Pediatric Neurofibromatosis Research Articles

NFS-06. MANAGEMENT TRENDS OF MEK INHIBITOR DERMATOLOGIC ADVERSE EVENTS FOR NEUROFIBROMATOSIS PATIENTS

Abstract BACKGROUND Selumetinib, a MEK inhibitor (MEKi), is approved for the treatment of plexiform neurofibromas (PN) in pediatric neurofibromatosis (NF) patients. In pivotal trials, nearly 70% of participants had PN shrinkage; however, 93% experienced a rash. This is the first study to characterize management trends of MEKi induced dermatologic adverse events (DAEs). METHODS Physicians treating NF patients were surveyed to assess MEKi DAE frequency, treatment, and effect on MEKi therapy. The survey was distributed using the Children’s Tumor Foundation listserv. RESULTS The survey was completed by MD/DOs (n=15) who were pediatric hematologists/oncologists (n=13) and pediatric neurologists (n=2). Physicians treated pediatric patients (n=8), adult patients (n=2), or both (n=5). Common DAEs included folliculitis (range:10-50% of treated patients; n=11), xerosis (range:1-80%;n=8), acneiform eruptions (range: 20-80%;n=10), eczematous dermatitis (range: 10-80%;n=12), paronychia (range: 10-80%;n=12), and seborrheic dermatitis (range:1-60%;n=8). Approximately half of physicians (n=8) used prophylactic DAE treatment. Prophylaxis for pre-pubertal patients included emollients (n=4), bleach baths (n=2), topical clindamycin (n=1), and doxycycline (n=1). Post-pubertal prophylaxis included emollients (n=5), doxycycline (n=5), topical clindamycin (n=4), bleach baths (n=1), and topical hydrocortisone (n=1). Almost all physicians modified MEKi treatment at least once because of a DAE (n=14), including dose hold (range: 1-25%;n=10), dose reduction (range:1-25%;n=10), and MEKi discontinuation (range:1-25%;n=8). Of the 10 physicians who reported dose holds, 6 were from physicians utilizing prophylactic therapy. Of the 8 physicians who reported MEKi discontinuations, only 3 were reported by physicians utilizing prophylactic therapy. CONCLUSIONS Most physicians modified MEKi treatment for DAEs, and many started prophylactic DAE therapy. The benefit of prophylactic treatment cannot yet be determined. Given the low response rate, future research will be aimed at collecting more data. There is a need for more studies to establish standardized treatment guidelines to reduce the frequency of MEKi modifications secondary to DAEs.

NFS-28. CLINICAL CHARACTERISTICS AND THERAPEUTIC INTERVENTIONS IN A CASE SERIES OF PEDIATRIC PATIENTS WITH VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2

Abstract BACKGROUND Pediatric neurofibromatosis type 2 (NF2) is an understudied genetic disorder with high incidence of tumors including vestibular schwannomas (VS) and meningiomas. Although predominately recognized as an adult disease, there is a shortage of comprehensive studies in pediatric NF2. This case series describes a large cohort of pediatric NF2 patients with VS and their disease management. METHODS Our study included 24 patients with initial symptoms of NF2 before age 19. The patients were treated at the Neurofibromatosis Clinic of The University of Texas MD Anderson Cancer Center between 1/1/2005-12/31/2023. Our analysis incorporated data from clinic notes, surgical reports, audiology reports, electromyography reports, pathology reports, and imaging studies. RESULTS Patients presented with NF2 at an age range from 18 months to 18 years (mean age 8.1 ± 5.2 years). Among the patients, 67% underwent surgical interventions, including auditory brainstem implants, cochlear implants, ventriculoperitoneal shunts, and/or craniotomies for tumor resection. Additionally, treatment in 21% of cases involved radiotherapy, employing stereotactic radiosurgery, intensity-modulated radiotherapy, and proton beam irradiation. Targeted therapies, including bevacizumab, lapatinib, everolimus, temsirolimus, brigatinib, or a combination thereof, were administered to eleven patients. The best exhibited response by most patients was stable disease for a median duration of 10 months, and clinical improvement/stabilization of the hearing loss. Most reported toxicities related to bevacizumab or temsirolimus. Overall, limited clinical improvement was observed within this cohort after interventions. CONCLUSION This study discusses the clinical presentation of pediatric NF2 with VS and highlights the need for effective therapeutic options to manage tumors and symptoms in this patient population. A notable research gap exists in pediatric NF2, compounded by the lack of preclinical models to study the disease. The absence of approved drugs underscores the necessity for more comprehensive studies to guide therapeutic strategies. Combination therapies may advance treatment approaches and achieve improved outcomes.

