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Vivian Reinhold,1 Antti Saarinen,2 Eetu Suominen,2 Stina Syrjänen,3,4 Minna Kankuri-Tammilehto1,5 1Institute of Biomedicine, University of Turku, Turku, Finland; 2Department of Paediatric Orthopaedic Surgery, University of Turku and Turku University, Turku, Finland; 3Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland; 4Department of Pathology, University of Turku, Turku University Hospital, Turku, Finland; 5Department of Clinical Genetics, Turku University Hospital and University of Turku, Turku, FinlandCorrespondence: Vivian Reinhold, Institute of Biomedicine, Department of Clinical Genetics, Turku University Hospital and University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland, Tel +358503453948, Email vivvis@utu.fiBackground: Neurofibromatosis 1 (NF1) is a relatively common genetic disorder linked to skeletal abnormalities and elevated risk of cancer. Early onset scoliosis is common in patients with NF1 although severe scoliosis is rare. Scoliosis complicates the normal development and growth and may lead to thoracic insufficiency syndrome. The increased risk for breast cancer in young NF1 female patients has been recently identified.Case Presentation: We describe a NF1 patient with dystrophic scoliosis symptoms emerged at childhood. At 37 years of age major scoliosis curve in the thoracolumbar region was 80 degrees. The patient was diagnosed with breast cancer at the age of 37 years, histologically the breast cancer was ductal, hormone receptor positive and Her2-positive.Results: A novel pathogenic variant in NF1 p.(Trp2348*) was identified by next-generation sequencing method. The patient did not have pathogenic variants in BRCA genes or in other currently known hereditary breast cancer genes.Conclusion: Here, we describe a novel pathogenic variant in NF1 named p.(Trp2348*) which may cause severe dystrophic scoliosis and deteriorate the quality of life and physical function, as well as Her-2 positive breast cancer. Untreated dystrophic scoliosis in patients with NF1 may result in significant spinal deformity and deteriorate the quality of life and physical function. Genetic counseling is recommended in all patients with NF1. Patients need routine follow-up throughout life. Multidisciplinary consulting is warranted in patients with neurofibromatosis 1.Keywords: spinal deformity, neurofibromatosis, breast cancer

Neurofibromatosis type 1 (NF1) results from germline mutations in the tumor-suppressor gene NF1 and predisposes patients to developing nervous system tumors. Twenty percent of NF1 patients harbor nonsense mutations resulting in premature termination codons (PTCs). Nonsense suppression therapies can facilitate ribosomal readthrough of PTCs to restore full-length protein, but their potential in NF1 is underexplored. We developed a minipig model of NF1 carrying a PTC to test whether nonsense suppression could restore expression of the NF1-encoded protein neurofibromin in vitro and in vivo. Nonsense suppression did not reliably increase neurofibromin in primary NF1−/− Schwann cells isolated from minipig neurofibromas but could reduce phosphorylated ERK. Gentamicin in vivo produced a similar plasma pharmacokinetic profile to humans and was detectable in clinically relevant tissues, including cerebral cortex, sciatic nerve, optic nerve, and skin. In gentamicin-treated animals, increased neurofibromin expression was seen in the optic nerve. Nonsense-mediated decay (NMD) causes degradation of transcripts with PTCs, which could impede nonsense suppression therapies. Nonsense suppression in combination with NMD inhibition restored neurofibromin protein expression in primary NF1−/− Schwann cells isolated from minipig neurofibromas. Thus, the effectiveness of nonsense suppression therapies can be improved in NF1 by the concurrent use of NMD inhibitors.

Segmental pigmentation anomalies can be further divided into segmental pigmentation disorder (SPD) complex and café-au-lait macules (CALMs). Both are congenital skin conditions characterized by hyper- or hypopigmentation. Segmental pigmentation disorder is a rare entity, whereas CALMs are common skin lesions that may be associated with various genetic conditions, especially when several are present and the patient has other indicators of a genetic abnormality. When the CALM is segmental, segmental neurofibromatosis (type V) may be considered in the differential diagnosis. Herein we present a 48-year-old woman with a history of malignant melanoma who presented with a large, linear, hyperpigmented patch on her shoulder and arm, present since around birth. The differential diagnosis consisted of CALM versus hypermelanosis (a subtype of SPD). Given a family history of a similar lesion, in addition to a personal and family history of melanoma and internal cancers, a hereditary cancer panel was completed demonstrating genetic variance of uncertain significance. This case brings attention to a rare dyspigmentation disorder and questions a possible association with melanoma.

