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.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

A Systematic Review on Visual-Processing Deficits in Neurofibromatosis Type 1: What Possible Impact on Learning to Read?

This systematic review aimed to examine the possible implication of visual-perceptual, visuo-attentional and oculomotor processing in the reading deficits frequently experienced by children with Neurofibromatosis type 1 (NF1), as previously shown in dyslexia. Using PRISMA methodological guidelines, we examined 49 studies; most of these reported visual-processing deficits in this population, raising the importance of directly studying the visuo-perceptual and visuo-attentional processes and eye-movement control involved in the learning-to-read process in NF1. The discussion provides a reflection for a better understanding of how visual-processing skills interact with reading deficits in NF1, as well as new avenues for their screening and care.

Robotic resection for splenic artery aneurysm associated with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is an autosomal-dominant disease characterized by café-au-lait spots and neurofibromas, as well as various other symptoms in the bones, eyes, and nervous system. Due to its connection with vascular fragility, neurofibromatosis type 1 has been reported to be associated with vascular lesions, such as aneurysms. However, there have been few reports of abdominal visceral aneurysms associated with neurofibromatosis type 1. Furthermore, there have been no reports of robotic treatment of aneurysms associated with neurofibromatosis type 1. In this report, we describe the case of a patient with neurofibromatosis type 1 with a splenic artery aneurysm who was successfully treated with robotic surgery. CASE PRESENTATION: This report describes a 41-year-old Asian woman with a history of neurofibromatosis type 1 who was referred to our hospital for evaluation of a 28 mm splenic artery aneurysm observed on abdominal ultrasound. The aneurysm was in the splenic hilum, and transcatheter arterial embolization was attempted; however, this was difficult due to the tortuosity of the splenic artery. Thus, we suggested minimally invasive robotic surgery for treatment and resection of the splenic artery aneurysm with preservation of the spleen. The postoperative course was uneventful, and the patient was discharged on the eighth day after surgery. At 1 year of follow-up, the patient was doing well, with no evidence of recurrence. CONCLUSION: We encountered a rare case of splenic artery aneurysm in a patient with neurofibromatosis type 1 who was successfully treated with robotic surgery. There is no consensus on treatment modalities for neurofibromatosis-related aneurysms, and endovascular treatment is considered safe and effective; however, surgery remains an important treatment modality. Especially in patients with stable hemodynamic status, robotic surgery may be considered as definitive treatment. To our knowledge, this is the first successfully treated case of a splenic artery aneurysm in a patient with neurofibromatosis type 1.

The management of neurofibromatosis type 1 (NF1) in children and adolescents.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder characterized by multiple organ system involvement and a predisposition to benign and malignant tumor development. With revised NF1 clinical criteria and the availability of germline genetic testing, there is now an opportunity to render an early diagnosis, expedite medical surveillance, and initiate treatment in a prompt and targeted manner. AREAS COVERED: The authors review the spectrum of medical problems associated with NF1, focusing specifically on children and young adults. The age-dependent appearance of NF1-associated features is highlighted, and the currently accepted medical treatments are discussed. Additionally, future directions for optimizing the care of this unique population of children are outlined. EXPERT OPINION: The appearance of NF1-related medical problems is age dependent, requiring surveillance for those features most likely to occur at any given age during childhood. As such, we advocate a life stage-focused screening approach beginning in infancy and continuing through the transition to adult care. With early detection, it becomes possible to promptly institute therapies and reduce patient morbidity. Importantly, with continued advancement in our understanding of disease pathogenesis, future improvements in the care of children with NF1 might incorporate improved risk assessments and more personalized molecularly targeted treatments.

Multidisciplinary team for patients with neurocutaneous syndromes: The little discussed importance of dentistry.

