Quality of life in neurofibromatosis 1: development and validation of a tool dedicated to cutaneous neurofibromas in adults.

BACKGROUND: Cutaneous neurofibromas (cNF), present in 95% of individuals with neurofibromatosis 1 (NF1), are considered as one of the greatest medical burden because of physical disfigurement. No specific score evaluates their impact on quality of life (QoL). OBJECTIVE: To develop a specific score assessing cNF-related QoL. METHODS: Through a multidisciplinary workshop including 10 patients, 3 expert-in-NF1 physicians, 3 health care workers (nurses and psychologist) and 1 methodologist, the French version of the Skindex-16 was modified by adding 3 items. The new cNF-Skindex was validated among patients with NF1 recruited in the ComPaRe online cohort, in France (N = 284). Construct validity was assessed by comparing it with the EQ-5D-5L, its visual analogue scale and the MYMOP2 and by assessing its association with patients' characteristics. Reliability was assessed by a test-retest. An English version of the tool was developed using a back-forward translation. RESULTS: A total of 228 individuals with NF1, with cNF answered the 19-item questionnaire. These items fitted into 3 domains: emotions, symptoms, functioning. One was dropped during analysis because >90% responders were not concerned. The cNF-Skindex significantly correlated with the EQ-5D-5L (N = 193) and MYMOP2 (N = 210) indicating good external validity: rs 0.38 (P < 0.001), and 0.58 (P < 0.001), respectively. Having >50 cNF was the only independent variable associated with the total score cNF-Skindex (ß = 15.88, 95%CI 6.96-24.81, P = 0.001), and with the 3 sub-scores: 'functioning' (ß = 2.65, 95%CI 0.71-4.59, P = 0.008), 'emotions' (ß = 17.03, 95%CI 4.11-29.96, P = 0.010) and 'symptoms' (ß = 3.90, 95%CI 1.95-5.85, P < 0.001). Test-retest reliability (N = 133) found an ICC at 0.96 demonstrating good reproducibility. CONCLUSION: The cNF-Skindex demonstrated excellent psychometric properties. The global and sub-scores were increased with higher number of cNF arguing for its use in further trials aiming to reduce their number or prevent their development. Cross-cultural validation and evaluation of its responsiveness are the next steps.

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients.

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.

Evolving pattern with age of cutaneous signs in neurofibromatosis type 1: a cross-sectional study of 728 patients.

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.

[18F]FDG Positron emission tomography with whole body magnetic resonance imaging ([18F]FDG-PET/MRI) as a diagnosis tool in Schwannomatosis.

Schwannomatosis is a rare autosomal dominant genetic syndrome characterized by the presence of multiple schwannomas. The main symptom is neurogenic pain. The diagnosis requires the presence of several schwannomas and whole-body [18F]FDG-PET/MRI might help detect extra schwannomas in patients when the diagnosis is uncertain. Among the 25 patients treated for Schwannomatosis in our tertiary center, three men and two women had had a [18F]FDG-PET/MRI performed, and the number of schwannomas detected by [18F]FDG-PET/MRI outnumbered the number of schwannomas suspected during the clinical examination. The majority of schwannomas exhibited a radiolabeling (median of 66.7%, range 28-93%). Our findings show that [18F]FDG-PET/MRI could prove useful when suspecting schwannomatosis to accelerate diagnosis and offer optimal care to patients.

Impact of neurofibromatosis 1 upon quality of life in childhood: a cross-sectional study of 79 cases.

BACKGROUND: Neurofibromatosis 1 (NF1) has a significant impact on quality of life (QoL). OBJECTIVES: To evaluate QoL in NF1 according to phenotype from the viewpoint of children and proxy. METHODS: One hundred and forty families with a child aged between 8 and 16 years, seen consecutively at the National Academic Paediatric Referral Centre for NF1 for a phenotype evaluation, were contacted by mail. Families agreeing to participate were sent two questionnaires, the DISABKIDS for children and proxy and the cartoon version of the Children's Dermatology Life Quality Index (CDLQI). QoL scores were compared with those in other major diseases and were analysed according to age, gender and phenotype. RESULTS: Eighty families agreed to participate, and 79 returned the questionnaires. Using DISABKIDS, NF1 had a higher impact on health-related QoL than asthma (mean+/-SD 75.18+/-18.22 vs. 79.78+/-13.41; P=0.005). The total score was more altered when assessed by proxy than by children (71.20+/-17.94 vs. 75.18+/-18.22; P=0.002). Orthopaedic manifestations, learning disabilities and presence of at least two plexiform neurofibromas were independently associated with a higher impact (P<0.01). The CDLQI score was slightly altered (11.3%). Dermatological signs, such as café-au-lait spots and freckling, did not have a significant impact. CONCLUSIONS: Orthopaedic manifestations, learning disabilities and plexiform neurofibromas are the main complications impacting on QoL during childhood NF1. QoL could be considered as an endpoint for intervention studies in this context.

Histopathologically dysplastic neurofibromas in neurofibromatosis 1: diagnostic criteria, prevalence and clinical significance.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) correspond to the most frequent and aggressive neoplasic complications associated with poor prognosis in neurofibromatosis 1. OBJECTIVES: To define the dysplastic neurofibroma potentially at risk of transformation and evaluate its prevalence and incidence. METHODS: According to our database, we retrospectively included, between 1 March 2000 and 31 August 2004, all patients who had subcutaneous and/or plexiform neurofibromas removed surgically. Tumour specimens were systematically reviewed; dysplastic neurofibroma was defined by the association of high cellularity and the presence of atypical cells. Clinically atypical and histopathologically dysplastic neurofibromas were analysed using Fisher's exact test. In addition, three high-grade MPNSTs were analysed retrospectively for the presence of associated histopathologically dysplastic neurofibroma. RESULTS: Among the 89 plexiform and/or subcutaneous neurofibromas surgically removed, high cellularity and cytonuclear atypia were observed in 19% and 17% of cases, respectively. Both criteria were associated in 8.9% of cases (n=8); Mib-1 immunostaining was negative in all cases (n=7). In univariate analysis, only neurological symptoms were significantly associated with dysplasia (P=0.02). Interestingly, dysplastic neurofibroma areas could be identified within or at the periphery of two MPNSTs. CONCLUSIONS: The association of hypercellularity and cytonuclear atypia could be considered as a potential histological prognostic factor of transformation leading to increased surveillance.