Beyond the commonly known clinical presentation of neurofibromatosis, vascular pathologies are increasingly becoming a known complication. We present a case of a 41-year-old adult with neurofibromatosis type 1 who came with a right-sided spontaneous hemothorax due to a ruptured 13-mm fusiform aneurysm of the right posterior T9 intercostal artery. Patient underwent a transcatheter angiographic embolization with subsequent video-assisted thoracic surgery (VATS) for a retained hemothorax. Patient was discharged home on Hospital Day 5, and follow-up imaging demonstrated a complete resolution of the hemothorax. This presented case contributes to literature by demonstrating intra-arterial embolization as a viable option to obtain hemostasis in fragile vessels. However, this may not always result in hemostasis, and VATS should be considered to achieve and ensure complete hemostasis. [ABSTRACT FROM AUTHOR]

Intravestibular schwannomas are rare tumors within the intralabyrinthine region and involve different management considerations compared to more common vestibular schwannomas. In this report, the authors review a case of a 52-year-old woman who presented with hearing loss and vestibular symptoms and was found to have a left intravestibular schwannoma. Given her debilitating vestibular symptoms, she underwent microsurgical resection. In this video, the authors review the relevant anatomy, surgical technique, and management considerations in these patients. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID2187.

Introduction Pseudarthrosis and bone defects are the most common consequence of neurofibromatosis type I in children, a rare hereditary disease. Destruction of bone tissue leads to severe deformities and impaired function of the limbs. Disability in such patients may reach 70 %. Surgical treatment of children with this pathology is long, laborious and multi-stage. Traditional orthopaedic methods for managing bone defects are often ineffective. The development of microsurgical methods enables to perform bone transfer of blood-supplied bone autografts. Purpose To prove the effectiveness of using microsurgical autologous transfer of the vascularized fibula for plastic surgery of bone defects in children with neurofibromatosis type I. Materials and methods A retrospective monocenter study included 27 pediatric patients who underwent reconstruction of bone defects with a vascularized fibular autograft from 2011 to 2021. The etiology of the bone defect in all patients was neurofibromatosis type I. A fibula graft was used to reconstruct 8 tibiae and 19 forearms. Bone defects averaged 12 cm. Median follow-up was 60 months. Results The fibula graft survival rate was 100 %. In 5 cases, nonunion of the proximal part of the fibula and the recipient zone was obtained which required iliac crest grafting. The overall rate of good and excellent results was 74 %. The average time to consolidation was 3 months. Discussion According to the literature, the use of autografting of vascularized bone fragments is a ather limited procedure in children with neurofibromatosis type I as it is associated with an increased risk of complications. Due to the restoration of blood flow in the transferred vascularized autograft, it retains its viability and the possibility of bone tissue remodeling. Conclusion Microsurgical autologous transfer of a vascularised fragment of the fibula is an effective and at times indispensable method of bone plasty in long bone defects in children with type 1 neurofibromatosis. Bone defects larger than 5 cm are an indication for free autologous transfer of a vascularized fragment of the fibula. This method, used in combination with traditional orthopedic methods for the treatment of children, allows obtaining good anatomical and functional results.

