Neurofibromatosis Type 1 Disease Research Articles

Visual Deficits and Diagnostic and Therapeutic Strategies for Neurofibromatosis Type 1: Bridging Science and Patient-Centered Care.

Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the Nf1 tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.

The Lack of Ad Hoc Neuropsychological Assessment in Adults with Neurofibromatosis: A Systematic Review.

Background: Neurofibromatosis Type 1 (NF1) is a genetic autosomal dominant disorder that affects both the central and peripheral nervous systems. Children and adolescents with NF1 commonly experience neuropsychological, motor, and behavioral deficits. The cognitive profile hallmark of this disorder includes visuospatial and executive function impairments. These cognitive disorders may persist into adulthood. This study aims to analyze previous research studies that have described cognitive dysfunctions in adults with NF1. The purpose of this analysis is to review the neuropsychological and psychological assessment methods used. Methods: A total of 327 articles were identified based on the search terms in their titles and abstracts. The evaluation was conducted by scrutinizing each article's title, abstract, and text. Results: Only 16 articles were found to be eligible for inclusion based on the pre-defined criteria. The selected studies primarily focus on the development of diagnostic protocols for individuals with NF1. Conclusions: The management of NF1 disease requires a multidisciplinary approach to address symptoms, preserve neurological functions, and ensure the best possible quality of life. However, cognitive impairment can negatively affect psychological well-being. This study suggested that cognitive functions in NF1 patients were not tested using specific measures, but rather were evaluated through intelligence scales. Additionally, the findings revealed that there is no standardized neuropsychological assessment for adults with NF1. To address this gap, it would be helpful to create a specific neuropsychological battery to study cognitive function in NF1 patients during clinical studies. This battery could also serve as a tool to design models for cognitive rehabilitation by using reliable and sensitive measures of cognitive outcomes.

Evaluation of ocular and genetic findings in patients with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease affecting multiple organ systems and showing many different clinical symptoms. The severity of the disease varies from person to person and progresses gradually over the years. In this study, 17 NF1 patients who had a definite diagnosis were evaluated in terms of genetic, ophthalmological, and nervous system investigations. Approximately 5000 patients who visited medical genetics clinic between 2012 and 2022 are recorded in our archive. In 17 of these patients, a definitive genetic diagnosis was made. In the course of the study, the researchers collected some clinical parameters such as antenatal, intrapartum, and postpartum history and family history. In the family history, the researchers did a detailed pedigree with at least 3 generations of analysis, questioned parental kinship, looked for similar members in families, and identified inheritance patterns of the disorder. Peripheral venous blood samples were taken from the patients and sent to a commercial laboratory for gene panels or WES while the karyotyping was carried out in our laboratory. After obtaining the definitive genetic diagnosis of all patients, we compiled a table with the other parameters we questioned. This study presented the genotype and phenotype findings of NF1 patients. Ophthalmological symptoms in patients were also examined. These new-generation genetic disease diagnosis methods can be routinely used in clinical practice by medical geneticists. The diagnosis of a disease is one step ahead of its treatment. Because if the necessary diagnosis is not made, treatment of the disease is not possible. While this situation was more difficult in the past, nowadays, with the developing technology, diseases can be diagnosed more easily. In NF1 disease, more information can be obtained as a result of genetics, imaging, and examinations of other branches.

