Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin-Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti-Interleukin-1 Therapy.

OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS), also known as NLRP3-associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain-of-function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin-1ß (IL-1ß). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal-dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn). METHODS: We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5). RESULTS: The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain-of-function variant. Administration of IL-1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. CONCLUSION: Our findings highlight the crucial role of early diagnosis and treatment with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high- and ultrahigh-frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Unilateral Choanal Atresia Presenting With Congenital Respiratory Distress and Recurrent Cyanotic Episodes.

Congenital unilateral choanal atresia (CA) is not considered an emergent condition and should not cause respiratory distress in the newborn. Therefore, surgical repair of unilateral CA is usually delayed. This description of a newborn with congenital unilateral CA that caused significant respiratory distress, recurrent cyanotic episodes, and severe feeding difficulties highlights an exception to that rule.

Post-operative MRI detection of residual cholesteatoma in pediatric patients - The yield of serial scans over a long follow-up.

OBJECTIVES: Non-echo-planar diffusion weighted magnetic resonance imaging (Non-EPI DWI MRI) is commonly used for follow-up after cholesteatoma surgery. MRI has a critical role in the evaluation of residual disease, where physical examination will commonly demonstrate an intact tympanic membrane. The aim of our study was to assess the timing of residual cholesteatoma identification on serial MRI scans and the yield of MRI follow up after canal wall up tympano-mastoidectomy. METHODS: A retrospective chart review of children that underwent canal wall up tympano-mastoidectomy due to cholesteatoma in Schneider Children's Medical Center during 2004-2016, and were followed up both clinically and with MRI. RESULTS: Seventy-seven children (89 ears) were included, who altogether underwent 166 surgeries (77 revisions). Average follow-up was 66 ± 34.4 months. During follow up, 244 scans were performed; 19 cases of residual disease were diagnosed by MRI and confirmed in surgery. The mean time from surgery and an MRI positive for residual disease was 29.7 ± 16 months (range: 10-66). In 9/19 cases (47%), at least one negative MRI preceded the scan positive for residual disease, and in 4 cases at least two initial scans were negative. CONCLUSIONS: MRI plays an important role in the diagnosis of residual disease after cholesteatoma surgery. In our cohort. Almost half of the cases diagnosed with residual disease had at least one negative scan prior to the positive one, emphasizing the importance of close radiological follow-up with serial scans after surgery.

Focal Epilepsy in Individuals with Laron Syndrome.

OBJECTIVE: The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS). METHODS: Data were retrieved from medical records of a single-center cohort of 75 patients with LS. RESULTS: We describe for the first time 4 patients with concomitant focal epilepsy and LS. Two of them experienced episodes of status epilepticus. Electroencephalogram examination in all 4 patients showed interictal epileptiform discharges in the temporal regions. Three achieved long-term seizure freedom on antiseizure medications. CONCLUSION: Patients with LS may be at risk of developing focal epilepsy, which seems to be unrelated to hypoglycemic episodes in childhood.

Congenital cholesteatoma: Clinical features and surgical outcomes.

OBJECTIVES: A typical presentation of congenital cholesteatoma (CC) is asymmetric conductive hearing loss (CHL). As CHL is usually associated with middle ear effusion, diagnosis of CC is frequently delayed. This study aimed to describe the clinical characteristics, treatment and outcomes of children with CC. METHODS: The medical files of children diagnosed with CC at a large tertiary pediatric medical center during 2000-2019 were reviewed. The primary outcome measures were: presenting symptoms, surgical findings, stage of disease, recurrence rate and hearing outcome. Imaging findings and the size of mastoid air cells were assessed in CT scans. RESULTS: Thirty-nine children were diagnosed with CC. The presenting symptom was unilateral CHL in 85%, with an average speech reception threshold of 41.5 ± 13.7 dB in the affected ear. The mean time from first symptoms to diagnosis was 1.3 years. The surgical approach was exploratory tympanotomy in 25% and canal wall up mastoidectomy in 69%. Seventy percent of the children presented with Potsic stage III-IV. The mean postoperative speech reception threshold was 26.4 ± 12.2 dB (P = 0.002). Recurrence of cholesteatoma occurred in 38% of the patients, mostly in stage III-IV. Mastoid air cell size was significantly smaller on the affected than the unaffected side. CONCLUSIONS: In children with persistent unilateral or asymmetric conductive hearing loss, CC should be suspected. Late diagnosis of CC is associated with a high recurrence rate. This highlights the need to promote awareness to the disease among primary physicians in the community health care system.