Abstract Background Neurofibromatosis type 2 is an autosomal dominant disorder, mainly characterized by multiple neurological lesions, such as schwannomas, meningiomas, neurofibromas and intramedullary ependymomas. Schwannomas are usually small circumscribed lesion. Sacral location of a schwannoma with cystic change is a very rare finding. We are presenting one such case with giant cystic schwannoma with fluid–fluid levels in sacral region. Case presentation We present a case of 13-year-old female patient, presenting with pelvic pain and gradually progressive bilateral lower limb weakness. On MRI, giant cystic schwannoma with internal fluid–fluid levels was noted in sacral region, extending anteriorly into the presacral region, causing mass effects on pelvic organs, which explained the cause of her symptoms. She also showed the presence of bilateral vestibular schwannoma and multiple small cerebral lesions, leading to the diagnosis of neurofibromatosis type 2. Conclusions Our current case of neurofibromatosis type 2, diagnosed by presence of bilateral vestibular schwannoma, shows atypically large sacral cystic schwannomas and cerebral subcortical lesions, probably representing glial microhamartomas. Sacral schwannomas can be of giant size with cystic changes and fluid–fluid levels, mimicking aneurismal bone cyst, as in current case.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with a prevalence of about 1/3000. The clinical diagnosis of NF1 is based on the presence of two or more of the following criteria: six or more café au lait spots, >2 neurofibromas of any type, freckling in the axillary or inguinal region, optic glioma, a distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis, and a first degree relative with NF1. We report A 7-year-old male with multiple café au lait spots diagnosed with Neurofibromatosis in Kigali-Rwanda by using next-generation sequencing and copy number variation analysis, the patient presented with painless nodular skin lesions that first developed 4 years earlier. Skin nodules initially appeared on the anterior chest wall and progressed to the posterior chest wall extending to the axilla region. His medical history and that of his family were unremarkable. To our knowledge, this is the first case to be diagnosed using this technology; The disease has numerous complications. The mutation rate for NF1-gene is high; 50% of all cases of NF1 are from new mutations. The gene protein product - neurofibromin plays an important role in tumor genesis as a tumor-suppressor gene. Combining both clinical findings and molecular genetic evaluation to identify disease-causing mutations is paramount in confirming the diagnosis. Patient care is best done in a multidisciplinary setting approach for proper patient satisfaction and better prediction of future prognosis.

Plexiform neurofibroma (PN) is an uncommon benign tumor, usually associated with neurofibromatosis type 1. As most PNs involve the craniomaxillofacial region, PN of the colon is very rare. Here we present a case of PN involving the sigmoid colon. A 43-year-old male patient presented to the outpatient clinic for the evaluation of an incidentally discovered sigmoid colon mass. A colonoscopic biopsy was performed for the mass, and the result revealed neuronal proliferation. The patient visited the outpatient clinic a year later with symptoms of abdominal pain and stool caliber change. Biopsy was repeated for the sigmoid colon mass, and the results showed mucosal Schwann cell proliferation and S-100 immunostaining positivity. Computed tomography and magnetic resonance imaging were performed for further evaluation, and neurofibroma or schwannoma was suspected based on the imaging studies. For an accurate diagnosis, the patient underwent surgery to remove the sigmoid colon mass. The final diagnosis of the mass was confirmed as PN. We hereby report a rare case of PN involving the sigmoid colon that could not be diagnosed before surgery.

Abstract Background Pure mucosal neuroma syndrome (MNS), an autosomal dominant neurocutaneous disorder, is a rare discrete subgroup in multiple endocrine neoplasia (MEN) type 2B, which present without associated endocrinopathies of MEN2B but with typical physical features such as prominent corneal nerves. Case presentation This report describes a 41-year-old patient with complaint of itchy eyes and irritation, presenting with blocked gland orifices in the upper and lower eyelids, light conjunctival hyperemia, a semitransparent neoplasm measuring 2 mm*2 mm on the nasal limbus suggestive of neuromas, and prominent corneal nerves. In vivo confocal microscopy (IVCM) revealed structural alterations—namely a prominent hyperreflective, thickened nerve plexus and a normal endothelium—in both eyes. Testing for SOS1 mutation was positive. This patient may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS), which presents with the characteristic appearance of MEN2B but without RET gene mutations. Conclusion Prominent corneal nerves have been described in some diseases, such as multiple endocrine neoplasia (MEN) type 1 and type 2A and 2B, congenital ichthyosis, Refsum’s disease, leprosy, etc. Ophthalmic assessment including prominent corneal nerves has proven valuable in asymptomatic individuals of MEN2B. Our case illustrates the importance of recognizing the ocular features of MNS, a rare presentation of MEN2B, in order to prevent prophylactic thyroidectomy in these patients for prophylactic thyroidectomy is not mandatory in MNS. However, regular monitoring and genetic counseling are still necessary.

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by germline alterations of the NF1 gene. Patients with NF1 are at increased risk for developing benign and malignant tumors, such as optic pathway glioma and peripheral nerve sheath neoplasms. The number of effective therapies for neurofibromatosis-related tumors has been historically limited. However, there have been recent advances in understanding and developing targeted therapies for these tumors, such as mitogen-activated kinase inhibitors and multiple tyrosine kinase inhibitors. Herein, we review the most prevalent tumors occurring in patients with NF1, updated management guidelines, and explore the approach to therapy in resource-limited settings.

