• Journal of Korean Neurosurgical Society
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• 제38권1호
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• pp.16-22
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• 2005

Objective : The authors characterize a syndrome of multiple neurogenic tumors in the spinal canal, which is unclassifiable by the current National Institute of Health[NIH] criteria for neurofibromatosis. Methods : We retrospectively examined cases in which two or more spinal neurogenic tumors were detected by magnetic resonance[MR] imaging and which had been pathologically confirmed. Eighteen patients were recruited between February 1986 and March 2002. According to NIH criteria, eight cases were neurofibromatosis type 1[NF1], four were type 2[NF2], and six were neither type 1 nor type 2 [Unclassifiable : UC]. The locations of lesions, clinical presentations, radiological findings, and pathological results with immunohistochemistry were reviewed. Results : In the case of NF2, three of four cases were intradural tumors. Pathological examinations revealed neurilemmomas in two of four NF2 and all of the UC cases. In the case of NF1, pathological examinations showed seven neurofibromas and one neurilemmoma. Concerning UC, the age at presentation was middle-aged to late [mean age 48.5, range 35 to 64], which contrasted with ordinary NF2, where patients tended to become symptomatic before 20years of age. The pathological examinations of UC cases revealed neurilemmoma similar to most of NF2 and the immunohistochemical study showed characteristic of NF1. Conclusion : Multiple neurogenic tumors in the spinal canal are an under-recognized disease entity. Further studies for genetic aberration in multiple spinal neurogenic tumors are needed.

• Molecules and Cells
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• 제43권2호
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• pp.153-159
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• 2020

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. NF1 patients are predisposed to formation of several type solid tumors as well as to juvenile myelomonocytic leukemia. Loss of NF1 results in dysregulation of MAPK, PI3K and other signaling cascades, to promote cell proliferation and to inhibit cell apoptosis. The RUNX1 gene is associated with stem cell function in many tissues, and plays a key role in the fate of stem cells. Aberrant RUNX1 expression leads to context-dependent tumor development, in which RUNX1 may serve as a tumor suppressor or an oncogene in specific tissue contexts. The co-occurrence of mutation of NF1 and RUNX1 is detected rarely in several cancers and signaling downstream of RAS-MAPK can alter RUNX1 function. Whether aberrant RUNX1 expression contributes to NF1-related tumorigenesis is not fully understood. This review focuses on the role of RUNX1 in NF1-related tumors and blood disorders, and in sporadic cancers.

• Clinical and Experimental Pediatrics
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• 제57권9호
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• pp.410-415
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• 2014

Purpose: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by an NF1 gene mutation. NF1 is also a multisystem disorder that primarily affects the skin and nervous system. The goal of this study was to delineate the phenotypic characterization and assess the NF1 mutational spectrum in patients with NF1. Methods: A total of 42 patients, 14 females and 28 males, were enrolled in this study. Clinical manifestations and results of the genetic study were retrospectively reviewed. Results: Age of the patients at the time of NF1 diagnosis was $15.8{\pm}14.6$ years (range, 1-62 years). Twelve patients (28.6%) had a family history of NF1. Among the 42 patients, $Caf\acute{e}$-au-lait spots were shown in 42 (100%), neurofibroma in 31 (73.8%), freckling in 22 (52.4%), and Lisch nodules in seven (16.7%). The most common abnormal finding in the brain was hamartoma (20%). Mental retardation was observed in five patients (11.9%), seizures in one patient (2.4%), and plexiform neurofibromas (PNFs) in four patients (9.5%). One patient with PNFs died due to a malignant peripheral nerve sheath tumor in the chest cavity. Genetic analysis of seven patients identified six single base substitutions (three missense and three nonsense) and one small deletion. Among these mutations, five (71.4%) were novel (two missense mutations: p.Leu1773Pro, p.His1170Leu; two nonsense mutations: $p.Arg2517^*$, $p.Cys2371^*$; one small deletion: $p.Leu1944Phefs^*6$). Conclusion: The clinical characteristics of 42 Korean patients with NF1 were extremely variable and the mutations of the NF1 gene were genetically heterogeneous with a high mutation-detection rate.