Yield of Brain Magnetic Resonance Imaging in Epilepsy Diagnosis from 1998 to 2020: A Large Retrospective Cohort Study.

BACKGROUND: We aimed to find the clinical significance of brain abnormalities on magnetic resonance imaging (MRI) in epilepsy and the lateralization of these findings with electroencephalogram (EEG). METHODS: We retrospectively analyzed the results of all EEGs and brain MRIs of 600 consecutive epilepsy patients from 1998 to 2020. RESULTS: Data were available for 563 cases (267 females). Ninety percent of the patients were 18 years old or younger. A total of 345 patients (61.3%) had focal epilepsy, 180 (32%), generalized, and 38 (6.7%), inconclusive. In 187 (33.2%), the first MRI was abnormal and in 81 (out of 108 repeated MRI), the second was pathological. The most frequent brain abnormalities were cortical dysplasia in 41 (18.1%), other structural abnormalities in 25 (11%), various phacomatoses in 23 (10.1%), and mesial temporal sclerosis in 17 (7.5%). Among 226 patients with abnormal MRI, 171 (75.6%) had focal epilepsy when compared with 36 (15.9%) with generalized epilepsy (p <0.001). In 121 patients (53.5%), the result of the abnormal MRI contributed significantly to the understanding of the epilepsy etiology. The side of abnormality was lateralized to the EEG focus in 120 cases (53%); in 10/15 cases with infantile spasms (66%), MRI was significantly abnormal. In 33, in whom the first MRI was normal, a second MRI revealed a significant abnormality. CONCLUSION: Brain MRI is an important tool in epilepsy diagnosis, mainly in focal seizures and infantile spasms. A repeat MRI is mandatory in intractable focal cases to improve the yield of this test.

Orbital Lymphatic-Venous Malformation Accompanied by an Intraocular Vascular Malformation: A Rare Case Study.

Lymphatic-venous malformations (LVMs) are development defects that result in abnormal connections between the lymphatic and venous systems. The authors describe a 7-weeks-old female infant who presented with a right orbital LVM extending to the ipsilateral cheek and subconjunctiva of the right eye, intracranial developmental venous anomalies in the right cerebellum, and a significant right eye intraocular retinal vascular malformation. Since orbital LVM is usually diagnosed in infancy or childhood, pediatric ophthalmologists should actively look for intraocular vascular malformations as such findings can poorly affect a patient's vision.

Crouzon Syndrome and Acanthosis Nigricans With Fibrous Dysplasia of the Maxilla: An Unreported Suggested Triad.

ABSTRACT: The aim of this report is to describe the combination of Crouzon syndrome and acanthosis nigricans with fibrous dysplasia of the maxilla. The diagnosis of fibrous dysplasia was confirmed clinically and pathologically during Le Fort III osteotomy and midface advancement with distraction osteogenesis. Crouzon syndrome with acanthosis nigricans is a known syndrome with an incidence of 1:1,000,000. This is the first report in the literature of Crouzon syndrome and acanthosis nigricans combined with fibrous dysplasia. As all 3 pathologies are related to fibroblasts, they may be different manifestations of malfunction of a single molecular pathway. The detection of fibrous dysplasia in a patient with Crouzon syndrome and acanthosis nigricans is important because it may complicate midface osteotomies and fixation of the hardware on the bones during craniofacial surgery.

Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in TSEN54 is the most frequent. Seizures have been reported in the large majority of patients. The probability of epilepsy developing increases with age, along with difficulties in differentiating seizures from dyskinetic movements. The aim of the present report was to describe the clinical symptoms and electroencephalogram (EEG) changes over time in three patients of Israeli Arab origin with PCH2A. All three, including two siblings and their first cousin, were homozygous for the TSEN54 p.A304S mutation. The patients demonstrated profound psychomotor retardation, severe spasticity and contractures, choreoathetoid movements, and seizures. The magnetic resonance imaging (MRI) scans and EEGs were reviewed by an experienced neuroradiologist and epileptologist, respectively. The MRI scans revealed a dragonfly-like cerebellar pattern in all patients. Despite the normal early EEG findings, all patients had characteristic features of epilepsy, with tonic seizures starting in the first days to months followed by focal to bilateral tonic-clonic seizures in early childhood which continued to adolescence. In conclusion, patients with PCH2A due to the missense mutation p.A304S in TSEN54 exhibit profound psychomotor delay, movement disorders, and intractable epilepsy. An evolution of EEG abnormalities and seizure semiology occurs over time. Similar to several other genetic epileptic encephalopathies, the normal early EEG tracing does not rule out the later occurrence of epilepsy.

Clinical and imaging evaluation of Congenital Midnasal Stenosis.

OBJECTIVES: To illustrate the clinical and radiological presentation of a rare etiology of nasal obstruction in neonates, midnasal stenosis (MNS), including a comparison of nasal dimensions with those of normal infants. METHODS: We retrospectively reviewed medical charts and computerized tomography (CT) imaging of neonates with nasal obstruction diagnosed as stenosis in the midnasal area in a tertiary pediatric medical center. MNS was defined clinically by inability to visualize the middle turbinate with an endoscope despite the absence of stenosis of the anterior aperture or any gross septal deviation. CT measurements of the midnasal width were taken by an experienced neuroradiologist. We compared widths between the bony inferior turbinate to the bony septum in the narrowest area of symptomatic patients, to widths in a control group of asymptomatic children. RESULTS: Nine neonates from birth to three months old presenting with nasal obstruction, severe stertor, and blocked nasal passage at the midnasal level in endoscopic examination, were diagnosed with MNS. 6/9 had CT scans. Four had isolated unilateral stenosis, two unilateral MNS and contralateral choanal atresia, and three bilateral MNS. All patients were managed conservatively, initially with nasal saline irrigation and local steroids and topical antibiotics; Median time to resolution of symptoms was 14 days. When comparing the dimensions at the midnasal narrowest area of the stenotic group with a control group of 139 healthy children, the median bony width was 1.7 mm vs. 3.2 mm, respectively (p < 0.00001). Average dimensions according to age groups until the age of 12 months are given. CONCLUSION: In neonates with nasal obstruction, when choanal atresia and pyriform aperture stenosis are excluded, stenosis of the midnasal area should be considered. Most of these neonates can be managed conservatively. LEVEL OF EVIDENCE: 4.

Sporadic desmoid tumors in the pediatric population: A single center experience and review of the literature.

BACKGROUND/PURPOSE: We present our long experience with desmoid tumors in children. METHODS: Data were retrospectively collected from 17 children/adolescents treated for sporadic desmoid tumors at a tertiary pediatric hospital in 1988-2016. There were 10 girls and 7 boys aged 1-17years. Tumor sites included head and neck, trunk, extremity, and groin. Eight patients underwent radical resection, with complete remission in 7 and local relapse in one which was treated with chemotherapy. Four patients underwent incomplete surgical resection, three with adjuvant chemotherapy. Five patients underwent biopsy only and chemotherapy. Two of the 9 chemotherapy-treated patients also had intraarterial chemoembolization. Chemotherapy usually consisted of vincristine and actinomycin-D with or without cyclophosphamide or low-dose vinblastine and methotrexate. Two patients also received tamoxifen. RESULTS: After a median follow-up of 3.3years, 10 patients were alive in complete remission, 5 had stable disease, and 2 had reduced tumor size. Five-year overall survival was 100%, and event-free survival, 87.5%. Ten were screened for CTNNB1 mutations. CTNNB1 gene sequencing yielded mutations in 5/10 samples tested: 3 T41A, 2 S45F. There was no association of CTNNB1 mutation with clinical outcome or prognosis. CONCLUSION: Pediatric desmoid tumors are rare, with variable biologic behavior and morbidity. Treatment requires a multidisciplinary approach. LEVEL OF EVIDENCE: LEVEL IV, treatment study.

