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26 pages, 12784 KiB

Open AccessArticle

Gender-Specific Fine Motor Skill Learning Is Impaired by Myelin-Targeted Neurofibromatosis Type 1 Gene Mutation

by Daniella P. Hernandez, Daniela M. Cruz, Celeste S. Martinez, Larisa M. Garcia, Ashley Figueroa, Marisol Villarreal, Liya M. Manoj, Saul Lopez, Karla D. López-Lorenzo and Alejandro López-Juárez

Cancers 2024, 16(3), 477; https://doi.org/10.3390/cancers16030477 - 23 Jan 2024

Viewed by 1739

Abstract

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and [...] Read more.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targeted Nf1 mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory–motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test—the complex wheel (CW; a wheel with unevenly spaced rungs)—to delineate fine motor skill learning curves following induction of an Nf1 mutation in pre-existing myelinating cells (pNf1 mice). We found that pNf1 mutant females experience delayed or impaired learning in the CW, while proper learning in pNf1 males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of an Nf1 mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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14 pages, 2235 KiB

Open AccessArticle

Sensory Processing in Children and Adolescents with Neurofibromatosis Type 1

by Natalie A. Pride, Kristina M. Haebich, Karin S. Walsh, Francesca Lami, Melissa Rouel, Alice Maier, Anita K. Chisholm, Jennifer Lorenzo, Stephen J. C. Hearps, Kathryn N. North and Jonathan M. Payne

Cancers 2023, 15(14), 3612; https://doi.org/10.3390/cancers15143612 - 14 Jul 2023

Cited by 2 | Viewed by 2046

Abstract

Despite the evidence of elevated autistic behaviors and co-occurring neurodevelopmental difficulties in many children with neurofibromatosis type 1 (NF1), we have a limited understanding of the sensory processing challenges that may occur with the condition. This study examined the sensory profile of children [...] Read more.

Despite the evidence of elevated autistic behaviors and co-occurring neurodevelopmental difficulties in many children with neurofibromatosis type 1 (NF1), we have a limited understanding of the sensory processing challenges that may occur with the condition. This study examined the sensory profile of children and adolescents with NF1 and investigated the relationships between the sensory profiles and patient characteristics and neuropsychological functioning. The parent/caregivers of 152 children with NF1 and 96 typically developing children completed the Sensory Profile 2 (SP2), along with standardized questionnaires assessing autistic behaviors, ADHD symptoms, internalizing symptoms, adaptive functioning, and social skills. Intellectual functioning was also assessed. The SP2 data indicated elevated sensory processing problems in children with NF1 compared to typically developing children. Over 40% of children with NF1 displayed differences in sensory registration (missing sensory input) and were unusually sensitive to and unusually avoidant of sensory stimuli. Sixty percent of children with NF1 displayed difficulties in one or more sensory modalities. Elevated autistic behaviors and ADHD symptoms were associated with more severe sensory processing difficulties. This first detailed assessment of sensory processing, alongside other clinical features, in a relatively large cohort of children and adolescents with NF1 demonstrates the relationships between sensory processing differences and adaptive skills and behavior, as well as psychological well-being. Our characterization of the sensory profile within a genetic syndrome may help facilitate more targeted interventions to support overall functioning. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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12 pages, 569 KiB

Open AccessArticle

Maintaining Engagement in Adults with Neurofibromatosis Type 1 to Use the iCanCope Mobile Application (iCanCope-NF)

by Frank D. Buono, Kaitlyn Larkin, Quynh Pham, Diane De Sousa, William T. Zempsky, Chitra Lalloo and Jennifer N. Stinson

Cancers 2023, 15(12), 3213; https://doi.org/10.3390/cancers15123213 - 16 Jun 2023

Cited by 1 | Viewed by 1459

Abstract

Introduction: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition in which chronic pain is a predominant issue. Given the rarity of the disease, there are limited psychosocial treatments for individuals with NF1 suffering with chronic pain. Using mobile applications can facilitate [...] Read more.

