Neurofibromatosis Research Articles

Multiple Cranial Nerve Involvement in a Complex Case of MISME Syndrome in a Paediatric Patient: A Case Report

Neurofibromatosis 2 (NF2) is characterised by numerous tumours in the central and peripheral nervous systems due to NF2 gene abnormalities that cause the tumour suppressor protein, Merlin, to disappear. Often referred to as Multiple Inherited Schwannomas, Meningiomas, and Ependymomas (MISME), a distinctive characteristic of NF2 is bilateral vestibular schwannomas manifesting in late adolescence with symptoms such as sensorineural hearing loss, tinnitus, and balance issues. Two distinct phenotypes, Wishart and Feiling-Gardner, characterise NF2. This case report discusses the case of a paediatric patient who presented with bilateral hearing loss, giddiness, and blurring of vision and sought a Magnetic Resonance Imaging (MRI) examination which revealed bilateral vestibular schwannomas, non vestibular schwannomas, left sphenoid wing meningiomas, multidirectional spinal schwannomas, spinal nerve sheath tumours, and lesions in the retroperitoneal region. Despite an absent family history, significant involvement of cranial nerves strongly indicates classical NF2. Management focuses on preserving function, and surgery is contemplated for symptomatic lesions and tumours causing cord compression. Gamma Knife radiosurgery and targeted therapies have been investigated.

Discrimination of benign, atypical, and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 using diffusion-weighted MRI.

Neurofibromatosis type 1 (NF1) is associated with the development of benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors. Recently described atypical neurofibromas (ANF) are considered pre-malignant precursor lesions to MPNSTs. Previous studies indicate that diffusion-weighted magnetic resonance imaging (DW-MRI) can reliably discriminate MPNSTs from BPNSTs. We therefore investigated the diagnostic accuracy of DW-MRI for the discrimination of benign, atypical, and malignant peripheral nerve sheath tumors. In this prospective explorative single-center phase II diagnostic study, 44 NF1 patients (23 male; 30.1 ± 11.8 years) underwent DW-MRI (b-values 0-800s/mm²) at 3T. Two radiologists independently assessed mean and minimum apparent diffusion coefficients (ADCmean/min) in areas of largest tumor diameters and ADCdark in areas of lowest signal intensity by manual contouring of the tumor margins of 60 BPNSTs, 13 ANFs, and 21 MPNSTs. Follow-up of ≥ 24 months (BPNSTs) or histopathological evaluation (ANFs + MPNSTs) served as diagnostic reference standard. Diagnostic ADC-based cut-off values for discrimination of the three tumor groups were chosen to yield the highest possible specificity while maintaining a clinically acceptable sensitivity. ADC values of pre-malignant ANFs clustered between BPNSTs and MPNSTs. Best BPNST vs. ANF + MPNST discrimination was obtained using ADCdark at a cut-off value of 1.6 × 10-3 mm2/s (85.3% sensitivity, 93.3% specificity), corresponding to an AUC of 94.3% (95% confidence interval: 85.2-98.0). Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

Quality of life and neurological symptoms in patients with neurofibromatosis type 2: a national database study in Japan.

This study examined the association between neurological symptoms and quality of life (QoL) in patients with neurofibromatosis type 2 (NF2) using a national database of all patients who newly claimed for medical expense subsidies in Japan from 2015 to 2019. The Japanese Ministry of Health, Labour and Welfare provided access to the "National Database of Designated Intractable Diseases of Japan" containing the "Medical Certificates of Designated Intractable Diseases" of all patients with NF2. The database included information on five items of QoL: "mobility," "self-care," "usual activities," "pain/discomfort," and "anxiety/depression." To examine the association between the presence/absence of neurological symptoms and QoL, multivariable logistic regression analyses were performed, adjusted for potential confounders. Data from 187 patients (97 females and 90 males; mean (standard deviation) age, 43.1 (17.9) years) were analyzed. Overall, 31% to 55% of patients were recorded as having moderate/severe impairment of QoL. Spinal dysfunction was significantly associated with deterioration of all components of QoL, whereas speech dysfunction and hemiparesis were specifically associated with physical health-related components of QoL. Spinal dysfunction, facial nerve palsy, and age 25-64 years were significantly associated with "anxiety/depression." In the present epidemiological study using a national database of NF2 in Japan, spinal dysfunction was significantly associated with deterioration of all components of QoL, including subjective and mental health-related components of QoL, whereas speech dysfunction and hemiparesis were specifically associated with physical health-related components of QoL.

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.

Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated. The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047). These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Unusual Presentations of Plexiform Neurofibroma: A Series of Three Cases

Neurofibroma is a benign peripheral nerve sheath tumour, and Plexiform Neurofibroma (PN) is pathognomonic of Neurofibromatosis Type 1 (NF1). It occurs equally in males and females and presents at birth or a very early age. The incidence is 1 in 2500 births per year, with an estimated genital association of 1.8%, where clitoral involvement is very rare in the Indian population. In the present case series, three patients were diagnosed with PN through surgical histopathology and Immunohistochemical (IHC) stains like S-100 and Cluster Differentiation 34 (CD34) at a tertiary care hospital. All three patients were children who had painless, gradually increasing swellings that underwent surgical treatment. Among them, a five-year-old girl presented with painless clitoromegaly, multiple café- au-lait spots, and underwent plastic surgery. She was later clinically diagnosed with NF1 after histopathological and IHC correlation. A two-year-old boy with a firm swelling over his left leg showed hyperintensity and multilobulation on magnetic resonance imaging. A 10-year-old boy with a similar swelling in his right upper arm showed multiple hypoechoic masses on ultrasonography. Both of them were later diagnosed with PN using the same methodology. Although it is benign, there is a risk of malignant transformation in diffuse PNs, and they should be managed by wide excision with a safety margin to prevent recurrence.

Response to "Epidemiology and Outcomes of Neurofibromatosis Type 1 (NF-1): Multicenter Tertiary Experience" [Letter

Response to "Epidemiology and Outcomes of Neurofibromatosis Type 1 (NF-1): Multicenter Tertiary Experience" [Letter

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Eligible participants aged ≥ 12 to< 18 years took 25mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. NCT05101148.

Next-generation variant exon screening: Moving forward in routine genetic disease investigations

PurposePatients with genetic diseases often seek testing to reach a firm diagnosis. Based on clinical phenotypes, exome sequencing for small-nucleotide variations or array-based methods for copy-number variations (CNVs) are commonly offered to identify the underlying causative genetic variants. In this study, we investigated whether data from a standard ES test could be used to additionally identify pathogenic CNVs and increase diagnostic yield. MethodsProspectively, 134 patients presenting with a skin condition suspected of being genetic in origin were offered the next-generation variant exon screening (ngVES) test. Sequencing data were analyzed for both single-nucleotide variants and CNVs using established algorithms. ResultsThe positive detection rate for skin diseases using ngVES was 66% (88/134) with the most common diagnoses being neurofibromatosis type1 (n = 48) and tuberous sclerosis type2 (n = 12). The diagnostic increased yield from 58% to 66% was the result of additional detection of pathogenic CNVs. Each of the 9 CNVs were verified by independent genetic tests. ConclusionThe advances in the ngVES bioinformatics pipeline are proofs of concept, which improved identification of genetic variants associated with skin disease. Simultaneous single-nucleotide variants/INDEL and CNV detection by this approach demonstrates ngVES potential as a first-tier screen for any suspected genetic disease.

Long-term distress throughout one's life: health-related quality of life, economic and caregiver burden of patients with neurofibromatosis type 1 in China.

Neurofibromatosis type 1 (NF1) is a rare genetic disorder, with lack of evidence of disease burden in China. We aimed to describe the economic burden, health-related quality of life (HRQL), and caregiver burden of NF1 patients in China. We conducted an online cross-sectional survey employing the China Cloud Platform for Rare Diseases, with 223 caregivers of NF1 pediatric patients (patients under 18), and 226 adult patients. Economic burden was estimated using direct and indirect costs related to NF1 in 2021, and the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI-GH). HRQL measures included EQ-5D-Y proxy version and PedsQL™ 4.0 Generic Core Scales (PedsQL GCS) proxy version for pediatric patients, and EQ-5D-5L and PedsQL™ 3.0 Neurofibromatosis Module (PedsQL NFM) for adult patients. Caregiver burden was estimated by Zarit Burden Interview (ZBI). For pediatric patients, the average direct cost in 2021 was CNY 33,614 (USD 4,879), and employed caregivers' annual productivity loss was 81 days. EQ-5D-Y utility was 0.880 ± 0.13 and VAS score was 75.38 ± 20.67, with 52.6% patients reporting having problems in "pain/discomfort" and 42.9% in "anxiety/depression." PedsQL GCS total score was 68.47 ± 19.42. ZBI score demonstrated that 39.5% of caregivers had moderate-to-severe or severe burden. For adult patients, average direct cost in 2021 was CNY 24,531 (USD 3,560). Patients in employment reported an absenteeism of 8.5% and presenteeism of 21.6% according to the results of WPAI-GH. EQ-5D-5L utility was 0.843 ± 0.17 and VAS score was 72.32 ± 23.49, with more than half of patients reporting having problems in "pain/discomfort" and "anxiety/depression" dimensions. PedsQL NFM total score was 68.40 ± 15.57. Both pediatric and adult NF1 patients in China had a wide-ranging economic burden and low HRQL, especially in the psychological dimension. Caregivers for NF1 pediatric patients experienced considerable caregiver burden. More attention and support from policymakers and stakeholders are required to relieve NF1 patients' and caregivers' distress.

The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants

The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants

Tumor resection and partial skin graft placement on the scalp in a patient with Neurofibromatosis type 1

Tumor resection and partial skin graft placement on the scalp in a patient with Neurofibromatosis type 1

Double-balloon enteroscopy for the detection of GIST in a patient with neurofibromatosis type 1.