Incidence of tethered cord syndrome in neurofibromatosis types 1 and 2 pediatric patients: a population-level analysis.

Tethered spinal cord syndrome (TCS) is characterized by cutaneous attachments on the filum terminale that stretch the spinal cord, leading to musculoskeletal and urogenital sequelae. While the neurocutaneous associations with TCS remain undefined, a recent study reports a high incidence of TCS among a pediatric neurofibromatosis (NF) cohort. This present study utilizes a population-level database to estimate TCS incidence among pediatric patients with neurofibromatosis types 1 and 2 (NF1, NF2). The TriNetX Research Network was queried to identify patients diagnosed with NF and/or TCS before the age of 21. Symptomatic TCS requiring surgical intervention was identified using corresponding procedural codes within 12months following TCS diagnosis. Odds ratios (OR) were calculated to measure the associations of NF1/NF2 with TCS. 19,426 pediatric NF patients were evaluated (NF1: 18,383, NF2: 1042). The average ages of TCS diagnosis among NF1, NF2, and non-NF patients were 12, 16, and 9years, respectively. The incidence of TCS was 1.2% in NF1 patients and 7.3% in NF2 patients, compared to 0.074% in the general population. The associations of NF incidence with TCS were significantly increased in both NF1 (OR 16.42; 14.38-18.76) and NF2 (OR 105.58; 83.56-133.40) patients compared to the general population. Symptomatic TCS requiring surgical intervention was not significantly associated with NF1/NF2 patients compared to the general TCS population. This analysis demonstrates a high incidence of TCS but delayed intervention in pediatric NF patients. Considering TCS counseling, spinal MRI, and earlier intervention may be warranted for NF patients experiencing musculoskeletal symptomatology.

Characterization of pre-malignant lesions in patients with pediatric neurofibromatosis type 1 using a novel whole-body magnetic resonance imaging technique.

TPS10637 Background: Neurofibromatosis Type 1 (NF-1) patients can develop benign tumors, plexiform neuromas (PN), that may transform into malignant peripheral nerve sheath tumors (MPNST)(Tucker, et al. 2009). MPNST are rare; but in NF1, the lifetime incidence is 8-13% and MPSTs present at younger ages(Miettinen, et al. 2017). MPNST are aggressive tumors requiring full resection for best outcomes (Mautner, et al. 2008). Emerging data suggests whole-body MRI (WB-MRI) can identify NF patients with higher PN tumor burden and maybe at risk of developing MPNST. We have created a rapid, motion-robust quantitative WB-MRI technique that is likely suitable for pediatric patients. High-resolution multiparametric tissue mapping, including T1, T2, and ADC (apparent diffusion coefficient), are acquired concurrently in a single scan, as shown in prior studies (Christodoulou, et al. 2018, Ma, et al. 2020, Nguyen, et al. 2016, Wang, et al. 2020). This project will evaluate the feasibility and reproducibility of novel WB-MRI for the characterization of pre-malignant lesions in NF-1 patients. Methods: Trial Design: Pilot study of novel WB-MRI technique in pediatric NF-1 patients with a goal of 15 patients between the ages of 5-17 years. Trial MRI scans are performed at baseline, 1 month, and then 12 months (+/-3 months). A clinical 3T MR scanner (Siemens MAGNETOM Vida) performs a head-to-knee WB-MRI in 70 minutes. Signal-to-noise ratio (SNR) and imaging quality scores will be evaluated. The lesion volume and mean T1/T2/ADC are measured for each lesion on the corresponding quantitative maps based on manual ROI’s (regions of interest). To assess scan-rescan reproducibility, image quality metrics (SNR and quality score), lesion identification, and lesion characteristics (T1, T2, and ADC) will be compared between the baseline and the 1-month scan using a Bland-Altman analysis and Schuirman’s equivalence. The coefficient of variation (CV = 100 [SD/mean] %) values for each of the quantitative values will be calculated. To evaluate for lesion characterization, changes in the mean in each MRI quantitative metrics (T1, T2, and ADC) will be measured for each lesion on the baseline and 12-month visit. Spaghetti plots will be used to visualize the change over time, and the difference in mean will be tested using an appropriate parametric or nonparametric test depending on the results of tests on normality and homoscedasticity. Intervention: WB-MRI at baseline, 1 month, and 12 months (+/-3 months) Eligibility: 5 to 17 years old not requiring sedation; Clinically or molecularly diagnosed NF-1 including mosaic/segmental subjects; Not Eligible: allergy to animal dander, animal-instigated asthma, pregnant, breastfeeding, or have intrauterine device; Current Enrollment (February 2023): 5 subjects (One unable to finish a non-sedated MRI). Clinical trial information: NCT04763109 .

