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.

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.

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.

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.

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.

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.

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.

Medical And Surgical Management Of Orbital Cellulitis In Children.

OBJECTIVE: The purpose of this study was to identify features of orbital cellulitis that predict response to conservative treatment without surgical intervention and factors associated with a decision for surgery. PATIENTS AND METHODS: The medical files of patients diagnosed with orbital cellulitis at a tertiary medical center in central Israel between 1995 and 2010 were reviewed for clinical data, diagnosis, complications, and type of treatment. Comparison was made between patients treated with antibiotics and patients treated with antibiotics and surgery. RESULTS: Fifty-one patients (35 male) with a mean age of 6.1 years were identified. Main clinical signs included fever (mean 38.5°C), proptosis (82.3%), extraocular motility restriction (74.5%), and ocular pain (41.1%). Forty-one patients were successfully treated with antibiotics and 10 required endoscopic sinus surgery. On between-group comparison, the surgery group had severe eye pain (p = 0.009), severe proptosis (P = 0.02), longer intravenous antibiotic treatment (13.2 vs. 9.2 days, p = 0.04), and several imaging findings. Additional factors associated with surgical intervention included older children, subperiorbital abscess, larger dimension of the abscess (mean 15 mm), involvement of frontal sinuses and findings of intraorbital air bubbles. There was no visual deterioration in either group and no late sequelae. CONCLUSION: Factors associated with surgery included age older than 9 years, severe ocular pain, severe proptosis, and subperiorbital large abscess. These may be used for early identification of patients at risk of failure of only medical management.

Regression of mesenchymal hamartoma of the liver with sarcoma chemotherapy.

We present a young patient with metastatic Ewing sarcoma that had hepatic lesions. As we were unaware of hepatic metastases in Ewing sarcoma, liver biopsy was performed. The pathologic findings were diagnostic of mesenchymal hamartoma of the liver. Surprisingly, the combined chemotherapy for metastatic sarcoma resulted in almost complete resolution of the hamartoma in the liver. This option may be useful in extreme cases when resection is not feasible.

Treatment of lymphatic malformations: a more conservative approach.

BACKGROUND/PURPOSE: Lymphatic malformation is a benign disfiguring lesion of the neck and face in children. This study investigated the application and outcome of different modes of treatment. METHODS: The medical files of all children with lymphatic malformation of the head and neck attending a tertiary medical center in 1999 to 2010 were reviewed. Findings were compared by treatment: surgery, OK-432 sclerotherapy, or observation. RESULTS: The study group included 46 patients, most (65%) with macrocystic disease. Twenty were treated by OK-432 sclerotherapy, and 15, by surgery; 11 (with minor disfigurement) were observed only. Mean follow-up time was 2.4 years. Complete removal or complete response to treatment was achieved in 67% of the surgery group and 45% of the OK-432 group; fair results (>50% reduction in swelling) were achieved in 20% and 50%, respectively. Sclerotherapy failure did not interfere with subsequent surgery. Complete spontaneous regression occurred in 5 patients under observation only. CONCLUSIONS: OK-432 sclerotherapy is associated with good aesthetic results in children with lymphatic malformation. Observation alone is sometimes sufficient. Surgery should be reserved for cases requiring a histologic diagnosis, microcystic disease, patients with an urgent clinical problem (eg, airway obstruction), and sclerotherapy failures.

Preoperative Visual Loss is the Main Cause of Irreversible Poor Vision in Children with a Brain Tumor.

