Case Of Neurofibromatosis Type Research Articles

Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome

Moyamoya vasculopathy secondary to various genetic disorders is classified as moyamoya syndrome (MMS). Recent studies indicate MMS occurs due to a combination of genetic modifiers and causative mutations for the primary genetic disorders. We performed whole-exome sequencing (WES) in 13 patients with various genetic disorders who developed MMS. WES successfully revealed the genetic diagnoses of neurofibromatosis type 1 (NF-1), Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia. The previously reported modifier genes, RNF213 and MRVI1, were confirmed in the NF-1 and Down syndrome cases. Further analysis revealed rare hypomorphic variants in the causative genes of the primary disorders underlying MMS, such as Alagille syndrome and Rasopathies, conferred susceptibility to MMS. Genes involved in the development of pulmonary arterial hypertension (PAH), such as ABCC8 and BMPR2, were also identified as potential modifiers. The rare variants in the MMS and PAH genes were significantly enriched in the eight Japanese patients with MMS compared with the 104 Japanese individuals from the 1000 Genomes Project. Disease genes associated with the arterial occlusive conditions represented by those of Rasopathies and PAH may provide novel diagnostic markers and future therapeutic targets for MMS as well as moyamoya disease with an unknown cause.

Cluster of Neurofibromatosis Cases in Remote Area of Northern Karnataka: A Case Series

Abstract Tumours of the nerve system and skin are hallmarks of neurofibromatosis, a neurocutaneous condition. One class of inherited illnesses known as phakomatoses includes neurofibromatosis type 1 (NF1) or von Recklinghausen disease. It may show up anywhere in the body, including the skin, eyes, bones, and organs. We report a visually recorded seven cases of NF1 from same area. Every single patient had some kind of skin symptom. We describe the presence of several isolated neurofibromas, café au lait macules, axillary and inguinal freckling, neurological or cognitive dysfunction, and Lisch nodules in 100% of the eyes as ocular symptoms. Also, a rare occurrence of plexiform neuroma seen. Rare and familial presentation and similar cases in the same region, these findings collectively underscore the complex nature of the patient's medical presentation, necessitating a multidisciplinary approach to management and care.

A case of neurofibromatosis type I due to a splicing mutation in the NF1 gene

A case of neurofibromatosis type I due to a splicing mutation in the NF1 gene

A Comprehensive Overview of NF1 Mutations in Iranian Patients.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.

LMIC-07. OUTCOMES OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED OPTIC PATHWAY GLIOMAS AT A SINGLE TERTIARY PEDIATRIC ONCOLOGY CENTER IN EGYPT: BORG EL ARAB UNIVERSITY HOSPITAL (BAUH) EXPERIENCE

Abstract BACKGROUND Neurofibromatosis type 1 (NF-1) is a multisystem disease inherited in an autosomal dominant fashion. About 15% of the pediatric cases have associated brain tumors, among which the optic pathway gliomas (OPG) remain the most common. Due to their location, OPG can cause visual impairment, and endocrinal dysfunction, hence requiring therapeutic interventions, more commonly in sporadic non-NF-1 cases. METHODS NF-1 children with associated OPG followed at a single tertiary pediatric oncology center since its establishment from 2018 to 2023 were retrospectively evaluated. RESULTS Forty patients were identified either as firstly diagnosed NF-1 cases in our center or referred to us for follow up. Twenty-three of them who had associated OPG (mean age at diagnosis 83.7 months) were included in our study. The commonest clinical presentation was the bilateral initial visual affection occurring in 13 patients. Six had hormonal imbalance and four presented with seizures. Biopsy was taken only in 30%, with histopathology being mainly pilocytic astrocytoma. In terms of treatment, 10 cases received only one line of chemotherapy, six patients were kept on follow up, and the rest received more than one line of therapy. Overall survival (OS) was 100% throughout the study period, and progression-free survival was 64.1% at 1.5 years, and 46.8% at 5 years. Visual assessment at the end of treatment was stable in 71%, better in 22%, and worse in 7% of cases. Same pattern was observed in MRI assessment post therapy showing 57% stable disease, 39% regression, and 4% progression. CONCLUSIONS Survival of children with OPG is different in every center of the world as decisions regarding their management being challenging. Therefore, NF-1 multidisciplinary clinics are important to be established, with a high emphasis on early detection and referral of patients, standardization of symptoms grading and indications to start treatment.