Consensus-Based Best Practice Guidelines for the Management of Spinal Deformity and Associated Tumors in Pediatric Neurofibromatosis Type 1: Screening and Surveillance, Surgical Intervention, and Medical Therapy.

Spinal conditions, such as scoliosis and spinal tumors, are prevalent in neurofibromatosis type 1 (NF1). Despite the recognized importance of their early detection and treatment, there remain knowledge gaps in how to approach these manifestations. The purpose of this study was to utilize the experience of a multidisciplinary committee of experts to establish consensus-based best practice guidelines (BPGs) for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric patients with NF1. Using the results of a prior systematic review, 10 key questions that required further assessment were first identified. A committee of 20 experts across medical specialties was then chosen based on their clinical experience with spinal deformity and tumors in NF1. These were 9 orthopaedic surgeons, 4 neuro-oncologists/oncologists, 3 neurosurgeons, 2 neurologists, 1 pulmonologist, and 1 clinical geneticist. An initial online survey on current practices and opinions was conducted, followed by 2 additional surveys via a formal consensus-based modified Delphi method. The final survey involved voting on agreement or disagreement with 35 recommendations. Items reaching consensus (≥70% agreement or disagreement) were included in the final BPGs. Consensus was reached for 30 total recommendations on the management of spinal deformity and tumors in NF1. These were 11 recommendations on screening and surveillance, 16 on surgical intervention, and 3 on medical therapy. Five recommendations did not achieve consensus and were excluded from the BPGs. We present a set of consensus-based BPGs comprised of 30 recommendations for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric NF1.

JS03.5.A Pediatric Neurofibromatosis type 1- associated Malignant Peripheral Nerve Sheath Tumors: a national experience

Abstract Background Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas and although less that 10% occur in the pediatric age, they are the most feared complication in the follow-up of Neurofibromatosis Type 1 (NF1) patients. NF1-children tend to have larger tumors and worse prognosis than non-NF1 patients. There is a lack of data regarding MPNST in pediatric populations with NF1, and the present work aims to characterize a Portuguese population of pediatric NF1 patients who developed a MPNST. Material and Methods Retrospective analysis of all NF1-pediatric patients diagnosed with MPNST between 2000 to 2021, from three centers in Portugal. Patient characteristics, treatment modalities and clinical outcomes were reviewed. Results 12 patients (6 males and 6 females) met the inclusion criteria. 7 had no family history of NF1. Median age at diagnosis was 14.1 years (range 10-18). 5 had been diagnosed previously with Plexiform Neurofibroma and were treated with selumetinib (2) and partial surgery (2). MPNSTs were mostly located in the retroperitoneum (7) and in the proximal lower limbs (2). Only 1 patient had a resectable tumor at diagnosis and 3 patients had metastatic disease. In the FDG-PET scan of evaluated patients (7), the mean maximum standardized uptake value of the main lesion was 6 (range 3.6-9.7).Neoadjuvant ifosfamide plus doxorubicin chemotherapy was used in 4 patients. The median overall survival in this population was 10.3 months (95% CI 0.1-20.6) 2 patients remain alive. Conclusion The prognosis of MPNSTs in NF1 pediatric patients is very poor. In a subset of patients, MPNSTs develop from known Plexiform Neurofibromas. Current surveillance ant treatment protocols need to be improved.

