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Plexiform neurofibromas. (a) Facial plexiform neurofibroma in a four year old girl who had presented at two months ofage. She had already' had a number ofsurgical procedures. (Reproduced with permission from Huson SM. Neurofibromatosis In: Swash M, Oxburv J, eds. Clinical neurology. Edinburgh: Churchill Livingstone (in press).) (b) Plexiform neurofibroma overlying lumbar spine of eight year old boy'. The lesion was asymptomatic and had been noted on routine examination at three years of age. Lumbar spine x rays were normal.
Source publication
The age of appearance and diagnostic value of the major defining features of von Recklinghausen neurofibromatosis (NF-1) have been studied in 168 cases from 73 families. In assessing children of an affected patient, those who have inherited the gene can be distinguished from their normal sibs on the basis of whether or not café au lait (CAL) spots...
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Background
Pheochromocytomas and Paragangliomas (PCC/PGL) are rare endocrine tumors that are mostly benign, but often hormone producing, causing significant morbidity and mortality due to excess catecholamine secretion and cardiovascular crises. It is estimated that 30% of PCC/PGL are due to germline mutations, including Neurofibromatosis type 1 (N...
Neurofibromas of the urinary bladder are an exceedingly rare entity and are considered mostly in conjunction with the disease of neurofibromatosis type 1. The fortuitous discovery of vesical plexiform neurofibromas without other stigmata of the disease is presented in a 57-year-old male patient. The course of his condition, modalities of investigat...
PURPOSE To evaluate the causes of ocular motility disturbances in a group of patients with orbitofacial
neurofibromatosis (OFNF) with neurofibromas on the lid, brow, face, or in the orbit
from infancy or early childhood.
METHODS The medical records of patients with OFNF from one institution were retrospectively reviewed;
selected patients were reex...
We have found that EGF-R expression is associated with the development of the Schwann cell-derived tumors characteristic of neurofibromatosis type 1 (NF1) and in animal models of this disease. This is surprising, because Schwann cells normally lack EGF-R and respond to ligands other than EGF. Nevertheless, immunoblotting, Northern analysis, and imm...
A 62-year-old female with neurofibromatosis type 1 (NF1; also von Recklinghausen's disease) was diagnosed with a giant, thick-walled tubular mass, mainly located in the right abdominal area on computed tomography, following an examination for intermittent abdominal pain and increasing abdominal distension. According to the clinical manifestations a...
Citations
... Among all the heterogeneous features related to NF1, approximately 30-50% of individuals may develop plexiform neurofibromas (pNFs) [4,5], which are benign neoplasms, primarily originating from Schwann cells yet comprising a diverse array of other cell types, including fibroblasts, perineural cells and mast cells, resulting in a heterogeneous tumor microenvironment [6]. ...
Background: Plexiform neurofibromas (pNFs) are benign neoplasms, primarily originating from Schwann cells, posing challenges in patients with type 1 neurofibromatosis (NF1) due to pain, disfigurement, compression of vital structures and potential for malignancy. Selumetinib, a MEK1/2 inhibitor, has shown promising results in treating inoperable pNFs, with clinical trials demonstrating tumor volume reduction and improved patient-reported outcomes. Despite its efficacy, dermatologic toxicities may impact the quality of life and treatment adherence. Evaluating the frequency and spectrum of such effects is crucial for effective management. Methods: In a four-year retrospective and prospective study, pediatric NF1 patients with symptomatic, inoperable plexiform neurofibromas (pNFs) were treated with selumetinib. Eligibility criteria included significant morbidity, pNF size exceeding 3 cm or surgical inoperability, and performance status >70%. Hematological, liver, lung and cardiac assessments established baseline health. Selumetinib, orally administered at 25 mg/m2 twice, was administered for two years unless a response warranting extension occurred. Cutaneous AEs were documented and graded by severity according to CTCAE v5.0, with evaluations every three to six months. The impact on symptoms and pNF size was systematically recorded, and biopsies characterized histopathological features in those patients requiring surgery. Results: Twenty patients were enrolled, with an average age at therapy initiation of 11.6 years. Cutaneous side effects were common, with all patients experiencing at least one and a median of two per patient. Xerosis, paronychia and acneiform rash were prevalent. Notably, pre-pubertal individuals were more susceptible to xerosis. Acneiform rash had a higher incidence in older patients and those with skin phototypes II and III. Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. Hair abnormalities, including color changes and thinning, occurred, with female patients at higher risk for the latter. Paronychia presented challenges, necessitating various interventions, including surgical approaches. AEs led to treatment suspension in 20% of patients, with tumor rebound observed in 75%. Conclusions: According to our experience, successful management of selumetinib-induced cutaneous AEs requires tailored strategies including surgery. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.