Neurofibroma of C2 root

Background: Intra and extradural neurofibromas of C2 root is a challenging pathology, usually with indolent evolution, that is why the onset symptoms are neurologic deficit just like upper cervical myelopathy symptoms and explains the late diagnosis of giant tumours with severe spinal cord compression with involvement and distortion of great vessels anatomy. These facts make surgeries more difficult. The follow-up of this type of surgery must be very close because CSF fistula can often occur. Case description: The present article reports a series of three cases of neurofibromas, two of them are giant dumbbell-shaped C2 neurofibromas and the third one is a case of neurofibromatosis type 1 of C2 roots bilaterally, C3 root unilateral with unusual postoperative course. Dural reconstruction was necessary in all cases. Conclusions: The patients in this series were very symptomatic with good recovery. The surgical procedures were challenging, total tumour removal was possible, and the reconstruction of dural defects was needed in all cases. In the case of NF1, the postoperative period was practically just the follow-up of complications and addressing them. This fact stresses the importance of meticulous preoperative planning and close follow-up. Postoperative quality of life was better than preoperative in all the cases. The purpose of the surgical treatment is the decompression of the spinal cord, tumour removal and prophylaxis of CSF fistula by closing the dural defects. Overall, the surgical C2 root neurofibromas resection is a safe procedure and is associated with good clinical outcomes.

A case of neurofibromatosis type 1 with cerebral venous sinus thrombosis due to iron deficiency anemia associated with gastrointestinal stromal tumor

A case of neurofibromatosis type 1 with cerebral venous sinus thrombosis due to iron deficiency anemia associated with gastrointestinal stromal tumor

A 63-Year-Old Man with Neurofibromatosis Type 1 and Intracerebral Astrocytoma: A Case Report

Background: Neurofibromatosis type 1 (NF-1) is one of the hereditary neurocutaneous disorders. Neurofibromatosis type 1 has broad clinical manifestations that can occur in the skin, bones, eyes, and nervous system. In progressive cases, NF-1 can malign and cause intracerebral tumor lesions. Astrocytoma, especially pilocytic astrocytoma, is one of the tumor classes that patients with NF-1 can develop with far-reaching disease progression. This case report presents a case of NF-1 with intracerebral astrocytoma.
 Case presentation: A 63-year-old man with whole body lumps since childhood presented with weakness in the right limbs 1 month ago. 3 months earlier, the patient also had a full-body seizure for 1 minute twice. The patient then underwent a magnetic resonance imaging (MRI) examination of the brain and found a mass in the left centrum semiovale, left corona radiata, left insular, left external capsule, and left frontotemporoparietal lobe with a size of 7.2 x 5.3 x 6.2 cm. The patient then underwent a VP shunt followed by tumor resection. The tumor was successfully evacuated, and histopathological examination with hematoxylin & eosin (HE) staining revealed glioblastoma multiformis. The patient also underwent histopathologic examination with Ki-67 immunohistochemistry (IHC) staining and showed pilocytic astrocytoma.
 Conclusion: Craniotomy of tumor excision is the definitive therapy in neurofibromatosis patients accompanied by intracerebral astrocytoma.

Evaluation of Neurofibromatosis Type 1 Associated Optic Pathway Gliomas

Background/Aims: Optic pathway gliomas (OPGs) are low-grade gliomas histologically represented by pilocytic astrocytoma (PA) in 90% of cases, can develop from any part of the visual pathways such as optic nerve, chiasm, optic tract, or optic radiations which frequently involve the hypothalamus. OPGs account for 3–5% of childhood central nervous system (CNS) tumors and about 2% of pediatric glial lesions. OPGs are believed to be the most prevalent intracranial tumor in patients with neurofibromatosis type 1 (NF-1) and can occur in 15–20% of NF-1 cases. The aim of this study is to evaluate the clinical features and treatment response in patients diagnosed with optic glioma and NF-1.
 Methods: All cases diagnosed with OPG and received treatment in the Pediatric Oncology Department, between January 2015 to January 2021 were retrospectively evaluated. Inclusion criteria include children and adolescents with OPG aged between 0 and 18 years. The medical records (gender, age, tumor entity, tumor location) of patients, as well as their treatment history and magnetic resonance imaging (MRI) scans, were examined. The diagnosis of OPG was made clinically and radiologically by the tumor board. The recommendations of the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group were used in the diagnosis and evaluation of treatment response. Patients received intravenous chemotherapy with SIOP LGG 2004 (vincristine- carboplatin) with or without bevacizumab (10 mg/kg, started every 2 weeks), therapy or vinblastine (3 mg/m2, weekly). 
 Results: This study included 27 cases during the study period from January 2015 to January 2021. In this study there were 14 male (51.8 %) and 13 female (48.1 %) patients. The median age was 4.8 (range: 0.5–14.9) years. Biopsy was performed in three patients and the diagnosis was low-grade glioma (pilocytic astrocytoma) for all of them. Chemotherapy was administered to 22 cases in total. Twelve patients received vincristine-carboplatine, 5 patients received vincristine-carboplatin with bevacizumab and 5 patients received vinorelbine. Radiological response was evaluated in all 22 patients at 3 months MRI. No patient had a radiological complete respons, 11 patients (50%) had partial response, 2 patients (9%) presented with a progressive disease, showing an increase in measurements of 35% and 9 patients(40.9%) had stable disease at the 3-month evaluation.
 Conclusions: Systemic and visual problems play a significant role in the selection of treatment for pediatric patients with optic gliomas. An essential treatment option for improving symptoms and reducing tumor size is systemic chemotherapy. A crucial therapy option for enhancing vision is bevacizumab for the patients with NF-associated OPG.