Abstract Introduction Neurofibromatosis (NF) is an inherited disease and a benign tumor originating from nerve sheath cells. Neurofibromatosis type I (NF1) is the most common type, and most cases are characterized by neurofibromas. Neurofibromas in NF1 are mainly treated by surgery. Our study explores the risk factors for intraoperative hemorrhage in Type I neurofibromatosis patients who underwent neurofibroma resection. Methods A cross-sectional comparison of the patients who had undergone resection of neurofibroma for NF1. Data regarding patient characteristics and data about operative outcomes were recorded. The definition of intraoperative hemorrhage group was the intraoperative blood loss greater than 200 ml. Results Of 94 eligible patients, 44 patients were in the hemorrhage group and 50 patients were in the non-hemorrhage group. Multiple logistic regression analysis demonstrated that the area of excision, classification, surgical site, primary surgical, and organ deformation were significant independent predictors of hemorrhage. Conclusion Early treatment can reduce the tumor cross-sectional area, avoid organ deformation, and reduce intraoperative blood loss. For plexiform neurofibroma or neurofibroma of the head and face, the amount of blood loss should be predicted correctly, and preoperative evaluation and blood preparation should be paid more attention to.

Neurofibromatosis is one of the most common genetic diseases. It is inherited in an autosomal dominant manner. It is divided into two genetically distinct subtypes, characterised by multiple skin lesions and tumours of the peripheral and central nervous system. Neurofibromatosis type 1, or Recklinghausen's disease, is the most common phakomatosis. The disease is genetically determined by a mutation of the neurofibromin- 1 gene on chromosome 17. Neurofibromatosis type 2 accounts for 3% of all cases. The disease is genetically determined - caused by a mutation of the neurofibromin-2 gene on chromosome 22. The diagnostic and therapeutic process of neurofibromatosis is a major challenge for clinicians. Given the complexity of the problem, we have reviewed the literature on the diagnostic and therapeutic possibilities of the disease.

Background: Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30–50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients. Methods: Adult patients and caregivers of paediatric patients self-enrolled in an online survey (March–April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL. Results: Mean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate–extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores. Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate–severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8). Conclusions: NF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity. [ABSTRACT FROM AUTHOR]

Neovascularization is a critical process in tumor progression and malignant transformation associated with neurofibromatosis type 1 (NF1). Indeed, fibroblasts are known to play a key role in the tumoral microenvironment modification by producing an abundant collagenous matrix, but their contribution in paracrine communication pathways is poorly understood. Here, we hypothesized that NF1 heterozygosis in human dermal fibroblasts could promote angiogenesis through exosomes secretion. The purposes of this study are to identify the NF1 fibroblast‐derived exosome protein contents and to determine their proangiogenic activity. Angiogenic proteome measurement confirmed the overexpression of VEGF and other proteins involved in vascularization. Tube formation of microvascular endothelial cells was also enhanced in presence of exosomes derived from NF1 skin fibroblasts. NF1 tissue‐engineered skin (NF1‐TES) generation showed a significantly denser microvessels networks compared to healthy controls. The reduction of exosomes production with an inhibitor treatment demonstrated a drastic decrease in blood vessel formation within the dermis. Our results suggest that NF1 haploinsufficiency alters the dermal fibroblast function and creates a pro‐angiogenic signal via exosomes, which increases the capillary formation. This study highlights the potential of targeting exosome secretion and angiogenesis for therapeutic interventions in NF1. [ABSTRACT FROM AUTHOR]

