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Neurofibromatosis 1 (NF1) is a multisystem disease that can affect nearly every organ system. The aim of our study was to describe the in-hospital population with NF1 in France. We conducted a nationwide retrospective cohort study using the French hospital administrative database. A total of 11,425 patients with NF1 (53.4% female, 19,080 person years) were identified from January 2013 to December 2019. A total of 23% had at least one diagnosis of a comorbidity or NF1-associated complication or disease, and it was highest in the age group of 10-15 years. A total of 2,601 (22.8%) had a diagnosis of cancer. There were 366 (3.2%) in-hospital deaths, and we observed a standardized mortality ratio of 4.14 (95% confidence interval = 3.71-4.56), with a higher standardized mortality ratio in women and in the age group of 10-15 years. The standardized incident ratio (SIR) of cancer was 10.3 (95% confidence interval = 9.6-11.1). We observed high SIR values for cancer in childhood, with a decrease toward that of the general population by age 70 years. We observed high SIRs for NF1-associated cancers: CNS SIR of 195.4 (95% confidence interval = 172.2-220.9) and small intestine SIR of 102.9 (95% confidence interval = 71.7-143.2). The study provides a better understanding of the prognosis in people living with NF1., (Copyright © 2023. Published by Elsevier Inc.)

Background: Neurofibromatosis 1 (NF1) is one of the most common inherited disorders characterized by mutations in the tumour suppressor gene NF1. Its clinical manifestations are highly variable and unpredictable. A specific NF1 mutation does not predict the severity or complications of the disease., Objective: The objective of this study was to build an empirical classification scheme without any a priori hypotheses to identify the underlying NF1 subtypes that best explain the observed heterogeneity., Methods: We performed latent class analysis (LCA) of 1351 consecutive NF1 patients aged >17 years seen between 2002 and 2014. Data and phenotypic features were collected prospectively on a standardized form., Results: The median age was 36.8 (17-81) years. A three-class model showed the best fit: 706 (52%) belonged to the LC1 'Cutaneous neurofibromas' class having preferentially cutaneous neurofibromas (99%), plexiform neurofibromas (63%) and blue-red macules (29%); 593 (44%) belonged to the LC2 'Subcutaneous neurofibromas' class characterized by the presence of at least 10 subcutaneous neurofibromas (21%) and a familial form (77%) and 52 (4%) belonged to the LC3 'Dysmorphic phenotype' class characterized by dysmorphic features (78%) and learning difficulties (87%). Patients in LC1 had a higher likelihood of developing scoliosis (RR = 1.7, 95% confidence interval (CI) [1.2-2.4]). Patients in LC2 were more likely to be men (RR = 1.4, 95% CI [1.1-1.7]). Patients in LC3 were at higher risk of having an optic pathway glioma (RR = 4.8, 95% CI [1.9-11.8]) and epilepsy (RR = 4.5, 95% CI [1.8-11.6])., Conclusion: Our findings invite the performance of a larger cohort study to test whether the various latent classes reflect different underlying genetic modifiers of these phenotypic traits., (© 2022 European Academy of Dermatology and Venereology.)

There is an increased risk of osteoporosis and an abnormal bone turn over in neurofibromatosis 1 (NF1). Our objective is to evaluate bone status in NF1 and to look for associations with cutaneous phenotype. We conducted a descriptive, monocentric study. We included 60 NF1 women, 18-51 years old, non-menopausal, divided in 2 groups: «at risk phenotype» (ARP) composed by 30 patients with at least 2 subcutaneous neurofibromas (SC-NF) and «classical phenotype» (CP) composed by 30 patients with none or 1 SC-NF. We evaluated low bone mineral density (BMD) risk factors and measured BMD, calcium and phosphorus homeostasis and bone turnover markers. Before 50 years old, Z-score has to be used to assess BMD. Z-score < - 2 is below expected range and represents 2.5% of the population. There was no difference between the two groups. Overall, Z-scores were low and 5 patients had a Z-score < - 2 (8.3%), which is 3 times general population low BMD frequency. 10 fragility fractures occurred in 8 patients, among which 2 were vertebral fractures. 85% had low calcium intake. 12 patients had hypophosphoremia, 25 elevated PTH. Vitamin D levels were low for 86.4%. 41 patients (69.5%) had at least one abnormal bone turnover markers. Low BMD is 3.3 times more frequent in NF1 than in general population, with high fracture risk, regardless of the skin phenotype, classical or at risk, because of high bone turn over and secondary hyperparathyroidism due to vitamin D deficiency and poor calcium intake.

