DRI Triton SS-OCT applied to detect choroidal nodules in paediatric patients affected by NF1.

Purpose: To examine whether image processing of non-mydriatic DRI Triton SS-OCT (Topcon Corporation, Tokyo, Japan) using the red free filter could assess the presence of choroidal nodules and thus include their detection as a diagnostic criterion in neurofibromatosis type 1 (NF1). Material and methods: We included 417 eyes from 210 patients, 377 - from 190 patients diagnosed with NF1 according to the criteria established by the National Institutes of Health Consensus Development Conference (NIH) and 40 from 20 healthy patients as a control group. The mean age was 9.4 years (range 2 years-18 years). All patients had their visual acuity measured by a test according to age, were examined for the presence of lisch nodules and an Optical Coherence Tomography (OCT) of the macular area was performed. All the OCT images were analysed to check if visible nodules could be identified. Results: Ages 14 (95% CI=(9.7,18.3)) and 12 years (95% CI=(9.1,14)) are the cut-off points that best separate those with choroidal nodules with Triton OCT and lisch with slit lamp, respectively, from those without. lisch nodules were detected in 50% of cases of NF1 patients. The presence of choroidal nodules did not present a statistically significant correlation with the occurrence of optic pathway glioma (p = 0.96) nor with the patient's visual worsening (p = 0.072). A statistically significant correlation was observed between the presence of choroidal nodules and the presence of lisch nodules (p < 0.05). Conclusion: The Topcon Triton OCT red free tool would not be a good tool to detect choroidal nodules in patients with NF1 because of its low sensitivity. If the presence of choroidal nodules were to be included in the diagnostic criteria for NF1, it would be convenient to use a device with red and infrared radiations.

Histologic correlates of "Choroidal abnormalities" in Neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as "choroidal abnormalities", choroidal "hyperpigmented spots" and "retinal vascular abnormalities" have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.

Functional and Radiological Outcomes of All-Posterior Surgical Correction of Dystrophic Curves in Patients with Neurofibromatosis Type 1.

Study Design: A retrospective cohort study. Purpose: To determine outcomes following all-posterior surgery using computed tomography navigation, hybrid stabilization, and multiple anchor point techniques in patients with neurofibromatosis type 1 (NF-1) and dystrophic scoliosis. Overview of Literature: Previous studies favored antero-posterior fusion as the most reliable method; however, approaching the spine anteriorly was fraught with significant complications. With the advent of computer assisted navigation and multiple anchor point method, posterior only approach is reporting successful outcomes. Methods: This study included patients who underwent all-posterior surgical deformity correction for dystrophic NF-1 curves. Coronal and sagittal Cobbs angles, apical rotation, and the presence of dystrophic features were evaluated before surgery. Postoperatively, sagittal, coronal, and axial correction, implant position, and implant densities were evaluated. The decline in curve correction and implant-related complications were evaluated at follow-up. Clinical outcomes were evaluated using the Scoliosis Research Society-22 revised index. Results: This study involved 50 patients with a mean age of 13.6 years and a mean follow-up duration of 5.52 years. With a mean coronal flexibility of 18.7%, the mean apical vertebral rotation (AVR), preoperative coronal Cobb angle, and sagittal kyphosis were 27.4°, 64.01°, and 47.70°, respectively. The postoperative mean coronal Cobb angle was 30.17° (p <0.05), and the sagittal kyphosis angle was 25.4° (p <0.05). The average AVR correction rate was 41.3%. The correction remained significant at the final mean follow-up, with a coronal Cobb angle of 34.14° and sagittal kyphosis of 25.02° (p <0.05). The average implant density was 1.41, with 46% of patients having a high implant density (HID). The HID had a markedly higher mean curve correction (29.30° vs. 38.05°, p <0.05) and a lower mean loss of correction (5.7° vs. 3.8°, p <0.05). Conclusions: Utilizing computer-assisted navigation, hybrid instrumentation, and multiple anchor point technique and attaining high implant densities, this study demonstrates successful outcomes following posterior-only surgical correction of dystrophic scoliosis in patients with NF-1.