... Neurofibromatosis type 1 (NF1) is an autosomaldominantly inherited disorder caused by a mutation of the cell growth regulating protein neurofibromin in the NF1 gene at 17q11.2. 1 NF1 is one of the most common hereditary neurocutaneous diseases with an estimated incidence of 1:2500-1:3000. 2,3 Development of benign peripheral nerve sheath tumors (BPNSTs) is a typical feature of NF1. BPNSTs can either appear as discrete nodules along the peripheral nerves or grow to large sizes across multiple nerve fascicles presenting as bulging and deforming plexiform neurofibromas typically located in the deep soft tissues. ...
Background
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.
Methods
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 0–800 s/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.
Results
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).
Conclusions
DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.
... NF1 displays complete penetrance and extremely variable expression [3]. It is a tumor predisposition syndrome with an incidence of 1 in 2500-3000 newborns [4]. The most prominent manifestations include café-au-lait spots (CALs), pathognomonic neurofibromas on and/or under the skin, freckling in the axillary/inguinal region and Lisch nodules on the retina [5]. ...
Neurofibromatosis type 1 (NF1) is a clinically heterogeneous neurocutaneous disorder inherited in autosomal dominant manner. Approximately 5–10% of the cases are caused by NF1 microdeletions involving the NF1 gene and its flanking regions. Microdeletions, which lead to more severe clinical manifestations, can be subclassified into four different types (type 1, 2, 3 and atypical) according to their size, the genomic location of the breakpoints and the number of genes included within the deletion. Besides the prominent hallmarks of NF1, patients with NF1 microdeletions frequently exhibit specific additional clinical manifestations like dysmorphic facial features, macrocephaly, overgrowth, global developmental delay, cognitive disability and an increased risk of malignancies. It is important to identify the genes co-deleted with NF1, because they are likely to have an effect on the clinical manifestation. Multiplex ligation-dependent probe amplification (MLPA) and microarray analysis are the primary techniques for the investigation of NF1 microdeletions. However, based on previous research, optical genome mapping (OGM) could also serve as an alternative method to identify copy number variations (CNVs). Here, we present a case with NF1 microdeletion identified by means of OGM and demonstrate that this novel technology is a suitable tool for the identification and classification of the NF1 microdeletions.
... [3,4]Cross sectional studies have previously demonstrated a 1-2% prevalence of MPNST among NF1 patients although a recent study showed these patients have a 10% lifetime risk of ultimately developing an MPNST . [5,6] The etiology is unknown but there is a higher incidence in patients with a history of radiation exposure . [7,8] MPNSTs generally occur in adulthood, typically between the ages of 20 and 50 years of age as in our case . ...
... In NF1, impaired neurofibromin production is thought to be a major factor in the development of peripheral nerve sheath tumors (PNST) and developmental disorders. Multiple neurofibromas are pathognomonic for NF1 [3,4]. Schwann cells or their precursors are the origin of tumor cells in NF1-associated PNST [5,6]. ...
... The tumor can reach significant size and affect development and growth of an entire body region (elephantiasis neuromatosa). PNF is considered a precancerous lesion [1][2][3][4][5][6]. Data on PNF frequency of the neck region in NF1 is limited because the reports refer to different sources or evaluation criteria of tumors [8]. ...
... The differences in the evaluation of tumor diagnosis and management concern both PNST definition and inclusion criteria of the patients, in particular consideration of the genetic background. With reference to other body regions, PNF arising in the head and neck regions is frequently diagnosed in NF1 [3]. ...
Purpose
Plexiform neurofibromas (PNF) are rare tumors arising from peripheral nerve sheath cells. PNF are a hallmark in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. PNF often grow invasively and destructively, what may complicate surgical treatment. Data on frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data of NF1 patients.