Sleep-disordered breathing in pediatric neurofibromatosis type 1.

The relationship between neurofibromatosis type 1 (NF1) and sleep-disordered breathing (SDB) has not been widely studied. The aim of the study was to analyze SDB in children with NF1 of the respiratory system. All children with NF1 followed between September 2008 and July 2020 who had a respiratory polygraphy (RP) were included. The clinical charts, cerebral and cervical magnetic resonance imaging (MRI), and RP were analyzed. Twenty-two patients (11 girls, median age at RP 8.3 [0.2-18.2] years) were included in the study. Nine patients (41%) had a NF1 involvement of the upper airways, 13 (59%) patients of the central nervous system (CNS), the cranial nerves (CN) and/or medulla, and 17 (77%) patients had a hypertrophy of the adenoids and/or tonsils. Five patients were treated with Continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) before their first evaluation because of severe obstructive sleep apnea (OSA). Accordingly, 10 (45%) patients had no OSA, one (5%) mild OSA, 2 (9%) moderate OSA, and nine (41%) severe OSA. None of the patients had central sleep apnea. Despite upper airway surgery, three patients required CPAP, two could be weaned and one died after a switch to tracheostomy. None of the patients treated with CPAP/NIV could be weaned, one patient required tracheostomy. Neither the clinical nor the MRI findings were able to predict OSA on a RP. The prevalence of OSA in NF1 is high, regardless of the nature of airway obstruction and the clinical and MRI findings, underlining the value of a systematic RP. CPAP may reduce the need of tracheostomy.

Choroidal Abnormalities in Pediatric NF1: A Cohort Natural History Study.

Simple SummaryChoroidal abnormalities (CAs) have recently been introduced as one of the criteria for the diagnosis of neurofibromatosis type 1 (NF1). The aim of the present study was to assess the natural history of CAs in a large pediatric population affected by NF1, evaluating, on a long-term follow-up, CAs progression both in number and dimensions. To avoid bias due to the growing process of the eye, the CAs dimensions were normalized for the optic disc size. Our study demonstrated, in 99 eyes of 53 pediatric patients, an increase in the number, area and perimeter of CAs. The present study thus provides evidence that, in NF1 pediatric patients, CAs change with time, increasing both in number and dimensions, independently from the physiological growth of the eye. While the increase of the CAs number occurs particularly at an earlier age, the increase in the CAs dimensions is a slow process that remains constant during childhood.The purpose of this study was to assess the long-term natural history of choroidal abnormalities (CAs) in a large pediatric neurofibromatosis type 1 (NF1) population, quantifying their progression in number and dimensions. Pediatric patients (<16 years old) affected by NF1 with a minimum follow-up of 3 years with at least one CA in one eye were consecutively recruited. Near-infrared (NIR) imaging was performed to identify CAs, which were quantified in number and size. The CAs area and perimeter were normalized for the optic disc dimensions to avoid possible bias related to the growing process of the eye. Ninety-nine eyes of 53 patients were evaluated. The CAs number, area and perimeter significantly increased during follow-up (p < 0.0001 for each parameter). The patient age at baseline was inversely correlated with the CAs number over time (coefficient = −0.1313, p = 0.0068), while no correlation was found between the patient age and CAs progression in size. In conclusion, we provide evidence that, in NF1 pediatric patients, CAs change over time, increasing both in number and dimensions, independently from the physiological growth of the eye. While the increase of the CAs number occurs particularly at an earlier age, the increase in the CAs dimensions is a slow process that remains constant during childhood.