The use of radiotherapy (RT) for the treatment of vestibulocochlear schwannomas is standard in patients with type 2 neurofibromatosis (NF2). In the general population, fractionated RT (FRT) can achieve good results compared to single-dose radiosurgery (SRS). We aimed to assess whether this is true for NF2 patients as well. This retrospective cohort study included 34 patients and 54 lesions treated between 2010 and 2023 in a single university hospital. Thirty-four patient charts were assessed. The median follow-up was 62.6 months (range, 7.1–135.8 months). Lesion size (median larger diameter, 2.5 cm) was correlated with the use of FRT (P > 0.001). Younger age also was correlated with FRT (P = 0.006). Median overall survival and progression-free survival (PFS) were not reached. The overall control rate was 76.5%, and the mean PFS was 49.8 months, compared with. 90.5% and 57.2 months, respectively, for SRS and 66.7% and 44.9 months, respectively, for FRT. There were no differences between the 2 groups in hearing loss, tinnitus, and facial palsy. In the NF2 population, FRT may yield worse control rates than SRS. Whenever possible, it is preferable to not fractionate treatment for these patients. Nevertheless, the FRT results were still good. More and larger prospective trials are warranted. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 is a genetic disorder impacting approximately 2.5 million people worldwide, often leading to development of numerous benign yet disfiguring cutaneous neurofibromas (cNF). Removal of cNF is limited to excision or laser ablation with common post-operation complications and scarring. The current case explores a new approach to removal or reduction of cNF by a minimally invasive and pain-reduced treatment modality. A 40-year-old female patient with numerous cNF across her body underwent a single treatment using a 20 MHz dermatologically focused ultrasound device on seven selected cNF on the upper back. Each cNF was treated in a single session of 20–60 s without anesthesia due to manageable pain. Only one minimal adverse reaction in the form of dyspigmentation in a single treated tumor was noted from treatment or during the healing of a thin scab that formed on each cNF a few days after treatment. At the 12-month follow-up, four out of seven treated cNF showed full remission, two showed partial or significant reduction in tumor volume, while two did not respond to treatment. The reason for the variability is not fully understood, but speculations include difference in tissue content, e.g., due to tumor age. The method is concluded to be a promising candidate for a new safe and minimally invasive treatment that can potentially be used for single-session removal/reduction of a large number of cNF. Further research should focus on refining treatment parameters and strategies to enhance response predictability. [ABSTRACT FROM AUTHOR]

Alipoma is one of the commonest types of benign tumor and a neurolipoma is one of its rarer variants. It is also called as Neurofibrolipoma (NFL) or lipomatosis of nerve. It can occur in a person with neurofibromatosis. The most common sites of occurrence are the volar aspects of the hands, wrists, and forearms. These NFLs are observed in young people, usually men. The median nerve is most commonly involved. Lower-extremity cases are extremely rare. We report here a rare case involving the lower limb without any skeletal deformities occurring in a young man. [ABSTRACT FROM AUTHOR]

Neurocutaneous syndromes (also known as phakomatoses) are heterogenous group of disorders that involve derivatives of the neuroectoderm. Each disease has diagnostic and pathognomonic criteria, once identified, thorough clinical examination to the patient and the family members should be done. Magnetic resonance imaging (MRI) is used to study the pathognomonic findings withing the CNS (Evans et al. in Am J Med Genet A 152A:327–332, 2010). This chapter includes the 4 most common syndromes faced by neurosurgeons and neurologists; neurofibromatosis types 1 and 2, tuberous sclerosis and Von Hippel-Lindau disease. Each syndrome has specific genetic anomaly that involves a tumor suppressor gene and the loss of inhibition of specific pathways. The result is a spectrum of cutaneous manifestations and neoplasms. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) affects cell growth in neural tissues, resulting in neurofibromas of the internal organs, peripheral nerves and/or autonomic nerves. We describe a highly unusual case of plexiform neurofibroma presenting with lacrimal gland enlargement in an 18 year old male, which led to a diagnosis of NF1. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We describe an immunocompromised 73‐year‐old male with a history of neurofibromatosis type 1 (NF1) who presented with a lesion on the thumb concerning for malignancy that was found to be histoplasmosis. This unique case highlights the importance of a thorough history and a broad differential diagnosis in the management of new osteoarticular lesions. [ABSTRACT FROM AUTHOR]

Gastrointestinal neuroendocrine tumors (GI-NET) are one of the rarest cancers that occur with an annual global incidence of 2.5-5/100000 patients. Gastrointestinal NET is the second cancer that affects any individuals, after cancer of the colorectal region. Early identification and early intervention will prevent the mortality of individuals dying due to gastrointestinal neuroendocrine tumors. The main element of prevention is early identification; hence clinicians can identify the rarest cases and can receive enlighten insights to reduce the mortality due to the rarest diseases. [ABSTRACT FROM AUTHOR]

Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor‐based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF‐ and SWN‐related tumor types, which are somewhat rare and perhaps lesser known to non‐specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre‐ and post‐test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders. [ABSTRACT FROM AUTHOR]