Methods
Localization and treatment data of 69 NF1 patients with neck PNF were analyzed. Frequency of lesions was recorded in coded colors on schematic neck drawings.
Results
The tumors showed no side preference, were located in the entire area under investigation, and did not respect anatomical units/dermatomes. However, the sternocleidomastoid region was particularly frequently affected. The mean number of surgical measures per patient was 1.33. Complications were extensive swelling, hematoma, and bleeding. Histological assessment usually confirmed the clinical assessment of neoplasm. However, histologic differentiation of PNST reveals differences in between tumors that have been unified in clinical assessment as PNF.
Conclusion
The color-coded, schematic overview of the frequency distribution of surgical neck interventions in NF1 patients with PNF proved a useful tool to gain assessment of preferred treatment needs. The imaging procedure may be suitable for controlling the external aspect of natural tumor development (growth, effects of aging) in the same way as the documentation of the post-surgical course. Treatment plans for patients with these tumors should consider that repeated interventions may be necessary to achieve a longer-term stable result.
... NF1 was first cloned in 1990 and is one of the largest human genes (350 kb and 60 exons) (Viskochil et al., 1990;Wallace et al., 1990). More than 500 variants in the NF1 gene have been identified; most result in loss of function (Ars et al., 2003;Carey et al., 1986;Huson et al., 1989). Recent scientific advances have begun to shed light on the complex function and regulation of the NF1 gene. ...
Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.
... Facial plexiform neurofibroma (FPNF) can cause significant aesthetic disfigurement and functional impairment. Data on the frequency of FPNF are uncertain because the records are based on different sources or evaluation criteria [1,2]. Among the body regions, craniofacial manifestations of PNF are frequently detected [3]. ...
Introduction
Facial plexiform neurofibromas (FPNF) are rare tumors frequently diagnosed in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. FPNF often grows invasively and destructively, which may complicate surgical treatment. Data on the frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data from a nationally networked reference center for the treatment of NF1 patients.
Material and Methods
The localization and treatment data of 179 NF1 patients with FPNF were analyzed. Photographically documented tumors of the study area, further determined by imaging, were manually transferred to a facial scheme and digitized. The digitized registrations of the facial extensions of the tumors of each patient were overlaid in a single image (Photoshop™), so that the file of the facial scheme contained the sum of the tumor localization. Finally, the frequency of tumor localization was indicated with a color code. The frequency of tumor extension-related coded colors was applied to outline the lesions' topography on schematic face drawings (heat map).
Results
The distribution of the tumors showed no side preference. The need for the treatment of patients with orbital/periorbital manifestations became evident in the graphic representations. Tumors do not respect anatomical units. However, the classification of the face according to dermatomes, especially the trigeminal nerve, offers indications of tumor spread and guides treatment planning. The mean number of surgical measures per patient was 2.21 (median: 1). Extensive swelling, hematoma, and delayed wound healing were all common postoperative complications.
Conclusion
The color-coded, schematic overview of the frequency distribution of cutaneous tumor spread in NF1 patients with FPNF illustrates the importance of orbital/periorbital and cheek tumor manifestations in patients' treatment needs. The imaging procedure is suitable for controlling natural tumor growth in the same way as the documentation of the post-surgical course. Repeated interventions in the region are included in surgical planning of the progressing tumor disease.
... An age cut-off value of 30 years was chosen because the probability that they could develop an SNF was very low [13]. In addition, we compared the phenotypes of the SNF cases with the previously described large-scale NF1-affected individuals with "classical" NF1 [1,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] already used in other genotype-phenotype studies on NF1 [9,10]. ...
... There were 68 females and 38 males with a median age of 47 (31-75) years. Furthermore, when data were available, the clinical features were also correlated with those previously reported in large-scale NF1 classical cohorts that had already been used in other genotype-phenotype studies [1,[18][19][20][21][22][23][24][25][26][27][28][29][30][31]. All comparisons are reported in Table 2. ...
