Multiple Cutaneous Neurofibromas Research Articles

High‐intensity focused ultrasound: Safety and efficacy of a novel treatment modality for neurofibromatosis type 1 cutaneous neurofibroma

AbstractBackgroundHigh‐intensity focused ultrasound (HIFU) is widely used in the treatment of deep tumours, but clinical trials on skin tumours are not yet available. Neurofibromatosis Type I (NF1) is among the most common single‐gene inherited conditions worldwide and predisposes to benign and malignant neoplasms of the nervous system. Multiple cutaneous neurofibromas (cNFs) often cause social and functional limitations, itching and pain.ObjectivesThe objective of this study was to investigate the safety, local tolerability and efficacy of a novel method utilizing HIFU for the treatment of cNFs.MethodsA 20 MHz HIFU‐device with an integrated dermoscopic guidance and a handpiece with a focus depth of 2.3 mm below the skin surface was used. Doses of acoustic energy with 0.7 J/dose and pulse duration of 250 ms/dose were manually positioned with 1–2 mm distance between each applied dose. Number of applied doses depended on the size of the cNF. No anaesthetic was applied.ResultsTwenty patients with NF1 were recruited in two centres, and 147 cNFs were treated. There were no serious adverse events. Immediate and transient wheal‐and‐flare reactions occurred at treatment sites and occasionally there was minor epidermal damage which healed in 1–2 weeks. Dyspigmentation occurred in some tumours after 3–9 months but no scarring was observed at 9‐month follow‐up. During treatment, the patient‐reported pain‐score median was 3.5 (range 1–7) on a 0–10‐point scale. Clinical rating of cNFs after 9 months showed 48.9% full or major tumour reduction. The median reduction in tumour thickness measured by ultrasound at 9 months was 0.53 mm (range: –100% to +19%).ConclusionsHIFU treatment is a new noninvasive, rapid and tolerable treatment modality that with high precision targets intradermal lesions. This study demonstrates acceptable safety, local tolerance and efficacy of HIFU for the treatment of cNFs that may further be developed also for other skin tumours.

Can isotretinoin be used in treating multiple neurofibromas thanks to its apoptotic effect?

The most common benign tumor of the peripheral nerve sheath is neurofibromas. The only known curative treatment is total surgical excision. In neurofibromatosis patients with multiple cutaneous neurofibromas, it is not possible to treat all neurofibromas with surgical excision. We happened on a case of neurofibromatosis type-1, whose neurofibromas shrank while using isotretinoin for the treatment of excessively oily skin and postadolescent acne. We think that isotretinoin executes this effect through its apoptotic mechanism of action.

Questions on surgical treatment of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome caused by a mutation in tumor suppressor gene NF1. The disease occurs with a frequency of 1:3000 of the population. Typical manifestations of NF1 are multiple cutaneous, subcutaneous and plexiform neurofibromas, which cause serious cosmetic defects in the appearance of patients. Since an effective method for the treatment of NF1 has not yet been introduced into clinical practice, which makes it possible to completely get rid of multiple neoplasms, surgical removal or the use of photodestruction methods remains the method of choice for the treatment of cutaneous and subcutaneous neurofibromas. However, plexiform neurofibromas infiltratively grow into the surrounding tissues, so their complete excision is often impossible. Therefore, surgical excision is indicated for localized forms of plexiform neurofibromas and in emergency situations when they are located near vital structures or in the presence of a mass effect. Moreover, excision of cutaneous and subcutaneous neurofibromas may initiate formation and growth of new tumors. This is due to the degranulation of mast cells in response to tumor damage, since the pathology of the immune system plays an important role in the development of neurofibromas. In order to avoid dissemination of tumors, it is also important to adhere to the principles of antiblastic surgery. Therefore, the most promising is the complex treatment of NF1 with the combined use of a classical approach, surgical laser, ketotifen, and an inhibitor of mitogen-activated kinase. This method can be recommended for the treatment of malignant peripheral nerve sheath tumors, as well as sporadic neoplasms, the resistance of which is caused by a somatic mutation in the NF1 gene. The goal of NF1 treatment is to improve the quality of life of the patient as a whole and reduce pain using an integrated multidisciplinary approach.

Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95-97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies. Here, we report two unrelated patients presenting with two different inversions that disrupt the NF1 coding sequence, resulting in an NF1 phenotype. In one subject, the inversion was associated with microdeletions spanning a few NF1 exons at both breakpoints, while in the other the rearrangement did not cause exon loss, thus testing negative by MLPA assay. Considering the high proportion of repeated regions within the NF1 sequence, we propose that intragenic structural rearrangements should be considered as possible pathogenic mechanisms in patients fulfilling the NIH diagnostic criteria of NF1 but lacking of molecular confirmation and in patients with NF1 intragenic microdeletions.

Prospects for the treatment of neurofibromatosis type 1: A review

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome with a prevalence of 1:3000 in human population. About 50% of NF1 cases are sporadic due to newly emerging germline mutations in NF1 gene. Protein product of NF1 is a neurofibromin, which inhibits RAS-RAF-MEK-ERK system. The prevalence of NF1 is increasing as patients are fertile. Therefore, it is important to use rapid diagnostic methods for NF1 mutations in NF1 families for prenatal prophylaxis. Mutations in NF1 gene play roles in sporadic carcinogenesis and in development of cancer resistance to chemotherapy. Specific for NF1 are multiple subcutaneous and cutaneous neurofibromas, age spots, skeletal abnormalities, mental retardation, tumors of the brain and optic nerves. Half of patients with NF1 develop plexiform neurofibromas, which disfigure them or compress vital organs. The difficulty in treating NF1 is due to involvement of immune system, since a large number of degranulating mast cells are found in neurofibromas. Mast cells secrete cytokines that dont provide a proper anti-tumor immune response, but initiate formation and growth of new neurofibromas. Therefore, long-term administration of ketotiphen was proposed for treatment of NF1 patients. Surgical removal of neurofibromas causes relapses and induction of the growth of new tumors; therefore, it is necessary to develop an effective therapy for NF1. The effectiveness of complex therapy of NF1 with use of ketotiphen, Lydase and Aevit, as well as monotherapy with an ATP-independent inhibitor of mitogen-activated protein kinase, has been described. For widespread clinical implementation of these methods, it is necessary to conduct studies on large sample of patients, as well as to make medicines available for patients. Gene therapy may become promising in the treatment of NF1, which requires identification of the type of mutation in NF1 gene in each individual and the use of specific microRNAs.

Neurofibromatosis 1 Presence in Breast Tissue: Case Report

Neurofibromatosis 1, also known as Von Recklinghausen disease, is the most common of the three neurofibromatoses. It is a multi-organ disease that is characterized by the development of cutaneous neurofibromas, plexiform neurofibromas, optic nerve gliomas, astrocytomas, Lisch nodules, and pheochromocytomas. We present a case of 66-year-old woman with NF-1. The disease presents with multiple cutaneous neurofibromas in both breasts. People living with NF-1 disease might have a different course of malignancy or other associated symptoms than the average individual without NF-1. It is essential that patients presenting with NF-1 symptoms are followed longitudinally to ensure that the progression of their symptoms are appropriately treated.

Analysis of the features of neurofibromatosis type 1 in the Republic of Bashkortostan

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome that occurs on average with a frequency of 1: 3000 people. Clinical features of NF1 include cafe-au-lait macules on the skin, multiple cutaneous, subcutaneous, and plexi-form neurofibromas, Lisch nodules, and optic gliomas. The disease is also characterized by damage to the musculoskeletal system, impaired intelligence and behavior. The cause of the disease is germinal mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. NF1 is characterized by pronounced polymorphism of clinical manifestations, from erased to severe, without geno-phenotypic correlations. Therefore, the role of modifier genes in the pathogenesis of NF1 is assumed. We carried out a clinical-epidemiological and molecular-genetic study of patients with NF1 from the Republic of Bashkortostan (RB). We searched for intragenic mutations by sequencing 57 exons of the NF1 gene, and identified deletions of the entire gene using microsatellite analysis. The prevalence of NF1 in RB is 10 per 100 000. We identified 14 intragenic mutations in the NF1 gene in 20 patients with NF1 and 2 extended deletion of NF1 gene in 3 patients from 2 unrelated families. We did not find a correlation between the type of mutation and the characteristics of the clinical manifestations of the disease. To determine the possible influence of modifier genes on pathogenesis of NF1, we carried out a comparative analysis of the clinical manifestations of NF1 depending on inheritance, ethnicity and association of systemic manifestations. Among the clinical manifestations of NF1 in RB, there was a low frequency of optic nerve gliomas (5,25%) and plexiform neurofibromas (5%). The incidence of brain cysts was 4,25% among patients with NF1. We identified 9 mutations for the first time in the world, 5 out of 14 identified mutations are known (c.2806A>T, c.2991-1G>C, c.3158C>G, c.4537C>T, c.6792C>A). The distribution of mutation types turned out to be random. We identified a protective role of crossbreeding for the development of severe manifestations of NF1. We determined a high incidence of scoliosis, short stature, facial dysmorphism and chest deformity in the inheritance of NF1 from the mother, which suggests the influence of modifier genes on the pathogenesis of NF1.