Neurocutaneous syndromes comprise a heterogeneous group of congenital or hereditary conditions that are known to be associated with the risk of different disorders and complications. Two of the most common neurocutaneous syndromes are Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC). Although there appears to be a general consensus on the importance of a multidisciplinary approach in managing these cases, there is still very little emphasis in discussions addressed in the literature on the role of dentistry in accordance with the perspective of comprehensive care. Evidence-based propositions, together with a broad discussion of new insights in this regard, should have the ability to strongly impact related future perspectives, aiming for greater advances and better outcomes for these patients. In this review article, the authors discuss updated general aspects of NF1 and TSC, and the potential additional roles of dentistry, in addition to addressing suggestions for actions in dentistry at related levels of care, as well as priorities for future research.

A Giant Scrotal Neurofibroma in a Child Masquerading as Filariasis: Uncommon Presentation of a Common Disease.

Neurofibroma of the scrotum is a very uncommon benign neoplasm, specifically when it affects teenagers and is not associated with neurofibromatosis type I. To the best of our knowledge, only a couple of cases of neurofibroma in children have been documented. Here, we report a case study of a 17-year-old boy who had a giant scrotal lump for ten years masquerading clinically as filariasis. A provisional diagnosis of benign nerve sheath neoplasm was made based on cytology findings. The lump was surgically removed from the patient, and a histopathological and immunohistochemistry examination established the diagnosis of neurofibroma. The combined clinical, preoperative cytological, histological, and immunohistochemistry findings were not presented in the literature in any of the formerly documented cases of scrotal neurofibroma. The current case expands the spectrum of differential diagnoses for scrotal tumours that clinicians have previously observed.

Acquired myelinated retinal nerve fiber layer in a child with neurofibromatosis 1-related optic pathway glioma.

Myelinated retinal nerve fiber layer (RNFL) is a rare structural anomaly that occurs from abnormal myelination extending anterior to the lamina cribrosa. Clinically, myelinated RNFL is characterized as a gray-white lesion with feathered, well-demarcated borders obscuring the retinal vasculature. Myelinated RNFL is typically congenital, benign, and asymptomatic. It is most commonly noted as an incidental finding on ophthalmic examination. However, cases of acquired myelinated RNFL have been reported. We report the case of a patient with neurofibromatosis type 1 and optic pathway glioma with unilateral acquired myelinated RNFL.

Multimodal Imaging of Choroidal Nodules in Neurofibromatosis Type I.

AIM: To clarify the possibilities and role of posterior segment imaging in patients with neurofibromatosis type I (NF1), and to show the prevalence of this disease in the pediatric population in Slovakia. MATERIAL AND METHODS: Until recently, ophthalmologic consultations in patients with NF1 were limited mainly to the observation of Lisch nodules of the iris and the presence of optic nerve glioma. However, advances in imaging capabilities have made it possible to investigate and describe new f indings concerning the ocular manifestations of this disease. Between October 2020 and November 2021, we examined the anterior and posterior segment of 76 eyes (38 children ­ 12 boys and 26 girls) with genetically confirmed NF1 gene mutation at our clinic. The age of the patients ranged from 4 to 18 years. The anterior segment was checked for the presence of Lisch nodules biomicroscopically with a slit lamp. On the posterior segment, the presence of choroidal nodules was checked by various imaging methods ­ fundus camera, infrared confocal selective laser ophthalmoscopy, MultiColor imaging, OCT, and OCT angiography. All the patients had magnetic resonance imaging performed in order to detect potential optic nerve gliomas for the purpose of diagnosis. We observed the correlation between the patients' age, presence of Lisch nodules and the presence of choroidal nodules. Eight patients also had other manifestations of the disease ­ optic nerve gliomas or microvascular changes (so-called "corkscrew" vessels). RESULTS: Out of 38 patients, Lisch iris nodules were present in 20 patients (53%) and choroidal nodules in 24 patients (63%). There was no positive correlation between the presence of these two manifestations within the same patient or eye, but there is a clear correlation between the presence of choroidal nodules and patient age. CONCLUSION: The results suggest that a previously unknown ocular manifestation of neurofibromatosis type I, namely choroidal nodules, has a higher prevalence than Lisch nodules also in the pediatric population and can be easily visualized using various imaging modalities. It will be important to include follow-up observation of this finding among the standard controls for ocular findings in NF1, and it will be very interesting to correlate this f inding with the exact NF1 mutation

