Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature

AIM:To detect the pathogenic gene variant in a family with neurofibromatosis type 1(NF1).METHODS:This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology.After detecting the suspicious pathogenic variant type,the pathogenic variant sites of the patient and the patient’s family members were verified by multiple ligation dependent probe amplification and Sanger sequencing.Sift,polyphen-2,Mutation Taster and GERP++software were used to predict the pathogenicity of the unknown loci.The clinical data,diagnosis and treatment process of the patients were reviewed.Using the keyword“NF1;frameshift pathogenic variant”,relevant literature was gathered for analysis from Chinese and international databases,with articles dating from the establishment of each database to April 2022.RESULTS:A heterozygous frameshift pathogenic variant of NF1 in exon 33 was detected in the patient.The insertion of adenine in coding region 4486 resulted in the replacement of isoleucine with asparagine in protein 1497.Sanger sequencing validation and segregation analysis were performed,which demonstrated that the NF1 gene was cosegregated with the disease phenotype in this family.This study identified a novel NF1 heterozygous frameshift mutation c.4486dupA(p.I1497Nfs*12).Relevant literature retrieval found 7 Chinese articles and 12 foreign articles.With NF1 gene mutation,mutation types are diverse,including point mutation,frameshift mutation,splice site mutation,exon mutation,chimeric mutation and de novo mutation.Foreign reports are based on autosomal dominant inheritance.CONCLUSION:This study’s results demonstrate that a novel deletion in exon 33 caused NF1 in this Chinese family,expanding the mutational spectrum of the NF1 gene.

Neurofibromatosis type 1 with multiple gastrointestinal stromal tumors:A case report

BACKGROUND Neurofibromatosis type 1(NF1)is characterized by café-au-lait patches on the skin and the presence of neurofibromas.Gastrointestinal stromal tumor(GIST)is the most common non-neurological tumor in NF1 patients.In NF1-associated GIST,KIT and PDGFRA mutations are frequently absent and imatinib is ineffective.Surgical resection is first-line treatment.CASE SUMMARY A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass.Physical examination was notable for multiple café-au-lait patches and numerous subcutaneous soft nodular masses of the skin of the head,face,trunk,and limbs.Her abdomen was soft and nontender.No masses were palpated.Digital rectal examination was unremarkable.Abdominal computed tomography was suspicious for GIST or solitary fibrous tumor.Laparoscopy was performed,which identified eight well-demarcated masses in the jejunum.All were resected and pathologically diagnosed as GISTs.The patient was discharged on day 7 after surgery without complications.No tumor recurrence was evident at the 6-mo follow-up.CONCLUSION Laparoscopy is effective for both diagnosis and treatment of NF1-associated GIST.

Analysis of the current Covid-19 infection and vaccination status in patients with neurofibromatosis type 1

Background:To investigate the common symptoms after Covid-19 infection,characteristics of adverse events after vaccination,changes in clinical manifestations related to Neurofibromatosis type 1(NF1),as well as the current vaccination status and factors related to vaccine hesitation among NF1 patients,in order to provide a basis for scientific protection and vaccine acceptance in NF1 individuals in the new phase of pandemic management.Methods:From December 29,2022,to January 10,2023,we conducted a self-assessment questionnaire survey among diagnosed NF1 patients.General data were provided including sex,age,main clinical presentations,and current treatment.This study mainly focused on the infection and vaccination status of Covid-19 among these patients with NF1.The data were statistically analyzed using SPSS26.0 software.Results:Of the 250 questionnaires distributed,226 were valid.Among the 164 patients(72.6%)with Covid-19 infection,the most common infection symptoms and incidence of patients were not significantly different from those in the normal population(P>0.05),but the incidence of symptoms such as nasal congestion,headache,myalgia,sore throat,abdominal pain,diarrhea,and eye discomfort was higher than that in the normal population(P<0.05),and no severe infection was observed;186 patients(82.3%)had completed the Covid-19 vaccination,and more than half of those who were not vaccinated had no plans for vaccination.Among the vaccinated patients,there was no significant difference in the incidence of adverse events,such as fever,pain,redness,and swelling at the injection site after vaccination,compared to the normal population(P>0.05),but the incidence of fatigue and headache was higher in NF1 patients(P<0.001).Most patients with NF1 believe that there is no significant progressive change in NF1-related clinical manifestations after Covid-19 infection and vaccination.Conclusion:Currently,some NF1 patients appear to be worried about the evolution of their disease after Covid-19 infection in the face of large fluctuations in the pandemic situation,and some patients hesitate to receive the vaccine due to their special disease condition.Thus,clinical trials should be conducted to develop a refined pandemic response and vaccination program for this special group.