Background: To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation., Methods: This retrospective study included 49 patients (15-60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival., Results: Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG ≤ 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; χ2 27.85; hazard ratio 13.27 [95% CI, 3.72-47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with χ2 ranging 14.41-19.12. The HIsuv index was not predictive of survival., Conclusion: Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and predict overall survival, with a higher specificity for the TLG. Conventional measures such as the SUVmax, and T/L ratio also demonstrate high prognostic value.

Background: Few studies have evaluated the efficacy of carbon dioxide (CO2) laser ablation for treating neurofibromatosis type 1 (NF1)., Objective: To evaluate laser treatment safety and patient satisfaction at the French National Referral Centre for Neurofibromatosis., Methods: Retrospective survey with a specific questionnaire. The principal outcome measures included pain evaluation and assessments of treatment safety., Results: We included 106 patients, 70% of whom had more than 50 neurofibromas. Laser treatment was performed mostly for aesthetic reasons, or due to pain, recurrent local trauma or familial influence, under a local anaesthetic, during outpatient visits. The mean pain score was 4.0 ± 2.7 during the administration of local anaesthesia, 2.4 ± 2.1 during laser treatment and <2 48 h after treatment in 56% of cases. The mean satisfaction score for the treatment was 4.6 ± 3.4 and was not associated with disease phenotype., Conclusions: CO2 laser treatment for NF could be considered more frequently and might help to decrease the social impact of the disease.

Background: Neurofibromatosis 1 (NF1) is the most common autosomal dominant disorder, with an incidence of 1 in 2,500-3,300 live births. NF1 is associated with significant morbidity and mortality because of complications, especially malignant peripheral nerve sheath tumors (MPNSTs), which mainly develop during adulthood. We evaluated our experience with management of NF1 with MPNSTs by standard chemotherapy with anthracycline and/or ifosfamide in terms of time to treatment failure and overall survival., Methods: We performed a retrospective review of consecutive patients with NF1 and a diagnosis of MPNSTs between 1993 and 2003 in our referral center for NF1. Prognostic factors were evaluated by univariate analysis., Results: We evaluated data for 21 patients with grade 1 (n=1), grade 2 (n=8) and grade 3 (n=12) MPNST; 16 presented localized disease and underwent surgery: margins for 6 were tumor-free (including 3 patients with amputation), 2 showed microscopic residual disease and 8 showed macroscopic residual disease. All patients received chemotherapy and 9 radiotherapy. Median time to treatment failure and overall survival were 7.8 and 17 months, respectively. Two patients were still alive at 138 and 167 months. We found no significant relationship between type of chemotherapy and time to treatment failure or overall survival., Conclusions: MPNSTs are highly aggressive in NF1. Conventional chemotherapy does not seem to reduce mortality, and its role must be questioned. Recent advances in the molecular biology of MPNSTs may provide new prognostic factors and targeted therapies.

Objective: To identify clinical characteristics associated with internal neurofibromas in children with NF1, as a means of ensuring the early identification of patients at high risk for malignant peripheral nerve-sheath tumors developed from preexisting internal neurofibromas., Patients and Methods: We used data from two NF1 populations, in France and North America, respectively. The French database comprised 1083 patients meeting NIH diagnostic criteria for NF1 and the Neurofibromatosis Institute Database of North America comprised 703 patients. Patients younger than 17 years of age were eligible for our study if they had been evaluated for internal neurofibromas using computed tomography and/or magnetic resonance imaging. Clinical characteristics associated with internal neurofibromas by univariate analysis (P ≤ 0.15) were entered into a multiple logistic regression model after checking for potential interactions and confounding. Multiple imputation was used for missing values., Results: Among the 746 children in the two databases, 357 (48%) met our inclusion criteria. Their mean age was 7.7 ± 5.0 years and there were 192 (53.8%) males. Internal neurofibromas were present in 35 (9.8%) patients. Internal neurofibromas developed earlier in females than in males and their prevalence increased during adolescence. Factors independently associated with internal neurofibromas were age (OR = 1.16 [1.07-1.27]), xanthogranulomas (OR = 5.85 [2.18-15.89]) and presence of both subcutaneous and plexiform neurofibromas (OR = 6.80 [1.52-30.44])., Conclusions: Several easily recognizable clinical characteristics indicate a high risk of internal neurofibromas in children with NF1 and, therefore, a need for very close monitoring.