Diagnostic value of 18F-FDG PET-CT in detecting malignant peripheral nerve sheath tumors among adult and pediatric neurofibromatosis type 1 patients

PurposeDetecting malignant peripheral nerve sheath tumors (MPNSTs) remains difficult. 18F-FDG PET-CT has been shown helpful, but ideal threshold values of semi-quantitative markers remain unclear, partially because of variation among scanners. Using EU-certified scanners diagnostic accuracy of ideal and commonly used 18F-FDG PET-CT thresholds were investigated and differences between adult and pediatric lesions were evaluated.MethodsA retrospective cohort study was performed including patients from two hospitals with a clinical or radiological suspicion of MPNST between 2013 and 2019. Several markers were studied for ideal threshold values and differences among adults and children. A diagnostic algorithm was subsequently developed.ResultsSixty patients were included (10 MPNSTs). Ideal threshold values were 5.8 for SUVmax (sensitivity 0.70, specificity 0.92), 5.0 for SUVpeak (sensitivity 0.70, specificity 0.97), 1.7 for TLmax (sensitivity 0.90, specificity 0.86), and 2.3 for TLmean (sensitivity 0.90, specificity 0.79). The standard TLmean threshold value of 2.0 yielded a sensitivity of 0.90 and specificity of 0.74, while the standard SUVmax threshold value of 3.5 yielded a sensitivity of 0.80 and specificity of 0.63. SUVmax and adjusted SUV for lean body mass (SUL) were lower in children, but tumor-to-liver ratios were similar in adult and pediatric lesions. Using TLmean > 2.0 or TLmean < 2.0 and SUVmax > 3.5, a sensitivity and specificity of 1.00 and 0.63 can be achieved.Conclusion18F-FDG PET-CT offers adequate accuracy to detect MPNSTs. SUV values in pediatric MPNSTs may be lower, but tumor-to-liver ratios are not. By combining TLmean and SUVmax values, a 100% sensitivity can be achieved with acceptable specificity.

Genetic diagnosis and follow-up study in pediatric neurofibromatosis 1 patients

Objective: Based on the genetic diagnosis and follow-up study on pediatric neurofibromatosis 1 (NF1) patients, interrogating the genotype-phenotype correlations of patients with NF1 mutations. Methods: 32 Patients from age of 2 months to 5 years old (17 male and 15 female) suspected for neurofibromatosis 1 were recruited during September 2016 to January 2018 in Shanghai Children's Medical Center retrospectively. Genetic diagnosis was applied to detect pathogenic variants. Long-term follow-up study were conducted to reveal progress of the disease and genotype-phenotype correlations. Results: 27 patients were detected with pathogenic NF1 variants, among them three were not reported. 3 patients inherited pathogenic variants from their NF1 diagnosed parents, all the other variants were de novo. Progressive development of phenotypes wasn't observed in most patients during the follow-up (14/27). Some patients were diagnosed with short stature, pulmonary artery stenosis and developmental delay during the follow-up(7/27). Short stature and pulmonary artery stenosis may be associated with missense mutation and severe truncation mutation of NF1 gene, respectively. Conclusions: Genetic diagnosis is required in young patients of NF1.Follow-up plan of pediatric patients should be adjusted based on genetic findings. Early follow-up of cardiovascular abnormalities should be noted in patients with missense mutation. Height development in patients with severe truncating variants are needed.

Epidemiological and clinical burden associated with plexiform neurofibromas in pediatric neurofibromatosis type-1 (NF-1): a systematic literature review