KIT and platelet-derived growth factor receptor α wild-type gastrointestinal stromal tumor associated with neurofibromatosis type 1: Two case reports

BACKGROUND Gastrointestinal stromal tumors(GISTs) associated with neurofibromatosis are uncommon compared to their gastrointestinal counterparts. Patients with neurofibromatosis type 1(NF-1) have an increased risk of developing gastrointestinal tumors, including rare types such as GIST.CASE SUMMARY A 60-year-old male Chinese patient was diagnosed with NF-1 10 years ago and presented with upper abdominal discomfort and black stools. Endoscopic ultrasonography and an enhanced abdominal computed tomography scan revealed a mass located 4 cm from the muscular layer of the descending duodenum. A 59-year-old Chinese woman who was diagnosed with NF-1 25 years ago presented with sudden unconsciousness and black stools. Multiple masses in the duodenum were noted by echogastroscopy and an enhanced abdominal computed tomography scan. Both patients presented with cutaneous neurofibromas. The histologic examination of tumors from both patients revealed spindle cells and low mitotic activity. Immunohistochemically, the tumor cells showed strong positivity for KIT(CD117), DOG-1, CD34, and Dehydrogenase Complex Subunit B, and negativity for SMA, desmin, S-100, and β-catenin. None of the six tumors from two patients had KIT exon 9, 11, 13, or 17 or platelet-derived growth factor receptor α exon 12 or 18 mutation, which is a typical finding for sporadic GISTs. None of the six tumors from the two patients had a BRAFV600 E mutation. The patients were alive and well during the follow-up period(range:0.6-5 yr).CONCLUSION There have been only a few previous reports of GISTs associated with NF-1.Although GISTs associated with NF-1 have morphologic and immunohistochemical similarities with GISTs, the pathogenesis, incidence,genetic background, and prognosis are not completely known. A medical history of NF-1 in a patient who has gastrointestinal bleeding or anemia and an intraabdominal mass with nonspecific computed tomography features may help in diagnosing GIST by virtue of the well-known association of these two entities.Molecular genetic studies of cases indicated that GISTs in NF-1 patients have a different pathogenesis than sporadic GISTs.

Intraductal papillary bile duct adenocarcinoma and gastrointestinal stromal tumor in a case of neurofibromatosis type 1

We report our experience with a synchronous case of gastrointestinal stromal tumor(GIST) and intraductal papillary neoplasm of the bile duct(IPNB) in anelderly woman with neurofibromatosis type 1(NF-1). A 72-year-old woman presented with a 2-mo history of right upper abdominal pain unrelated to diet and indigestion. Fourteen years earlier, she had been diagnosed with NF-1, which manifested as café au lait spots and multiple nodules on the skin. Computed tomography(CT) revealed a multilocular low-density mass with septation, and mural nodules in the right hepatic lobe, as well as a 1.7-cm-sized well-demarcated enhancing mass in the third portion of the duodenum. The patient subsequently underwent right hepatectomy and duodenal wedge resection. We present here the first report of a case involving a synchronous IPNB and GIST in a patient with NF-1. Our findings demonstrate the possibility of various tumors in NF-1 patients and the importance of diagnosis at an early

Effect of sunitinib on metastatic gastrointestinal stromal tumor in patients with neurofibromatosis type 1: A case report