Introduction: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition in which chronic pain is a predominant issue. Given the rarity of the disease, there are limited psychosocial treatments for individuals with NF1 suffering with chronic pain. Using mobile applications can facilitate psychosocial treatments; however, there are consistent issues with engagement. Utilizing a mixed methodology, the current study evaluated the customized iCanCope mobile application for NF1 on increasing engagement through the usage of contingency management. Methods: A mixed methods study from a subset of data coming from a randomized clinical trial that occurred from January 2021 to August 2022 was undertaken. Two groups (iCC and iCC + CM) were exposed to the customized iCanCope mobile application in which engagement data were captured in real-time with daily check-ins for interference, sleep, mood, physical activity, energy levels, goal setting, and accessing article content (coping strategies). Additionally, semi-structured interviews were conducted to gain insight into the participants’ experience at the end of the trial. Results: Adults (N = 72) were recruited via NF patient advocacy groups. Significant differences were noted between the groups in total articles read (p = 0.002), goals achieved (p = 0.017), and goals created (p = 008). Additionally, there were significant differences observed between user-generated goals and those that were app recommended (p < 0.001). Both groups qualitatively reported positive feedback on the customized mobile application, indicating that continued usage and engagement of the mobile application were acceptable. Conclusions: Employing customized mobile applications for adults with NF1 along with contingency management can leverage self-managed pain treatments while providing auxiliary resources to this population. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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10 pages, 239 KiB

Open AccessArticle

Vinblastine/Methotrexate for Debilitating and Progressive Plexiform Neurofibroma in Children and Young Adults with Neurofibromatosis Type 1: A Phase 2 Study

by Chelsea Kotch, Kristina Wagner, J. Harris Broad, Eva Dombi, Jane E. Minturn, Peter Phillips, Katherine Smith, Yimei Li, Ian N. Jacobs, Lisa M. Elden, Michael J. Fisher and Jean Belasco

Cancers 2023, 15(9), 2621; https://doi.org/10.3390/cancers15092621 - 5 May 2023

Viewed by 1821

Abstract

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable [...] Read more.

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m² and MTX 30 mg/m² weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3–20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

11 pages, 2282 KiB

Open AccessArticle

Evaluating Focal Areas of Signal Intensity (FASI) in Children with Neurofibromatosis Type-1 (NF1) Treated with Selumetinib on Pediatric Brain Tumor Consortium (PBTC)-029B

by Natasha Pillay-Smiley, James Leach, Adam Lane, Trent Hummel, Jason Fangusaro and Peter de Blank

Cancers 2023, 15(7), 2109; https://doi.org/10.3390/cancers15072109 - 31 Mar 2023

Cited by 5 | Viewed by 2544

Abstract

Background: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. Methods: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated [...] Read more.

Background: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. Methods: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children’s Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests. Results: Sixteen age-matched pairs were assessed (age range: 2.8–16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm² [88.4–182.0] for the treated subjects vs. 121.6 cm² [79.6—181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (−41.3% (LGG) versus −10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (−10.7% (treated FASI) versus −17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = −0.04, p = 0.88). Conclusions: Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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17 pages, 1498 KiB

Open AccessArticle

Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213

by Marzia Ognibene, Marcello Scala, Michele Iacomino, Irene Schiavetti, Francesca Madia, Monica Traverso, Sara Guerrisi, Marco Di Duca, Francesco Caroli, Simona Baldassari, Barbara Tappino, Ferruccio Romano, Paolo Uva, Diego Vozzi, Cristina Chelleri, Gianluca Piatelli, Maria Cristina Diana, Federico Zara, Valeria Capra, Marco Pavanello and Patrizia De Marco Show full author list Hide full author list

Cancers 2023, 15(6), 1916; https://doi.org/10.3390/cancers15061916 - 22 Mar 2023

Cited by 4 | Viewed by 2418

Abstract

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a [...] Read more.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events. RNF213 gene mutations have been associated with MMD, so we investigated whether rare variants of RNF213 could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients’ DNA and gene burden tests, we found that RNF213 seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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18 pages, 2082 KiB

Open AccessArticle

Demographic and Disease-Related Predictors of Socioemotional Development in Children with Neurofibromatosis Type 1 and Plexiform Neurofibromas: An Exploratory Study

by Yang Hou, Xian Wu, Dan Liu, Staci Martin, Mary Anne Toledo-Tamula, Taryn Allen, Andrea Baldwin, Andy Gillespie, Anne Goodwin, Brigitte C. Widemann and Pamela L. Wolters

Cancers 2022, 14(23), 5956; https://doi.org/10.3390/cancers14235956 - 1 Dec 2022

Viewed by 2087

Abstract

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 [...] Read more.

