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.

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.

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.

Vascular anomaly in the levator aponeurosis of neurofibromatosis type 1

Dear Editor,I am Satoru Kase,from the Department of Ophthalmology,Faculty of Medicine and Graduate School of Medicine,Hokkaido University,Sapporo City,Japan.I write to present a case of neurofibromatosis type 1（NF1）showing massive hemorrhage during involutional blepharoptosis surgery.

Neuroretinal dysfunction in patients affected by neurofibromatosis type 1

AIM:To examine neuroretinal function by using the multifocal electroretinography(mf ERG)test in patients with neurofibromatosis type 1(NF1)without optic pathway gliomas(OPGs).METHODS:This study was conducted on 35 patients(35 eyes)with NF1 and 30 healthy subjects(30 eyes)for the control group.Each subject underwent a complete ophthalmological examination including spectral domainoptical coherence tomography(SD-OCT)and mf ERG.The 1.5-Tesla magnetic resonance imaging(MRI)scan of the brain was performed in NF1 patients to assess the presence of OPGs.All participants were recruited having a best corrected visual acuity(BCVA)of no less than 20/20 in each eye.The amplitude and implicit time of the P1 wave(first-order Kernel component)were evaluated on mf ERG.Data analysis was carried out in the two central degrees and in the four quadrants from two to 25 degrees of visual field.RESULTS:Statistically significant results were obtained for the P1 wave amplitudes in the 4 quadrants in NF1 patients compared to healthy controls,while the reduction was not significant in the 2 central degrees between the groups.A statistically significant difference was observed among the P1 wave amplitudes as recorded in the 4 quadrants within the NF1 group,with lower amplitudes detected in the nasal quadrants.No differences in the implicit times were recorded in the 2 central degrees and in the 4 quadrants as compared between NF1 patients and controls.CONCLUSION:Impaired neuroretinal function in NF1 patients is expressed in a decreased amplitude of the P1-wave between 2 and 25 central retinal degrees on mf ERG.Altered intracellular signal transduction due to abnormal neurofibromin-mediated cyclic adenosine monophosphate(c AMP)generation,can be involved.The possible use of mf ERG as subclinical retinal damage indicator has a potential utility in clinical practice for the follow-up of NF1 patients.

Hemorrhagic shock due to ruptured lower limb vascular malformation in a neurofibromatosis type 1 patient:A case report

BACKGROUND Neurofibromatosis type 1(NF-1)is a common autosomal dominant genetic disorder.It is characterized by café-au-lait spots and cutaneous neurofibromas.Although NF-1 typically involves the skin,nerves,bones,and eyes,vascular manifestation in the form of devastating hemorrhage can occur rarely.CASE SUMMARY We present the case of a 47-year-old female with NF-1 who had a ruptured right lower limb arterial malformation.She presented with sudden right lower limb swelling for two hours and symptoms of hemorrhagic shock on admission.The physical examination revealed a right lower limb presenting as elephantiasis and visible dark-brown pigmentation over a large area.Computed tomography angiography showed right lower limb arteriovenous malformation.Therefore,the patient underwent emergency right lower limb digital subtraction angiography(DSA)and vascular embolization after blood transfusions.However,after DSA,vascular embolization,and repeated blood transfusions,the anemia and right lower limb swelling and tenderness did not improve.As a result,the patient underwent right lower extremity above-knee amputation.After amputation,the patient's hemoglobin level improved significantly without blood transfusion,and she was discharged from the hospital after the incision healed.Postoperative pathological examination suggested neurogenic tumors.No other complications had occurred 1-year follow-up.CONCLUSION Vascular malformation and rupture are fatal complications of NF-1.Embolization may not provide complete relief,the patient might need to undergo neurofibroma resection or amputation.

Neurofibromatosis Type 1: About a Series of 5 Cases

We report in this series 5 cases of neurofibromatosis type 1 (NF1). The mean age of the patients was 14.8 years (±9.65) with extremes ranging from 3 to 27 years. Three patients were female (60%) and two were male (40%). Three of our patients (60%) had no history of NF1 and two were monophthalmic because of plexiform neurofibromas involving the eyelid. Both cutaneous and plexiform neurofibromas were found in all our patients. The latter were of variable location: one on the chin, two on the left temporofacial region and two on the left upper eyelid. They were the cause of complications such as blindness in two patients. Café au lait macule (CALMs) was also present in all our patients. No cases of optic nerve glioma were found in the 3 patients (60%) who underwent an orbitocerebral CT scan. Lish nodules were observed in 4 patients (80%). With the exception of the 3-year-old female patient who was not old enough to go to school, all the other four patients dropped out of school because of the stigma attached to them.