Gastrointestinal stromal tumor （GIST） represents the most common mesenchymal malignancy of the gastrointestinal （GI） tract. In neurofibromatosis （NF）, the increased incidence of tumor needs to be considered even in non-symptomatic individuals. Patients with neurofibromatosis NF type 1 have an increased risk of developing GI tumors including rare types such as GIST. We report a case of GIST in a 53-year-old male patient with neurofibromatosis. The patient was diagnosed with NF four years ago and his medical history revealed that he was hospitalized 5 times with a provisional diagnosis of massive lower gastrointestinal bleeding. GIST was diagnosed at explorative laparotomy and the tumor was 21 cm × 13 cm × 7 cm in size. Immunohistochemical examination showed that vimentin, actin and CDl17 were positive. Computerized tomography showed peritoneal implants three months later. Imatinib mesylate （600 mg/d） was initiated. However, control computerized tomography revealed liver and omental metastasis. The dosage was elevated to 800 mg/d. Despite high dosage, the progression of the metastatic lesions continued in the liver and omentum. The patient started oral sunitinib malate （Sutent~ Pfizer Inc, New York, NY, USA） 50 mg per day for 4 consecutive weeks, followed by 2 wk off per treatment cycle. The metastatic lesions in the liver and omentum were decreased in size after four courses, suggesting that sunitinib is also an effective treatment modality for metastatic GIST in NF patients.

Multiple gastrointestinal stromal tumors and bilateral pheochromocytoma in neurofibromatosis

The coincidence of a gastrointestinal stromal tumor (GIST) and a neuroendocrine tumor (NET) in neurofibromatosis type 1 (NF1) is described only five times within the literature. We report on a 63 year old Caucasian female with the rare condition of neurofibromatosis type 1 coinciding with recurrent gastrointestinal stromal tumor plus bilateral pheochromocytoma (PCC). After a history of palpitations and dizziness that lasted for years, a left adrenal mass was detected by CT. Laparotomy revealed a pheochromocytoma of the left adrenal gland while an ileoterminal GIST was found incidentally intraoperatively. After six months contralateral PCC and multiple recurrent GIST were resected again. After four years the patient is doing well without any signs of further recurrent tumors. Discussion includes review of the literature.

A novel NF1 frame-shift mutation c.703＿704delTA in a Chinese pedigree with neurofibromatosis type 1

We analyzed the clinical features and NF1 gene mutation in a Chinese pedigree of neurofibromatosis type 1（NF1）. Three members of this family were NF1 patients presenting with different clinical phenotypes and the others were asymptomatic. Exons of NF1 were amplified by polymerase chain reaction, sequenced, compared with a reference database. One novel NF1 frame-shift mutation c.703_704delTA, which resulted in a premature stop signal at codon 720 and the synthesis of truncated, was revealed. This mutation segregated with the NF1 members is likely responsible for the pathogenesis of NF1 in the family.

Neurofibromatosis type 1-associated multiple rectal neuroendocrine tumors: A case report and review of the literature

Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.

The R1947X mutation of NF1 causing autosomal dominant neurofibromatosis type 1 in a Chinese family

Neurofibromatosis type 1 is a common autosomal dominant disorder with a high rate of penetrance. It is caused by the mutation of the tumor suppressor gene NF1, which encodes neurofibromin. The main function of neurofibromin is down-regulating the biological activity of the proto-oncoprotein Ras by acting as a Ras-specific GTPase activating protein. In this study, we identified a Chinese family affected with neurofibromatosis type 1. The known gene NF1 associated with NF1 was studied by linkage analysis and by direct sequencing of the entire coding region and exon-intron boundaries of the NF1 gene. The R1947X mutation of NF1 was identified, which was co-segregated with affected individuals in the Chinese family, but not present in unaffected family members. This is the first report, which states that the R1947X mutation of NF1 may be one of reasons for neurofibromatosis type 1 in Chinese population.