• Journal of Genetic Medicine
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• 제19권2호
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• pp.94-99
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• 2022

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited purine metabolic disorder that accompanies neurodevelopmental problems. Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant inherited genetic disorder characterized by tumors in various systems. Some children with NF1 also accompanies neurodevelopmental problems. Here, we describe a 5-year-old boy with a maternally inherited pathogenic variant in NF1 and hypoxanthine-guanine phosphoribosyltransferase (HPRT). He was referred for severe neurodevelopmental impairment and hyperuricemia. His mother was diagnosed with NF1 and the patient was also suspected of having NF1 because of cafe au lait macules. He had dystonia, rigidity, cognitive deficit, and speech/language impairment. Serum and urine uric acid concentrations were elevated. He had more severe neurodevelopmental delay than patients with only NF1, so his clinical symptoms could not be fully understood by the disease alone. To find the cause of his neurologic symptoms and hyperuricemia, the patient and his mother underwent a whole-exome sequencing test. As a result, the pathogenic variant c.151C>T (p.Arg51Ter) in HPRT1 was identified as hemizygote in the patient and heterozygote in his mother. The pathogenic variant c.7682C>G (p.Ser2561Ter) in NF-1 was identified as heterozygotes in both of them. Although the clinical symptoms of both diseases were overlapping and complicated, genetic testing was helpful for accurate diagnosis and treatment. Therefore, we suggest to consider preemptive genetic evaluation if there are symptoms not sufficiently explained by known existing diseases. And it is considered valuable to review this rare case to understand the clinical course and possible synergic effects of these diseases.

• Journal of Yeungnam Medical Science
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• 제30권2호
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• pp.105-108
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• 2013

Type 1 neurofibromatosis (von Recklinghausen's disease, NF-1) is an autosomal-dominant neurocutaneous-disorder characterized by systemic cafe'-au-lait spots, multiple cutaneous neurofibromas, axillary or inguinal freckling, and Lisch nodules (pigmented iris hamartomas). Approximately 10-25% of NF1 patients have gastrointestinal neoplasms. Gastrointestinal stromal tumor (GIST) in patients with neurofibromatosis is most commonly found in the small bowel and the stomach, and approximately 60% of such patients have multiple tumors or multiple tumor sites. Although, the increased incidence of GIST in patients with neurofibromatosis is well documented in pathology literature in English, but has rarely been documented in Korea. Here, we report a case of multiple GISTs in a 48-year-old woman accompanied by NF1. She was admitted to Yeung-nam University Hospital with complaints of melena and dyspnea. A contrast-enhanced computed tomography (CT) scan revealed that multiple soft tissue masses were occupying the entire peritoneal cavity. An ultrasonogram- guided biopsy was performed and the tumors were found to have been composed of tumor cells that were positive for c-kit protein. The patient was put on Imatinib mesylate treatment, and further follow-up will be carried out.

• Journal of Genetic Medicine
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• 제14권2호
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• pp.56-61
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• 2017

Purpose: Neurofibromatosis type 2 (NF2) is characterized by multiple tumors, including vestibular schwannoma (VS) and others affecting cranial and peripheral nerves. NF2 is caused by mutation of the NF2 gene. The mutation spectrum of NF2 has not been characterized in Korean patients. In the current study, the clinical and genetic characteristics of Korean NF2 patients were analyzed. Materials and Methods: Twenty-five unrelated Korean families were enrolled according to the Manchester criteria. Genetic analysis was performed by direct sequencing and multiplex ligation-dependent probe amplification methods using genomic DNA from peripheral lymphocytes or tumor tissues. Results: All patients had bilateral/unilateral VS and/or other cranial and peripheral nerve tumors. Two patients were familial cases and the other 24 patients were sporadic. Germline NF2 mutations were detected in peripheral lymphocytes from both familial cases, but only in 26.1% of the 23 sporadic families. Somatic mutations were also found in tumor tissues from two of the sporadic families. These somatic mutations were not found in peripheral lymphocytes. A total of 10 different mutations including 2 novel mutations were found in 40.0% of studied families. Five mutations (50.0%) were located in exon 6 of NF2, the FERM domain coding region. Conclusion: Family history was an important factor in identifying germline NF2 mutations. Further study is required to investigate whether exon 6 is a mutation hotspot in Korean NF2 patients and its correlation to phenotypic severity.

