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Neurofibromatosis

Neurofibromatosis is normally a benign (non-cancerous) condition. NF is a range of genetic disorders which cause tumours to grow along various types of nerves and can also affect the bones and skin. The majority of cases are von Recklinghausen's Disease (NF type 1) often characterised by cafe-au-lait spots on the skin. Neurofibromatosis 2 (NF2) is much rarer, this is characterised by multiple tumours on the nerves of the brain and spine, and can affect hearing.

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Latest Research Publications

Information Patients and the Public (7 links)


Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Krakowczyk Ł, Maciejewski A, Szymczyk C, et al.
Face Transplant in an Advanced Neurofibromatosis Type 1 Patient.
Ann Transplant. 2017; 22:53-57 [PubMed] Related Publications
BACKGROUND The human face is a one-of-a-kind structure with unique morphology, complexity, and function, in which different subunits are not even similar to other parts of the body. Therefore, extended complex deficits of the face are usually difficult to reconstruct, and autologous tissue restoration is generally not able to give a satisfactory aesthetic and functional outcome. The main goal of face allotransplantation is to restore symmetry, contour, and appearance as well as function of the face, especially control of orbicularis oculi and oris muscle physiology. We present the case of a total face transplant in an advanced neurofibromatosis type 1 patient - the second face transplant in Poland. CASE REPORT The recipient was a 28-year-old female with neurofibromatosis type I limited to the head region. During 24 years she underwent more than 35 surgical procedures, but for the last 3 years a significant decrease of her functionality and appearance was observed, including serious problems with speech, eating, and vision. In December 2013 she was qualified for a face transplant procedure. When the donor was found, she was matched on several clinical and biochemical characteristics including negative T and B cell cross-matching. Similarly, the transplantation procedure was done using two connected operating rooms; in the first, the donor's face was harvested, and in the second, the recipient's face was prepared - the tumor mass was resected and vascular and nervous structures were prepared. Due to the extension and complexity of the potential defect, more than 75% of head soft tissues were harvested including both auriculae, left and right eyelids, and scalp down to the occipital lower line. CONCLUSIONS Our case showed that neurofibromatosis is a real indication for a face transplantation procedure. Also, the results of rehabilitation, quality of life, motor and sensory recovery, and physiological status were comparable, showing that face transplantation based on careful selection of recipients and procedure planning is a real alternative, allowing achievement of excellent results that are far away from the outcomes of conventional reconstructions.

Shamsuyarova A, Kamil Z, Delabie J, et al.
Primary Cutaneous Follicular Helper T-cell Lymphoma in a Patient With Neurofibromatosis Type 1: Case Report and Review of the Literature.
Am J Dermatopathol. 2017; 39(2):134-139 [PubMed] Related Publications
Patients with neurofibromatosis type 1 (NF-1) have a well-known predisposition for certain types of malignancies, including lymphoproliferative disorders. Cutaneous T-cell lymphoma (CTCL) has been reported in patients with NF-1, although it is considered a rare entity in this subset of patients. Cutaneous follicular helper T-cell lymphoma (CTFHCL) is a recently emerged rare subtype of CTCL with peculiar clinical and histopathological features and represents a diagnostic and therapeutic challenge. Only a few cases of CTFHCL have been reported in the literature. We report a case of CTFHCL in a patient with NF-1 and compare our findings with previously reported cases. We aim to raise awareness among pathologists regarding this rare subtype of CTCL and emphasize characteristic histological features of CTFHCL, which can be confused with B-cell lymphomas and lead to mismanagement.

Dombi E, Baldwin A, Marcus LJ, et al.
Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.
N Engl J Med. 2016; 375(26):2550-2560 [PubMed] Related Publications
Background Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. Methods We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. Results A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. Conclusions Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Calì F, Chiavetta V, Ruggeri G, et al.
Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform.
Eur J Med Genet. 2017; 60(2):93-99 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.

Duru N, Göktaş E, Özköse A, et al.
Evaluation of anterior segment parameters in patients with neurofibromatosis type 1.
Eur J Ophthalmol. 2016; 26(6):564-567 [PubMed] Related Publications
PURPOSE: To evaluate anterior segment parameters in patients with neurofibromatosis type 1 (NF1) in comparison to healthy individuals.
METHODS: A total of 34 eyes from 17 patients with NF1 and 34 eyes from 17 age- and sex-matched healthy individuals were included in this study. Each participant underwent a comprehensive ophthalmic assessment including best-corrected visual acuity, slit-lamp biomicroscopy, stereoscopic fundus examination, and intraocular pressure. Central corneal thickness, corneal volume, corneal curvatures (K1 and K2), anterior chamber depth, anterior chamber volume, iridocorneal angle, and pupil size values were measured by Pentacam Scheimpflug camera.
RESULTS: The mean anterior chamber depth, iridocorneal angle, and anterior chamber volume measurements revealed significantly lower values when compared with the control group (p<0.001, p<0.001, and p = 0.041, respectively). However, the mean pupil size was significantly larger when compared with the control group (p = 0.008). Central corneal thickness, corneal volume, K1, and K2 values were similar between the study and control groups (p = 0.875, p = 0.549, p = 0.066, and p = 0.166, respectively).
CONCLUSIONS: Our results reveal that NF1 is associated with statistically significant alterations in anterior chamber depth, iridocorneal angle, anterior chamber volume, and pupil size in patients with NF1 when compared with healthy controls.

