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Skinmed 2023A 13-year-old Hispanic boy with no significant medical etymology presented with a chief complaint of widespread brown macules and patches. He had a large and evenly...
A 13-year-old Hispanic boy with no significant medical etymology presented with a chief complaint of widespread brown macules and patches. He had a large and evenly pigmented brown patch, with a centrally located 2.2 cm × 1.2 cm soft and darkly pigmented plaque, which became more apparent with tension applied to the surrounding skin (Figure 1). The patient's mother stated that the plaque was present since birth and had increased in size over time. The clinical differential diagnoses included a congenital melanocytic nevus (CMN), a large café au lait macule (CALM), and a Becker's nevus with a congenital smooth muscle hamartoma.
Topics: Male; Humans; Adolescent; Neurofibroma, Plexiform; Skin; Hamartoma; Cafe-au-Lait Spots; Nevus, Pigmented
PubMed: 37634103
DOI: No ID Found -
Biochemical Genetics Apr 2024Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that affects the development and growth of various tissues. NF1 is a major risk factor for the...
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that affects the development and growth of various tissues. NF1 is a major risk factor for the development of malignancies, particularly malignant peripheral nerve sheath tumors, optic gliomas, and leukemia. NF1 encodes a neurofibromin. Three genes, EVI2A, EVI2B, and OMGP, are embedded within intron 27b of NF1. However, the function of these genes remains unclear. EVI2A and EVI2B encode for putative transmembrane proteins. Mouse homologs are associated with viral insertions involved in leukemia in mice. Mouse Evi2b has been identified as a direct target gene of C/EBPα, a transcription factor critical for myeloid differentiation. Also possible is that these genes are related to the leukemia observed in patients with NF1. These genes might act as modifiers of NF1 phenotypic variations. Therefore, we investigated the EVI2B gene in leukemia and NF1 tumors. We analyzed DNA from 10, 20, and 3 patients with NF1, leukemia, and NF1-leukemia, respectively, and six NF1 tumor tissues. DNA sequencing analysis was used to identify the viral integration sequence, and the protein amounts and EVI2B gene expression were analyzed by flow cytometry and quantitative real-time PCR techniques. The EVI2B gene expression was increased in cutaneous neurofibroma compared with the control both at the level of protein and mRNA. However, its expression in plexiform neurofibroma was decreased significantly at protein level and increased at mRNA level compare to control. Moreover, integration of 455 bases near the 3' end of the exon was detected. When this integrated sequence was blasted into the NCBI retroviral genome database, an 87% match with the HIV-1 virus envelope gene was obtained. These preliminary results show that EVI2B might be important in NF1 tumorigenesis and leukemia.
Topics: Animals; Humans; Mice; Leukemia, Myelomonocytic, Juvenile; Neurofibromatosis 1; Neurofibromin 1; RNA, Messenger; Virus Integration
PubMed: 37584733
DOI: 10.1007/s10528-023-10480-z -
The American Journal of Case Reports Aug 2023BACKGROUND Neurofibromatosis 1 is a neurocutaneous disorder with multisystemic manifestations. When patients are lacking overt cutaneous manifestations, diagnosis may be...
BACKGROUND Neurofibromatosis 1 is a neurocutaneous disorder with multisystemic manifestations. When patients are lacking overt cutaneous manifestations, diagnosis may be delayed and may complicate diagnosis and management of atypical presentations of this disease. It is thus important to strive to obtain relevant and/or complete history to arrive at the appropriate diagnosis. Furthermore, maintaining an index of suspicion in cases of vague abdominal pain may guide the clinician in establishing the correct diagnosis of mesenteric plexiform neurofibroma in the setting of known/presumed neurofibromatosis 1 patients presenting with acute and/or chronic vague abdominal symptoms. CASE REPORT This is a case of a teenage boy who presented with acute, vague abdominal pain over a period of 2 weeks. Laboratory tests and physical exam findings in primary and secondary care settings were unremarkable, and thus the patient was discharged home only to continue with abdominal pain, thus seeking additional medical care. After admission to our facility and exhaustive history taking, physical examination, and imaging, a prospective diagnosis of neurofibromatosis with mesenteric neurofibroma was made. Upon surgical exploration, a mesenteric mass with corresponding volvulized, ischemic small bowel was removed. Histopathology confirmed a plexiform neurofibroma. The patient recovered adequately and was discharged home without complications. CONCLUSIONS This case highlights the importance of exhaustive history taking to obtain an accurate diagnosis as well as the importance of a high index of clinical suspicion for mesenteric neurofibromatosis in patients with presumed or known neurofibromatosis and presenting with vague abdominal symptoms.