Whole-Body Positron Emission Tomography with 18F-Fluorodeoxyglucose/Magnetic Resonance Imaging as a Screening Tool for the Detection of Malignant Transformation in Individuals with Neurofibromatosis Type 1.

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1.

Impact of neurofibromatosis type 1 on quality of life using the Skindex-29 questionnaire quality of life in NF1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common RASopathies predisposing affected patients to melanic lesions and benign tumors. NF1 is associated with considerable esthetic and functional burden negatively affecting the patient's quality of life (QoL). This study aims to assess the clinical features of NF1 patients and evaluate their impact on QoL. We identified NF1 patients from a public health database of a region in Spain. All patients underwent clinical and ophthalmological evaluation for NF1 features. We measured QoL using the Spanish version of the Skindex-29. RESULTS: Forty patients fulfilled the NF1 National Institute of Health criteria when we recruited patients. The median age was 42.00 years (IQR 26.5 -53.75). The median total Skindex-29 score was 12.3 (IQR 5.9-22.4); (emotion: 15.0, IQR 5.0-37.5; symptoms 8.9, IQR 0.0-17.9 and functioning 8.3; IQR 0.5-18.3). Women and NF1 patients with lower educational levels were associated with poorer QoL scores. We identified itching and sleep troubles to influence NF1 patients' QoL negatively. CONCLUSION: NF1 considerably influences the psychological well-being of NF1 patients. We observed that female and low-educated patients scored higher on the emotional dimension of the Skindex-29 and could, therefore, be more at risk of depression. We also pointed out some "minor symptoms" that negatively impact NF1 patients' QoL such, as itching and sleep troubles which doctors could treat if sought by doctors.

Highly Active Relapsing-Remitting Multiple Sclerosis with Neurofibromatosis Type 1: Radiological Aspects and Therapeutic Challenges - Case Report.

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease which can rarely co-exist with neurofibromatosis 1 (NF1), a neurocutaneous inherited disorder that predisposes to oncogenesis. Patients who suffer from both conditions can be challenging cases for clinicians, as clinical symptoms and radiological findings may overlap, while MS immune-modifying treatments could further increase the risk of oncogenesis. Case Presentation: In this study, we describe the case of a 27-year-old woman who presented with signs and symptoms of optic neuritis and was then diagnosed with both MS and NF1. As the patient continued to experience MS relapses despite initial interferon-beta treatment, she was subsequently switched to natalizumab and responded well. Conclusion: This case illustrates how MRI lesion differentiation with the co-existence of MS and NF1 can be difficult due to overlaps in lesion characteristics, while treatment decisions can be challenging mainly due to scarce data on the oncogenic risk of MS immunomodulary therapies. Therefore, clinicians need to balance out the risk of malignancy development with the risk of progressive neurological disability when treating such patients.

Patient characteristics, treatment patterns, healthcare resource utilization, and costs among patients diagnosed with neurofibromatosis type 1 with and without plexiform neurofibromas in Japan.

OBJECTIVES: The objectives of this study were to retrospectively investigate the patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs related to management of neurofibromatosis type 1 (NF1) in Japan. METHODS: Cohorts of NF1 patients with or without plexiform neurofibromas (PN) were identified from the Medical Data Vision database in 2008-2019. Baseline characteristics, NF1 medications, HCRU, and associated costs were assessed using descriptive statistics. All-cause HCRU and costs following the first confirmed NF1 diagnosis date were analyzed per patient per year (PPPY) in Japanese Yen (JPY) and United States Dollar (USD). RESULTS: A total of 4394 NF1 patients without PN and 370 NF1 patients with PN were identified. The mean age was 35.0 and 36.9 years, respectively. The proportion of patients with PN treated with medications was higher than that in patients without PN (except for antirheumatic/immunologic agents). Analgesics/non-steroidal anti-inflammatory drugs were the most frequently prescribed NF1 medications (44.3% and 56.0% in patients without and with PN, respectively), followed by inpatient prescriptions of opioids/opioid-like agents (17.8% and 27.6%, respectively). Inpatient admissions accounted for the highest costs in both cohorts with the average cost PPPY being JPY 2,133,277 (USD 19,861) for patients without PN and JPY 1,052,868 (USD 9802) for patients with PN. CONCLUSIONS: NF1 is treated primarily with supportive care with analgesics/non-steroidal anti-inflammatory drugs being the most frequently prescribed NF1 medications in Japan. Findings underscored the unmet need and substantial economic burden among patients with NF1 and highlighted the need for new treatment options for patients with this disease.