Cases of Mixed Schwannoma-Meningioma With and Without Neurofibromatosis 2 with Emphasis on Tumorigenesis.

Concurrent occurrence of schwannoma and meningiomas are rare, and are found especially in association with neurofibromatosis type 2 (NF2). Occurrence of mixed tumor without the aforementioned conditions is extremely rare. We present three cases of mixed tumor in different locations, including two with NF2 and one without NF2. We analyse the relationship of mixed tumor with NF2 and its clinical implications. Presence of mixed schwannoma-meningioma should prompt screening for NF2. Thus aids in early diagnosis of unsuspected NF2 cases. We observed that irrespective of different locations, cases with NF2 showed frequent recurrence of schwannoma as compared to case who did not fit in the existing clinical criteria for NF2. Collision tumor and thereby NF2 mutations indicates the prognosis and recurrence of the tumor, thereby guides in deciding the management.

A multidisciplinary approach in the management of a patient with familial von Recklinghausen’s disease: A case report and review of literature

Abstract Neurofibromatosis type 1 (NF1), also known as von Recklinghausen’s disease (VRD), is an autosomal dominant genetic disorder caused by gene mutations located on chromosome 17. Of these, 90% are point mutations, and the rest have larger deletions, affecting nearly one in every 3500 births. The same gene is responsible for the synthesis of a protein known as neurofibromin, which helps in the regulation of normal cell growth. This disorder is characterized by the development of swellings all over the body along the distribution of nerves, skin changes, visual abnormalities, and bony deformities in some individuals. In addition to this, it is also a neoplastic predisposition syndrome that is associated with both benign and malignant tumors of the brain and spinal cord. In 20% of the cases with NF1, it is associated with gliomagenesis, which often affects the optic pathway and brain stem. In the early phases, it is associated with benign gliomas, whereas in the later stages, it is associated with malignant gliomas. But nevertheless, high-grade gliosarcomas (grade IV) of the brain are rare entities with reported higher risks in both children and adults. We report a case of familial NF1 (VRD) in a patient with an associated high-grade right parieto-temporo-occipital lobe glioma. Surgical excision via gross total resection is the mainstay of treatment. However, a multidisciplinary approach is also vital. This is described here, whereby timely intervention from neurology, ophthalmology, radiology, orthopedics, neurosurgery, and radiotherapy led to the successful management of the patient.

Neurofibromatosis type 1, from gene mutation to clinical presentation

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with a prevalence of about1/3000. The clinical diagnosis of NF1 is based on the presence of two or more of the followingcriteria: six or more café au lait spots, >2 neurofibromas of any type, freckling in the axillary oringuinal region, optic glioma, a distinctive osseous lesion such as sphenoid dysplasia or thinning oflong bone cortex with or without pseudoarthrosis, and a first degree relative with NF1.We report A 7-year-old male with multiple café au lait spots diagnosed with Neurofibromatosisin Kigali-Rwanda by using next-generation sequencing and copy number variation analysis, thepatient presented with painless nodular skin lesions that first developed 4 years earlier. Skinnodules initially appeared on the anterior chest wall and progressed to the posterior chest wallextending to the axilla region. His medical history and that of his family were unremarkable. To ourknowledge, this is the first case to be diagnosed using this technology; The disease has numerouscomplications. The mutation rate for NF1-gene is high; 50% of all cases of NF1 are from newmutations. The gene protein product - neurofibromin plays an important role in tumor genesis asa tumor-suppressor gene.Combining both clinical findings and molecular genetic evaluation to identify disease-causingmutations is paramount in confirming the diagnosis. Patient care is best done in a multidisciplinarysetting approach for proper patient satisfaction and better prediction of future prognosis.

SPONTANEOUS RUPTURED OF RIGHT DEEP BRACHIAL ARTERY PSEUDOANEURYSM WITH UNDERLYING NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 (NF-1) is known to develop vascular lesions, yet they are uncommon. If missed or ignored, it can be limb-threatening. When a ruptured pseudoaneurysm is clinically identified, rapid surgical intervention is required. We discuss a case of NF-1 that involved a spontaneous rupture of the right deep brachial artery. A 41-year-old woman reported sudden right arm swelling and intensifying pain. She was hemodynamically stable; however, her right arm was enlarged and tense on examination. A radiological test revealed a deep brachial artery haemorrhage. The patient was promptly referred to a vascular surgeon and had endovascular intervention performed. Early detection, emergency angiography, and endovascular treatment for vascular lesions should be initiated immediately.