Awake craniotomy for auditory brainstem implant in patients with neurofibromatosis type 2:Four case reports

BACKGROUND The auditory brainstem implant(ABI)is a significant treatment to restore hearing sensations for neurofibromatosis type 2(NF2)patients.However,there is no ideal method in assisting the placement of ABIs.In this case series,intraoperative cochlear nucleus mapping was performed in awake craniotomy to help guide the placement of the electrode array.CASE SUMMARY We applied the asleep-awake-asleep technique for awake craniotomy and hearing test via the retrosigmoid approach for acoustic neuroma resections and ABIs,using mechanical ventilation with a laryngeal mask during the asleep phases,utilizing a ropivacaine-based regional anesthesia,and sevoflurane combined with propofol/remifentanil as the sedative/analgesic agents in four NF2 patients.ABI electrode arrays were placed in the awake phase with successful intraoperative hearing tests in three patients.There was one uncooperative patient whose awake hearing test needed to be aborted.In all cases,tumor resection and ABI were performed safely.Satisfactory electrode effectiveness was achieved in awake ABI placement.CONCLUSION This case series suggests that awake craniotomy with an intraoperative hearing test for ABI placement is safe and well tolerated.Awake craniotomy is beneficial for improving the accuracy of ABI electrode placement and meanwhile reduces non-auditory side effects.

Surgical resection of rare internal jugular vein aneurysm in neurofibromatosis type 1

Neurofibromatosis type 1 is a congenital condition affecting neurons and connective tissue integrity including vasculature.On extremely rare occasions these patients present with venous aneurysms affecting the internal jugular vein.If they become large enough there presents a risk of rupture,thrombosis,embolization or compression of adjacent structures.In these circumstances,or when the patient becomes symptomatic,surgical exploration is warranted.We present a case of one of the largest aneurysms in the literature and one of only five associated with Neurofibromatosis type 1.A 63-year-old female who initially presented for a Hinchey Ⅲ diverticulitis requiring laparotomy developed an incidentally discovered left neck swelling prior to discharge.After nonspecific clinical exam findings,imaging identified a thrombosed internal jugular vein aneurysm.Due to the risks associated with the particularly large size of our patient's aneurysm,our patient underwent surgical exploration with ligation and excision.Although several techniques have been reported,for similar presentations,we recommend this technique.

Coexistent vestibular schwannoma and meningioma in a patient without neurofibromatosis:A case report and review of literature

BACKGROUND The simultaneous occurrence of schwannoma and meningioma in the absence of neurofibromatosis(NF)or a previous history of irradiation is exceedingly rare,as only 10 intracranial cases have been reported to date.Herein,we report a case of a coexistent cavernous sinus meningioma and ipsilateral vestibular schwannoma(VS)in a female patient without NF or a history of exposure to irradiation.CASE SUMMARY A 63-year-old woman presented with progressive left-side hearing loss and tinnitus over the previous year.In the past 6 mo,she developed facial numbness and intermittent headaches.Magnetic resonance imaging showed two lesions that were located on the left side of the cerebellopontine angle and parasellar region.Both lesions were totally resected via the left retrosigmoid approach.Histopathological examination revealed a VS and a meningioma.The patient did not have a family history or clinical or radiological signs of NF.CONCLUSION The coincident occurrence of VS and meningioma within close vicinity is very rare,and the pathogenesis is unclear.A careful whole-body examination needs to be conducted to exclude NF.Surgical treatment with the goal of total tumor resection is the best therapy.Additional studies are needed for a better understanding of the mechanisms that lead to the development of tumor growth in multiple locations.

Synchronic Duodenal Gastrointestinal Stromal Tumor and Neuroendocrine Tumor in Association with Neurofibromatosis Type 1: A Case Report

Introduction: The coexistence of synchronic duodenal gastrointestinal stromal tumor (GIST) and neuroendocrine tumor in a patient with neurofibromatosis type 1 (NF1) is extremely rare, and only eight cases were described in the literature. Clinical Case: This is a rare case of a 38-year-old female patient with NF1 who developed synchronic GIST and neuroendocrine tumor, which were both in the second portion of the duodenum. The first symptoms were abrupt digestive bleeding and anemia. Upper digestive endoscopy revealed two tumors, sizes 2.5 and 3.0 cm, in the second portion of duodenum, with biopsies identifying a GIST and a neuroendocrine tumor. Therapeutic decision was to proceed to surgical resection, and Whipple’s procedure was indicated. Surgical procedure was performed with good outcome. Currently the patient has excellent quality of life and maintains follow up for thirty months without recurrence. Discussion: Long-term disease-free survival and excellent quality of life are reported when these tumors are fully resected in this context. However, it is not always easy to access the gastrointestinal tract, especially the small intestine, and proceed to the histopathologic diagnosis of these tumors. Conclusion: It is important to be aware of the possibility of the coexistence of various tumors in the NF1 scenario for adequate screening, staging, and surgical treatment of these patients, as good prognosis can be achieved when such tumors are detected and treated properly.