Tibial Dysplasia in Neurofibromatosis-1: A Rare Case Report and Review of Literature.

Background: Neurofibromatosis-1 (NF-1) is a neurocutaneous disorder, primarily affecting the skin and nervous system. Concomitant multi-system involvement is also seen. Orthopedic manifestations of NF-1 are one area that is understudied and underreported, highlighting the importance of this case report. Case Report: A 16-year-old male presented with painless swelling on the posteromedial aspect of the lower right tibia, which was confirmed to be a dysplastic mass on biopsy. Physical examination also revealed cafe au lait macules and axillary freckling, leading to a diagnosis of NF-1. Discussion: Bony lesions in NF-1 patients mainly include the spine and tibia. Congenital tibial dysplasia is commonly associated with NF-1 and may progress to pseudoarthrosis if early management is not started. Treatment modalities include excision, bracing, and fixation. Conclusion: Further research is required to have a more comprehensive view of NF-1 and orthopedics, to diagnose and manage such bony complications.

Giant gluteal and vesical plexiform neurofibromas in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is a neurocutaneous genetic disorder caused by mutations in the NF1 gene, resulting in the formation of benign tumors called neurofibromas. The most common type of tumor seen in patients with neurofibromatosis type 1 is the slow-growing and benign neurofibroma, with a subtype called plexiform neurofibroma being particularly common and causing pain, functional impairment, and cosmetic disfigurement. CASE PRESENTATION: We report the case of a 20-year-old North African female patient with a history of neurofibromatosis type 1 who presented with a growing mass in her right gluteal region, which was later diagnosed as a giant cutaneous neurofibroma. Imaging studies revealed infiltration in several regions, including the urinary bladder wall, resulting in significant bilateral hydronephrosis. The patient is currently being monitored, and no excisional procedures are planned. CONCLUSIONS: Neurofibromatosis type 1 can cause a variety of clinical symptoms, including the development of large plexiform neurofibromas. It is important to closely monitor patients with neurofibromatosis type 1 for the early detection of neurofibromas. Early detection and prompt surgical intervention are essential for preventing complications.

A simplified technique for correction of complete ptosis secondary to palpebral neurofibromatosis.

PURPOSE: To present a simplified technique in management of complete ptosis secondary to neurofibromatosis. METHODS: This prospective, non-comparative, clinical interventional study included 13 patients with complete ptosis secondary to histologically proved plexiform neurofibromas. It was conducted at the Orbital Unit of Assiut University Hospital, the referral center of Upper Egypt in the period between June 2013 and October 2021. In all cases, a simplified technique of 5 surgical steps was applied: (A) Division of the involved eyelid surgically into three parts by drawing 2 curvilinear lines, the superior line 11 mm below and parallel to the lower eyebrow hairline and the inferior one 10 mm above the lid margin, (B) Resection (full-thickness) of the large middle part which involves the main pathology and lies between the 2 lines, (C) Preservation of the upper part with identification, dissection and clamping of the levator muscle, (D) Refinement of the lower part by removal of any tissue between the skin and the debulked tarsus and (E) Re-suturing of the upper and lower parts in layers; conjunctiva to conjunctiva, levator to tarsus (after resection of a part that corrects the ptosis) and skin to skin. RESULTS: Ptosis was completely corrected in 8 cases (61.5%) and residual mild ptosis occurred in 5 patients (38.5%). No exposure keratopathy or tumor growth was reported during the follow-up period of minimum 1 year. CONCLUSIONS: This simplified technique could be considered as a surgical basis for correction of complete ptosis in neurofibromatosis.