Simple Summary
At present, no systematic study of the clinical spectrum and molecular characteristics of NF1 patients with spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), has been carried out. Here, we provide evidence that SNF patients are at high risk of problematic neurofibromas, presenting not only bilateral neurofibromas involving all spinal roots, but also a higher incidence of internal neurofibromas and nerve root swelling. From a histopathological view, not only neurofibromas, but also neurogangliomas are present in SNF. The analysis of 19 families with at least 1 member affected by SNF showed a high phenotypic variability within the SNF families. Furthermore, we discovered a higher prevalence of missense mutations in SNF compared to classical NF1. Both clinical features and genetic testing can help in identifying cases at risk of SNF, and that are more likely to benefit from a spinal MRI scan.
Abstract
Spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), is characterized by bilateral neurofibromas involving all spinal roots. In order to deepen the understanding of SNF’s clinical and genetic features, we identified 81 patients with SNF, 55 from unrelated families, and 26 belonging to 19 families with at least 1 member affected by SNF, and 106 NF1 patients aged >30 years without spinal tumors. A comprehensive NF1 mutation screening was performed using NGS panels, including NF1 and several RAS pathway genes. The main features of the SNF subjects were a higher number of internal neurofibromas (p < 0.001), nerve root swelling (p < 0.001), and subcutaneous neurofibromas (p = 0.03), while hyperpigmentation signs were significantly less frequent compared with the classical NF1-affected cohorts (p = 0.012). Fifteen patients underwent neurosurgical intervention. The histological findings revealed neurofibromas in 13 patients and ganglioneuromas in 2 patients. Phenotypic variability within SNF families was observed. The proportion of missense mutations was higher in the SNF cases than in the classical NF1 group (21.40% vs. 7.5%, p = 0.007), conferring an odds ratio (OR) of 3.34 (CI = 1.33–10.78). Two unrelated familial SNF cases harbored in trans double NF1 mutations that seemed to have a subclinical worsening effect on the clinical phenotype. Our study, with the largest series of SNF patients reported to date, better defines the clinical and genetic features of SNF, which could improve the management and genetic counseling of NF1.
... Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by seizures, developmental delay, and facial angiomas (Vogt's triad) (1). Neurofibromatosis type 1 (NF1) is another neurogenetic tumor syndrome caused by the mutation of the NF1 gene (2). There are similarities in clinical symptoms between TSC with NF1, which might cause misdiagnosis. ...
Tuberous sclerosis complex (TSC) is an inherited disorder that typically presents with seizures, developmental delay, cutaneous lesions, and facial angiomas. Clinical diagnosis of TSC based on symptoms is sometimes challenging due to its clinical similarities with neurofibromatosis type 1 (NF1), another type of neurogenetic tumor syndrome. Differential diagnosis should be carefully performed on the basis of clinical presentations, imaging, laboratory, and genetic testing. Here, we presented a case of a patient with an aggressively enlarged right upper limb in the NF1 clinic, who was initially suspected of a giant plexiform neurofibroma. However, differential diagnosis revealed TSC as the final diagnosis. The treatments for NF1 and TSC vary significantly, and misdiagnoses can lead to serious threat to the patients’ health. We also systematically reviewed all previous cases regarding differential diagnoses between NF1 and TSC. This case report can help clinicians make more accurate diagnoses and benefit the potential patient community.
... Estos tumores pueden presentarse en el periodo neonatal y aumentan en número con la edad, especialmente durante la pubertad y el embarazo, debido -en parte-a la presencia de receptores de progesterona 3,5 . Así, los NF cutáneos se observan en 10% de los menores de 10 años y hasta en el 99% de los adultos con NF-1 8,9 . Se definen como tumores benignos derivados de la vaina neural de los nervios periféricos 3 . ...
Obje tivo:
Describir y clasificar los neurofibromas asociados a la NF-1 a través de un caso clínico.
Caso Clínico:
paciente masculino de 18 años con diagnóstico desde la infancia de NF-1 que presenta múltiples nodulos ovalados en cara, zona occipital y muñeca, máculas rojo-azuladas en dorso y placa rosada atrófica en muslo. El estudio ecográfico de los nódulos fue compatible con neurofibromas y el estudio histopatológico de las lesiones de dorso y muslo compatibles con neurofibromas cutáneos.
Conclusión:
El caso presentado permite ilustrar la variada presentación clínica de los neurofibromas en la adolescencia. El reconocimiento de estos tumores cutáneos es fundamental para un diagnóstico precoz en el control pediátrico habitual.