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 children with NF1 and PNs (aged 6–18 years old, M = 12.05, SD = 3.62, 57% male) in a natural history study. Neuropsychological assessments were administered three times over six years. There are large variabilities in socioemotional development in the study participants. Developmental patterns varied across socioemotional domains, respondent type (parent-report [PR] vs. child-report [CR]), demographic factors, and NF1 disease-related factors. For instance, lower parental education was associated with a greater decline in internalizing problems (PR) but a greater increase in school disconnectedness (CR) over time. Non-White (vs. White) children were more likely to experience increased adaptive skills (PR) but decreased personal adjustment (CR). Children with more visible tumors experienced a greater decrease in school disconnectedness (CR). Children with more NF1 complications experienced a greater decrease in externalizing problems (PR). These findings indicate the necessity of using multi-informants and investigating subdomains of socioemotional functions. They also highlight the importance of developing individualized approaches to patient care and interventions. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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17 pages, 31132 KiB

Open AccessArticle

Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs

by Yuehua Li, Manhon Chung, Rehanguli Aimaier, Chengjiang Wei, Wei Wang, Lingling Ge, Beiyao Zhu, Zizhen Guo, Mingyang Wang, Yihui Gu, Haibing Zhang, Qingfeng Li and Zhichao Wang

Cancers 2022, 14(23), 5798; https://doi.org/10.3390/cancers14235798 - 24 Nov 2022

Cited by 6 | Viewed by 2447

Abstract

(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the [...] Read more.

(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the progression of MPNST remains unclear. (2) Methods: by GEO database, MPNST tissue microarray, and NF1-related tumour tissues and cell lines were used to explore NCOR2 expression level in the MPNSTs. The role and mechanism of NCOR2 in NF1-derived MPNSTs were explored by experiments in vivo and in vitro and by transcriptome high-throughput sequencing. (3) Results: NCOR2 expression is significantly elevated in NF1-derived MPNSTs and is associated with patient 10-year survival time. Knockdown of NCOR2 suppressed NF1-derived MPNST cell proliferation by blocking the cell cycle in the G0/G1 phase. Moreover, decreased NCOR2 expression could down-regulate MAPK signal activity through the BDNF/TrkB pathway. (4) Conclusions: our findings demonstrated that NCOR2 expression is significantly elevated in NF1-derived MPNSTs. NCOR2 knockdown can inhibit NF1-derived MPNST cell proliferation by weakened BDNF/TrkB/ERK signalling. Targeting NF1-derived MPNSTs with TrkB inhibitors, or in combination with ERK inhibitors, may be a novel therapeutic strategy for clinical trials. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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17 pages, 2646 KiB

Open AccessArticle

Mutation of PTPN11 (Encoding SHP-2) Promotes MEK Activation and Malignant Progression in Neurofibromin-Deficient Cells in a Manner Sensitive to BRAP Mutation

by Ritsuko Harigai, Ryo Sato, Chikako Hirose, Toshiki Takenouchi, Kenjiro Kosaki, Takanori Hirose, Hideyuki Saya and Yoshimi Arima

Cancers 2022, 14(10), 2377; https://doi.org/10.3390/cancers14102377 - 12 May 2022

Cited by 2 | Viewed by 2545

Abstract

Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that [...] Read more.

Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, PTPN11, encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of PTPN11 and NF1 mutations induces the pathological activation of the RAS pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of BRAP, which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by BRAP (G370A) were not detected in NF1-intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by BRAP (G370A) may serve as a basis for the development of new treatment strategies for NF1. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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Review

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12 pages, 227 KiB

Open AccessReview

Cerebral Vasculopathy in Children with Neurofibromatosis Type 1

by Laura L. Lehman and Nicole J. Ullrich

Cancers 2023, 15(20), 5111; https://doi.org/10.3390/cancers15205111 - 23 Oct 2023

Cited by 2 | Viewed by 1420

Abstract

Cerebrovascular abnormalities are a severe and often underrecognized complication of childhood neurofibromatosis type 1 (NF1). There are no prospective studies of cerebral vasculopathy in NF1; thus, the estimated frequency of vasculopathy varies between studies. The data is difficult to interpret due to the [...] Read more.