PurposePatients with neurofibromatosis type-1 (NF-1) and associated plexiform neurofibromas (PNs) often have a high burden of illness owing to debilitating symptoms of these tumors and limited management options. To investigate this complex disease, a systematic literature review (SLR) was conducted on the epidemiology of pediatric NF-1 and associated PNs, the burden of illness, and outcomes of surgical resection of these tumors.MethodsSearches of MEDLINE and Embase (from database inception to October 2019) and conference proceedings (2017–2019) were performed to identify relevant studies. The review methodology was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.ResultsTwenty studies were identified. Evidence confirmed NF-1 is rare but that occurrence may differ geographically. Only limited data on the birth incidence of NF-1 were identified. Prevalence estimates for pediatric NF-1 varied from one per 960 individuals (aged 17 years) to one per 5681 children (aged < 16 years) across five large registry/surveillance studies (each involving > 19,000 individuals). The prevalence of associated PNs was 0–29.6%. PNs carried increased mortality risk in pediatric NF-1 in both studies that explored this potential association. Patients with PNs reported high use of analgesics. The complication rate post-surgery for PNs was around 17–19%. The recurrence rate (18–68%) was dependent on the extent of excision achieved during surgery.ConclusionsData suggest NF-1 is a rare disease with increased morbidity and mortality in children with associated PNs. Surgical outcomes for PNs are often poor. These findings suggest significant unmet needs in patients with NF-1-associated PNs.

Options and strategies for hearing restoration in pediatric neurofibromatosis type 2.

In this article, we will review the mechanisms and natural history of hearing loss in neurofibromatosis type 2 (NF2) and discuss the hearing outcomes with different rehabilitation options. Review of the published literature. NF2 is a rare autosomal dominant syndrome characterized by vestibular schwannomas and other intracranial and spinal tumors. Bilateral vestibular schwannomas are the hallmark of the disease which occur in 90 to 95% of the patients. As a result, hearing loss will eventually occur in almost all NF2 patients. Deafness can occur from tumor progression or from treatment of vestibular schwannomas and is among the most debilitating aspects of NF2. A number of surgical and non-surgical rehabilitation options are available for these patients including cochlear and auditory brainstem implants. The audiologic outcomes with surgical rehabilitation options have been variable but most patients are able to achieve sound awareness and benefit from auditory cues in lip reading. Early identification and treatment of NF2 patients can help in achieving better hearing outcomes in the pediatric population. An increasing number of NF2 patients are receiving open set word understanding with refinement in surgical techniques.

Pediatric Diffuse Midline Gliomas H3 K27M-Mutant and Non-Histone Mutant Midline High-Grade Gliomas in Neurofibromatosis Type 1 in Comparison With Non-Syndromic Children: A Single-Center Pilot Study.

Background: Pediatric neurofibromatosis type 1 (NF1) patients rarely develop aggressive central nervous system tumors. Among high-grade gliomas (HGGs), histone mutant diffuse midline gliomas (DMGs H3 K27M-mutant) have exceptionally been reported. The aim of this retrospectives single-center study was to compare the clinical behavior of DMGs H3 K27M-mutant and non-histone mutant midline HGGs in NF1 vs. non-syndromic children and to report imaging features of NF1 HGGs.Method: We conducted a retrospective review of cerebral DMGs H3 K27M-mutant or non-histone mutant HGGs in 18 patients with or without NF1 followed at our institution between 2010 and 2018. Differences in outcomes, notably progression-free survival (PFS) and overall survival (OS), were evaluated.Results: Two patients were identified with genetically confirmed diagnosis of NF1 and cerebral HGGs (one DMG H3 K27M-mutant and one histone wild type). Both subjects presented with midline mass lesions with imaging features of aggressive biological activity on advanced MRI or amino-acid PET. During the same time period, 16 non-NF1 patients (11 subjects with DMGs H3 K27M-mutant and 5 with non-histone mutant midline HGGs) were treated at our institution. The two patients with NF1 and HGGs presented a PFS of 3 months and an OS of 5 and 7 months. Median PFS and OS of children without NF1 were respectively 6 and 10 months in DMGs H3 K27M-mutant, and 6 and 11 months in H3 K27M wild-type tumors. Seventy-five percent of subjects with non-NF1 HGGs presented a PFS >4 months compared to 0% in NF1 patients. The 8-month OS of patients with non-NF1 HGGs was 81% compared to 0% in NF1 patients.Conclusions: Cerebral HGGs arising in midline structures rarely occur in pediatric patients with NF1 and present with extremely poor prognosis, worse than HGGs developing in non-NF1 patients, independent of the presence or absence of H3 K27M mutation. Imaging features of aggressive biological activity on advanced MRI or amino-acid PET imaging suggest prompt neuropathological and molecular investigations.