CO2 Laser Ablation for the Manifestations of Multiple Cutaneous Neurofibromas in an Adult with Neurofibromatosis Type 1(NF1)

Introduction: Neurofibromatosis type 1 is a rare genetic disorder that is characterized by the growth of noncancerous neurocutaneous tumors that form near the spinal cord and along the peripheral nerves in the body. Symptoms NF-1 are usually detected in infancy or early childhood. However, in some cases, children and adults without family history may have a spontaneous genetic mutation of unknown cause. There are several modalities to treat NF-1, which include conventional surgery removal and CO2 laser ablation. The review of literature aims to compare the efficacy and outcomes of these two modalities.
 Case presentation: A 32-year old post-partum Australian woman is presented to the neurosurgery department outpatient clinic. When she was around 20-year old, non-painful multiple noncancerous growth along her spine and peripheral nerves and multiple café-au-lait spots started to appear. The size and numbers of growth and spots are gradually increasing as she aged. The diagnosis of NF-1 was made according to the presence of four of the seven diagnostic criteria of the National Institute of Health Consensus Development Conference. Patient is scheduled to go to NF clinic 2 months after the meeting, in which the patient is planned to undergo a treatment of CO2 laser ablation.
 Conclusions: Studies have shown that CO2 has outperformed conventional surgery in managing the clinical manifestation of NF-1 in term of effectivity and cosmetic outcomes.
 Keywords: neurofibromatosis type I, von Recklinghausen’s disease, adult, post-partum woman, CO2 laser ablation

1611 Not All Polyps Are Created Equal: Schwann Cell Hamartoma Incidentally Found on Screening Colonoscopy

INTRODUCTION: Majority of colorectal polyps are epithelial in origin, such as adenomas (tubular, tubulovillous, and villous) and serrated polyps (hyperplastic, traditional serrated, sessile serrated). Mesenchymal polyps are rare, but detection is improving with high-quality screening colonoscopies. Mucosal Schwann cell hamartomas (MSCH) of the gastrointestinal tract are mesenchymal tumors that were first described in 2009. The median age at diagnosis is 59 years (range 34-88 years), with a slight female predominance. CASE DESCRIPTION/METHODS: A 70-year-old white male with coronary artery disease, persistent atrial fibrillation, and obstructive sleep apnea was referred for screening colonoscopy. This revealed 2 sessile polyps (Paris 0-1s) in the sigmoid colon, measuring 2 mm and 7 mm in size. The polyps were completely removed by cold biopsy polypectomy and cold snare polypectomy, respectively. The second polypectomy site oozed slightly and was closed using 2 hemoclips, with anticipation that the patient would be resuming anticoagulation the same day. Pathology of the polyps were consistent with mucosal Schwann cell hamartoma, staining positive for S-100 protein. DISCUSSION: MSCH are a group of neuronal polyps purely composed of Schwann cells that are positive for S-100 in a strong, diffuse pattern, with both nuclear and cytoplasmic staining. They typically cause no symptoms and may present as small polyps (1-8 mm) incidentally found during colonoscopy, predominantly in the rectosigmoid. They are not associated with any inherited syndromes. The diagnosis is made after excluding other lesions that resemble spindle cell proliferation and other neuronal tumors. These include neurofibroma, leiomyoma, and gastrointestinal stromal tumor (GIST). Neurofibromas, while also composed of Schwann cells, are often associated with neurofibromatosis type 1 (NF1). NF1 is usually accompanied by multiple cutaneous neurofibromas. Purely colorectal neurofibromas without skin manifestations are extremely rare. GIST can be easily excluded by negative immunoreactivity of c-Kit and CD117. Leiomyomas stain positive for smooth muscle actin. In summary, MSCH’s are rare lesions with a benign course and no known association with inherited polyposis syndromes. Diagnosis depends on pathology demonstrating lack of axons on pathology, and immunohistochemistry staining strongly for S-100 protein. Our case highlights that accurate diagnosis can prevent overly aggressive or unnecessary treatments.

Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1.

Cutaneous neurofibromas (cNF) are physically disfiguring, painful, and cause extensive psychologic harm in patients with neurofibromatosis type 1 (NF1). There is currently no effective medical treatment and surgical procedures are inaccessible to most NF1 patients globally. While research is underway to find an effective medical treatment for cNF, there is an urgent need to develop surgical approach that is accessible to all NF1 patients in the world with the skill set and equipment found in most general medical office settings. Here, we present a robust surgical approach to remove cNF that does not require sterile surgical field, utilizes accessible clinical equipment, and can be performed by any health care providers including family practitioners, and physician assistants. In a prospective case-series, patients with NF1 underwent this surgical procedure which removes multiple cutaneous neurofibromas. The Dermatology Life Quality Index was given to subjects before and after the procedure as surrogate for patient satisfaction. 83 tumors were removed throughout the body from twelve individuals. Examination at follow-up visits revealed well-healed scars without infection or adverse events including aberrant scarring. Patient satisfaction with the procedure was high with significant improvements in symptoms, daily activities, leisure, personal relationships, and treatment experience (P = 0.00062). This study demonstrates a robust surgical approach to management cutaneous neurofibromas which can be accessed world-wide to individuals with NF1 and performed by a wide-variety of medical specialists with high clinical efficacy and patient satisfaction.

Primary Meningeal Rhabdomyosarcoma of the Spinal Cord of a Young Dog with Neuromelanocytosis and Multiple Cutaneous Neurofibromas

A 7-week-old male black Labrador retriever puppy was presented for post-mortem examination following progressive hindlimb paralysis and multiple masses within the skin. A highly compressive and infiltrative intradural mass was found within the T9-T11 spinal cord. Microscopical and immunohistochemical analysis revealed features compatible with spindle cell rhabdomyosarcoma (RMS). The adjacent spinal cord had numerous melanin-containing cells, arranged in small nodules, predominantly within the grey matter (proposed term of 'micronodular neuromelanocytosis') and the left lateral thorax had multifocal dermal neurofibromas. In this case, the constellation of proliferative/neoplastic lesions represents a unique case presentation with unclear aetiology. Primary canine meningeal RMS of the spinal cord has not been reported previously and represents a novel differential diagnosis for spinal tumours of young dogs. Moreover, such cases should be assessed for the presence of additional congenital abnormalities.

Oral Manifestation of Neurofibromatosis Type I: a Case Report

Neurofibromatosis is a hereditary condition with at least 8 identified forms; neurofibromatosis type I is the most common. The type I form is characterized by multiple café-au-lait spots and cutaneous neurofibromas, freckles in the axillary and inguinal regions, a brownish spot on the iris, skeletal dysplasias, benign and malignant nervous system tumor growth, and usually a first-degree relative with the same condition. A 35-year-old woman presented with café-au-lait spots and multiple cutaneous neurofibromas, with the oral manifestation as nodules in the palate, alveolar ridge, buccal mucosa, and tongue. A panoramic radiography analysis did not show any change. The histological evaluation of an incisional biopsy of the palate lesion was compatible with the neurofibromatosis diagnosis. Due to difficulty in swallowing caused by the palate lesion, it was surgically removed and a histological evaluation confirmed the diagnosis. The patient continues to be under follow-up with the oral medicine team.

THSD7A-associated membranous nephropathy in a patient with neurofibromatosis type 1

Target antigens in idiopathic membranous nephropathy (MN) include the phospholipase A2 receptor (PLA2R), and in some cases, the thrombospondin type 1 domain-containing 7A (THSD7A). A notable phenomenon is the high rate of cancer (reported to be as high as 20%) in patients with THSD7A-associated MN. Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by NF1 gene mutation, and clinically characterized by multiple cutaneous neurofibromas and café-au-lait spots. In this article, we report a patient with NF1 who developed THSD7A-associated MN when the NF1 skin lesions deteriorated. The patient, a 62-year-old male, was referred to us for nephrotic syndrome for 6 months. Physical examination revealed multiple cutaneous nodules throughout the entire body, and the patient noted recent increase in the numbers of these skin lesions. Cutaneous nodules excisional biopsy suggested NF1 and Sanger sequencing using genomic DNA extracted from peripheral blood revealed a previously reported heterozygous frameshift NF1 mutation (c.1541_1542delAG, p. Gln514fs). Renal biopsy revealed MN and immunohistochemistry (IHC) showed enhanced staining of THSD7A as well as PLA2R along the glomerular basement membrane whereas the serum level of THSD7A and PLA2R were both within normal range. The neurofibroma tissues were positive for THSD7A but not for PLA2R on IHC. The patient did not respond to 6-month treatment with glucocorticosteroid and cyclophosphamide. In this exceptional case, strong positive staining of THSD7A in both skin and renal biopsy samples, together with the temporal association between nephrotic syndrome and skin lesions and lack of treatment response, suggested the possibility that MN could be the result of immune response to THSD7A in NF1. This report may improve understanding of the mechanistic link between MN and cancer.