Cerebrovascular abnormalities are a severe and often underrecognized complication of childhood neurofibromatosis type 1 (NF1). There are no prospective studies of cerebral vasculopathy in NF1; thus, the estimated frequency of vasculopathy varies between studies. The data is difficult to interpret due to the retrospective data collection and variability in whether imaging is done based on screening/surveillance or due to acute neurologic symptoms. The prevalent NF1-associated cerebral vasculopathy is moyamoya syndrome (MMS). Vascular changes can present without symptoms or with acute TIA or stroke-like symptoms or a range of progressive neurologic deficits. Advanced imaging may enhance sensitivity of neuroimaging in children. Medical and/or surgical interventions may prevent short- and long-term complications. Challenges for establishment of a screening protocol for cerebral vasculopathy in children with NF1 include the relatively large number of patients with NF1, the potential need for sedation to achieve quality imaging and the broad age range at time of detection for cerebral vascular changes. The goal of this review is to present the epidemiology, clinical presentation, imaging features and medical/surgical management of cerebral arteriopathies in children with NF1. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

14 pages, 2517 KiB

Open AccessReview

Inhibition of Anaplastic Lymphoma Kinase (Alk) as Therapeutic Target to Improve Brain Function in Neurofibromatosis Type 1 (Nf1)

by Joseph B. Weiss and Jacob Raber

Cancers 2023, 15(18), 4579; https://doi.org/10.3390/cancers15184579 - 15 Sep 2023

Cited by 1 | Viewed by 1420

Abstract

Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in [...] Read more.

Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in 50–70% of children with Nf1 and include specific problems with attention, visual perception, language, learning, attention, and executive function. These behavioral alterations and cognitive deficits are observed in the absence of tumors or macroscopic structural abnormalities in the central nervous system. No effective treatments for the behavioral and cognitive disabilities of Nf1 exist. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. Even if the incidence of adverse reactions of currently available Alk inhibitors was reduced to half the dose, we anticipate that a long-term treatment would pose challenges for efficacy, safety, and tolerability. Therefore, future efforts are warranted to investigate alternative, potentially less toxic and more specific strategies to inhibit Alk function. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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18 pages, 1657 KiB

Open AccessReview

Dermatologic Manifestations of Neurofibromatosis Type 1 and Emerging Treatments

by Dina Poplausky, Jade N. Young, Hansen Tai, Ryan Rivera-Oyola, Nicholas Gulati and Rebecca M. Brown

Cancers 2023, 15(10), 2770; https://doi.org/10.3390/cancers15102770 - 16 May 2023

Cited by 4 | Viewed by 8562

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that increases one’s risk for both benign and malignant tumors. NF1 affects every organ in the body, but the most distinctive symptoms that are often the most bothersome to patients are the [...] Read more.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that increases one’s risk for both benign and malignant tumors. NF1 affects every organ in the body, but the most distinctive symptoms that are often the most bothersome to patients are the cutaneous manifestations, which can be unsightly, cause pain or pruritus, and have limited therapeutic options. In an effort to increase awareness of lesser-known dermatologic associations and to promote multidisciplinary care, we conducted a narrative review to shed light on dermatologic associations of NF1 as well as emerging treatment options. Topics covered include cutaneous neurofibromas, plexiform neurofibromas, diffuse neurofibromas, distinct nodular lesions, malignant peripheral nerve sheath tumors, glomus tumors, juvenile xanthogranulomas, skin cancer, and cutaneous T-cell lymphoma. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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21 pages, 2518 KiB

Open AccessReview

Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype–Phenotype Correlations

by Cristina Peduto, Mariateresa Zanobio, Vincenzo Nigro, Silverio Perrotta, Giulio Piluso and Claudia Santoro

Cancers 2023, 15(4), 1217; https://doi.org/10.3390/cancers15041217 - 14 Feb 2023

Cited by 17 | Viewed by 7442

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000–3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included [...] Read more.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000–3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype–phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype–phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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16 pages, 1072 KiB

Open AccessReview

Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

by Ling-Ling Ge, Ming-Yan Xing, Hai-Bing Zhang and Zhi-Chao Wang

Cancers 2022, 14(18), 4513; https://doi.org/10.3390/cancers14184513 - 17 Sep 2022

Cited by 11 | Viewed by 3542

Abstract

Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of [...] Read more.

Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs. Full article

(This article belongs to the Special Issue Frontiers in Neurofibromatosis)

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