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Background/Aims: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment. Methods: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12–17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment. Results: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%–96%), followed by oral medication (54%–93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%–75%). Adolescent and caregivers were least willing to risk pain (72%–78%) and nausea/vomiting (59%–81%) as a cutaneous neurofibroma treatment side effect. Conclusions: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments. [ABSTRACT FROM AUTHOR]

Cutaneous neurofibromas (cNFs) are a hallmark of patients with the neurofibromatosis type 1 (NF1) genetic disorder. These benign nerve sheath tumors, which can amount to thousands, develop from puberty onward, often cause pain and are considered by patients to be the primary burden of the disease. Mutations of NF1 , encoding a negative regulator of the RAS signaling pathway, in the Schwann cell (SCs) lineage are considered to be at the origin of cNFs. The mechanisms governing cNFs development are poorly understood, and therapeutics to reduce cNFs are missing, mainly due to the lack of appropriate animal models. To address this, we designed the Nf1-KO mouse model that develops cNFs. Using this model, we found that cNFs development is a singular event and goes through 3 successive stages: initiation, progression, and stabilization characterized by changes in the proliferative and MAPK activities of tumor SCs. We found that skin trauma accelerated the development of cNFs and further used this model to explore the efficacy of the MEK inhibitor binimetinib to cure these tumors. We showed that while topically delivered binimetinib has a selective and minor effect on mature cNFs, the same drug prevents their development over long periods. [ABSTRACT FROM AUTHOR]

Abstract Background Neurofibromatosis type 1 is an inherited condition with variable phenotypic expression and a high medical and social burden. The objectives of this patient survey were to better understand the real-world experiences of patients living with cutaneous neurofibromas (cNF), to perceive their satisfaction and feelings about cNF current management (only laser and surgery are currently available), and to highlight their expectations of new therapeutic modalities. Results One hundred seventy patients from 4 European countries took part in the study, 65% (n = 110) were women and mean age was 39 years old. 96% (n = 164) of respondents have cNF on visible parts of the body and the survey confirmed that total number of cNF and visibility increase with age. Patients reported that cNF mainly impacts everyday mood, general daily life and social life. The visibility of cNF had a higher impact than their number. 92% (n = 156) of patients have a regular and multidisciplinary medical follow-up. The dermatologist is one of the most consulted healthcare professionals. 76% (n = 130) of respondents have treated their cNF: 65% (n = 111) had surgery and 38% (n = 64) had multiple laser sessions. Frequency of operations and regrowth of cNF were the two most unsatisfactory aspects with both treatments for patients. Indeed, after removal, new cNF appear in more than 75% (n = 128) of cases. As a future treatment, patients expected a topical (30%, n = 51) or oral medication (29%, n = 50). Around 2 out of 3 patients would agree to take it at least once a day or more for life but they would like a well-tolerated treatment. According to patients, the most important effectiveness criteria of a new treatment are to block cNF growth and reduce their number. 70% (n = 119) of patients would consider a future treatment moderately effective to very effective if it could clear 30% of cNF. Conclusions This first cNF European patient community survey confirmed that the visible stigma and unaesthetic aspect of cNF have an important impact on patients’ quality of life. The survey highlighted that patients were not entirely satisfied with the actual surgery and laser treatments and revealed their clear and realistic expectations for future treatment of cNF.

