Abstract
ObjectivesTo 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 methodsProspective 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).ResultsCases 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.ConclusionThe 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.Registration detailsORPHA86301
Highlights
Neurofibromatosis type 1 (NF-1 [MIM 162200]) is a common autosomal dominant disorder associated with increased morbidity and mortality[1]
Subcutaneous neurofibromas (SC-NFs) were more strongly associated with internal neurofibromas in patients with ten or more SC-NFs than in patients with fewer NF-SCs
The association with SC-NFs was stronger for diffuse, intradural, and > 3 cm internal neurofibromas than with other internal neurofibromas
Summary
Neurofibromatosis type 1 (NF-1 [MIM 162200]) is a common autosomal dominant disorder associated with increased morbidity and mortality[1]. They are benign tumors that arise from connective tissue of nerve sheaths, especially the surrounding structures. A recent study demonstrated that having at least two SC-NFs was independently associated with having internal neurofibromas [6]. This association needs to be characterised in detail. A strong association between peripheral neuropathy and SC-NFs has been reported [7]. We hypothesized that this association was related to an association between SC-NFs and internal neurofibromas located along the nerve roots
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