Acute Cerebellitis in Children: A Many-Faceted Disease.

Acute cerebellitis is a rare inflammatory condition. It may have a benign, self-limiting course or present as a fulminant disease resulting in severe cerebellar damage or even sudden death. We present the clinical, laboratory, and radiologic data in 9 children diagnosed with acute cerebellitis, who were identified by database search in our pediatric medical center from January 2000 to November 2014. The main presenting symptom was headache, and the main presenting sign was ataxia. Bilateral diffuse hemispheric involvement was the most common imaging finding at presentation. Mycoplasma pneumoniae was the most common infectious pathogen found. Treatment included steroids in all cases, antibiotics in 4, and intravenous immunoglobulins in 6. Six patients had a full recovery, and 3 had residual neurologic complications. Magnetic resonance imaging (MRI) is the modality of choice for diagnosis. The course of acute cerebellitis varies from a commonly benign and self-limiting disease to an occasionally fulminant disease, resulting in severe cerebellar damage or sudden death.

Re-evaluation of bone pain in patients with type 1 Gaucher disease suggests that bone crises occur in small bones as well as long bones.

Bone crises in type 1 Gaucher disease are reported in long bones and occasionally in weight bearing bones and other bones, but rarely in small bones of the hands and feet. We retrospectively examined the incidence of bone pain in patients followed at the Rabin Medical Center, Israel, before and following the initiation of enzyme replacement therapy (ERT) and evaluated them for bone crises. Of 100 type I Gaucher disease patients, 30 (30%) experienced one or more bone crises. Small bone crises represented 31.5% of all bone crises and were always preceded by crises in other bones. While the incidence of long bone crises reduced after the initiation of ERT, small bone crises increased. Almost 60% of patients with bone crises were of the N370S/84GG genotype suggesting a greater susceptibility of N370S/84GG patients to severe bone complications. These patients also underwent the greatest number of splenectomies (70.6% of splenectomised patients). Splenectomised patients showed a trend towards increased long and small bone crises after surgery. Active investigation of acute pain in the hands and feet in patients in our cohort has revealed a high incidence of small bone crises. Physicians should consider imaging studies to investigate unexplained pain in these areas.

Interictal regional delta slowing in cerebral sinus vein thrombosis.

The electroencephalographic finding of regional delta activity should alert to the possibility of an underlying structural abnormality of the brain as a cause. A 5-year-old boy, who presented with severe headache and focal seizures, had normal neurological examination and brain CT findings. The initial electroencephalograph showed focal delta activity. An emergent brain MRI disclosed a thrombosis of the left sigmoid sinus and jugular vein, but no parenchymal lesions. The regional delta activity can presumably serve as a marker for brain tissue damage in cerebral sinus vein thrombosis, and sometimes, even to add information to that gained from imaging studies.

Pattern of hearing loss following cochlear implantation.