Mikirova N, Hunnunghake R, Scimeca RC, et al.
High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report.
Am J Case Rep. 2016; 17:774-781 [PubMed] Free Access to Full Article Related Publications
BACKGROUND In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. CASE REPORT We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7-15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. CONCLUSIONS This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment.

Deng A, Zhang HQ, Tang MX, et al.
Posterior-only surgical correction of dystrophic scoliosis in 31 patients with neurofibromatosis Type 1 using the multiple anchor point method.
J Neurosurg Pediatr. 2017; 19(1):96-101 [PubMed] Related Publications
OBJECTIVE The objective of this study was to evaluate the clinical efficacy of posterior-only surgical correction of dystrophic scoliosis in patients with neurofibromatosis Type 1 (NF1) using a multiple anchor point method (MAPM). METHODS From 2005 to 2014, 31 patients (mean age 13.5 years old, range 10-22 years old) suffering from dystrophic scoliosis associated with NF1 underwent posterior-only surgical correction using a MAPM. The apex of the deformity was thoracic (n = 25), thoracolumbar (n = 4), and lumbar (n = 2). The mean preoperative coronal Cobb angle was 69.1° (range 48.9°-91.4°). The mean Cobb angle on the side-bending radiograph of the convex side was 58.2° (range 40°-79.8°). The mean flexibility and apical vertebral rotation (AVR) were 15.6% (range 8.3%-28.2%) and 2.5° (range 2°-3°), respectively. The mean angle of sagittal kyphosis was 58.3° (range 34.1°-79.6°). RESULTS The mean follow-up period was 53 months (range 12-96 months). The mean postoperative coronal Cobb angle was 27.4° (range 16.3°-46.7°). Postoperatively, the mean AVR and angle of sagittal kyphosis were 1.2° (range 1°-2°) and 22.4° (range 4.2°-36.3°), respectively. All patients showed good correction of all indices postoperatively. The mean postoperative correction rate was 58.7% (range 46.3%-74.1%). At the final follow-up evaluation, the corrective loss rate of the Cobb angle was only 2.3%. Only 1 patient required revision surgery. No severe complications such as spinal cord, neural, or large vascular injury occurred during the operation. CONCLUSIONS Posterior-only surgical correction of dystrophic scoliosis in patients with NF1 using a MAPM could yield satisfactory clinical efficacy of correction and fusion.

Kudose S, Kyriakos M, Awad MM
Gastric plexiform schwannoma in association with neurofibromatosis type 2.
Clin J Gastroenterol. 2016; 9(6):352-357 [PubMed] Related Publications
Plexiform schwannoma (PS) is an uncommon variant of schwannoma characterized by a multinodular (plexiform) growth pattern. It comprises up to 5 % of all schwannomas. The association between PS and neurofibromatosis type 1 or type 2 (NF1/NF2) is only rarely reported. Most cases of PS occur in the skin and subcutaneous soft tissue, with only a few reports of digestive tract involvement. We describe an 18-year-old male with NF2 who had bilateral vestibular schwannomas and multiple cutaneous PSs, and a 3-year history of abdominal pain. The patient ultimately underwent a distal gastrectomy for a partially obstructing submucosal antral mass, associated with an overlying ulcer. Histopathologic examination showed the mass to be a PS. The patient is alive and well, without symptoms, 12 months postoperatively. A review of the English language medical literature yielded only ten examples of PS arising in the digestive tract. Our patient is the first to be reported to have a gastric PS, and only the second patient to be reported with a digestive tract PS to have NF2, and the only patient reported to have both digestive tract and cutaneous PSs. Despite its rare occurrence with NF2, the finding of PS at any site should stimulate an examination for other manifestations of this disorder.
CLINICAL TRIAL REGISTRATION: None.

Vagge A, Nelson LB, Capris P, Traverso CE
Choroidal Freckling in Pediatric Patients Affected by Neurofibromatosis Type 1.
J Pediatr Ophthalmol Strabismus. 2016; 53(5):271-4 [PubMed] Related Publications
Greater understanding of choroidal freckling in patients affected by neurofibromatosis type 1 (NF1) has changed the previous belief that choroidal lesions are unusual in eyes with this disease. In fact, the high frequency of freckling suggests that the choroid is a structure commonly affected in patients with NF1. A review of patients aged 16 years or younger was performed. Recent studies using near-infrared reflectance imaging have shown that choroidal freckling frequently occurred in pediatric patients. As a result of these findings, some authors have suggested that choroidal freckling should be considered as a new diagnostic criterion for NF1. [J Pediatr Ophthalmol Strabismus. 2016;53(5):271-274.].