Pretreatment Endocrine Disorders Due to Optic Pathway Gliomas in Pediatric Neurofibromatosis Type 1: Multicenter Study.

Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce. The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment. Multicenter retrospective study. Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers. We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification. Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002). Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement.

Posterior only instrumented fusion provides incomplete curve control for early-onset scoliosis in type 1 neurofibromatosis

BackgroundThe mid-long term outcomes of posterior spinal fusion in pediatric neurofibromatosis type 1 (NF-1) patients are rarely reported, so does the effectiveness of itsorthopeidc maintenance function. This study aims to evaluate the mid-long term surgical outcomes of posterior only instrumented spinal fusion for early-onset scoliosis (EOS) in NF-1 patients.MethodsA retrospective review was performed on a cohort of 10 NF-1 patients having EOS from 2008 to 2014 in our hospital, the age averaged at 7.8 years old when they underwent posterior only instrumented spinal fusion for their EOS. Both general clinical data and surgical specific data of the patients were collected and reviewed, and the dystrophic progression of EOS was evaluated during the follow-up.ResultsThe average duration of follow-up was 54 months (24 to 88 months). All patients underwent posterior only instrumented spinal fusion at 1 stage. The primary curves of EOS were thoracic in 9 cases and 1 patient had lumbar scoliosis. Preoperative major curve was significantly corrected (from 66.1 to 31.1 degrees). However, the major curve deteriorated significantly to 40.1 degrees on average at the end of the follow-up. The T1-S1 distance increased 2.8 cm on average and kept increasing at a rate of 0.6 cm/year during the follow-up.ConclusionsPosterior only fusion surgery was not a good option to treat the EOS in NF-1 patients despite the relatively short segments involvement in the disease. The maintenance of orthopedic effect after treatment was not satisfactory.

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders.

The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Pediatric neurofibromatosis type 2: clinical and molecular presentation, management of vestibular schwannomas, and hearing rehabilitation

This study aims to describe the clinical and molecular presentation of pediatric neurofibromatosis type 2 (NF2) and the subsequent management of vestibular schwannomas (VS) and hearing rehabilitation. This is a single-center retrospective study of neurofibromatosis type 2 diagnosed before the age of 18years old from 1997. Natural history of vestibular schwannomas and surgical outcomes were evaluated using volumetric MRI, hearing, and facial nerve assessment. Patients included in chemotherapy protocols were excluded. From a database of 80 patients followed up for NF2 on a regular basis, 25 patients were eligible (11 sporadic cases, 14 inherited in five families). The mean age at diagnosis was 11.6years old. The average clinical follow-up was 6.5years. NF2 mutation was identified in 81% of the probands. The average growth rate based on the maximum linear diameter (DGR) was 1.68mm/year (n=33, average follow-up 4.22years) and 545mm3/year in volumetric assessment (VGR) for VS larger than 1cm (n=21, average follow-up 3.4years). In unoperated ears, hearing was stable in about 50% of ears. The mean change in dB HL was 9.5dB/year for pure-tone average and 3.5 for speech-recognition threshold (n=34, 5.5years 1-12). Eight children required removal through a translabyrinthine approach (mean follow-up was 4.5years), six patients were operated on for hearing preservation (mean postoperative follow-up 4.3years). Six patients were eligible for hearing rehabilitation with cochlear implantation (I), and five received placement of an auditory brainstem implant. Early diagnosis and treatment of small growing VS should be carefully discussed considering familial history and possible rehabilitation with a CI.

Clinical course of vestibular schwannoma in pediatric neurofibromatosis Type 2.

