The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features

Abstract

Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4-74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non-SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café-au-lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14-13.11], which were more frequent in SNF vs MNFSR (p = 0.0271).

Spinal neurofibromatosis and phenotypic heterogeneity in NF1

“…As noted by Ruggieri et al , this phenotype overlaps with that of the more typical NF1. Many NF1 patients have neurofibromas involving multiple spinal nerve roots, and some have massive enlargement of multiple spinal nerves.…”

Emerging genotype–phenotype relationships in patients with large NF1 deletions

“…One of these relates to spinal neurofibromatosis (SNF) which is characterised by bilateral neurofibromas located at all 38 spinal nerve roots. The risk of having SNF versus NF1 without spinal neurofibromas, or NF1 with neurofibromas affecting only some but not all spinal nerve roots, is significantly increased in individuals harbouring NF1 missense mutations (Ruggieri et al 2015). Furthermore, the recurrent three base-pair in-frame deletion, c.2970-2972 delAAT, within exon 17 of the NF1 gene leads to the loss of a single amino acid (p.Met992del) and is associated with a relatively mild NF1 phenotype that is characterised by the occurrence of CALS and skinfold freckling but a lack of externally visible cutaneous or plexiform neurofibromas (Upadhyaya et al 2007).…”

Use of optical magnification and microsurgical technique in general surgery

“…32 Ultimately, the proper surgical approach of PNSTs (neurofibromas and schwannomas) is tumour removal from the involved nerve under magnification using microsurgical technique. [33][34][35][36] Andrological microsurgery plays an important role especially in patients with non-obstructive azoospermia (NOA), where microscopic testicular sperm extraction (micro-TESE) is a valid support for assisted reproduction techniques (ART). 37 In the management of male infertility, the use of microsurgery is a widespread and established procedure in many diseases, like varicocele and obstructive OA.…”