Bone mineral density, vitamin D and osseous metabolism indices in neurofibromatosis type 1: A systematic review and meta-analysis.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic autosomal neurocutaneous syndrome correlated with skeletal dysplasia and defects in the osseous microarchitecture. The physiological mechanism for the development of NF1-related bone abnormal turnover is still unclear. OBJECTIVES: A meta-analysis was performed to investigate the effects of NF1 on bone mineral density (BMD) and osseous metabolic indices in order to provide clinical evidence for the pathogenesis of the associated skeletal deformities. METHODS: A systematic literature review search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed/Medline and Web of Science databases from the date of inception of each database through to 10 September 2023. Specific inclusion and exclusion criteria were applied for the identification of studies examining the effects of NF1 on bone strength and metabolism. The Newcastle-Ottawa and Jadad scales were applied to assess the quality of the included studies. RevMan 5.3 software was used for the analysis of the data, and MedCalc was applied to examine publication bias. RESULTS: Overall, 13 studies met the inclusion criteria comprised of 5 cross-sectional, 6 case-control and 2 retrospective studies. 703 patients and 973 healthy subjects formed the NF1 and control group, respectively. The results of the meta-analysis displayed that lumbar (SMD = -3.85, 95%CI = -7.53 to -0.18, Z = 2.05, p = 0.04) and femoral (SMD = -4.78, 95%CI = -8.86 to -0.69, Z = 2.29, p = 0.02) BMD was reduced in the NF1 group. Both in children and adults the serum levels of 25 hydroxyvitamin D3 were also decreased in NF1 group, but without any statistical significance (SMD = -0.62, 95%CI = -1.34 to -0.11, Z = 1.66, p = 0.10). Serum Parathyroid hormone (PTH) (SMD = 0.73, 95%CI = 0.31 to 1.15, Z = 3.43, p = 0.0006) and C-telopeptide of type 1 collagen (CTX) (SMD = 0.82, 95%CI = 0.33 to 1.30, Z = 3.29, p = 0.001) were elevated in NF1 patients, while serum calcium (SMD = -0.10, 95%CI = -0.74 to 0.53, Z = 0.32, p = 0.75) phosphorous (SMD = 0.33, 95%CI = -0.38 to 1.05, Z = 0.92, p = 0.36), alkaline phosphatase (ALP) (SMD = -0.36, 95%CI = -0.77 to 0.05, Z = 1.71, p = 0.09), osteocalcin (SMD = 1.81, 95%CI = -0.37 to -3.98, Z = 1.63, p = 0.10) and bone formation markers (SMD = 0.28, 95%CI = -0.37 to -0.94, Z = 0.85, p = 0.39) were not. CONCLUSION: NF1 is associated with decreased BMD at the lumbar spine and femur. Taking into account that the serum levels of PTH, CTX were increased whereas the concentrations of vitamin D, calcium, phosphorous, ALP, osteocalcin and bone formation markers were not altered significantly in the NF1 patients compared with the healthy subjects, a vitamin D independent dysregulated bone cellular activity could be considered. STUDY REGISTRATION: Registered on PROSPERO (CRD42023424751).

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Hypertension in NF1: A closer look at the primacy of essential hypertension versus secondary causes.