Novel, heterozygous, de novo pathogenic variant (c.4963delA: p.Thr1656Glnfs*42) of the NF1 gene in a Chinese family with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) presents an autosomal dominant, haploinsufficient, and multisystemic disorder with patches of skin café-au-lait spots, lisch nodules in the iris, even tumors in the peripheral nervous system or fibromatous skin. In this study, a Chinese young woman who suffered from NF1 disease with first-trimester spontaneous abortion was recruited. Analysis for whole exome sequencing (WES), Sanger sequencing, short tandem repeat (STR), and co-segregation was carried out. As results, a novel, heterozygous, de novo pathogenic variant (c.4963delA:p.Thr1656Glnfs*42) of the NF1 gene in the proband was identified. This pathogenic variant of the NF1 gene produced a truncated protein that lost more than one-third of the NF1 protein at the C-terminus including half of the CRAL-TRIO lipid-binding domain and nuclear localization signal (NLS), thus leading to pathogenicity (ACMG criteria: PVS1 + PM2 + PM2). Analysis for NF1 conservation in species revealed high conservation in different species. Analysis of NF1 mRNA levels in different human tissues showed low tissue specificity, which may affect multiple organs presenting other symptoms or phenotypes. Moreover, prenatal NF1 gene diagnosis showed both alleles as wild types. Thus, this NF1 novel variant probably underlays the NF1 pathogenesis in this pedigree, which would help for the diagnosis, genetic counseling, and clinical management of this disorder.

Novel, heterozygous, pathogenic variant (c.4272delA: p.I1426Ffs*2) for the NF1 gene in a large Chinese family with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant with haploinsufficient, and multisystemic disorder including patches of skin Café-au-lait spots, Lisch nodules in the iris, and tumors in the peripheral nervous systems or fibromatous skin. Blood samples were collected and DNA was extracted from a large Chinese pedigree suffering from NF1 disease with three spontaneous abortions or death for proband. Analysis for whole exome sequencing (WES), Sanger sequencing, and co-segregation was carried out. Prenatal gene diagnosis was also carried out in amniotic fluid DNA. The expression of NF1 was conducted by bioinformatics. A large Chinese pedigree with NF1 was recruited and a novel, heterozygous, variant (c.4272delA: p.I1426Ffs*2) for the NF1 gene in the proband was identified. This variant of NF1 produced a truncated protein that losses half of NF1 protein at the C-terminus including the CRAL-TRIO lipid-binding domain, NLS, and a small portion of Ras-GAP domain, thus leading to pathogenicity (ACMG criteria: PVS1 + PM2). NF1 expressions in different human tissues showed low tissue specificity, which may affect multiple organs presenting different phenotypes. Moreover, prenatal gene diagnosis for NF1 showed both alleles as wild types in the fetus of the proband. We thus successfully identified a novel, pathogenic, heterozygous variant (c.4272delA:p.I1426Ffs*2) in the NF1 gene of NF1 disorder, expanding the NF1 mutation spectrum, that will help elucidate the molecular pathogenesis of NF1 disease and to contribute to the NF1 diagnosis, genetic counseling, clinical management in this large Chinese family.

Clinical Outcome After Pencil Beam Scanning Proton Therapy of Patients With Non-Metastatic Malignant and Benign Peripheral Nerve Sheath Tumors

ObjectivePeripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally invasive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the genetic disorder neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of the dose delivered to organs at risk and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT.MethodsWe retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty-eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. The median age was 32 years (range, 3–75), and 25 (69%) patients were male. mPNST and PNST were diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to Common Terminology Criteria for Adverse Events, version 4.1 (CTCAE v4.1). Overall survival (OS), local control (LC), and distant control (DC) were estimated using the Kaplan–Meier method.ResultsWith a median follow-up time of 31 months (range, 4–194), 13 (36%) patients died from a progressive disease, 8 (22%) experienced local failure, and 14 (39%) experienced distant failure after PBSPT. Estimated 2-year OS, LC, and DC were 75.5%, 73.5%, and 61.2%, respectively. Acute grade 3 toxicity (dermatitis, mucositis, and pain) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis were both observed in 1 (3%) patient at 34 and 194 months after PBSPT, respectively. There was no late grade >3 toxicity or radiation-induced secondary cancer.ConclusionTo our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy using a PBS delivery paradigm. In our cohort, consisting mainly of patients with mPNSTs, we report reasonable oncological outcomes and low toxicity rates after PBSPT.

Verbal learning and memory in youth with neurofibromatosis type 1 and plexiform neurofibromas: Relationships with disease severity.