The purpose of this study was to characterize the severe postoperative irreversible visual loss induced by optic neuropathy in some children with a brain tumor. The computerized database (2003-2008) of a neuro-ophthalmology service of a major pediatric tertiary center was reviewed for all children with severe irreversible visual loss (counting fingers or less) due to brain-tumor-related optic neuropathy at their last follow-up examination. Data on age, gender, etiology, initial symptoms, and signs, visual acuity before and after surgery and at last examination, neuroimaging findings, and treatment were collected. Of 240 children, 198 were operated. Of those, 10 (5%, 5 boys and 5 girls) met the study criteria. Data for the initial visual examination were available for eight children: one had binocular blindness (uncertain light perception, counting fingers); three had monocular blindness already at diagnosis (no light perception, counting fingers, no fixation); three had 6/60 vision in the worse eye; and one had good vision bilaterally (6/10). Four children had direct optic nerve compression, four papilledema, and three gliomas. Four children (40%; with craniopharyngioma, pineal germinoma, or posterior fossa tumor) exhibited a rapid deterioration in vision after tumor depression (one direct optic nerve compression and three increased intracranial pressure); two had monocular visual loss postoperatively; vision remained stable in four (after ≥5 follow-up visits), but did not improve. This study shows that tumor-related optic neuropathy may be associated with marked visual loss inspite of successful tumor resection; in 40% of children, the deterioration occurs perioperatively. Direct compression is the main cause of visual loss, while papilledema usually resolved without visual sequelae. However, autoregulatory changes may be responsible for rapid visual loss following decompression for chronic papilledema. Clinicians need reminding about the problem of postoperative visual loss and we speculate on how it can be avoided.

Invasive fungal infections in pediatric oncology.

BACKGROUND: Data on the epidemiology and outcome of invasive fungal infections in children with cancer are limited. The aim of the study was to delineate the epidemiologic, clinical features, risk factors, and outcome of invasive fungal infections in this population. PROCEDURE: The medical records of all children with malignancies diagnosed with an invasive fungal infection in 1998-2006 at a tertiary pediatric medical center were reviewed for demographic, clinical, and laboratory data. Invasive fungal infection was diagnosed according to the latest EORTC/MSG criteria. RESULTS: Of the 1,047 children hospitalized in the hematology/oncology department during the study period, 75 (7.2%) were diagnosed with a proven (n = 16, 21.3%), probable (n = 18, 24%), or possible (n= 41, 54.7%) invasive fungal infection. Fifteen (20%) had candidemia (non-albicans in 60%), and 60 (80%) had a mold infection (non-Aspergillus in 55%). Crude mortality was 21.7%. The most common underlying diseases were myeloid leukemia (n = 26, 34.7%) and acute lymphoblastic leukemia (n = 24, 32%). Compared to other malignancies, acute myeloid leukemia was significantly associated with the development of invasive fungal infections. Profound neutropenia and high treatment intensity were present in 89% and 73% of patients with IFI respectively. CONCLUSIONS: The current mortality rates of invasive fungal infection in children with cancer are lower than previously reported in children and adults. However, the proportion of non-albicans candidemia is increasing, and non-Aspergillus molds are emerging as important pathogens, which may have important implications for prophylaxis and empiric therapy. Improved prevention, early detection, and advanced treatment strategies are needed to improve the outcome.

Familial hydrocephalus with normal cognition and distinctive radiological features.

Hydrocephalus is a clinically and genetically heterogeneous condition. Individuals with posterior fossa abnormalities have an increased risk of developing hydrocephalus. The Dandy-Walker malformation, Dandy-Walker variant, and mega-cisterna magna (MCM) seem to represent a continuum of developmental anomalies of the posterior fossa. Here we describe the natural clinical history and the radiological features of a family with autosomal or X-linked dominant inheritance of MCM and hydrocephalus of variable severity. The affected family members demonstrate similar structural brain abnormalities including midline cyst, colpocephaly, MCM with a large posterior fossa and minimal vermian hypoplasia. The cognitive development of the affected individuals is normal. L1CAM and FOXC1 gene involvement in the pathogenesis of the disease in this family was excluded. The rare possibility of autosomal dominant or X-linked dominant inheritance and variable penetrance and expressivity must always be considered in genetic counseling of families with hereditary hydrocephalus.

Long-term ophthalmological follow-up of children with Parinaud syndrome.