• The Korean Journal of Physiology and Pharmacology
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• 제7권5호
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• pp.289-293
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• 2003

Mutations in the NF2 tumor suppressor gene cause neurofibromatosis type 2, an autosomal dominant inherited syndrome predisposed to the multiple tumors of the nervous system. Merlin, the NF2 gene product was reported to block Ras-mediated cell transformation and represses Ras-induced expression of cyclin D1. However, the potential mechanism underlying the anti-Ras function of merlin on the cyclin D1 is still unclear. In this study, we investigated whether merlin decreases Ha-ras-induced accumulation of cyclin D1 at the transcriptional level, and demonstrated that merlin suppressed Ras-induced cyclin D1 promoter activity mediated by the cyclic AMP-responsive element (CRE) in SK-N-BE(2)C neuroblastoma cells. Furthermore, we found that merlin attenuated active Ras and forskolin-induced CRE-driven promoter activity. These results suggest that the transcriptional repression of the cyclin D1 expression by merlin may contribute to the inhibition of Ras-induced cell proliferation.

• 대한두경부종양학회지
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• 제37권2호
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• pp.77-80
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• 2021

Plexiform neurofibromas (PNFs) represent an uncommon variant (30%) of neurofibromatosis type 1 (NF-1), in which neurofibromas arise from multiple nerves as bulging and deforming masses involving connective tissue and skin folds. We report the case of a 17-year-old man with known NF-1 presenting with bilateral occipital neuralgia that began in his late adolescence. His chief complaint was radiating pain in the occiput induced by protective helmet wear when riding alpine skiing. Craniofacial magnetic resonance imaging (MRI) confirmed the presence of fusiform masses arising from the bilateral greater occipital nerves. Histopathological examination of the biopsy samples showed PNFs. After surgical treatment, the patient's symptoms completely improved. Unlike cutaneous neurofibromas, PNFs have different clinical characteristics and have the risk of malignant mutations. Correct diagnosis and adequate surgical treatment are necessary for PNFs.

• 대한영상의학회지
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• 제82권2호
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• pp.417-422
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• 2021

제1형 신경섬유종증은 상염색제 우성으로 유전되는 신경외배영성 질환으로 다양한 악성 종양이 발생할 수 있다. 하지만 유방암이 발생한 보고는 드물다. 이에 저자들은 제1형 신경섬유종증 환자에서 발생한 양측성 유방암 증례를 영상 소견과 함께 보고하고자 한다.

• Molecules and Cells
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• 제20권2호
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• pp.196-200
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• 2005

The neurofibromatosis type2 (NF2) tumor suppressor gene product, merlin, is structurally related to the ezrin-radixin-moesin (ERM) family of proteins that anchor the actin cytoskeleton to specific membrane proteins and participate in cell signaling. However, the basis of the tumor suppressing activity of merlin is not well understood. Previously, we identified a role of merlin as an inhibitor of the Ras-ERK signaling pathway. Recent studies have suggested that phosphorylation of merlin, as of other ERM proteins, may regulate its function. To determine whether phosphorylation of merlin affects its suppression of Ras-ERK signaling, we generated plasmids expressing full-length merlin with substitutions of serine 518, a potential phosphorylation site. A substitution that mimics constitutive phosphorylation (S518D) abrogated the ability of merlin to suppress effects of the Ras-ERK signaling pathway such as Ras-induced SRE transactivation, Elk-mediated SRE transactivation, Ras-induced ERK phosphorylation and Ras-induced focus formation. On the other hand, an S518A mutant, which mimics nonphosphorylated merlin, acted like wild type merlin. These observations show that mimicking merlin phosphorylation impairs not only growth suppression by merlin but also its inhibitory action on the Ras-ERK signaling pathway.