Topics: Male; Adolescent; Humans; Child; Neurofibromatosis 1; Neurofibroma, Plexiform; Intestinal Volvulus; Prospective Studies; Neurofibromatoses; Vascular Diseases; Abdominal Pain
PubMed: 37571808
DOI: 10.12659/AJCR.918041 -
International Journal of Molecular... Jul 2023Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to...
Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl's plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.
Topics: Female; Humans; Child; Neurofibroma, Plexiform; Genes, Neurofibromatosis 1; Mosaicism; Neurofibromatosis 1; Mutation
PubMed: 37569527
DOI: 10.3390/ijms241512154 -
Journal of Maxillofacial and Oral... Sep 2023Facial plexiform neurofibromas (FPNF) are rare tumors frequently diagnosed in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. FPNF often...
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.
PubMed: 37534339
DOI: 10.1007/s12663-022-01838-8 -
American Journal of Medical Genetics.... Oct 2023Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic... (Review)
Review
Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.
Topics: Humans; Neurofibromatoses; Neurilemmoma; Genetic Testing; Counseling; Neurofibromatosis 1; Neurofibromatosis 2
PubMed: 37485904
DOI: 10.1002/ajmg.a.63346 -
Cureus Jun 2023Peripheral nerve sheath tumours comprise benign tumours; namely schwannomas and neurofibromas, and only rarely comprise hybrid benign tumours and their malignant...
INTRODUCTION
Peripheral nerve sheath tumours comprise benign tumours; namely schwannomas and neurofibromas, and only rarely comprise hybrid benign tumours and their malignant counterpart, malignant peripheral nerve sheath tumours (MPNST). There may be diagnostic difficulties in histopathology analysis, especially in core needle biopsies where there is a limited amount of tissue. Immunohistochemistry (IHC) can play a beneficial role, especially in atypical and cellular histological variants and rarely hybrid tumours.
METHODS
A total of 45 cases of benign peripheral nerve sheath tumours were included in the study; there were 27 cases of neurofibroma including variants like plexiform and cellular neurofibromas and 18 cases of schwannomas including variants like ancient schwannoma and cellular schwannoma. Immunohistochemical staining (IHC) on these tumour tissues using S-100, CD56 and calretinin was done and scoring was done based on extent and intensity.
RESULTS AND DISCUSSION
No significant differences were observed between neurofibromas and schwannomas on patient age and anatomical locations of these tumours. IHC results did not show statistically significant patterns of expression of S-100 protein between the schwannoma and neurofibromas groups (p=0.75). CD56 protein was expressed strongly (3+) in 90% of cases of schwannoma and negative in 86% of neurofibromas, the differential expression between the two groups was found to be statistically significant (p <0.0001). Calretinin was positive in 39% of schwannomas including one case of cellular schwannoma and negative in all (100%) cases of neurofibroma while the differential expression of calretinin between schwannoma and neurofibroma groups was found to be statistically significant (p < 0.005).
CONCLUSION
Our study shows that S-100 does not show differential expression between schwannomas and neurofibromas. CD56 could be a potentially useful IHC marker to aid in the diagnosis of peripheral nerve sheath tumours with significantly higher expression in schwannomas compared to neurofibromas. Calretinin was also found to be preferentially expressed in schwannomas, though the difference is statistically significantly lower compared to CD56. A panel of all these markers could be used for accurate diagnosis.
PubMed: 37485115
DOI: 10.7759/cureus.40751 -
Clinical Cancer Research : An Official... Sep 2023Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options...
PURPOSE
Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity.
EXPERIMENTAL DESIGN
Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice.
RESULTS
Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo.
CONCLUSIONS
These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
Topics: Humans; Mice; Animals; Neurofibroma, Plexiform; Neurofibromatosis 1; MAP Kinase Signaling System; Proteomics; Nerve Sheath Neoplasms; Protein Kinase Inhibitors; Neurofibroma; Cyclin-Dependent Kinase 4
PubMed: 37406085
DOI: 10.1158/1078-0432.CCR-22-2854 -
BMC Medicine Jul 2023Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel...
Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1-related unresectable plexiform neurofibromas.
BACKGROUND
Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN.
METHODS
This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles.
RESULTS
Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug-related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing.
CONCLUSIONS
FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.
Topics: Humans; Adult; Neurofibromatosis 1; Neurofibroma, Plexiform; Protein Kinase Inhibitors
PubMed: 37400844
DOI: 10.1186/s12916-023-02927-2