Faucett EA, Larsen BT, Khan R, et al.
A Diagnostic Dilemma: Multiple Primary Intracranial Tumors Without Vestibular Schwannomas.
Ann Otol Rhinol Laryngol. 2016; 125(11):938-942 [PubMed] Related Publications
Sinonasal schwannomas with intracranial extension are exceedingly rare, with only 7 cases reported in the literature. Schwannomas can be isolated or multiple and are commonly associated with familial disorders such as neurofibromatosis 2 (NF 2) or familial schwannomatosis or in sporadic cases seen in sporadic schwannomatosis. Nearly all people with NF2 older than 30 years of age will have the hallmark of bilateral vestibular schwannomas (VS). This case highlights a reported case of an adult with separate primary intracranial tumors. We review the diagnostic criteria of NF2 and schwannomatosis, a recently described third variant of neurofibromatosis. In this case, we incorporate family history, histopathology, and the pathophysiology of both disorders to help determine a diagnosis for this patient.

Parkhurst E, Abboy S
Optic Gliomas in Neurofibromatosis Type 1.
J Pediatr Ophthalmol Strabismus. 2016; 53(6):334-338 [PubMed] Related Publications
PURPOSE: To examine the incidence, presentation, and outcome of optic gliomas in children with neurofibromatosis type 1 (NF1) in Southern California Kaiser Permanente.
METHODS: The authors queried the Southern California Kaiser Permanente electronic medical record database to find patients diagnosed as having NF1. Genetics, ophthalmology, and imaging medical records of patients with optic glioma were reviewed.
RESULTS: A total of 708 patients younger than 21 years had a diagnosis of NF1 in Southern California Kaiser Permanente and 30 (4.2%) had a diagnosis of optic glioma. The average age of diagnosis was 5 years, with a range of 18 months to 12 years. Half (15 of 30) of the patients diagnosed as having optic glioma presented with symptoms (eg, vision loss, proptosis, and precocious puberty). Eight of 15 of the symptomatic patients were treated with surgery and/or chemotherapy. Symptomatic children were diagnosed later than those diagnosed through routine screening (5.7 vs 3.9 years old). The oldest child presented with symptoms at age 12 years. One asymptomatic patient had prophylactic chemotherapy. Sixty-three percent (19 of 30) of the gliomas were bilateral, 23% (7 of 30) were right-sided, and 13% (4 of 30) were left-sided. Fifty-three percent (17 of 30) of the gliomas involved the optic chiasm.
CONCLUSIONS: Screening practices for optic glioma are inconsistent. Most children with NF1 at risk for optic glioma do not have even one visit with an ophthalmologist. Children with NF1 can develop asymptomatic optic glioma as early as age 1 year. Annual ophthalmologic examination and screening for precocious puberty in children with NF1 is important for early diagnosis of optic gliomas and may reduce morbidity. [J Pediatr Ophthalmol Strabismus. 2016;53(6):334-338.].

Friedrich RE, Nuding MA
Optic Pathway Glioma and Cerebral Focal Abnormal Signal Intensity in Patients with Neurofibromatosis Type 1: Characteristics, Treatment Choices and Follow-up in 134 Affected Individuals and a Brief Review of the Literature.
Anticancer Res. 2016; 36(8):4095-121 [PubMed] Related Publications
UNLABELLED: Optic pathway glioma (OPG) is a rare neoplasm and a defining feature of neurofibromatosis type 1 (NF1), a tumor suppressor genetic disorder. OPG predominantly arises during childhood. In contrast to sporadic OPG, this neoplasm frequently appears to show a more favorable course. Outcome appears to depend on localization of tumor; however, the correlation of imaging findings and visual acuity is in general low. Treatment for symptomatic OPG is not well standardized. Furthermore, determination of visual acuity as the most important parameter of follow-up control is often difficult to determine, particularly in children. Focal abnormal signal intensity (FASI) is a characteristic finding on magnetic resonance imaging (MRI) of NF1 patients. The aim of this study was to evaluate clinical and imaging findings of NF1 patients affected with OPG.
PATIENTS AND METHODS: Data of 925 NF1 patients with appropriate MRI cranial sectional images (N=1,948) were evaluated. A further 50 patients with cranial computed tomograms were included in the study. We compared imaging and clinical findings with respect to localization of OPG. Furthermore, we compared follow-up in treated individuals to those who were only regularly re-examined. The presence of FASI on MRI was determined and correlated to the occurrence of OPG. Dodge classification was applied to categorize OPG location.
RESULTS: OPG was diagnosed in 134 patients. The mean age of patients with symptomatic OPG was 7.6 years (n=57, 42.5%) and 11.6 years (n=77, 57.5%) in asymptomatic patients. The female to male ratio was about 1.1:1. In 48 symptomatic patients, the findings of initial ophthalmological investigations were available. In symptomatic patients, reduced visual acuity was the predominant finding. Strabismus (25%), exophthalmos (22.9%) and amblyopia (20.8%) were most frequently noticed, followed by endrocrinological abnormalities (14.6%). However, these findings did not differ between patients who were treated or who were subjected to a 'wait-and-see' policy. We could not verify an effect of therapy on vision in patients treated for OPG compared to symptomatic patients without treatment. OPG affecting the total optic pathway was more frequently diagnosed in symptomatic patients. FASI did not correlate with functional OPG status.
CONCLUSION: OPG in NF1 is symptomatic in slightly less than 50% of affected individuals. This neurological finding may show a wide range of symptoms. At present, no established treatment protocol emerges from the history of the patients of this study and also from the literature. Although the onset of symptomatic OPG is strongly associated with early childhood, late onset of symptomatic OPG is a feature of adult NF1. Research for association of FASI to neurological findings in these patients should be based on other issues than association with OPG.