BACKGROUND: We aimed to analyze hypertension in neurofibromatosis type 1 (NF1) in a Finnish population-based cohort in 1996-2014. METHODS: A cohort of 1365 individuals with confirmed NF1 was compared with a control cohort of 13,923 individuals matched for age, sex, and area of residence. Diagnoses of hypertension were retrieved from the Finnish Care Register for Health Care. These registered data were separately analyzed for secondary and essential hypertension. Purchases of antihypertensive drugs were queried from the Finnish Register of Reimbursed Drug Purchases. RESULTS: We identified 115 NF1 patients with hospital diagnosis of hypertension. Our findings revealed a hazard ratio (HR) of 1.64 (95% CI 1.34-2.00, p < 0.001) in NF1 versus controls. NF1 patients presented with a significantly increased hazard for both secondary hypertension (n = 9, HR 3.76, 95% CI 1.77-7.95, p < 0.001) and essential hypertension (n = 98, HR 1.73, 95% CI 1.39-2.14, p < 0.001). No difference in the HR of hypertension was observed between men and women, while NF1 patients with essential hypertension were, on average, younger than the controls. The proportions of individuals with antihypertensive medication did not differ between NF1 patients and controls (OR 0.85). CONCLUSION: NF1 is a risk factor for hypertension. Despite the recognized risk for secondary hypertension, essential hypertension is the predominant type in NF1.

"Cornflake nevoid" lesions, mimicking choroidal lesions of neurofibromatosis 1, in the absence of neurofibromatosis 1: An imaging-based hypothesis.

Whitish hypermelanocytic flake-like lesions on scanning laser ophthalmoscopy (SLO) multicolor posterior pole imaging (PPI) can correspond to several conditions, including simple nevi or shallow choroidal melanomas, paraneoplastic fundus lesions like bilateral diffuse uveal melanocytic proliferation, or choroidal melanocytic lesions found in neurofibromatosis type 1 (NF1). We report three cases with unilateral flake-shaped choroidal lesions on SLO multicolor PPI, similar to choroidal NF1 lesions, monitored their evolution and analyzed their potential nature using multimodal imaging including SLO multicolor and classical PPI, infrared autofluorescence (IRAF), spectral-domain-optical coherence tomography (SD-OCT), enhanced-depth imaging-OCT (EDI-OCT), OCT-angiography as well as fluorescein angiography, and indocyanine green angiography (ICGA). Two oncologic patients and one healthy patient presented unilateral whitish cornflake-shaped lesions on SLO multicolor and IRAF PPI, faintly or not visible on fundus photography, hypofluorescent on the intermediate-phase ICGA, but isofluorescent on the late-phase ICGA corresponding to hyperreflective areas in the choroid immediately under the retinal pigment epithelium on SD-OCT. The lesions were nonevolutive. Multimodal imaging determined that these "nevoid" lesions were melanocytic but could not be assimilated to classical nevi, having a looser structure that allowed some indocyanine green impregnation explaining the isofluorescence on the late-phase ICGA. The lesions were similar to those described in NF1 cases and were unrelated to the oncologic status.

A Lesion on the "King of Kings": Neurofibromas in the Parthian Empire's Arsacid Dynasty.

Multiple kings of the Arsacid Dynasty of the ancient Parthian Empire are depicted on their coinage with a recurrent facial lesion, one that is found across multiple generations. Multiple theories have attempted to explain this phenomenon, from basal cell carcinoma to hereditary trichoepithelioma. In this paper, we suggest that these lesions are possibly a representation of the neurofibromas found in Neurofibromatosis 1, an autosomal dominant disease process.

Neurofibromin 1 mutations impair the function of human induced pluripotent stem cell-derived microglia.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human microglia-like (hiMGL) cells heterozygous for three different NF1 gene mutations found in patients with NF1. Whereas all NF1-mutant and isogenic control hiMGL cells expressed classical microglia markers and exhibited similar transcriptomes and cytokine/chemokine release profiles, only NF1-mutant hiMGL cells had defects in P2X receptor activation, phagocytosis and motility. Taken together, these findings indicate that heterozygous NF1 mutations impair a subset of the functional properties of human microglia, which could contribute to the neurological abnormalities seen in children with NF1.

Employment, occupation, and income in adults with neurofibromatosis 1 in Denmark: a population- and register-based cohort study.

