal are invariably associated with malformations of the middle ear space and ossicles. Isolated ossicular malformations are uncommon. Syndromes associated with external and middle ear malformations are frequently associated with abnormal development of first and second pharyngeal arch derivatives. Chronic inflammatory disorders include cholesteatoma, cholesterol granuloma, and tympanosclerosis.

Syndromic Hearing Loss in Children.

Pattern recognition of specific temporal bone radiological phenotypes, in association with abnormalities in other organ systems, is critical in the diagnosis and management of syndromic causes of hearing loss. Several recent publications have demonstrated the presence of specific radiological appearances, allowing precise genetic and/or syndromic diagnosis, in the right clinical context. This review article aims to provide an extensive but practical guide to the radiologist dealing with syndromic causes of hearing loss.

CTNNB1 and APC Mutations in Sinonasal Myxoma : Expanding the Spectrum of Tumors Driven By WNT/ß-catenin Pathway.

Sinonasal myxoma (SNM) is a rare, benign mesenchymal neoplasm with distinct clinicopathologic features and aberrant nuclear localization of ß-catenin by immunohistochemistry. The molecular underpinnings have been linked to that of a "myxoid variant" of desmoid fibromatosis. Herein, we describe a series of 8 cases of SNM and propose clinical and biologic differences compared with desmoid fibromatosis. Our patient cohort is comprised of 5 males and 3 females (age range: 10 mo to 12 y), 6 of whom are aged less than or equal to 24 months. All presented with facial swelling, reflecting lesions involving the maxillary bone, and all underwent resection. All tumors were variably cellular and comprised of bland spindled to stellate cells in a profusely myxoid background with diffuse nuclear ß-catenin expression. All cases of SNM were analyzed by next-generation sequencing using the Oncopanel assay. Three cases failed sequencing, 2 of 5 successful cases exhibited exon 3 CTNNB1 alterations involving the ubiquitin recognition motif, and 3 had adenomatous polyposis coli ( APC ) deletions. One patient had APC germline testing which was negative. No germline testing was available for the remaining 7 patients. Follow-up data over a range of 1 month to 23 years was available for 7 of the 8 SNMs. One case patient had local recurrence, and all were alive without evidence of disease. This is in contrast to the high recurrence rate typically seen in desmoid fibromatosis, particularly after resection. Our findings expand the spectrum of tumors with underlying WNT/ß-catenin pathway and highlight the histologic, clinical, and genetic differences of SNM compared with desmoid fibromatosis. APC deletion raises the possibility of underlying germline alteration and familial adenomatous polyposis.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

A multi-disciplinary team approach to pediatric malignant mandibular tumors.

OBJECTIVE: Mandibular tumors in the pediatric population are rare. These malignancies are variable in their histology, and combined with their rarity, has made it difficult to describe their clinical course, and treatment guidelines. The aim of this paper is to describe the experience of Boston Children's Hospital, a pediatric tertiary referral center, with treating malignant mandibular malignancies, as well as provide multi-disciplinary team approach in managing this clinical entity. METHODS: A retrospective search was performed for mandibular malignancies in pediatric patients between 1995 and 2020 via the pathological database at Boston Children's Hospital. Only patients with malignant solid mandibular neoplasms were included, leaving 15 patients for final analysis. RESULTS: The median age at presentation was 10.1 ± 10.3 years. Nine of 15 patients (60%) presented with jaw mass which was the most common clinical presentation. The most commonly identified histological diagnosis was rhabdomayosarcoma and osteosarcoma (n = 4, 26% each). A mandibulectomy was performed in 12 (80%) cases. Reconstruction of the mandible was performed using a fibular free flap in 6 (40%) cases, and a plate in 3 (20%) cases. Mean follow-up was 4.6 ± 4.9 years. CONCLUSION: Malignant tumors most commonly present with a jaw mass, however asymptomatic and incidental presentations follow closely and pathologies can vary greatly. Surgical resection and reconstruction is often indicated, multidisciplinary tumor board review is required to determine when children are best treated with neo-/adjuvant treatment with chemo- and radiotherapy.

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.

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.

Magnetic Resonance Imaging Features and Clinical Findings in Pediatric Idiopathic Intracranial Hypertension: A Case-Control Study.

The purpose of this study is to identify salient magnetic resonance imaging (MRI) findings of pediatric IIH, to determine the relevance of these findings with regard to disease pathogenesis, and to relate these findings to the clinical presentation towards identification of risk factors of disease. A retrospective, a case-control study of 38 pediatric patients with and 24 pediatric patients without IIH from the ophthalmology department at a tertiary care center was performed. Clinical data, including ophthalmic findings and lumbar puncture results, were recorded. Neuroimaging, including both MRI and magnetic resonance venography (MRV), was evaluated for perioptic subarachnoid space diameter enlargement, posterior globe flattening, optic nerve head protrusion, empty or partially empty sella turcica, dural venous sinus abnormalities, skull base crowding, and prominent arachnoid granulations. Compared with controls, IIH patients had larger perioptic subarachnoid space diameters, higher incidences of posterior globe flattening, protrusion of the optic nerve heads, an empty sella turcica, and dural venous sinus abnormalities. A perioptic subarachnoid space diameter of ≥5.2 mm was identified as an independent predictor of IIH (p < 0.001) with sensitivity of 87% and specificity of 67%. Several significant MRI findings in pediatric IIH were identified. Using a model that uniquely incorporated clinical and MRI findings at presentation, we provide a framework for risk stratification for the diagnosis of pediatric IIH which may be utilized to facilitate diagnosis. Future prospective work is needed to further validate the model developed in this study.