Cochlear implantation is associated with deterioration in hearing. Despite the fact that the damage is presumed to be of sensory origin, residual hearing is usually assessed by air-conduction thresholds alone. This study sought to determine if surgery may cause changes in air- and bone-conduction thresholds producing a mixed-type hearing loss. The sample included 18 patients (mean age 37 years) with an air-bone gap of 10 dB over three consecutive frequencies and measurable masked and reliable bone-conduction thresholds of operated and non-operated ears who underwent cochlear implant surgery. All underwent comprehensive audiologic and otologic assessment and imaging before and after surgery. The air-bone gap in the treated ears was 17-41 dB preoperatively and 13-59 dB postoperatively over 250-4,000 Hz. Air-conduction thresholds in the treated ears significantly deteriorated after surgery, by a mean of 10-21 dB. Bone-conduction levels deteriorated nonsignificantly by 0.8-7.5 dB. The findings indicate that the increase in air-conduction threshold after cochlear implantation accounts for most of the postoperative increase in the air-bone gap. Changes in the mechanics of the inner ear may play an important role. Further studies in larger samples including objective measures of inner ear mechanics may add information on the source of the air-bone gap.

Brain imaging findings and social/emotional problems in Israeli children with neurofibromatosis type 1.

UNLABELLED: A potential association between brain MRI findings and social/emotional difficulties in children with neurofibromatosis type 1 (NF1) was examined. Twenty-eight children with NF1 filled in the Strengths and Difficulties Questionnaire (SDQ), and possible associations between their responses and findings in their brain MRI were sought. T2 bright foci were identified in MRI scans of 24 patients (85 %). There were no associations between the presence of the bright foci in any specific brain region and any of the SDQ scores for the emotional/behavioral measures. Male patients had significantly abnormal SDQ scores and peer problems. Patients with abnormal SDQ scores were younger than those with normal SDQ scores (mean 13.2 years vs 14.3 years, respectively; p = 0.23). A comparison of the scores obtained in ours and in another group of 11 children with NF1 yielded a significant difference between the groups. CONCLUSION: We believe that the lack of correlation between the MRI findings and the social/emotional parameters of the SDQ is another demonstration of the marked clinical variability characteristic of NF1.

Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.

We describe two pairs of siblings from a consanguineous family manifesting autosomal recessive hereditary spastic paraplegia caused by a novel mutation in the EXOSC3 gene, previously reported in pontocerebellar hypoplasia type 1. Clinical findings included delayed motor milestones, early-onset spastic paraplegia, variable cognitive disability, and cerebellar signs. Cerebral imaging demonstrated enlarged cisterna magna and mild hypoplasia and atrophy of the lower vermis with a normal pons. Genetic analysis using homozygosity mapping followed by whole exome sequencing identified homozygous c.571G>T; p.G191C mutation in the EXOSC3 gene. We suggest that EXOSC3 mutations may present not only as pontocerebellar hypoplasia type 1, but also as a complicated form of hereditary spastic paraplegia without pontine hypoplasia or atrophy.

Abnormal brain magnetic resonance imaging in two patients with Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome ascribed to an interstitial deletion in chromosome 17p11.2. Seventy percent of SMS patients have a common deletion interval spanning 3.5 megabases (Mb). Clinical features of SMS include characteristic mild dysmorphic features, ocular anomalies, short stature, brachydactyly, and hypotonia. SMS patients have a unique neurobehavioral phenotype that includes intellectual disability, self-injurious behavior and severe sleep disturbance. Little has been reported in the medical literature about anatomical brain anomalies in patients with SMS. Here we describe two patients with SMS caused by the common deletion in 17p11.2 diagnosed using chromosomal microarray (CMA). Both patients had a typical clinical presentation and abnormal brain magnetic resonance imaging (MRI) findings. One patient had subependymal periventricular gray matter heterotopia, and the second had a thin corpus callosum, a thin brain stem and hypoplasia of the cerebellar vermis. This report discusses the possible abnormal MRI images in SMS and reviews the literature on brain malformations in SMS. Finally, although structural brain malformations in SMS patients are not a common feature, we suggest baseline routine brain imaging in patients with SMS in particular, and in patients with chromosomal microdeletion/microduplication syndromes in general. Structural brain malformations in these patients may affect the decision-making process regarding their management.