An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots, Freckling, and Neurofibromas. An Update. Part I. Dermatological Clinical Criteria Diagnostic of the Disease

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic café-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are café-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management.

Neurofibromatosis tipo 1: más que manchas café con leche, efélides y neurofibromas. Parte II. Actualización sobre otras manifestaciones cutáneas características de la enfermedad. NF1 y cáncer

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic café-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are café-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management.

Dermatoglifia de Pacientes Portadores de Neurofibromatose Tipo 1

Introduction. NF1 is an autosomal dominant disorder with an inci­dence of about 1 in 3,000 individuals4. The disease is mainly charac­terized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Objective. The aim of this study is to describe the dermatoglyphic profile of Bra­zilian patients with NF1, in order to contribute to the diagnosis of individuals with suspected NF1. Method. The sample consisted of 86 NF1 patients from Clinical Genetics Service from Campos dos Goy­tacazes, Rio de Janeiro, Brazil, of both sexes, aged between 1 and 65. The group underwent an evaluation to identify the dermatoglyphic profile by means of fingerprinting, according to Cummins &Mid­lo (1961). Results. The dermatoglyphic profile found was: SQTL: 127.8; D10: 13.2, L> W: 29.4%, W> L: 35.3% (A): 6.0% (L): 56.0% (W): 38.0. Final Considerations. There is a significant increase in the number of whorls followed by a reduction in the incidence of loops in patients with NF1 compared with normal controls. An increase in the number of whorls has also been observed in previous studies.

The curious case of a man with freckles and obscure gastrointestinal bleed

1. Castleman B, Towne VW. CASE records of the Massachusetts General Hospital Weekly Clinicopathological Exercises: Case 40011. N Engl J Med. 1954;250:26–30. 2. Kimura T, Inoue T, Katayama K, Hirose K, Imamura Y, Yamaguchi A. Mesenteric Castleman’s disease: report of a case. Surg Today. 2002;32:651–4. 3. Rosai J. Rosai and Ackerman’s surgical pathology. 9th ed. New Delhi: Elsevier; 2004:1905–8. 4. Francis ND, Hollowood K, Gabriel R. Angiofollicular lymph node hyperplasia. J Clin Pathol. 1988;41:353–4. 5. Cesarman E, Knowles DM. Kaposi’s sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Semin Diagn Pathol. 1997;14:54–66. 6. Frizzera G. Castleman’s diesease: more questions than answers. Hum Pathol. 1985;156:202–5. 7. Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, et al. Pathogenic significance of interleukin-6 (IL-6/ BSF-2) in Castleman’s disease. Blood. 1989;74:1360–7. unremarkable except for multiple cutaneous neurofibromas, axillary freckles and cafe au lait spots (Figure 1). Haematological tests revealed microcytic hypochromic anaemia and faecal occult blood was positive. Both upper GI endoscopy (UGIE) and colonoscopy were normal. CT angiogram of the abdomen (Figure 2) revealed the presence of two masses 3 cm × 2 cm in size, enhancing well with contrast, located in the proximal and mid jejunum and supplied by branches of the superior mesenteric artery. After obtaining an informed consent and preoperative packed cell transfusions, the patient was taken up for diagnostic laparoscopy. Findings at laparoscopy included two jejunal tumours as described above and additional

Multiple neurofibromas as the presenting feature of familial atypical multiple malignant melanoma (FAMMM) syndrome