BACKGROUND: Little is known about employment status, occupation, and disposable income in adults with NF1. METHODS: From the Danish National Patient Registry and database of two national Centers for Rare Diseases, we identified 1469 adults with NF1, who were matched to 11,991 randomly selected population comparisons on sex and birth year and month. Annual information on employment, occupation and disposable income was ascertained from national registries in 1980-2019. RESULTS: Adults with NF1 had a lower odds ratio (OR) for employment [OR 0.71, 95% confidence interval (CI) 0.61-0.83] and higher OR for health-related unemployment (OR 2.94, 95% CI 2.16-3.96) at age 30 years than population comparisons, which persisted at age 40 and 50 years. Somatic diagnoses were associated with a higher OR for health-related unemployment in adults with NF1 than in the population comparisons. Adults with NF1 had a slightly lower disposable income, with a 14% (0.82-0.89) reduction observed among the youngest birth cohort. Furthermore, adults with NF1 were less likely to be in a high skilled occupation at ages 30, 40 and 50 years. CONCLUSION: Adults with NF1 have a lower employment rate, which was mainly due to health-related reasons and a slightly lower disposable income than adults without NF1. Thus, anticipation guidance for employment should be part of the management of NF1 families.

Congenital Pseudoarthrosis of Tibia With Anterolateral Bowing Treated With Ilizarov Ring Fixator: A Case Report.

Congenital pseudarthrosis of the tibia (CPT) is a rare, dysplastic condition that is characterized by a "false joint" in the tibia, leading to potential disability. We present a rare case report of a 12-year-old male from India with a history of neurofibromatosis type 1 (NF1) and anterolateral bowing of the tibia since birth. He sustained a tibial fracture during play. X-ray evaluation confirmed the fracture, and a clinical diagnosis of CPT was established. The treatment involved corticotomy for deformity correction and stabilization using Ilizarov's ring fixation. The procedure was successful, with post-operative radiological evaluations showing significant improvement in the center of rotation of angulation (CORA) from 60° pre-operatively to 25° post-operatively. The patient was discharged with an external fixator and after seven months, transitioned to full weight-bearing ambulation with a specialized brace. The Ilizarov procedure proved to be a safe and effective treatment for CPT, offering benefits such as limb lengthening and ankle stabilization.

An Isolated Case of Unilateral Macro-Ophthalmia With Resultant Anisometropic Amblyopia in Neurofibromatosis 1.

The most common causes of vision loss in neurofibromatosis 1 (NF1) patients are sequelae from tumors such as optic pathway glioma, plexiform neurofibroma, or secondary glaucoma. Here we report the case of a six-year-old female with anisometropic amblyopia resulting from an isolated unilateral macro-ophthalmia with a known history of NF1. Our patient progressed to light perception vision in the left eye due to a non-neoplastic cause associated with NF1 with at least two years of documented unilateral macro-ophthalmia without any ophthalmology referral or evaluation. This case aims to highlight the importance of early and deliberate ophthalmologic examination in all patients with neurofibromatosis 1 to assess for appropriate visual development and early intervention.

Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis.

OBJECTIVE: To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2). STUDY DESIGN: We conducted a systematic search of NF1 and NF2 incidence or prevalence studies, in OVID Medline, OVID Embase, Web of Science, and Cinahl. Studies were appraised with the Joanna Briggs Institute Prevalence Critical Appraisal tool. Pooled incidence and prevalence rates were estimated through random-effects meta-analysis. RESULTS: From 1,939 abstracts, 20 studies were fully appraised and 12 were included in the final review. Pooled NF1 prevalence was 1 in 3,164 (95%CI: 1 in 2,132-1 in 4,712). This was higher in studies that screened for NF1, compared to identification of NF1 through medical records (1 in 2,020 and 1 in 4,329, respectively). NF1 pooled birth incidence was 1 in 2,662 (95%CI: 1 in 1,968-1 in 3,601). There were only 2 studies on NF2 prevalence, so data were not pooled. Pooled NF2 birth incidence was 1.08 per 50,000 births (95%CI: 1 in 32,829-1 in 65,019). CONCLUSION: We present updated estimates of the incidence and prevalence of NF1 and NF2, to help plan for healthcare access and allocation. The prevalence of NF1 from screening studies is higher than from medical record studies, suggesting that the disease may be under recognized. More studies are needed regarding the prevalence of NF2.