Cost-effective Whole Exome Sequencing discovers pathogenic variant causing Neurofibromatosis type 1 in a family from Jammu and Kashmir, India

Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir–India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large.

Neurofibromatosis Type 1-Associated Multiple Malignant Peripheral Nerve Sheet Tumors: A Case Report and Literature Review

Background: Neurofibromatosis type 1 (NF-1) is a genetic disorder characterized by café-au-lait macules, freckling, Lisch nodules, and neurofibromas. NF-1 patients have a special predisposition to tumorigenesis due to genetic mutations, affecting the tumor regulator systems. Malignant Peripheral Nerve Sheet Tumor (MPNST) is a highly aggressive soft tissue tumor that is usually associated with NF-1. Case presentation: A 32-year-old woman was presented complaining of weakness, severe fatigue, weight loss, peripheral paresthesia, progressive generalized myalgia, bone pain, and a mass sensation in her right thigh since three months ago. She was a known case of NF-1 since childhood. After clinical and radiological evaluation, multiple masses were detected in the retroperitoneal cavity adjacent to the left kidney, uterus, and right thigh. Finally, the patient was planned for surgical excision of two masses with subsequent chemotherapy. Both excised masses were confirmed as MPNSTs by histopathological examination. Conclusion: Regarding the predisposition of NF-1 patients to tumorigenesis and the high prevalence of peripheral nerve tumors among these patients, any masses changing their character should raise suspicion for malignancy. One of the serious malignant lesions is MPNST. The primary treatment plan for these malignant lesions is surgical excision with subsequent chemotherapy or radiotherapy based on individual characteristics.

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

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

Therapeutic advances in treatment of patients with neurofibromatosis type 1 and type 2

Background: Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are rare tumoral suppressor syndromes, triggered by an abnormal mutation in a tumour suppressor gene (TSG) (1). Each of these syndromes represents an orphan disease (by itself), but the tumours encountered in these patients are the most frequent lesions of the nervous system. Between the two of these diseases, NF1 presents a greater risk of malignancy, hence the importance of an accurate diagnosis and distinction between the two pathological entities. The purpose of this paper is to describe our department's practice protocol with neurofibromatosis and review the current literature regarding clinical diagnosis and management of these complex diseases.
 Methods: Our paper is a retrospective study that comprehends 25 patients with neurofibromatosis treated in our clinic between 2011 and 2018.
 Results: Our study included 16 female patients (64%) and 9 male patients (36%). The mean age at presentation was 48,7 (range 14-72 years). There were 7 cases (28%) of NF1 and 18 cases (72%) of NF2. Seven cases (28%) had a positive family history and 18 patients did not (72%). The most common symptoms at presentation were hearing loss, vertigo, and headache.
 Conclusions: Neurofibromatosis is a very complex disease in which the tumours may have an unforeseeable growth pattern. New tumours can grow over the years and the symptoms are unpredictable. Surgical treatment is best to be reserved for symptomatic tumours. Non-surgical procedures are also an important step of the treatment, but further studies are required to decide their effectiveness.

A Case of Neurofibromatosis Type1 with Sphenoid Bone Defect in which Orbitoplasty with a Titanium Mesh Plate and DuraGen<sup>®</sup> was Effective in resolving Pulsating Exophthalmos

A Case of Neurofibromatosis Type1 with Sphenoid Bone Defect in which Orbitoplasty with a Titanium Mesh Plate and DuraGen<sup>®</sup> was Effective in resolving Pulsating Exophthalmos

A Case of Neurofibromatosis Type 1 Diagnosed with Pheochromocytoma after Breast Cancer Surgery

A Case of Neurofibromatosis Type 1 Diagnosed with Pheochromocytoma after Breast Cancer Surgery

A Case of Neurofibromatosis Type 1 with Severe Mood and Behavioral Symptoms

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a genetic disorder caused by a mutation in the NF1 gene. In addition to physical manifestations, complications such as cognitive and behavioral deficits have been described. CLINICAL FINDINGS: We describe a case of a 14-year-old male with a past psychiatric history of obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and multiple suicide attempts, who presented with suicidal ideation and command hallucinations. The patient became aggressive, physically assaulting hospital staff, and required sedative medication and physical restraints for several days. He required inpatient hospital admission due to rhabdomyolysis. Throughout his admission, the patient was intermittently verbally and physically abusive to people around him. They described his outbursts as impulsive and thought to be out of motivation to get what he wants. He preferred to keep to himself and did not have relationships with people at his home. CONCLUSION: This case report provides insight into the behavioral characterization of children diagnosed with NF1. While the mechanism of how NF1 relates to behavioral issues is unknown, the association between NF1 and behavioral issues should be carefully considered in NF1 patients presenting with aggression.