Morris KA, Parry A, Pretorius PM
Comparing the sensitivity of linear and volumetric MRI measurements to detect changes in the size of vestibular schwannomas in patients with neurofibromatosis type 2 on bevacizumab treatment.
Br J Radiol. 2016; 89(1065):20160110 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
OBJECTIVE: To compare the sensitivity of linear and volumetric measurements on MRI in detecting schwannoma progression in patients with neurofibromatosis type 2 on bevacizumab treatment as well as the extent to which this depends on the size of the tumour.
METHODS: We compared retrospectively, changes in linear tumour dimensions at a range of thresholds to volumetric tumour measurements performed using Brainlab iPlan(®) software (Feldkirchen, Germany) and classified for tumour progression according to the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria.
RESULTS: Assessment of 61 schwannomas in 46 patients with a median follow-up of 20 months (range 3-43 months) was performed. There was a mean of 7 time points per tumour (range 2-12 time points). Using the volumetric REiNS criteria as the gold standard, a sensitivity of 86% was achieved for linear measurement using a 2-mm threshold to define progression.
CONCLUSION: We propose that a change in linear measurement by 2 mm (particularly in tumours with starting diameters 20-30 mm, the majority of this cohort) could be used as a filter to identify cases of possible progression requiring volumetric analysis. This pragmatic approach can be used if stabilization of a previously growing schwannoma is sufficient for a patient to continue treatment in such a circumstance.
ADVANCES IN KNOWLEDGE: We demonstrate the real-world limitations of linear vs volumetric measurement in tumour response assessment and identify limited circumstances where linear measurements can be used to determine which patients require the more resource-intensive volumetric measurements.

Képénékian L, Mognetti T, Lifante JC, et al.
Interest of systematic screening of pheochromocytoma in patients with neurofibromatosis type 1.
Eur J Endocrinol. 2016; 175(4):335-44 [PubMed] Related Publications
OBJECTIVE: Pheochromocytoma (PHEO) may occur in 0.1-5.7% of patients presenting with a neurofibromatosis type 1 (NF1). Current recommendations are to explore only symptomatic patients. The objective of the study is to evaluate the prevalence and the interest of a systematic PHEO screening in this population.
DESIGN: A prospective study in a French tertiary center including consecutive NF1 patients older than 18 years.
METHODS: A systematic screening combining abdominal imaging and urinary fractionated metanephrines was proposed. In case of positivity of one or both exams, (123)I-metaiodobenzylguanidine scintigraphy or [(18)F]-fluoro-dihydroxyphenylalanine PET imaging was performed. The diagnosis of secreting PHEO was retained in case of elevated urinary metanephrines associated with positive scintigraphy and non-secreting PHEO when urinary metanephrines were normal with a positive scintigraphy.
RESULTS: Between January 2014 and August 2015, 234 patients were included and 156 patients (66.7%) completed both exams. In these 156 patients, 12 PHEOs were diagnosed, representing a prevalence of 7.7%. Of these, six PHEOs were secreting, with only two symptomatic patients. The tumor size of these PHEOs were bigger than that of non-secreting PHEO (25.2 ± 6.6 vs 14 ± 6.9 mm, P = 0.0165). One lesion was bilateral. Mean metanephrine and normetanephrine levels were 3.2 ± 2.6N and 2.8 ± 1N respectively. Three patients underwent surgery. The six patients with non-secreting PHEO were asymptomatic. One of them had bilateral lesion and one underwent surgery.
CONCLUSIONS: PHEO in NF1, whether or not secreting, are mostly asymptomatic. The current strategy to explore only symptomatic patients leads to an underestimation of prevalence with the risks inherent to the existence of an unrecognized PHEO.