To provide a comprehensive characterization of verbal learning and memory (VLM) abilities in youth with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and to evaluate disease severity as a predictor of VLM functioning over time. As part of a longitudinal natural history study, youth with NF1 and PNs were administered repeat neuropsychological assessments, including measures of VLM and ratings of NF1 disease severity completed by a medical professional. This sub-study analyzed data from 89 patients (M age baseline=13.1, SD=4.3 years, range 6-24 years) who had completed tests of VLM abilities and verbal attention at either baseline and/or 36 months. VLM scores across the sample fell predominantly within the average range of functioning at both time points. However, relative to peers with mild NF1 disease severity, youth with moderate/severe NF1 disease showed lower functioning across multiple VLM domains at 36 months, even after controlling for the effects of verbal attention. Exclusive use of overall domain scores does not fully characterize VLM functioning in youth with NF1 and PNs. Additionally, children and adolescents with more severe NF1 disease should be monitored more closely for verbal memory challenges and targeted for interventions.

Impact of neurofibromatosis type 1 in an adult community population.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome with varying manifestations and severity. Adult NF1 patients often experience fragmented care, so we sought to characterize the health and demographic features of a community-based population of adults with NF1 and hypothesized that lack of a specialty clinic for adult NF1 patients correlates with unmet needs. Retrospective case-control study of all adult cases of NF1 among 4.06 million medical records in a Pacific Northwest population. 122 case charts were reviewed to ascertain NF1 disease features, comorbidities, and severity of disease. A 1:1 control cohort was selected by matching case/control by age, sex, and ZIP code to compare demographic features and health status. Adult NF1 patients were less likely to have private insurance, be employed, and have children, but were equally likely to be married. One half of cases had disease features compromising health and well-being, and care involved 26 different specialties. Excluding neurofibromas, 43% of cases had cancer compared to 10% of controls [P < .0001, OR 5.38 (2.53-11.4)]. Only 27% of women ages 30-50 had undergone age-appropriate enhanced breast cancer surveillance. Behavioral health problems were found in 60% of NF1 patients compared to 37% of controls [P < .001, OR 2.61 (1.52-4.50)]. 93% of cases referred to a NF1 specialty center underwent a change in management upon establishing care. NF1 patients may benefit from coordinated management of care in a specialty center.

Exploring associations between constipation, severity of neurofibromatosis type 1 and NF1 mutational spectrum

Neurofibromatosis type 1 (NF1) is inherited in an autosomal dominant manner and is a rather common rare disease. Until recently, studies on gastrointestinal symptoms in patients with NF1 have been few and mostly described as case reports. In three previously published studies, the frequency of constipation in patients with NF1 has been found to be as high as 30%. In this study, associations between the frequency of constipation and NF1 disease severity and NF1 mutational spectrum were investigated. Among 277 patients with NF1, 49 had constipation. The highest rate of constipation was found among patients with a high perception of NF1 illness burden, and patients with constipation had a significantly higher NF1 illness burden when comparing the “not bothered” and the “very bothered” (p = 0.013). We found no significant association between constipation and the remaining measures on severity of NF1, nor between constipation and genetic variants. When observing the NF1 mutational spectrum, one variant (c.1013A>G (p.Asp338Gly/p.?) was identified in three patients with constipation of which two patients were related. The variant c.2970_2972delAAT (p.Met992del) associated with a mild NF1 phenotype was identified in two related patients with constipation. This study is the first to explore the association between symptoms of constipation, NF1 severity, and NF1 mutational spectrum. The results suggest an association between constipation and a high degree of illness burden. Awareness of this association among physicians could lead to more patients with NF1 being diagnosed with constipation. Constipation impacts on quality of life, hence a timely diagnosis and treatment will improve quality of life.

Neurofibromatosis type 1: evaluation by chest computed tomography.