Novel in-frame deletion mutation c.177_179del TAC of neurofibromatosis type 1 in a Chinese 4-year-old boy with binocular blindness

Dear editor,I am Dr.Jie Peng,from the Department of Ophthalmology,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China.I write to present a case report of a novel in-frame deletion mutation c.17779del TAC of neurofibromatosis type 1 in a Chinese boy with bilateral blindness.Neurofibromatosis type 1(NF1;OMIM#162200),an autosomal dominant disease,is caused by mutations in the NF1gene.The incidence of this disease is around 1 in 3500

Oral Manifestations of Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF-1) is a common genetic disorder with a highly variable phenotype. The disease affects both proliferation and differentiation of cells of neurectodermal origin. The presence of tumors is very common like benign nodular neurofibromas. Tumors with unclear prognosis may be present like plexiform neurofibromas whose prognosis is more uncertain. While many organs exhibit pathologies, most commonly affected are the nervous system, skin, gastrointestinal tract and heart. Oral abnormalities are also very common: 72% of NF-1 patients exhibit pathologies in oral mucosa, gums, maxillary and temporomandibular joints, and teeth. The incidence of NF-1 and its relationship to the prevalence of caries have been discussed in other researches. It is known that poor oral hygiene plays a key role in the development of periodontal disease and caries. Here we review the oral manifestations of neurofibromatosis type 1 that we illustrate by a patient followed in the center of rare diseases of the hospital Henri Mondor, clinical service in which we work.

PD-L1 Expression and Tumor Infiltrating Lymphocytes in Neurofibromatosis Type 1-Related Benign Tumors and Malignant Peripheral Nerve Sheath Tumors:An Implication for Immune Checkpoint Inhibition Therapy

Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neurofibromas,named cutaneous and plexiform neurofibromas.The latter type may transform into malignant peripheral nerve sheath tumors(MPNSTs).Surgical resection is difficult to perform owing to the complex tissue structure of neurofibromas;therefore,it is necessary to develop novel and effec­tive therapies for the treatment of these tumors.Programmed cell death protein 1(PD-1)/programmed cell death-ligand 1(PD-L1)-related immune checkpoint inhibitors have been proven effective for various cancers,and the positive expression of PD-L1 and tumor-infil­trating lymphocytes(TILs)has been recognized as a biomarker for the response to immune checkpoint therapy.Methods We conducted immunohistochemistry(IHC)staining to detect PD-L1 expres­sion in plexiform neurofibroma and MPNST tissue samples.Reverse transcription-poly­merase chain reaction(RT-PCR)and western blotting were performed to detect PD-L1 and PD-1 expression in MPNST cell lines.IHC staining was used to show immune cell infiltra­tion in NF1 and MPNST tissues.Results IHC staining showed PD-L1 positive expression in neurofibromas and MPNST tumor tissues.In addition,qPCR and western blotting showed high expression of PD-L1 in MPNST tumor cells.IHC staining revealed that aberrant T lymphocytes infiltrated the plexiform neurofibroma and MPNST tumor tissues.Conclusion These results indicate that immune checkpoint mechanisms may play a pivotal role in the development of NF1-related tumors,and immune checkpoint inhibitors may be effective for managing neurofibromas and MPNSTs.Combined therapy with other molecular agents may be explored in the future.

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

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.

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 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.

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.

Massive, Spontaneous Facial Hematoma in a Neurofibromatosis Type 1 Patient

Significant hemorrhage in Neurofibromatosis Type 1 (NF-1) patients occurs infrequently, but has potentially devastateing consequences when occurring in the head and neck region. There have been no prior reports of patients with hemodynamically significant, rapidly-expanding lesions into a neurofibroma in the head and neck region without preceding trauma. This case describes the management of a spontaneous, rapidly expanding facial hematoma in an NF-1 patient with an extensive facial and skull base plexiform neurofibroma. The patient underwent angioembolization of his left external carotid artery prior to operative management. The strategies utilized can be extended to management of facial hematomas arising from more common situations such as fractures, lacerations, and pseudoaneursyms, along with bleeding from subacute conditions like other head and neck cancers.

Gestational diabetes mellitus combined with fulminant type 1 diabetes mellitus, four cases of double diabetes: A case report

BACKGROUND Fulminant type 1 diabetes mellitus(FT1DM)that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM(PF),always without history of abnormal glucose metabolism.Here,we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus(GDM).CASE SUMMARY The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected,and the patients and their infants were followed up.All patients were diagnosed with GDM during the second trimester and were treated.The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM.Two patients had an insulin allergy,and two had symptoms of upper respiratory tract infection before onset.One patient developed ketoacidosis,and three developed ketosis.Two patients had cesarean section deliveries,and two had vaginal deliveries.The growth and development of the infants were normal.C-peptide levels were lower than those at onset,suggesting progressive impairment of islet function.The frequencies of the DRB109:01,DQB103:03,DQA103:02,DPA101:03,DPA102:02,DPB105:01,DRB401:03,G 01:01,and G 01:04 human leukocyte antigen(HLA)-G alleles were high in the present study.CONCLUSION In comparison with pregnancy-associated FT1DM(PF),patients with GDM combined with FT1DM had an older age of onset,higher body mass index,slower onset,fewer prodromal symptoms,and less acidosis.The pathogenesis may be due to various factors affecting the already fragileβ-cells of GDM patients with genetically susceptible class II HLA genotypes.We speculate that GDM combined with FT1DM during pregnancy,referred to as“double diabetes,”is a subtype of PF with its own unique characteristics that should be investigated further.