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and ß tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

Facial Paralysis From Post-transplant Lymphoproliferative Disorder.

OBJECTIVE: We report a case of facial paresis and profound hearing loss from post-transplant lymphoproliferative disorder (PTLD) in a pediatric patient with neuroblastoma. PATIENT: Three-year-old boy with rapidly progressive right facial paresis and sensorineural hearing loss. High-risk neuroblastoma had been diagnosed 1 year earlier, treated with chemotherapy and resection of the adrenal primary tumor. Two months after two autologous hematopoietic stem cell transplantations (HSCT), the patient developed facial paralysis. Magnetic resonance imaging (MRI) showed bilateral progressive internal auditory canal (IAC) enhancing lesions with a mass lesion on the right and wispy enhancement on the left and enhancement within the right cochlea. Lumbar puncture (LP) was positive for Epstein-Barr virus (EBV) making the diagnosis of PTLD most probable. Biopsy of the right IAC lesion was deferred because of potential procedural risks including intradural spread of tumor or fungus. The patient was treated with anti-fungal therapy and systemic rituximab without improvement. Subsequent intrathecal rituximab resulted in improvement of lesions on MRI and clearance of EBV from the cerebrospinal fluid (CSF). INTERVENTIONS: Mastoidectomy for biopsies from the mastoid and middle ear. Intrathecal treatment with rituximab. MAIN OUTCOME MEASURES: Imaging assessment of IAC lesion, CSF EBV titers, facial nerve function. RESULTS: Gradual resolution of IAC mass lesions, remission of PTLD, and facial improvement from House-Brackmann score of 4 to 3. CONCLUSIONS: PTLD causing facial paresis after autologous HSCT has not been previously reported and may be considered in the differential diagnosis of lesions causing facial paresis in patients who have received a stem cell or solid organ transplant.

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.

Role of Surgery in Rhabdomyosarcoma of the Head and Neck in Children.

OBJECTIVES: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The goal of this research is to analyze the role of surgery in the management of pediatric parameningeal (PM) and non-PM head and neck RMS (HNRMS). STUDY DESIGN: Retrospective review. METHODS: Retrospective chart review of patients <20 years of age treated for HNRMS between 1970 and 2015. Clinical presentation, tumor characteristics, treatment, recurrence, follow-up, and outcome data were collected. RESULTS: Of 97 patients with HNRMS, 56% were male. Overall median (IQR: interquartile range) age at diagnosis was 5.8 (3.3-9.8) years. Sixty-five patients (67%) had PM tumors. Of 75 patients with histologic subtype identified, 51 (53%) had embryonal and 20 (21%) alveolar RMS. Almost all patients received chemotherapy (99%) and radiotherapy (95%). Forty-four patients (45%) underwent surgery. Surgery was more likely to be conducted in patients with lesions of a non-PM site. Median follow-up time was 3.4 years (IQR: 1.1-10.8). In 5 years of follow-up, 20% (17 of 85) died and 29% (20 of 70) had recurrence. The estimated 5-year survival rate was 72% (95% CI, 57.8, 81.5%). Surgery was associated with a reduced risk of mortality after accounting for TNM stage 4 and tumor site (adjusted HR 0.24; 95% CI, 0.07, 0.79; P = .02). The association between surgery and risk of mortality was similar in PM and non-PM tumors. CONCLUSION: A multimodal protocol for treatment including chemotherapy, surgery, and radiotherapy is the mainstay for management of children with HNRMS. While surgery is more commonly used to treat non-PM HNRMS, patients who are able to undergo surgery have significantly higher 5-year survival. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E984-E992, 2021.

Desmoid tumors of the head and neck in the pediatric population: Has anything changed?

INTRODUCTION: Pediatric head and neck desmoid tumors are rare neoplasms that can cause significant morbidity due to infiltration of vital anatomic structures. The goal of this study is to review presentation, evaluation, and management of these tumors. METHODS: Retrospective study of children with head and neck desmoid tumors treated from 1999 to 2018 and literature review. RESULTS: 11 patients (5 boys, 6 girls) were included. Presentation included firm neck mass (n = 8), trismus (n = 2) and tongue lesion (n = 1). All patients had preoperative imaging with CT (n = 2), MRI (n = 1) or both (n = 8). Five patients underwent needle biopsy, five had open biopsy and one was diagnosed on pathology from primary excision. Seven patients were treated by primary surgical resection, with positive surgical margins in six cases due to proximity to vital neurovascular structures. None needed chemotherapy, had disease recurrence or progression. Three patients with unresectable disease were treated with chemotherapy. One patient was monitored with imaging without any treatment and did not have disease progression. Follow-up ranged from 6 months to 6 years (median 21 months). Ten patients (7 surgical, 2 chemotherapy, 1 observation) were either disease-free or had stable disease at last follow-up. CONCLUSION: Pediatric head and neck desmoid tumors, though rare and histologically benign, are locally infiltrative and aggressive. When feasible, surgical treatment results in good disease control despite positive margins. A balance between achieving negative margins and minimizing functional deficits should be considered. Chemotherapy can be successfully utilized in patients where surgery entails a high risk of morbidity and mortality.