Aydin S, Kurtcan S, Alkan A, et al.
Relationship between the corpus callosum and neurocognitive disabilities in children with NF-1: diffusion tensor imaging features.
Clin Imaging. 2016 Nov - Dec; 40(6):1092-1095 [PubMed] Related Publications
PURPOSE: Mild neurocognitive disabilities are commonly observed in children with neurofibromatosis type 1 (NF-1). Enlargement of the corpus callosum (CC) is one of the findings in NF-1, but the pathogenesis has not yet been clarified. In this study, we investigated whether diffusion tensor imaging (DTI) features of CC differed between children with NF-1 and healthy control subjects, and we tried to evaluate the association between the microstructural integrity of CC and neurocognitive disabilities, based on apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values.
MATERIALS AND METHODS: The study population consisted of 37 children with NF-1 and 31 healthy controls. Midsagittal CC surface area measurements were obtained from volumetric sagittal T1-weighted turbo spin echo images. FA and ADC values were obtained from the genu and splenium of CC. The results were compared to that of controls. The correlations between neurocognitive test results and measurements of ADC, FA, and surface areas of midsagittal CC in NF-1 patients were investigated.
RESULTS: Total CC area in children with NF-1 was significantly larger than healthy controls. ADC values obtained from the genu of CC were significantly higher in NF-1 children. A negative correlation was observed between the ADC values of the genu of the CC and the arithmetic and digit span scores and between the FA values of the genu and coding scores in children with NF-1.
CONCLUSION: The DTI changes in the genu of CC in children with NF-1 may indicate subtle structural damage, although conventional MRI is normal. ADC and FA changes in the genu may be due to loss of axonal integrity and vasogenic-like edema in the axons responsible for some intellectual functions. DTI may help clarify the underlying pathophysiology of CC changes in relation to neurocognitive function disorders in children with NF1.

Guraya SS, Prayson RA
Peripheral nerve sheath tumors arising in salivary glands: A clinicopathologic study.
Ann Diagn Pathol. 2016; 23:38-42 [PubMed] Related Publications
Primary salivary gland peripheral nerve sheath tumors (PNST) are uncommon. This study is a retrospective, clinicopathologic review of 9 cases of PNST (5 neurofibromas, 3 schwannomas and 1 malignant peripheral nerve sheath tumor (MPNST)) arising from the salivary glands, encountered between 1990 and 2015. All patients with neurofibromas were male (ages 1-62 years) and had a single parotid lesion of which 2 were diffuse, 2 plexiform and one mixed diffuse/plexiform. Four had a history of neurofibromatosis I. Four of 5 presented with symptoms related to mass effect including facial swelling, facial drooping, and dysphagia. All underwent de-bulking surgery and recurred due to continued growth. Of the 3 patients with schwannomas, 1 was male and 2 were female (ages 19, 44 and 56 years). One tumor each arose in the sublingual, submandibular, and parotid glands. Two of 3 presented with soreness and swelling local to the affected gland, especially while chewing. There was no recurrence of these tumors after resection. An MPNST in a male presented as a tender mass in the patient's left parotid; the tumor was resected. There was no evidence of tumor elsewhere in the body. The tumor did not recur in 12 years of follow-up. The most common tumor type in the current series was neurofibroma; most arose in the background of neurofibromatosis type I and all of which recurred after initial subtotal resection. Most PNST arose in the parotid gland.

Mendonça FT, de Moura IB, Pellizzaro D, et al.
Anesthetic management in patient with neurofibromatosis: a case report and literature review.
Acta Anaesthesiol Belg. 2016; 67(1):48-52 [PubMed] Related Publications
OBJECTIVE: We report the anesthesia management of a 15 years-old patient with neurofibromatosis type 1, scheduled for resection of a tumor located in the occipitocervical region. In addition, we review the pertaining literature, emphasizing the anesthetic implications of neurofibromatosis manipulation. CASE : A 15-years-old female patient, with Neurofibromatosis type 1 was diagnosed with a large tumor in occipitocervical region suggestive of a plexiform neurofibroma. She presented with cervical instability, difficulty in positioning due to the large cervical mass and other predictors of airway difficulty. Awake intubation was carried out with fiberoptic bronchoscopy after anesthetic block of the airway and remifentanil infusion at low doses (0.05 mcg/kg/min). An inadvertent lesion in the left vertebral artery during the surgical procedure was well controlled by fluid replacement, red blood cell and plasma infusion and norepinephrine. The histopathological report revealed a malignant peripheral nerve sheath tumor originated from a neurofibroma in the craniocervical region. Two months after surgery the patient presented a right crural deficit due to tumor recurrence.
CONCLUSION: This case report demonstrates the importance of knowing the anesthetic peculiarities of patients affected by Neurofibromatosis type 1 submitted to surgery. Neurofibromatosis is a rare pathology in surgical centers, which requires special attention from the anesthesiologist.