Young women with Neurofibromatosis type 1 (NF1) have a high risk of developing breast cancer and poorer survival following breast cancer diagnosis. International guidelines recommend commencing breast screening between 30 and 35 years; however, the optimal screening modality is unestablished, and previous reports suggest that breast imaging may be complicated by the presence of intramammary and cutaneous neurofibromas (cNFs). The aim of this study was to explore potential barriers to implementation of breast screening for young women with NF1. Twenty-seven women (30–47 years) with NF1 completed breast screening with breast MRI, mammogram and breast ultrasound. Nineteen probably benign/suspicious lesions were detected across 14 women. Despite the presence of breast cNFs, initial biopsy rate for participants with NF1 (37%), were comparable to a BRCA pathogenic variant (PV) cohort (25%) (P = 0.311). No cancers or intramammary neurofibromas were identified. Most participants (89%) returned for second round screening. The presence of cNF did not affect clinician confidence in 3D mammogram interpretation, although increasing breast density, frequently seen in young women, impeded confidence for 2D and 3D mammogram. Moderate or marked background parenchymal enhancement on MRI was higher in the NF1 cohort (70.4%) than BRCA PV carriers (47.3%), which is an independent risk factor for breast cancer. Breast MRI was the preferred mode of screening over mammogram, as the majority (85%) with NF1 demonstrated breast density (BI-RADS 3C/4D), which hinders mammogram interpretation. For those with high breast density and high cNF breast coverage, 3D rather than 2D mammogram is preferred, if MRI is unavailable. [ABSTRACT FROM AUTHOR]

Aneurysmal coronary artery disease (ACAD) has been reported rarely in patients with neurofibromatosis type 1 (NF1), mostly in adults. We report on a female newborn affected by NF1 with ACAD disclosed during investigation for an abnormal prenatal ultrasound along with a review of the previously reported cases. The proposita had multiple café‐au‐lait spots and had no cardiac symptoms. Echocardiography, and cardiac computed tomography angiography confirmed aneurysms on the left coronary artery, left anterior descending coronary artery, and of the sinus of Valsalva. Molecular analysis detected the pathogenic variant NM_001042492.3(NF1):c.3943C>T (p.Gln1315*). Literature findings on ACAD in NF1 indicated that this mostly occurs in males, showing predilection for the development of aneurysms at the left anterior descending coronary artery, and manifesting predominantly as acute myocardial infarction, inclusively in teenagers, though it may be also asymptomatic as in our case. This report documents the first case of ACAD in a patient with NF1 diagnosed at birth, emphasizing that its early diagnosis is essential to prevent potential life‐threatening events attributable directly to coronary lesions. [ABSTRACT FROM AUTHOR]

PurposeBy incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.ResultsWe reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.ConclusionThe revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Appendiceal neurofibromas are exceedingly rare, with neither experimental nor observational data to support evidence-based diagnosis or treatment. We describe the case of a 52-year-old woman with neurofibromatosis 1 (NF1) complicated by aqueductal stenosis and resultant hydrocephalus needing a ventriculoperitoneal shunt (VPS). She presented to the emergency department with abdominal pain and was found to have abnormalities in the right hemiabdomen on cross-section imaging, also a Staphylococcus epidermidis growth at the distal portion of the VPS. She was initially treated with two rounds of intravenous antibiotics and VPS removal without improvement. She ultimately underwent an appendectomy, which revealed pathologic evidence of NF. The appendectomy was key to ruling out malignancy, addressing further symptoms and preventing future malignant transformation. This case highlights the importance of including appendiceal neurofibromas in the differential diagnoses of abdominal pain in patients with NF1.

ObjectivesTo investigate the clinical presentation, treatment breakdown, and overall survival (OS) outcomes of patients with neurofibromatosis type 2 (NF2)-associated bilateral vestibular schwannoma (NVS).MethodsThe 2004 to 2016 National Cancer Database was queried for patients with a diagnosis of VS. The "Laterality" code was used to stratify patients into sporadic unilateral vestibular schwannoma (UVS) and NVS.ResultsOf the 33,839 patients with VS, 155 (0.46%) were coded for NVS with an average age and tumor size of 37.4 ± 20.5 years and 23.5 ± 18.2 mm. Patients underwent observation (45.3%), surgery (29.3%), and radiotherapy (20.0%), and had a 5.8% 5-year mortality rate. Compared with UVS, NVS was negatively associated with receiving surgery (40.2% versus 29.3%, p = 0.02) while watchful observation was more prevalent (30.1% versus 45.3%, p = 0.001). In NVS, undergoing surgery was associated with larger tumor size (34.5 ± 21.2 versus 17.8 ± 13.3 mm, p = 0.001) and shorter diagnosis-to-treatment time (49.1 ± 60.6 versus 87.0 ± 78.5 d, p = 0.02), radiotherapy was associated with older age (44.4 ± 18.9 versus 35.2 ± 20.6 yr, p = 0.02) and longer diagnosis-to-treatment time (85.9 ± 77.9 versus 53.9 ± 65.5 d, p = 0.04), and observation was associated with smaller tumor size (17.8 ± 15.9 versus 28.0 ± 19.2 mm, p = 0.01). Kaplan-Meier log-rank analysis demonstrated similar 10-year OS between NVS and UVS patients (p = 0.58) without factoring the earlier age of presentation. Furthermore, there were no temporal changes in presentation/management of NVS, and OS was not dependent on the received treatment (p = 0.30).ConclusionsWith younger age, larger tumors, and more conservative management, NVS's OS was not treatment-dependent and was similar to sporadic UVS, though the latter should not be interpreted as similar life expectancies due to the much earlier presentation.

