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.

Neurofibromatosis type Ⅰ caused by a splicing mutation in NF1 using targeted next generation sequencing

Objective Neurofibromatosis typeⅠ(NF1)is an autosomal dominant disorder which is caused by loss-of-function mutations in neurofibromin 1 gene(NF1).Clinically,NF1 mainly manifests several typical features,such as multiple neurofibromas and café-au-lait spots,as well as axillary freckling and Lisch nodules in iris.The aim of the current study is to identification a splicing mutation and genotype-phenotype correlation.

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

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.

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.

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.

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.

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.

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 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.

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.

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.

Gene diagnosis of infantile neurofibromatosis type I:A case report

BACKGROUND Neurofibromatosis is an autosomal dominant genetic disorder with various manifestations.Systemic multiple neurofibromatosis is rare in infancy.The disease is difficult to identify in the early stage,and it is prone to misdiagnosis and missed diagnosis.In the presence of lower limb swelling with subcutaneous nodules of unknown cause,café-au-lait spots,and axillary freckles,this disease must be considered.This report presents the clinical manifestations,early detection,diagnosis and treatment,and prognosis of infantile neurofibromatosis type I(NF1).CASE SUMMARY The clinical manifestations,imaging examinations,and gene results of a 3-mo-old male infant with NF1 were analyzed retrospectively.He had“swelling of both legs”at the onset and developed café-au-lait spots,axillary freckles,and multiple neurofibromas later.He had a family history of similar conditions.Gene detection showed a heterozygous mutation of c.4537C>T in the NF1 gene,leading to a nonsense mutation of amino acids(p.R1513x),which originated from the mother of the infant.He was diagnosed with NF1.CONCLUSION Gene diagnosis plays an important role in the early diagnosis of NF1.

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.

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.

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