Deniz Bulut M, Yavuz A, Bora A, et al.
Imaging Findings for Bilateral Giant Vestibulocochlear Schwannoma.
Arch Iran Med. 2016; 19(7):518-20 [PubMed] Related Publications
Neurofibromatosis type 2 mostly develops with multiple neoplasms of the central and peripheral nervous system and is associated with ocular abnormalities. The presented case is a 19-year-old female patient with bilateral vestibulocochlear schwannomas in both pontocerebellar corners, intradural intra-extramedullary masses, and multiple neurofibromas in the spinal canal. The clinical picture for NF-2, also called central neurofibromatosis, is completely different from von Recklinghausen disease. Untreated bilateral vestibulocochlear schwannoma may cause hydrocephalus in NF-2, and lead to death. Therefore, it is recommended to carefully monitor and treat bilateral vestibulocochlear schwannoma in accordance with its stage.

Alshikho MJ, Noureldine SI, Talas JM, et al.
Zollinger-Ellison Syndrome Associated with von Recklinghausen Disease: Case Report and Literature Review.
Am J Case Rep. 2016; 17:398-405 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
BACKGROUND: Pancreatic endocrine tumors (PETs) are rare and can occur as part of neurofibromatosis type 1 (NF1). Gastrinomas are functional PETs that are rarely associated with NF1. Only two cases of their occurrence have been reported in the literature.
CASE REPORT: A 28-year-old woman was admitted for further evaluation of epigastric soreness, heartburn, nausea, vomiting, diarrhea, and a significant weight loss. Physical examination was remarkable for cutaneous findings (axillary freckling and multiple café-au-lait spots) as well as neurofibromas (dermal, plexiform). A diagnosis of NF1 was confirmed. Esophagogastroduodenoscopy (EGD) revealed multiple ulcers in the duodenum and the upper jejunum. A fasting gastrin level exceeded ten times the normal limit. An abdominal multi-slice 128 computed tomography (CT) scan revealed an oval mass of 26 mm in diameter adjacent to the second section of the duodenum. The patient was examined carefully to rule out multiple endocrine neoplasia type 1 (MEN1). Surgical resection was performed and a gastrinoma, causing Zollinger-Ellison syndrome (ZES), was diagnosed by histological examinations of the extirpated mass. The serum gastrin level decreased to normal limits shortly after surgery. Continuous follow-up revealed that the symptoms and the EGD findings completely resolved without recurrences.
CONCLUSIONS: Although NF1 has common skeletal, visual, neurological, and cardiovascular complications, it also has a rare association with duodenal or pancreatic gastrinomas. Vigilance for this possible association is important to promote timely and careful management to help eliminate serious and potentially life-threatening complications.

Friedrich RE, Hagel C
Expansive Extracranial Growth of Intracranial Meningioma in Neurofibromatosis Type 2.
Anticancer Res. 2016; 36(6):3161-7 [PubMed] Related Publications
The purpose of this report is to detail three rare cases of neurofibromatosis type 2 (NF2) with symptomatic extracranial extension of intracranial meningioma. We present ocular findings, imaging techniques applied, pathological findings of the space-occupying lesions, and therapy. One of these patients, the daughter of one of the other individuals, presented with a large neck mass, but no surgically treatable findings associated with the external growth of the meningioma. The patients complained of symptoms associated with the extracranial portion of the intracranial meningioma, rather than of the intracranial primaries. However, facial and neck surgical care is very limited in patients with such advanced-stage tumours. The prolongation of life was unquestionably predominantly determined by the behaviour of the intracranial tumour. Head and neck surgeons should be aware of the rare possibility that solid tumours of this region could be extracranial-extending meningioma in an inherited disease.

Helfferich J, Nijmeijer R, Brouwer OF, et al.
Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas.
Crit Rev Oncol Hematol. 2016; 104:30-41 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

Lee JM, Chang JW, Choi JY, et al.
Hearing Restoration in Neurofibromatosis Type II Patients.
Yonsei Med J. 2016; 57(4):817-23 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
Patients with neurofibromatosis type II will eventually succumb to bilateral deafness. For patients with hearing loss, modern medical science technology can provide efficient hearing restoration through a number of various methods. In this article, several hearing restoration methods for patients with neurofibromatosis type II are introduced.

Lekovic GP, Schwartz MS, Go JL
Multifocal granulocytic sarcoma of the spine mimicking neurofibromatosis Type 2: case report.
J Neurosurg Spine. 2016; 25(4):523-527 [PubMed] Related Publications
In this report the authors report on a patient with a very indolent course of granulocytic sarcoma, characterized by steroid-induced remission of spinal and cranial tumors and recurrence over a period of several years. This 24-year-old man with history of leukemia presented with rapid-onset quadriparesis secondary to multiple extraaxial masses of the cervicothoracic spine, from C-5 to T-3, and lumbosacral spine, from L-5 to the coccyx. Although the imaging features were highly suggestive of neurofibromatosis Type 2, the patient's history and clinical course were consistent with granulocytic sarcoma; repeat imaging and, later, needle biopsy definitively established the diagnosis of granulocytic sarcoma. Laminectomy and surgical decompression of the spine were not required and, arguably, could have posed unnecessary risk to the patient. This case illustrates that the successful management of a patient presenting with profound neurological deficits due to intradural spinal cord tumors may sometimes be nonsurgical.