NF1 is an autosomal dominant hereditary disease, with a prevalence of at least 1 in 4000-5000 population. The diagnosis criteria of NF1 included typical manifestations such as café-au-lait spots, frecking in the axilla or inguinal region, multiple neurofibromas, Lisch nodeules, and distinctive osseous lesions. Genetic testing shows NF1 mutation. It is essential for tumor surveillance in NF1 patients because their life expectancy is about 54 years due to malignancy. A case of NF-1 patient receive laparoscopic small bowel resection and finally diagnosed as adenocarcinoma and ganglioneuroma. About 25% of NF1 patients had GISTs , most of them were asymptomatic and some may manifest with abdominal pain, bowel obstruction, or gastrointestinal bleeding. CT and MRI are commonly used imaging modalities for GIST in NF1, while they may be negative sometimes. As DBE a more practical and non-invasive method now, we consider it is a valuable method for screening and early detecting small intestine disease for NF1 patients.

Self-evaluation of disease visibility in patients with neurofibromatosis type 1: development of an online scale

Self-evaluation of disease visibility in patients with neurofibromatosis type 1: development of an online scale

Revisiting the NPcis mouse model: A new tool to model plexiform neurofibroma.

Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.

A Rare Case of Diffuse Neurofibroma Mimicking as Hairy Naevus or Vascular Malformation: A Surgeon’s Perspective

Nevi are areas of melanocytic hyperplasia or neoplasia. These collections can be found in the epidermis, partially in the dermis, or completely within the dermis. They commonly develop in childhood and young adulthood and sometimes spontaneously regress. Exposure to Ultraviolet (UV) radiation is associated with increased density of these lesions. In contrast, neurofibromas are benign proliferations made up of all nerve elements and arise as fleshy and non tender, sessile, or pedunculated masses on the skin. They can arise sporadically or in association with type 1 Neurofibromatosis (NF), and in these cases, are associated with café-au-lait spots and Lisch nodules. In the present report, authors present a case diagnosed clinically as a giant naevus on the dorsum of the right hand in an adult patient (26-year-old female) with no other associated secondary swellings elsewhere in the body. However, further radiological investigations revealed a case of vascular malformation. Postoperatively, histopathological examination showed features of diffuse neurofibroma. The present case report enables the surgeon to consider various rare differential diagnosis for swelling in the extremities, even when it is not reflected in the clinical or radiological findings. Thus, a detailed history, physical examination, and various diagnostic tests, keeping in mind all possible differential diagnosis, should be performed.

Surgical treatment of dystrophic kyphoscoliosis secondary to neurofibromatosis type 1: Is three-column osteotomy necessary?

Surgical treatment of dystrophic kyphoscoliosis secondary to neurofibromatosis type 1: Is three-column osteotomy necessary?

A Case Report of an Isolated Calvarial Defect in the Region of the Lambdoid Suture: A Rare Bone Manifestation of Neurofibromatosis Type 1

The Calvarial bone defects in the lambdoid suture region are a rare bone manifestation of neurofibromatosis type 1. They may be isolated or associated with an adjacent structural lesion, such as a dural ectasia or plexiform neurofibroma. The underlying pathophysiology for the development of these types of skull defects is still unclear. We present the case of a Calvarial defect in the region of the lambdoid suture in a 7-year-old boy with a medical history of neurofibromatosis type 1 who was referred for a brain scan to explore a palpable skull defect in right parieto-occipital region , noticed by his doctor.

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

Macular Anatomy and Abnormalities in Neurofibromatosis Type 2

Purpose: To describe macular anatomy and abnormalities on Spectral-Domain Optical Coherence Tomography (SD-OCT) in a large series of patients with Neurofibromatosis Type 2 (NF2). Methods: Retrospective review of all consecutive patients with NF2. Results: A total of 166 eyes in 83 patients with NF2 were identified from February 2014 to May 2015. Macular SD-OCT was available for 124 eyes (75%). Isolated epiretinal membrane (ERM) was diagnosed in 52% of patients (n=43) with bilateral ERM in 15 cases. ERM was commonly fine (64%), non-retractile (90%), extra-foveolar (90%), discontinuous (78%) and without posterior vitreous detachment (93%). Combined Hamartoma of the Retina and Retinal Pigmented Epithelium (CHRRPE) was seen in 12% of patients (n=10); three of which were bilateral. Additional OCT anomalies identified include Congenital Hypertrophy of Retinal Pigment Epithelium (CHRPE), internal limiting membrane irregularities, inner retinal tufts, serpentine-like extensions into the vitreoretinal interface, focal alterations of inner retinal lamination and infiltration of the posterior vitreous cortex. All retinal anomalies identified suggest pathological involvement of Müller cells. Conclusion: Our series underscores the utility of macular SD-OCT in patients with NF2. While ERM and vitreoretinal interface abnormalities are the most common macular pathology identified in NF2, all SD-OCT pathology suggests Muller cell involvement.