ObjectiveThe aim of this study was to evaluate chest computed tomography (CT) findings in patients diagnosed with neurofibromatosis type 1 (NF1).Material and MethodsThis was a retrospective study in which we reviewed the chest CT scans of 14 patients diagnosed with NF1 and neurofibromatosis-associated diffuse lung disease (NF-DLD). The sample comprised eight women and six men. The median age was 55 years (range, 11-75 years). The diagnosis of NF1 was made on the basis of the diagnostic criteria established by the U.S. National Institutes of Health. The images were analyzed by two chest radiologists, who reached decisions by consensus.ResultsThe predominant CT finding of NF-DLD was multiple cysts, which were observed in 13 patients (92.9%), followed by emphysema, in eight (57.1%) and subpleural bullae, in six (42.9%). Other findings included subcutaneous neurofibromas, in 12 patients (85.7%), ground-glass opacities, in one (7.1%), and tracheobronchial neurofibromas, in one (7.1%). The pulmonary abnormalities were bilateral in 12 cases (85.7%). The abnormalities were predominantly in the upper lung fields in eight cases (57.1%), and their distribution was random in 11 (78.6%).ConclusionPulmonary cysts, emphysema, and subpleural bullae appear to be the chest CT findings that are most characteristic of NF-DLD.

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design.

Simple SummaryWe herein describe the relevance of Vitamin D for human health, with a special focus on its role in Neurofibromatosis type 1 (NF1) disease. Indeed, epidemiological studies revealed that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of NF1. NF1 is an autosomal dominant syndrome with a severe predisposition in developing tumors and for which limited treatment options are thus far available. In this context, vitamin D or its analogues has been used to treat both skin and bone lesions in NF1 patients, alone or in association with other therapeutic agents. We provide an exhaustive and detailed analysis of the most relevant preclinical and clinical studies aimed at analyzing the correlation between vitamin D deficiency and NF1 lesion progression. This review can add a valuable contribution to the current knowledge of NF1 disease investigating possible therapeutic strategies to ameliorate NF1 conditions.Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production—occurring in the skin and dependent on sun exposure—contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.

Treatment of malignant peripheral nerve sheath tumors in pediatric NF1 disease

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas. Children with neurofibromatosis type 1 (NF1) have a 10% lifetime risk for development of MPNST. Prognosis remains poor and survival seems worse for NF1 patients.MethodsThis narrative review highlights current practices and pitfalls in the management of MPNST in pediatric NF1 patients.ResultsPreoperative diagnostics can be challenging, but PET scans have shown to be useful tools. More recently, functional MRI holds promise as well. Surgery remains the mainstay treatment for these patients, but careful planning is needed to minimize postoperative morbidity. Functional reconstructions can play a role in improving functional status. Radiotherapy can be administered to enhance local control in selected cases, but care should be taken to minimize radiation effects as well as reduce the risk of secondary malignancies. The exact role of chemotherapy has yet to be determined. Reports on the efficacy of chemotherapy vary as some report lower effects in NF1 populations. Promisingly, survival seems to ameliorate in the last few decades and response rates of chemotherapy may increase in NF1 populations when administering it as part of standard of care. However, in metastasized disease, response rates remain poor. New systemic therapies are therefore desperately warranted and multiple trials are currently investigating the role of drugs. Targeted drugs are nevertheless not yet included in first line treatment.ConclusionBoth research and clinical efforts benefit from multidisciplinary approaches with international collaborations in this rare malignancy.

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review.

Neurofibromatosis type 1 (NF1) is one of the most frequent monogenetic disorders. It can be associated with cognitive dysfunctions in several domains such as executive functioning, language, visual perception, motor skills, social skills, memory and/or attention. Neuroimaging is becoming more and more important for a clearer understanding of the neural basis of these deficits. In recent years, several studies have used different imaging techniques to examine structural, morphological and functional alterations in NF1 disease. They have shown that NF1 patients have specific brain characteristics such as Unidentified Bright Objects (UBOs), macrocephaly, a higher volume of subcortical structures, microstructure integrity alterations, or connectivity alterations. In this review, which focuses on the studies published after the last 2 reviews of this topic (in 2010 and 2011), we report on recent structural, morphological and functional neuroimaging studies in NF1 subjects, with special focus on those that examine the neural basis of the NF1 cognitive phenotype. Although UBOs are one of the most obvious and visible elements in brain imaging, correlation studies have failed to establish a robust and reproducible link between major cognitive deficits in NF1 and their presence, number or localization. In the same vein, the results among structural studies are not consistent. Functional magnetic resonance imaging (fMRI) studies appear to be more sensitive, especially for understanding the executive function deficit that seems to be associated with a dysfunction in the right inferior frontal areas and the middle frontal areas. Similarly, fMRI studies have found that visuospatial deficits could be associated with a dysfunction in the visual cortex and especially in the magnocellular pathway involved in the processing of low spatial frequency and high temporal frequency. Connectivity studies have shown a reduction in anterior-posterior “long-range” connectivity and a deficit in deactivation in default mode network (DMN) during cognitive tasks. In conclusion, despite the contribution of new imaging techniques and despite relative advancement, the cognitive phenotype of NF1 patients is not totally understood.

Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment.

Neurofibromatosis type 1 (NF1) is the most common of a group of rare diseases known by the term, "Neurofibromatosis," affecting 1 in 3000 to 4000 people. NF1 patients present with, among other disease complications, café au lait patches, skin fold freckling, Lisch nodules, orthopedic complications, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, cognitive impairment, and chronic pain. Although NF1 patients inevitably express pain as a debilitating symptom of the disease, not much is known about its manifestation in the NF1 disease, with most current information coming from sporadic case reports. Although these reports indicate the existence of pain, the molecular signaling underlying this symptom remains underexplored, and thus, we include a synopsis of the literature surrounding NF1 pain studies in 3 animal models: mouse, rat, and miniswine. We also highlight unexplored areas of NF1 pain research. As therapy for NF1 pain remains in various clinical and preclinical stages, we present current treatments available for patients and highlight the importance of future therapeutic development. Equally important, NF1 pain is accompanied by psychological complications in comorbidities with sleep, gastrointestinal complications, and overall quality of life, lending to the importance of investigation into this understudied phenomenon of NF1. In this review, we dissect the presence of pain in NF1 in terms of psychological implication, anatomical presence, and discuss mechanisms underlying the onset and potentiation of NF1 pain to evaluate current therapies and propose implications for treatment of this severely understudied, but prevalent symptom of this rare disease.

Malignant Peripheral Nerve Sheath Tumor Is a Challenging Diagnosis: A Systematic Pathology Review, Immunohistochemistry, and Molecular Analysis in 160 Patients From the French Sarcoma Group Database.

An accurate histopathologic diagnosis is essential for an adequate treatment of soft tissue sarcomas. The diagnosis of malignant peripheral nerve sheath tumor (MPNST) can be complex, particularly outside the neurofibromatosis type 1 (NF1) context. MPNST is a rare malignancy, and due to the lack of specific histologic criteria, several differential diagnoses must be considered. A total of 350 patients diagnosed with MPNST (from 1990 to 2013) were retrieved from the French sarcoma network (RRePS) and the Conticabase (Connective Tissue Cancer Network database). Tumor samples were available for 160 cases (45.2%). Pathology review, immunohistochemistry (IHC), and molecular analysis (when dealing with a monomorphic sarcoma) were systematically performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic factors for the definitive primary MPNST (n=106) cohort. Twenty-nine tumors (18.1%) initially diagnosed as MPNST were reclassified on the basis of histologic review, IHC, and molecular analysis. Patients with NF1 disease comprised 64% of the remaining cohort. The 5-year overall survival for patients from the entire cohort was 47%, 34.8% for NF1 patients, and 68.5% for patients without NF1 disease, making NF1 syndrome an independent poor prognostic factor of survival. Positive margins and lack of radiation therapy were independent predictors of local recurrence. The Fédération Nationale des Centres de Lutte Contre le Cancer tumor grade was an independent prognostic indicator of metastasis. Given the therapeutic implications of a misdiagnosis, the systematic pathology review, IHC, and molecular analysis (when dealing with monomorphic sarcoma) strategy allowed reclassification of 20% of cases, mainly the sporadic MPNSTs.

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor.

Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS-MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5-10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

Teenagers and young adults with neurofibromatosis type 1 are more likely to experience loneliness than siblings without the illness.