Su SY, Zhou X, Pang XM, et al.
NF1 frameshift mutation (c.6520_6523delGAGA) association with nervous system tumors and bone abnormalities in a Chinese patient with neurofibromatosis type 1.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
Neurofibromatosis type 1, also known as NF1 or von Recklinghausen's disease, is a common neurocutaneous syndrome that presents with multiple café-au-lait patches, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. The mutations of the gene NF1, encoding the protein neurofibromin, have been identified as the cause of this disease. Here, we report a clinical and molecular study of a Chinese patient with multiple café-au-lait skin freckles, dermatofibroma, central and peripheral nervous system tumors, and bone abnormalities attributed to NF1. The patient showed >6 café-au-lait spots on the body and multiple dermatofibromas. A brain glioma and multiple nerve sheath tumors inside and outside the vertebral canal were identified by magnetic resonance imaging, which also showed multiple intercostal nerve schwannomas and hydrocephalies above the cerebellar tentorium. Talipes equinus was also apparent. A mutation analysis of the NF1 gene revealed a novel frameshift mutation in exon 43, consisting of a heterozygous deletion of four nucleotides (GAGA) between positions 6520 and 6523. No NF1 mutations were detected in the patient's parents or younger brother. These results extend the list of known mutations in this gene. The absence of the NF1 mutation in the healthy family members suggests that it is responsible for the NF1 phenotype. To our knowledge, this frameshift mutation represents a novel NF1 case, and may be associated with nervous system tumors and bone abnormalities.

Radek M, Tomasik B, Wojdyn M, et al.
Neurofibromatosis type 2 (NF 2) or schwannomatosis?--Case report study and diagnostic criteria.
Neurol Neurochir Pol. 2016; 50(3):219-25 [PubMed] Related Publications
INTRODUCTION: Neurofibromatosis type 2 (NF2) and schwannomatosis are entities that may, due to the similarity of clinical symptoms, cause diagnostic difficulties. Incidence rate of both diseases is similar and estimated between 1:25,000 and 1:40,000. The genes associated with the development of the aforementioned disorders are located on chromosome 22 and lay in proxmity. Schwannomatosis is characterized by an incomplete penetrance and the risk of its transmission to the offspring is significantly lower than in the case of NF 2. Schwannomatosis clinical characteristic is similar to the NF2, however vestibular schwannomas are not present. Therefore the imaging studies evaluated by an experienced radiologist play a key role in the diagnostic process.
CASE REPORT: Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache. She was diagnosed with a schwannomatosis, recently distinguished, the third form of neurofibromatosis. MRI imaging revealed craniocervical junction tumor. Suboccipital craniectomy with concomitant C1-C2 laminectomy was done in order to remove the lesion. After the surgery the patient did not present any deficits in neurological examination and was discharged from hospital in good general condition.
CONCLUSIONS: The patient was diagnosed with schwannomatosis, recently established neurofibromatosis entity which may resemble NF2 clinically. In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely.

Ouerdani A, Goutagny S, Kalamarides M, et al.
Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2.
Cancer Chemother Pharmacol. 2016; 77(6):1263-73 [PubMed] Related Publications
PURPOSE: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus.
METHODS: Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action.
RESULTS: We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen.
CONCLUSION: The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.

Takeuchi A, Yamamoto N, Hayashi K, et al.
Tenosynovial giant cell tumors in unusual locations detected by positron emission tomography imaging confused with malignant tumors: report of two cases.
BMC Musculoskelet Disord. 2016; 17:180 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
BACKGROUND: A tenosynovial giant cell tumor (T-GCT) is a benign synovial tumor arising from the synovium, bursae, or tendon sheath. It can be intra- or extra-articular and localized or diffuse. Diffuse T-GCT is considered as a locally aggressive. Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose with computed tomography (FDG PET/CT) is widely used to differentiate malignant from benign tumors and to detect distant metastasis. However, FDG PET/CT is limited by false-positive findings. In this study, we present two cases of T-GCT that developed in unusual locations and were confused with malignant tumors. The final diagnoses were histologically confirmed as T-GCTs.
CASE PRESENTATION: Case 1. A 45-year-old Japanese female presented with a left choroidal melanoma and an abnormal lesion adjacent to the first cervical (C1) lamina confirmed by a PET scan (maximum standardized uptake value [SUVmax] =9.9 g/ml). MRI of the neck also detected a soft tissue mass (14.6 × 7.7 × 7 mm) adjacent to the C1 lamina. The choroidal melanoma was treated by heavy carbon ion radiotherapy. Although the size of the C1 soft tissue tumor remained unchanged, a CT-guided biopsy confirmed the diagnosis of the neck mass as a T-GCT. Case 2. A 15-year-old Japanese male with multiple type 1 neurofibromatosis presented with a soft tissue mass (26.1 × 24.7 × 11.5 mm) of the extra-articular hip joint that was coincidentally detected by FDG PET/CT during examination of a mediastinal soft tissue mass. SUVmax of the mediastinal lesion was 2.6 g/ml and of the hip lesion was 12.8 g/ml. Thus, differentiation from a malignant tumor, such as a malignant peripheral nerve sheath tumor, was necessary. An open biopsy was performed, and the frozen section was diagnosed as T-GCT. The tumor was excised, and the final histological diagnosis confirmed T-GCT.
CONCLUSION: T-GCT can show high FDG uptake, which might be confused with malignancy. Although MRI findings and location might help in the diagnosis of a T-GCT, careful assessment is mandatory, especially in unusual locations.