Neurofibromatosis Type 2 (NF2) is an autosomal-dominant inherited disease, characterized by multiple neoplasia syndromes, including meningioma, schwannoma, glioma, and ependymoma. In this report, the authors present their clinical experience with pediatric NF2 patients. In particular, they focused on the clinical course of vestibular schwannoma (VS), including the natural growth rate, tumor control, and functional hearing outcomes. From May 1988 to June 2012, the authors recruited patients who were younger than 18 years and fulfilled the Manchester criteria. In total, 25 patients were enrolled in this study. The authors analyzed the clinical course of these patients. In addition, they measured the natural growth rate of VS before any treatment in these children with NF2. Then, they evaluated the tumor control rate and functional hearing outcomes after the treatment of VS. The mean age at the onset of NF2-related symptoms was 9.9 ± 4.5 years (mean ± SD, range 1-17 years). The mean age at the diagnosis of NF2 was 12.9 ± 2.9 years (range 5-17 years). The mean follow-up period was 89.3 months (range 12-311 months). As initial manifestations, nonvestibular symptoms were frequently observed in pediatric patients with NF2. The mean natural growth rate of VS was 0.33 ± 0.41 cm(3)/year (range 0-1.35 cm(3)/year). The tumor control rate of VS was 35.3% at 3 years after Gamma Knife surgery (GKS). The actuarial rate of useful hearing preservation was 67% in the 1st year and 53% in the 5th year after GKS. Clinical manifestations in children with NF2 were highly variable, compared with their adult counterparts. The natural growth rate of VS in children is slow, and this oncological feature may explain the diverse clinical manifestations besides vestibular symptoms in children with NF2. The treatment outcome of GKS for VS in children with NF2 was not favorable compared with previous reports of affected adults.

Pediatric neurofibromatosis 1 and parental stress: a multicenter study

BackgroundNeurofibromatosis 1 (NF1) is a complex and multifaceted neurocutaneous syndrome with many and varied comorbidities. The literature about the prevalence and degree of maternal stress and the impact of NF1 in the parent–child interaction is still scant. The aim of this study was to evaluate the prevalence of maternal stress in a large pediatric sample of individuals affected by NF1.MethodsThirty-seven children (19 boys, 18 girls) of mean age 7.86±2.94 (range 5–11) years affected by typical NF1 and a control group comprising 405 typically developing children (207 boys, 198 girls; mean age 8.54±2.47 years) were included in this study. To assess parental stress, the mothers of all individuals (NF1 and comparisons) filled out the Parenting Stress Index-Short Form test.ResultsThe two study groups were comparable for age (P=0.116), gender (P=0.886), and body mass index adjusted for age (P=0.305). Mothers of children affected by NF1 reported higher mean Parenting Stress Index-Short Form scores on the Parental Distress domain (P<0.001), Difficult Child domain (P<0.001), and Total Stress domain than the mothers of typically developing children (controls) (P<0.001). No significant differences between the two groups were found for the Parent-Child Dysfunctional Interaction domain (P=0.566) or Defensive Responding domain scores (P=0.160).ConclusionNF1 is considered a multisystemic and complex disease, with many still unrecognized features in pediatric patients and in their families. In this light, our findings about the higher levels of maternal stress highlight the importance of considering the environmental aspects of NF1 management in developmental age.

Spectrum and Prevalence of Vasculopathy in Pediatric Neurofibromatosis Type 1

To describe the spectrum and associated clinical features of peripheral and cerebral vasculopathy in pediatric patients with neurofibromatosis type 1, children seen at a single center from 2000 to 2010 with appropriate imaging studies were identified. Scans were assessed for vascular disease by 2 pediatric neuroradiologists. Of 181 children, 80 had pertinent imaging studies: 77 had brain imaging, 6 had peripheral imaging, and 3 had both. Vasculopathy was identified in 14/80 children (18%, minimum prevalence of 14/181; 8%). Of those with vascular abnormalities, 2/14 had peripheral vasculopathy (1% minimum prevalence) and 12/14 had cerebrovascular abnormalities (7% minimum prevalence). No associations were found between vasculopathy and common clinical features of neurofibromatosis type 1, including optic pathway glioma, plexiform neurofibroma, skeletal abnormalities, attention-deficit hyperactivity disorder (ADHD), or suspected learning disability. Both peripheral and cerebral vasculopathy are important complications of pediatric neurofibromatosis type 1 and should be considered in the management of this complex disease.