Abstract Background Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a predisposition to develop multiple benign tumors. A major feature of NF1 is the development of localized cutaneous neurofibromas. Cutaneous neurofibromas manifest in > 99% of adults with NF1 and are responsible for major negative effects on quality of life. Previous reports have correlated increased burden of cutaneous neurofibromas with age and pregnancy, but longitudinal data are not available to establish a quantitative natural history of these lesions. The purpose of this study is to conduct a prospective natural history study of 22 adults with NF1 over an 8-year period to quantify cutaneous neurofibroma number and size. Results The average monthly increase in volume for cutaneous neurofibromas was 0.37 mm3 in the back region (95% CI (0.23, 0.51), p

Cutaneous neurofibromas (cNFs) are a hallmark of patients with the neurofibromatosis type 1 (NF1) genetic disorder. These benign nerve sheath tumors, which can amount to thousands, develop from puberty onward, often cause pain and are considered by patients to be the primary burden of the disease. Mutations of NF1, encoding a negative regulator of the RAS signaling pathway, in the Schwann cell (SCs) lineage are considered to be at the origin of cNFs. The mechanisms governing cNFs development are poorly understood, and therapeutics to reduce cNFs are missing, mainly due to the lack of appropriate animal models. To address this, we designed the Nf1-KO mouse model that develops cNFs. Using this model, we found that cNFs development is a singular event and goes through 3 successive stages: initiation, progression, and stabilization characterized by changes in the proliferative and MAPK activities of tumor SCs. We found that skin trauma accelerated the development of cNFs and further used this model to explore the efficacy of the MEK inhibitor binimetinib to cure these tumors. We showed that while topically delivered binimetinib has a selective and minor effect on mature cNFs, the same drug prevents their development over long periods., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a predisposition to develop multiple benign tumors. A major feature of NF1 is the development of localized cutaneous neurofibromas. Cutaneous neurofibromas manifest in > 99% of adults with NF1 and are responsible for major negative effects on quality of life. Previous reports have correlated increased burden of cutaneous neurofibromas with age and pregnancy, but longitudinal data are not available to establish a quantitative natural history of these lesions. The purpose of this study is to conduct a prospective natural history study of 22 adults with NF1 over an 8-year period to quantify cutaneous neurofibroma number and size.Results: The average monthly increase in volume for cutaneous neurofibromas was 0.37 mm3 in the back region (95% CI (0.23, 0.51), p < 0.0001), 0.28 mm3 in the abdominal region (95% CI (0.16, 0.41), p < 0.0001), and 0.21 mm3 in the arm/leg region (95% CI (0.08, 0.34), p = 0.0022). The number of cutaneous neurofibromas significantly increased in the back (slope = 0.032, p = 0.011) and abdominal (slope = 0.018, p = 0.026) regions, while the leg/arm regions retained a positive trend (slope = 0.004, p = 0.055).Conclusions: The number and volume of cutaneous neurofibromas significantly increased over an 8-year timespan; however, the rate of increase is variable by individual and body region. These findings may provide insight into cutaneous neurofibroma development and benefit researchers considering clinical trials targeting cutaneous neurofibromas. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1, (NF1) is a complex, autosomal dominant disorder characterized by benign and malignant tumors which result from NF1 gene mutations. The molecular mechanisms that underlie NF1 tumorigenesis are still poorly understood although inactivation of other modifying loci in conjunction with NF1 mutations is postulated to be involved. These modifying loci may include deficiencies in mismatch repair genes and elements involved in cell cycle regulation ( TP53, RB1, and CDKN2A). We have analyzed the somatic mutations in 89 cutaneous neurofibromas derived from three unrelated NF1 patients with high tumor burden, by loss of heterozygosity (LOH) analysis of the NF1, TP53, RB1, and CDKN2A genes, by assessing microsatellite instability (MSI), by direct sequencing of the NF1, TP53, and several mismatch repair (MMR ) genes and by multiplex ligation-dependent probe amplification of the NF1 and TP53 genes. The aim was both to assess the possible clonality of these tumors and also to assess the involvement of other potential genetic loci in the development of these neurofibromas. Somatic NF1 mutations were identified in 57 (64%) of neurofibroma samples. Each mutation was distinct demonstrating the independent origin of each tumor. While somatic LOH of the TP53 gene was identified in four tumors, no specific deletions or sequence variations were identified. LOH of markers flanking the RB1 gene was also found in one tumor but no CDKN2A mutations were detected. Although evidence of MSI was seen in 21 tumors, no MMR gene alterations were identified. The identification of LOH involving TP53 and RB1 loci is a novel finding in benign cutaneous neurofibromas possibly demonstrating an alternative underlying molecular mechanism associated with the development of these benign tumors from this cohort of patients. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by skin tumours derived from peripheral nerves. It is a clinically diagnosed disorder of a mainly cosmetic concern. There are different excision modalities for treatment of cutaneous neurofibromas; however, none is considered to be universally accepted treatment. This study was conducted to evaluate a non-excision treatment of multiple cutaneous neurofibromas, using surface and interstitial approaches of neodymium:yttrium aluminum garnet (Nd:YAG) laser (1,064 nm) photocoagulation, depending upon the size and location of the lesions. Twelve patients with multiple cutaneous neurofibromas were included. Surface laser photocoagulation by long-pulsed Nd:YAG laser has been used for treatment of flat lesions, while interstitial laser photocoagulation by continuous wave (CW) Nd:YAG laser has been used for treatment of bulkier lesions. After 14 months of follow up, both approaches of laser photocoagulation have shown different success rates, as denoted by the regression of the lesions, an overall acceptable cosmetic outcome, and, generally, patients’ satisfaction. Within the limitations of the present study, laser photocoagulation has proven to be a promising technique that may be an alternative or additive modality for treatment of multiple cutaneous neurofibromas. It is a minimally invasive, office-based technique that could be used safely and effectively, with a limited rate of complications. Surface laser photocoagulation has proven to be an effective tool for treatment of flat lesions, especially those located in exposed areas, with a favourable cosmetic result, while interstitial laser photocoagulation could be reserved for bulkier lesions, especially those located in non-exposed areas. However, further studies are necessary to refine the procedure, and to confirm the present encouraging findings, especially over a longer period of follow up, as well as to evaluate laser parameters for optimization of the technique. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 is an inherited condition with variable phenotypic expression and a high medical and social burden. The objectives of this patient survey were to better understand the real-world experiences of patients living with cutaneous neurofibromas (cNF), to perceive their satisfaction and feelings about cNF current management (only laser and surgery are currently available), and to highlight their expectations of new therapeutic modalities.Results: One hundred seventy patients from 4 European countries took part in the study, 65% (n = 110) were women and mean age was 39 years old. 96% (n = 164) of respondents have cNF on visible parts of the body and the survey confirmed that total number of cNF and visibility increase with age. Patients reported that cNF mainly impacts everyday mood, general daily life and social life. The visibility of cNF had a higher impact than their number. 92% (n = 156) of patients have a regular and multidisciplinary medical follow-up. The dermatologist is one of the most consulted healthcare professionals. 76% (n = 130) of respondents have treated their cNF: 65% (n = 111) had surgery and 38% (n = 64) had multiple laser sessions. Frequency of operations and regrowth of cNF were the two most unsatisfactory aspects with both treatments for patients. Indeed, after removal, new cNF appear in more than 75% (n = 128) of cases. As a future treatment, patients expected a topical (30%, n = 51) or oral medication (29%, n = 50). Around 2 out of 3 patients would agree to take it at least once a day or more for life but they would like a well-tolerated treatment. According to patients, the most important effectiveness criteria of a new treatment are to block cNF growth and reduce their number. 70% (n = 119) of patients would consider a future treatment moderately effective to very effective if it could clear 30% of cNF.Conclusions: This first cNF European patient community survey confirmed that the visible stigma and unaesthetic aspect of cNF have an important impact on patients' quality of life. The survey highlighted that patients were not entirely satisfied with the actual surgery and laser treatments and revealed their clear and realistic expectations for future treatment of cNF. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type I (NF) or Von Recklinghausen disease is an autosomal dominant genodermatosis manifested by abnormalities of the skin, nervous system, bones and endocrine glands. The diffuse plexiform diffuse neurofibromas characteristic of this disease are often congenital, always visible before five years and tend to develop from adolescence. They are found in 20 to 25% of the patients and are located in 97% of the cases in the upper eyelid. We report the case of a 78-year-old patient with painless, soft swelling since the age of 8, with the left-thigh buttock margin as the insertion zone and terminating in the lower third of the left thigh. It measures 25 cm on its length, 5 cm at its base and 10 cm at its free edge. For some time, the patient reported a feeling of heaviness of the left thigh. The clinical examination has objectified 10 coffee-milk spots on the trunk, numerous cutaneous neurofibromas on the trunk and limbs. Note that his son had similar lesions. Ophthalmologic examination revealed age-related progressive cataract. The rest of the clinical examination was normal. We have discussed three diagnostic hypotheses: a diffuse plexiform plexiform neurofibroma, a molluscum pendulum and a liposarcoma. The diagnosis of neurofibroma type I was retained in front of diffuse plexiform neurofibroma, cutaneous neurofibromas, coffee-to-milk spots and the presence of similar lesions in his son. [ABSTRACT FROM AUTHOR]