Neurofibromatosis Type 1 in Four Children Cases

Neurofibromatosis Type 1 (NF-1 or Von Recklinghausen disease) is an autosomal dominant genetic disease, characterized by an extreme variability of its clinical expression which is also found in the same family. Our work focuses on the exploitation of four cases of patients with NF-1 who were enrolled in the paediatric neurology consultation at Rabat Children’s Hospital. They are two infants and two children. Otherwise the diagnosis was made in front of the existence of café au lait and lentiginous spots in two boys, also the existence of café au lait spots and abnormalities in brain imaging in two girls. Thus an evolution was marked by a favorable outcome for three patients and neurological sequelae in one patient.

SURGICAL TREATMENT OF SCOLIOSIS CAUSED BY NEUROFIBROMATOSIS TYPE 1

Objective To retrospectively analyze the relationship between curve types and clinical results in surgical treatment of scoliosis in patients with neurofibromatosis type 1 (NF-1). Methods Forty-five patients with scoliosis resulting from NF-1 were treated surgically from 1984 to 2002. Mean age at operation was 14.2 years. There were 6 nondystrophic curves and 39 dystrophic curves depended on their radiographic featu- res. According to their apical vertebrae location, the dystrophic curves were divided into three subgroups: thoracic curve (apical vertebra at T8 or above), thoracolumbar curve (apical vertebra below T8 and above L1), and lumber curve (apical vertebra at L1 and below). Posterior spine fusion, combined anterior and posterior spine fusion were administrated based on the type and location of the curves. Mean follow-up was 6.8 years. Clinical and radiological manifestations were investigated and results were assessed. Results Three patients with muscle weakness of low extremities recovered entirely. Two patients with dystrophic lum- bar curve maintained their low back pain the same as preoperatively. The mean coronal and sagittal Cobb’s angle in nondy- strophic curves was 80.3o and 61.7o before operation, 30.7o and 36.9o after operation, and 32.9o and 42.1o at follow-up, respectively. In dystrophic thoracic curves, preoperative Cobb’s angle in coronal and sagittal plane was 96.5o and 79.8o, postoperative 49.3o and 41.7o, follow-up 54.1o and 45.3o, respectively. In thoracolumbar curves, preoperative Cobb’s angle in coronal and sagittal plane was 75.0o and 47.5o, postoperative 31.2o and 22.8o, follow-up 37.5o and 27.8o, respectively. In lumbar curves preoperative Cobb’s angle in coronal plane was 55.3o, postoperative 19.3o, and follow-up 32.1o. Six patients with dystrophic curves had his or her curve deteriorated more than 10 degrees at follow-up. Three of them were in the thoracic subgroup and their kyphosis was larger than 95 degrees, and three in lumbar subgroup. Hardware failure occurred in 3 cases. Six patients had 7 revision procedures totally. Conclusions Posterior spinal fusion is effective for most dystrophic thoracic curves in patients whose kyphosis is less than 95 degrees. Combined anterior and posterior spinal fusion is stronger recommended for patients whose kyphosis is larger than 95 degrees and those whose apical vertebra is located below T8. Patients should be informed that repeated spine fusion might be necessary even after combined anterior and posterior spine fusion.