Our clinical observations raised concern that teenagers and young people with neurofibromatosis type 1 (NF1) might feel lonely and we decided to investigate their experiences and compare them with unaffected siblings. We also assessed predictive factors of loneliness. We evaluated 60 NF1 patients aged 17 (±3.1) years and 23 siblings aged 17 (±2.9) years with a self-report questionnaire that assessed loneliness, depression, shyness, self-esteem, social support, bullying and difficulties making friends. Objective assessments of NF1 disease severity and visibility and somatic NF1-related and social support-related variables were carried out. Multiple linear regression analysis was performed. Of the 60 patients with NF1, 11 (18%; CI: 8-28%) said that they felt lonely often or always and felt a higher degree of loneliness, but none of the siblings said that they felt lonely. Predictors of loneliness were depression, shyness, bullying, self-perceived conception of illness burden and a low level of social support from friends. Teenagers and young adults with NF1 experienced a higher prevalence and higher degree of loneliness than siblings of NF1 patients. As loneliness affects social, affective and cognitive functions, increased attention on loneliness and the predictive factors described in this study are required.

Development and validation of the English Pain Interference Index and Pain Interference Index-Parent report.

Measurement of pain interference in children is challenged by a lack of validated measures with a parent proxy report. This study investigated the psychometric properties of the Pain Interference Index (PII), a six-item questionnaire originally developed in Swedish, in chronically ill youth. We adapted the PII for English-speaking participants and created a parallel parent proxy measure. Respondents indicate how much pain has interfered with the child's life in the past 2 weeks (0-6 scale); higher scores indicate more pain interference. Eligible participants included individuals 6-25 years with neurofibromatosis type 1 (NF1) and cancer. Internal consistency was assessed; validity was examined by correlating PII scores with existing measures of pain interference (Modified Brief Pain Inventory [MBPI]) and pain intensity (visual analogue scale [VAS]), and with measures of disease severity. Among 60 participants (mean age 14.7 years, range 6-24) and their parents, PII internal consistency was 0.84 and 0.96, respectively. PII scores correlated with MBPI (r = 0.81, P < 0.0001) and VAS (r = 0.55, P < 0.0001) scores and differentiated between patients with mild vs moderate/severe NF1 disease severity (P < 0.05). The PII-Parent was significantly correlated with the mothers' and fathers' VAS rating of the child's pain intensity (Ps < 0.01). Internal consistency of the English PII is high; validity is supported by the PII's correlations with other measures of pain interference and pain intensity, and with disease severity in patients with NF1. Preliminary data indicate that the English PII is a reliable, valid, feasible pain interference measure for youth with NF1 and cancer.

An Unusual Case of Obscure Gastrointestinal Bleeding in a Patient With Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is the most common (0.03%) autosomal dominant inherited disorder.1 In NF1, neurogenic and carcinoid tumors occur as a result of transformation of an endodermal-ectodermal complex that is present near the ampulla of Vater. The mutation of the NF1 gene (17q11.2) is responsible for NF1 disease. This gene encodes for neurofibromin, a guanosine triphosphatase protein involved as a negative regulator of the Ras pathway and in particular of mammalian target of rapamycin function, whose overactivation may be a key event in neuroendocrine tumor development in this area.

Neurofibromatosis Type 1 (von Recklinghausen's disease) in Pregnancy: cesarean delivery outcomes – case report

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen’s disease, is a genetic neurological disorder characterized by cutaneous and plexiform neurofibromas, café-au-lait spots, Lisch nodules, freckling in axillary and inguinal regions, optic gliomas, bone abnormalities and an increased risk of malignancy. It is also reported to be associated with adverse perinatal outcome in pregnant women. This article presents a case of a pregnant woman with a known NF1 disease since childhood, with a Fourth Ventricle benign tumor surgery, a permanent ventriculoperitoneal shunt and a Right Bundle Branch Block (RBBB). However, this is a case with a normal obstetric outcome, without the aggravation of dermatological lesions of the condition during pregnancy.