Genetically confirmed coexistence of neurofibromatosis type 1 and Cherubism in a pediatric patient.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder typified by various combination of numerous Café-au-lait macules, cutaneous and plexiform neurofibromas, freckling of inguinal or axillary region, optic glioma, Lisch nodules and osseous lesions. Cherubism is a rare genetic syndrome described by progressive swelling of the lower and/or upper jaw due to replacement of bone by fibrous connective tissue. Patients are reported in the literature with NF1 and cherubism-like phenotype due to the NF1 osseous lesions in the jaws. The purpose of this case report is the description of a young male genetically diagnosed with both NF1 and cherubism. METHODS AND RESULTS: A 9 years and six month old patient with clinical findings of NF1 and cherubism in whom both diseases were genetically confirmed, is presented. The patient was evaluated by a pediatrician, a pediatric endocrinologist, an ophthalmologist, and an oral and maxillofacial surgeon. A laboratory and hormonal screening, a histological examination, a chest X-ray, a magnetic resonance imaging (MRI) of the orbit and a digital panoramic radiography were performed. Genetic testing applying Whole Exome Sequencing was conducted. CONCLUSIONS: A novel and an already reported pathogenic variants were detected in NF1 and SH3BP2 genes, respectively. This is the first described patient with coexistence of NF1 and cherubism. The contribution of Next Generation Sequencing (NGS) in gene variant identification as well as the importance of close collaboration between laboratory scientists and clinicians, is highlighted. Both are essential for optimizing the diagnostic approach of patients with a complex phenotype.

Treatment With Selumetinib for Café-au-Lait Macules and Plexiform Neurofibroma in Pediatric Patients With Neurofibromatosis Type 1.

This case report describes 4 patients with a rare autosomal dominant multisystem disorder resulting from NF1 variants that leads to café-au-lait macules and neurofibromas.

The Relationship Between Choroidal Abnormalities and Visual Outcomes in Pediatric Patients With NF1-Associated Optic Pathway Gliomas.

BACKGROUND: Choroidal abnormalities (CAs) visualized on near-infrared reflectance (NIR) imaging are a new diagnostic criterion for neurofibromatosis type 1 (NF1), but the association between the presence of CAs and visual function remains unknown. This study evaluated the relationship between visual acuity (VA) with the presence, number, or total area of CAs visualized by NIR in children with NF1-associated optic pathway gliomas (NF1-OPGs). METHODS: Patients (<18 years) enrolled in a prospective longitudinal study of children with NF1-associated OPGs from 3 institutions were eligible if they had optical coherence tomography (OCT) of the macula (Heidelberg Spectralis) with ≥1 year of follow-up. The central 30° NIR images were reviewed by 2 neuro-ophthalmologists who manually calculated the number and total area of CAs. VA (logMAR) was measured using a standardized protocol. Cross-sectional associations of presence, number, and total area of CAs with VA, retinal nerve fiber layer thickness (RNFL), and ganglion cell-inner plexiform layer thickness were evaluated at the first and most recent visits using regression models. Intereye correlation was accounted for using generalized estimating equations. RESULTS: Eighty-two eyes of 41 children (56% female) were included. The mean ± SD age at the first OCT was 10.1 ± 3.3 years, with a mean follow-up of 20.4 ± 7.2 months. At study entry, CAs were present in 46% of eyes with a mean number of 2.1 ± 1.7 and a mean total area of 2.0 ± 1.7 mm 2 per eye. At the most recent follow-up, CAs were present in 48% of eyes with a mean number of 2.2 ± 1.8 lesions and a mean total area of 2.3 ± 2.1 mm 2 per eye. Neither VA nor OCT parameters at first and follow-up visits were associated with the presence, number, or total area of CAs (all P > 0.05). CONCLUSIONS: CAs are prevalent but not ubiquitous, in children with NF1-OPGs. Although CAs are a diagnostic criterion for NF1, their presence and size do not appear to be associated with visual function.