BACKGROUND AND OBJECTIVE: To assess the long-term ophthalmological outcome of Parinaud syndrome. PATIENTS AND METHODS: The files of 6 children with tumor-related Parinaud syndrome diagnosed and observed from 2000 to 2007 were reviewed. All had papilledema indicating increased intracranial pressure. RESULTS: Mean presentation-to-diagnosis delay was 3.6 weeks. Treatment consisted of surgical shunting and complete or partial resection with adjuvant chemotherapy (n = 4) and radiation (n = 3). Visual acuity remained stable or improved in 8 of 9 eyes with 20/30 visual acuity at diagnosis; improved bilaterally in 1 patient from 20/100 to 20/25; and deteriorated bilaterally in 1 patient from 20/30 and 20/200 to counting fingers and hand motions, respectively. The most improvement was achieved within 4 months. Findings at follow-up (mean: 4.2 years) included up gaze limitation (minimal in 2 patients), abnormal convergence, convergence retraction nystagmus, and light-near dissociation. One child had bilateral optic atrophy. CONCLUSION: Children with tumor-related Parinaud syndrome tend to have subtle but measurable residual ophthalmological findings years after diagnosis and treatment.

Giant cystic lesion in neurofibromatosis.

In the case of an asymptomatic 10-year-old girl with neurofibromatosis type 1, a concomitant cystic brain lesion was demonstrated on cranial magnetic resonance imaging. The nature of these cysts is unknown: they may represent cellular degeneration of the lesions imaged as unidentified bright objects, cystic cortical dysplasia, or giant Virchow-Robin spaces. The novel finding in this child of coexisting unusual cystic lesion and neurofibromatosis could be coincidental; however, recent report of an asymptomatic cystic lesion in two patients with neurofibromatosis suggests otherwise.

Optic-pathway glioma: natural history demonstrated by a new empirical score.

The optic pathway glioma uniquely involves the optic pathway in a relatively constant pattern, allowing for recurrent measurements of its extent and comparison within patients with the same diagnosis. Its natural history, however, is unpredictable. We sought to formulate an empirical score to quantify optic-pathway involvement and disease course. The sample comprised 23 children with a diagnosis of optic-pathway glioma who attended a pediatric tertiary medical center from 1975-2004 and underwent at least two annual magnetic resonance imaging examinations over an average of 7 years. Each scan was evaluated for the larger diameters of intraorbital and retro-orbital parts of the optic nerve, chiasma, and optic tract. Findings were analyzed by time from diagnosis. In untreated children, tumors generally remained stable for about 3 years, and diminished thereafter. Children with neurofibromatosis-1 had a better course than children with sporadic disease. Young children fared similarly to older ones. Worse outcomes occurred in children who eventually required treatment; this group might have done better with earlier diagnosis, and requires careful follow-up. Our new empirical score can define the natural history of optic-pathway gliomas, and identify prognostic factors. It may help identify tumors in neurofibromatosis-1 children who potentially require treatment.

Unusual clinical presentation of tuberless tuberous sclerosis complex.

Cortical tubers are the hallmark of tuberous sclerosis. Their presence is expected on brain imaging, especially when seizures begin before 1 year of age with concomitant significant developmental delay. Increased tuber counts have been reported to be associated with seizures and poor cognitive outcome. We present a 3-year-old girl with intractable seizures that started as infantile spasms at 2 months of age and who was diagnosed with clinically definitive tuberous sclerosis. Poor prognostic signs included multiple seizure types, seizure onset before 1 year of age, and multifocal electroencephalographic abnormalities. However, on repeated brain magnetic resonance imaging scans, the known radiological findings associated with tuberous sclerosis complex were absent, raising a diagnostic dilemma. Therefore, genetic analysis was performed. A mutation was detected in the TSC2 gene, confirming the diagnosis. To the best of our knowledge, this is the first reported case of tuberless tuberous sclerosis complex associated with intractable epilepsy and developmental delay.