Giant Mediastinal Neurofibroma in a Child with Neurofibromatosis Type I

Aim: There are a variety of malignant tumors related to neurofibromatosis type 1 (NF1). This report describes a rare pediatric NF1 case with an unresectable giant mediastinal tumor. Case: A 6-year-old girl with wheezing was admitted to our institution for the further evaluation of a right mediastinal mass on plain chest radiography. On examination, there were multiple café au lait spots mainly on the trunk, and a well-defined, immobile, painless mass was palpable on her neck. The mediastinal lesion was detected as nonuniform mass surrounding the aortic arch, pulmonary artery, and right main bronchus on the contrast-enhanced CT and MRI. Open biopsy was useful to rule out malignancy and revealed neurofibroma, and contributed to follow up and treatment. Discussion: Open biopsy was useful to rule out malignancy, such as malignant peripheral nerve sheath tumor, revealed neurofibroma, and also contributed to follow up and treatment. The authors report successful management by open biopsy and discuss several clinical points regarding mediastinal neurofibroma for NF1.

Neurofibromatosis type 2 gene mutation and progesterone receptor messenger RNA expression in the pathogenesis of sporadic orbitocranial meningioma

AIM: To investigate neurofibromatosis type 2(NF2) gene mutation at mRNA levels in sporadic orbitocranial meningioma and its association with progesterone receptor(PR) mR NA expression.METHODS: This was a case-control study. Thirty-four sporadic meningioma patients with no familial NF2-related meningioma history were recruited. They were interviewed for their obstetric, gynecologic, and contraception history. PR investigation was performed with real-time polymerase chain reaction(PCR). NF2 mutation was investigated using Qbiomarker Somatic Mutation PCR Assay at NF2 mRNA level after its cDNA extraction(four mRNA mutation cytoband coordinates for nucleotide change: c.634 C>T/p.Q212, c.655 G>A/p.V219 M, c.784 C>T/p.R262 and c.1228 C>T/p. Q410). RESULTS: After mutation analysis at mRNA level, NF2 gene mutation was found in 35.29% patients. Non-mutation group was strongly associated with exogenous hormonal exposure(non-mutation vs mutation: 95.5% vs 83.3%, P<0.001). PR mR NA was found significantly lower in nonmutation group(P=0.033) which presumed as long term exogenous progesterone exposure. However, mutation group was associated with higher rate of progression to gradeⅡ(mutation vs non-mutation, 18.2% vs 5%, P<0.001) and was associated more in fibrous and anaplastic tumor tissue.CONCLUSION: NF2 mutation-meningioma is associated with higher grade of meningioma. Non NF2 mutationmeningioma is strongly associated with exogenous progesterone exposure and lower PR expression.

Treatment of Neurofibromatosis with Chinese Herbal Drugs

Neurofibromatosis is a dominantly inheriteddefect of the ectoderm,characterized by cafe au laitspots since the childhood and multiple tumorsderived from elements of peripheral and cranialnerves.Hernia-like tumors of various sizes can oftenbe felt under the skin and serve as a valuablecharacteristic in making diagnosis.However,theycan also affect brain,vegetative nerve system or othertissues and lead to bony abnormalities,mentaldisturbances and sometimes,endocrine abnormalities,

Type Ⅰ neurofibromatosis with spindle cell sarcoma: A case report

BACKGROUND Neurofibromatosis type Ⅰ(NF1) is the most frequent subtype of neurofibromatosis. Its related tumor-suppressor syndromes are characterized by a predisposition to multiple tumor types and other disorder presentations. In addition, the incidence of tumors is much higher in patients with neurofibromatosis type Ⅰ. However, there are very few reports at home and abroad on this topic. Here, we present a case of NF1 with spindle cell sarcoma.CASE SUMMARY A 50-year-old male was found to have a right axillary mass for 20 years.Specialist examination found cafe-au-lait spots on many parts of the skin,rounded nodules in the skin, a bulge in the right armpit, touching a lump(10 cm× 6 cm, hard, unclear boundary, poor mobility, local tenderness). The anterior side of the thigh felt weakened on the opposite side;in the right groin a swollen lymph node(hard, clear border, good mobility, local tenderness). According to the results of positron emission tomography/computed tomography, puncture pathology and immunohistochemistry, genetic testing, a diagnosis of NF1 with spindle cell sarcoma was confirmed. According to the genetic testing result, the patient was given a targeted treatment with crizotinib.CONCLUSION Surgery, chemotherapy and radiotherapy are the main treatment methods of NF1. However, with the continuous progress of molecular biology research,molecular targeted therapy may bring benefits for patients.