Mutations in the cyclin-dependent kinase inhibitor-2A (CDKN2A) gene have been associated with a number of malignancies, most notably cutaneous malignant melanoma (CMM). Mutations in this gene have also been associated with pancreatic cancer and breast cancer, as well as astrocytomas and other nervous system tumors (NST). Among NST, rare solitary internal neurofibromas have been reported, but multiple cutaneous neurofibromas have only been described in two families. In the first family, the affected individuals all carried a heterozygous G>C mutation at the splice acceptor site of intron 1 resulting in skipping of CDKN2A exon 2, while the affected individuals in the second family had a deletion that encompassed the whole CDKN2A/CDKN2B/ANRIL locus. We now report on a proposita presenting with multiple biopsy-proven cutaneous neurofibromas and a solitary spinal neurofibroma found to have a deletion of 14 nucleotides in exon 2 of CDKN2A, providing further evidence that p14, p16, and/or ANRIL are specifically involved in the pathogenesis of neurofibromas as a feature of the familial atypical multiple malignant melanoma spectrum.

Usefulness of (18)F-FDG-PET/CT in Evaluating a Brainstem Glioma in an Adult Patient with Neurofibromatosis Type 1.

We describe a case of a brainstem glioma (BSG) occurred in an adult patient with neurofibromatosis type 1 (NF1) and evaluated by Flourine-18-Fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT). A 32-year-old male patient with NF1 underwent brain magnetic resonance imaging (MRI) for the onset of diplopia, facial paresis and cerebellar signs and symptoms. MRI showed a brainstem lesion compatible with BSG. Biopsy was not performed. 18F-FDG-PET/CT demonstrated intense 18F-FDG uptake in the brainstem lesion, suggesting an aggressive neoplasm. The patient was referred to radiotherapy but he developed rapid disease progression. In this case, 18F-FDG-PET/CT provided useful information about this rare NF1-associated tumor (Figs. ​(Figs.11 and ​and22). Fig. 1 We report the case of a 32-year-old male patient with neurofibromatosis type 1 (NF1) affected by a brainstem glioma (BSG). The patient underwent brain magnetic resonance imaging (MRI) for the onset of diplopia, facial paresis and cerebellar signs and ... Fig. 2 The biopsy of the lesion was not performed and the patient underwent 18F-FDG-PET/CT for the metabolic characterization of this brainstem lesion. Before 18F-FDG injection, the patient had fasted for at least 6 h; at the time of the radiopharmaceutical ... Subsequently, the patient was referred to radiotherapy, but he developed rapid disease progression and died 3 months later. NF-1 is an autosomal dominant disorder characterized by multiple cafe-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules [1]. NF-1 is also characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors such as malignant peripheral nerve sheath tumors or central nervous system high-grade gliomas [1, 2]. NF1-associated BSGs are less common than NF1-associated optic gliomas (OGs) and seem to represent a particular entity which tend, as a whole, to have a more favorable prognosis and a more indolent course than BSGs in patients without NF1 [3–5]; nevertheless, some NF1-associted BSG may rapidly progress [4]. 18F-FDG-PET/CT has demonstrated to provide useful information to the surveillance of OGs in children with NF1, particularly to identify progressive, symptomatic tumors [6–8]. To the best of our knowledge, there are no data about the usefulness of 18F-FDG-PET/CT in adult patients with NF1-associated BSG. In our case, 18F-FDG-PET/CT has been useful in evaluating this rare NF1-associated tumor.

Radiofrequency Ablation and Excision of Multiple Cutaneous Lesions in Neurofibromatosis Type 1

BackgroundVon Recklinghausen disease or neurofibromatosis type 1 is an autosomal dominant genetic disorder of chromosome 17q11.2. The most common characteristic findings of NF 1 include multiple and recurrent cutaneous neurofibromas associated with psychosocial distress.MethodsSixteen patients (9 female, 7 male; average age, 31 years; range, 16 to 67 years) with multiple cutaneous neurofibromas between March 2010 and February 2012 were included in the study. All patients were treated with radiosurgical ablation and excision under general anesthesia.ResultsAll 16 patients were satisfied with the results, when questioned directly during the outpatient department follow-up. The only complaint from a few patients was minimal scarring, but acceptable results were obtained in the end.ConclusionsThe radiofrequency procedure is almost bloodless and quick, creating a smaller necrotizing zone. Therefore, instead of employing the time consuming traditional surgery, such as laser therapy and electrosurgical excision, that produces uncertain results and can affect normal adjacent tissue, treatment of neurofibromas with radiofrequency ablation and excision can be an alternative choice of treatment for patients with a large number of neurofibromas.