Lutterodt CG, Mohan A, Kirkpatrick N
The use of electrodessication in the treatment of cutaneous neurofibromatosis: A retrospective patient satisfaction outcome assessment.
J Plast Reconstr Aesthet Surg. 2016; 69(6):765-9 [PubMed] Related Publications
INTRODUCTION: Neurofibromatosis I (NF-1) is an autosomal dominant disease giving rise to hundreds of cutaneous neurofibromas. In addition to localised symptoms such as pain and pruritus, these lesions can have a devastating psychosocial impact. To date, there is no consensus on the optimal management of these lesions. We present the clinical and patient-reported outcomes of a series of NF-1 patients treated with electrodessication by one surgeon.
METHODS: All patients treated by electrodessication for cutaneous neurofibromas between 2012 and 2015 by one clinician were retrospectively reviewed. Clinical and patient-reported outcomes were measured using a patient satisfaction questionnaire and review of the notes.
RESULTS: Six patients were operated on during the study period (five women and one man). Prior to this new technique, patients had on average eight episodes (range 4-20) of excisional procedures under local anaesthesia removing one to five lesions. With electrodessication, patients had on average three (range 1-5) electrodessication episodes under general anaesthesia, treating hundreds of lesions per session. All patients were treated as a day case. One patient experienced a minor wound infection and another minor bleeding. Five of six patients preferred electrodessication to surgical excision.
CONCLUSION: Electrodessication enables the treatment of hundreds of neurofibromas in a single operation. The procedure has low complication rates with high levels of clinical and patient-reported outcomes.

Ilić A, Raljević S, Adzić T, et al.
Lung parenchima changes in neurofibromatosis type 1.
Vojnosanit Pregl. 2016; 73(2):202-4 [PubMed] Related Publications
INTRODUCTION: Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is one of the most common single-gene disorders (mutation on chromosome 17q) and usually associated with cutaneous, musculoskeletal and neurological disorders in humans. NF1 is generally complicated with one or more neurobehavioral disorders or tumors located in the peripheral nervous system such as neurofibromas, peripheral nerve sheath tumor, pheochromocytoma, etc. In the available medical literature, the thoracic manifestations of NF1 have been rarely described in these patients. There are few reports about intrathoracic neurogenic tumors, kyphoscoliosis, pneu- monitis and pulmonary fibrosis in patients with NF1.
CASE REPORT: A 65-year-old female was admitted to the Intensive Care Unit at the Lung Clinic of Belgrade University Clinical Center of Serbia. The patient's general condition was poor with shortness of breath and present cyanosis. At the same time, the skin changes similar to NF1 were noticed, which were additionally documented by her medical history and diagnosed as NF1. After the application of noninvasive mechanical ventilation and other emergency respiratory medicine measures, the patient soon felt better. The parenchymal changes were viewed by subsequent X-rays and CT scanning of the thorax.
CONCLUSION: This is a case report presenting the NF1 associated with the abnormality of lung parenchyma established during diagnostic procedures at the Intensive Care Unit, Clinic of Pulmonology.

Dova S, Ktenidis K, Karkos P, et al.
A rare case of a spontaneous neck hematoma in a patient with type 1 neurofibromatosis.
Auris Nasus Larynx. 2016; 43(5):591-4 [PubMed] Related Publications
Neurofibromatosis type 1 (NF-1) is a genetic disorder that affects one in 3000 individuals. Although NF-1 notably involves nerves and connective tissue, vascular involvement in large series is estimated to range from 0.4% to 6.4%. Jugular vein involvement in these patients is rare. Spontaneous neck hematomas and hemorrhages are also unusual. We present a case of a NF-1 patient with a spontaneous neck hematoma with possible leakage from the left internal jugular vein, presenting as a lateral neck mass. The fragility of the vein wall and the surrounding tissue led patient to a severe intraoperative bleeding. Pathological examination revealed degenerated neurofibroma which was in contact with or infiltrated the vein wall. ENT and other clinicians should be aware of this potentially fatal entity considering that it may present as a lateral neck mass.

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