Abstract Background Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that may affect multiple systems of the body. Autosomal recessive bestrophinopathy (ARB) is a rare retinal dystrophy caused by autosomal recessively mutations in bestrophin 1 (BEST1) gene. So far, we have not retrieved any case report of the same patient with both NF1 and BEST1 gene mutations. Case presentation An 8-year-old female patient with café-au-lait spots, freckling on skin presented to our ophthalmology clinic for routine ophthalmological examination. Her best corrected visual acuity (BCVA) was 20/20 in both eyes. Slit-lamp examination of both eyes revealed few yellowish-brown dome-shaped Lisch nodules over the iris surface. Fundus examination was notable for bilateral confluent yellowish subretinal deposits at macula, few yellow flecks at temporal retina, and cup-to-disc ratio of 0.2. Optical coherence tomography (OCT) revealed subretinal fluid (SRF) involving the fovea, elongated photoreceptor outer segments and mild intraretinal fluid (IRF) at bilateral macula. Fundus autofluorescence demonstrated hyperautofluorescence in the area corresponding to the subretinal deposits. Whole-exome sequencing and Sanger sequencing were used to investigate genetic mutation in the patient and her parents. A BEST1 gene heterozygous missense c.604 C > T (p.Arg202Trp) was identified in the patient and her mother. Also, the patient carries an NF1 nonsense mutation c.6637 C > T (p.Gln2213*) with the mosaic generalized phenotype. There were no visual impairments or obvious neurological, musculoskeletal, behavioral or other symptoms in this patient, so she was managed conservatively and advised to follow up regularly for a long time. Conclusions ARB and NF1, which are caused by two different pathogenic gene mutations, have rarely coexisted in the same patient. The discovery of pathogenic gene mutations may play a crucial role in more accurate diagnostics and genetic consultations for individuals and their families.

We treated a 39-year-old Japanese man who was admitted for an abdominal mass. He had had neurofibroma-like skin lesions since childhood. Computed tomography and endoscopic ultrasound results were consistent with a tumor in the small intestine. Although the tumor was undetectable by single-balloon endoscopy, the patient’s background and imaging results led us to suspect a gastrointestinal stromal tumor (GIST). He also met the diagnostic criteria for neurofibroma type 1 (NF1). We performed a surgical removal of the tumor, and the biopsy results led to a definitive diagnosis of GIST. Small bowel GISTs should be considered in cases of NF1.

The article discusses the medical management of neurofibromatosis (NF), a genetic disorder characterized by tumors along the nervous system. Various pharmacological agents like sirolimus, pegylated interferon alfa‐2b, selumetinib, and tipifarnib have shown potential in stabilizing the disease, alleviating symptoms, and reducing tumor burden. Studies highlight the efficacy and safety of these treatments, emphasizing the need for personalized approaches and ongoing research to optimize therapeutic strategies for individuals with NF. [Extracted from the article]

An 11‐year‐old female with neurofibromatosis type 1 (NF‐1) and history of optic glioma presented with a progressive cutaneous plexiform neurofibroma of the breast. The lesion was treated with topical application of a mitogen‐activated protein kinase inhibitor, trametinib, resulting in stable, non‐progression cutaneous plexiform neurofibroma for greater than 2 years. This case demonstrates the potential application of topical trametinib for NF1‐associated superficial cutaneous plexiform neurofibroma without the toxicities associated with systemic treatment. [ABSTRACT FROM AUTHOR]

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.