Objectives: To assess associations between subcutaneous neurofibromas (SC-NFs) and internal neurofibromas in patients with neurofibromatosis type 1 (NF-1) and to determine whether the association between SC-NFs and peripheral neuropathy was ascribable to internal neurofibromas., Patients and Methods: Prospective multicentre case-control study. Between 2005 and 2008, 110 NF-1 adults having two or more SC-NFs were individually matched for age, sex and hospital with 110 controls who had no SC-NF. Patients underwent standardized MRI of the spinal cord, nerve roots and sciatic nerves and an electrophysiological study. Analyses used adjusted multinomial logistic regression (ORa) to estimate the risk of the presence of internal neurofibromas or peripheral neuropathies associated with patients presented 2 to 9 SC-NFs, at least 10 SC-NFs as compared to patients without any (referential category)., Results: Cases had a mean age of 41 (± 13) years; 85 (80%) had two to nine SC-NFs and 21 (19%) at least ten SC-NFs. SC-NFs were more strongly associated with internal neurofibromas in patients with ten or more SC-NFs than in patients with fewer NF-SCs (e.g., sciatic nerve, aOR = 29.1 [8.5 to 100] vs. 4.3 [2.1 to 9.0]). The association with SC-NFs was stronger for diffuse, intradural, and > 3 cm internal neurofibromas than with other internal neurofibromas. Axonal neuropathy with slowed conduction velocities (SCV) was more strongly associated with having at least ten SC-NFs (aOR = 29.9, 5.5 to 162.3) than with having fewer SC-NFs (aOR = 4.4, 0.9 to 22.0). Bivariate analyses showed that the association between axonal neuropathy with SCV and sciatic neurofibromas was mediated by the association between SC-NFs and sciatic neurofibromas., Conclusion: The at-risk phenotype of NF-1 patients (i.e. NF-1 patients with SC-NFs) is ascribable to associations linking SC-NFs to internal neurofibromas at risk for malignant transformation and to axonal neuropathies with slowed conduction velocities. Axonal neuropathies with SCV are particularly common in patients with at least ten SC-NFs.

Background: Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006., Methods: Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death., Results: Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%)., Conclusions: We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males.

Background: Neurofibromatosis type 1 is fully penetrant by the age of 8 years, and 3 criteria of diagnosis are dermatological: café-au-lait spots (CLS), intertriginous freckling and neurofibromas (NF)., Objectives: The aim of our study was to determine the evolving pattern of cutaneous manifestations during adulthood., Methods: Phenotypic data of patients seen in our center between March 2003 and December 2009 were studied. Patients were classified in 10-year groups. Following clinical characteristics, the number of CLS and the number of cutaneous and subcutaneous NF were compared according to age., Results: 728 subjects, 404 females and 324 males (mean age of 32.4 years, range 6-80 years) were studied. Four hundred eighty-nine patients were over 20 years old (67%). The number of CLS (small or large) was significantly decreased with age while the number of cutaneous and subcutaneous NF was strongly increased (p < 0.001)., Conclusions: The decrease in CLS with age has not been previously reported while an increase in the number of NF is well described during puberty and pregnancy and with age., (Copyright © 2011 S. Karger AG, Basel.)

NF-1 is associated with a 15-year decrease in life expectancy. Internal neurofibromas are associated with increased morbidity and mortality through malignant transformation and compression of neighboring organs. Our purpose was to develop and to validate a clinical score for predicting internal neurofibromas in adults. The development sample comprised 208 patients and the validation sample 191 patients. The score was developed using logistic regression. Discrimination and calibration of the model were evaluated. Four variables were independently associated with internal neurofibromas: at least two subcutaneous neurofibromas (odds ratio (OR)=4.7, [2.1-10.5]), age < or =30 years (OR=3.1, [1.4-6.8]), absence of cutaneous neurofibromas (OR=2.6, [0.9-7.5]), and fewer than six café-au-lait spots (OR=2.0 [0.9-4.6]). The score computed by linear combination of the rounded coefficients of these four variables ranged from 0 to 40 (mean, 12.8+/-10.8). The probability of internal neurofibromas was computed as exp (-2.93+0.11Score)/exp (1+(-2.93+0.11Score)). Probabilities agreed well with the observed frequencies indicating good calibration, and discrimination was adequate (AUC-ROC, 0.75) in both data sets. The presence of internal neurofibromas can be accurately predicted using a simple clinical score. Further work will establish the score threshold that identifies patients at high risk for complications.