Breast density in NF1 women: a retrospective study.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by neurofibromin haploinsufficiency due to pathogenic variants in the NF1 gene. Tumor predisposition has long been associated with NF1, and an increased breast cancer (BC) incidence and reduced survival have been reported in recent years for women with NF1. As breast density is another known independent risk factor for BC, this study aims to evaluate the variability of breast density in patients with NF1 compared to the general population. Mammograms from 98 NF1 women affected by NF1, and enrolled onto our monocentric BC screening program, were compared with those from 300 healthy subjects to verify differences in breast density. Mammograms were independently reviewed and scored by a radiologist and using a Computer-Aided Detection (CAD) software. The comparison of breast density between NF1 patients and controls was performed through Chi-squared test and with multivariable ordinal logistic models adjusted for age, body mass index (BMI), number of pregnancies, and menopausal status.breast density was influenced by BMI and menopausal status in both NF1 patients and healthy subjects. No difference in breast density was observed between NF1 patients and the healthy female population, even after considering the potential confounding factors.Although NF1 and a highly fibroglandular breast are known risk factors of BC, in this study, NF1 patients were shown to have comparable breast density to healthy subjects. The presence of pathogenic variants in the NF1 gene does not influence the breast density value.

The role of scoliosis on the comorbidity and demographics of neurofibromatosis type 1 patients: A retrospective analysis of the National Inpatient Sample database.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome in the United States, affecting every 1 in 3000 individuals. NF1 occurs due to non-functional mutations in the NF1 gene, which expresses neurofibromin, a protein involved in tumour suppression. As a result, NF1 typically presents with non-cancerous neoplasm masses called neurofibromas across the body. Out of all NF1 abnormalities, the most common skeletal abnormality seen in around 10%-30% of NF1 patients is scoliosis, an improver curvature of the spine. However, there is a lack of research on the effects of scoliosis on demographics and morbidities of NF1 patients. We performed a national analysis to investigate the complex relationship between NF1 and scoliosis on patients' demographics and comorbidities. We conducted a retrospective cross-sectional analysis of the 2017 US National Inpatient Sample database using univariable Chi-square analysis and multivariable binary logistic regression analysis to determine the interplay of NF1 and scoliosis on patients' demographics and comorbidities. Our query resulted in 4635 total NF1 patients, of which 475 (10.25%) had scoliosis and 4160 (89.75%) did not. Demographic analysis showed that NF1 patients with scoliosis were typically younger, female and white compared to NF1 patients without scoliosis. Comorbidity analysis showed that NF1 patients with scoliosis were more likely to develop malignant brain neoplasms, epilepsy, hydrocephalus, pigmentation disorders, hypothyroidism, diabetes with chronic complications and coagulopathy disorders. NF1 patients with scoliosis were less likely to develop congestive heart failure, pulmonary circulation disease, peripheral vascular disease, paralysis, chronic pulmonary disease, lymphoma and psychosis. NF1 patients with scoliosis were predominantly younger, female, white patients. The presence of scoliosis in NF1 patients increases the risks for certain brain neoplasms and disorders but serves a protective effect against some pulmonary and cardiac complications.

Survival outcomes of malignant peripheral nerve sheath tumors (MPNSTs) with and without neurofibromatosis type I (NF1): a meta-analysis.

INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that demonstrate nerve sheath differentiation in the peripheral nervous system. They can occur sporadically or be associated with neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, with up to 13% of patients developing MPNSTs in their lifetimes. Previous studies have suggested conflicting findings regarding the prognosis of NF1 for patients with MPNSTs. The elucidation of NF1 as an independent prognostic factor on mortality has implications for clinical management. We aim to investigate the role of NF1 status as an independent prognostic factor of overall survival (OS) and disease-specific survival (DSS) in MPNSTs. METHODS: An electronic literature search of PubMed and MEDLINE was performed on studies reporting OS or DSS outcomes of MPNSTs with and without NF1. A grey literature search by reviewing bibliographies of included studies and review articles was performed to find pertinent studies. Data was extracted and assessed in accordance with the PRISMA guidelines. A meta-analysis was performed to calculate hazard ratios (HRs) using a random-effects model. The primary and secondary outcomes were all-cause and disease-specific mortality, respectively, with NF1 as an independent prognostic factor of interest. RESULTS: A total of 59 retrospective studies involving 3602 patients fulfilled the inclusion criteria for OS analysis, and 23 studies involving 704 MPNST patients were included to evaluate DSS outcomes. There was a significant increase in the hazard of all-cause mortality (HR 1.63, 95% CI 1.45 to 1.84) and disease-specific mortality (HR 1.52, 95% CI 1.24 to 1.88) among NF1 as compared to sporadic cases. Subgroup analyses and meta-regression showed that this result was consistent regardless of the quality of the study and year of publication. CONCLUSION: NF1 is associated with a substantially higher risk of all-cause and disease-specific mortality. This finding suggests that closer surveillance is required for NF1 patients at risk of developing MPNSTs.

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.

Perception and recognition of primary and secondary emotions by children with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic disease that can lead to impaired social adaptation and functioning, thus affecting quality of life. To date, studies of these children's social cognition abilities have been scant and far from exhaustive. Therefore, the purpose of the present study was to assess the ability of children with NF1, compared with controls, to process facial expressions of emotions - not only including the usual primary emotions (happiness, anger, surprise, fear, sadness and disgust), but secondary emotions, too. To do so, the links between this ability and the characteristics of the disease (mode of transmission, visibility, and severity) were examined. A total of 38 children with NF1 aged 8-16 years 11 months (mean = 11.4, SD = 2.3) and 43 sociodemographically comparable control children performed the emotion perception and recognition tests of a social cognition battery. Results confirmed that the processing of primary and secondary emotions is impaired in children with NF1, but there were no significant links with either mode of transmission, severity, or visibility. These results encourage further comprehensive assessments of emotions in NF1, and suggest that investigations should be extended to higher level social cognition skills, such as theory of mind and moral judgments.

Neuropsychological factors associated with performance on the rey-osterrieth complex figure test in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) are at considerable risk for cognitive difficulties, including visuospatial deficits and executive dysfunction. This study aimed to (1) assess the overall performance of children with NF1 on the Rey-Osterrieth Complex Figure Test (RCFT) compared to unaffected siblings and (2) examine neuropsychological predictors of RCFT performance in children with NF1. A retrospective clinical audit was performed on neuropsychological records from a multidisciplinary NF1 Clinic in Australia. We searched for children that had completed an assessment between 2000 and 2015 which included the RCFT and other neuropsychological outcomes in this study. These included the Wechsler Intelligence Scale for Children, Judgment of Line Orientation (JLO), Tower of London test, Conners ADHD Scales, and the Behavioral Rating Inventory of Executive Function (BRIEF). The study population consisted of 191 children with NF1 aged 6-16 years, and 55 unaffected siblings recruited from a separate study. Results revealed that 62% of children with NF1 performed at or below the first percentile on the RCFT copy, which was significantly worse than their unaffected siblings. Visuospatial skills, parent-rated executive abilities, ADHD symptoms, and intellectual skills all predicted poorer performance on the RCFT copy, however the best fitting multiple regression model only contained the JLO, BRIEF Metacognition Index, and chronological age. The JLO emerged as the strongest predictor of RCFT performance. This study provides evidence that visuospatial deficits are a key driver of reduced RCFT performance in NF1 and that executive skills as well as a younger age are also independent predictors of RCFT performance.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.