A Translational Approach to Spinal Neurofibromatosis: Clinical and Molecular Insights from a Wide Italian Cohort

Abstract

Spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), is characterized by bilateral neurofibromas involving all spinal roots. In order to deepen the understanding of SNF’s clinical and genetic features, we identified 81 patients with SNF, 55 from unrelated families, and 26 belonging to 19 families with at least 1 member affected by SNF, and 106 NF1 patients aged >30 years without spinal tumors. A comprehensive NF1 mutation screening was performed using NGS panels, including NF1 and several RAS pathway genes. The main features of the SNF subjects were a higher number of internal neurofibromas (p < 0.001), nerve root swelling (p < 0.001), and subcutaneous neurofibromas (p = 0.03), while hyperpigmentation signs were significantly less frequent compared with the classical NF1-affected cohorts (p = 0.012). Fifteen patients underwent neurosurgical intervention. The histological findings revealed neurofibromas in 13 patients and ganglioneuromas in 2 patients. Phenotypic variability within SNF families was observed. The proportion of missense mutations was higher in the SNF cases than in the classical NF1 group (21.40% vs. 7.5%, p = 0.007), conferring an odds ratio (OR) of 3.34 (CI = 1.33–10.78). Two unrelated familial SNF cases harbored in trans double NF1 mutations that seemed to have a subclinical worsening effect on the clinical phenotype. Our study, with the largest series of SNF patients reported to date, better defines the clinical and genetic features of SNF, which could improve the management and genetic counseling of NF1.

Expression analysis of NF1‐mutated alleles in a rare compound heterozygous spinal NF1 patient by digital PCR

“…Interestingly, the SNF patient carrying the in trans double NF1 missense variants, as well as another unrelated SNF patient carrying in trans NF1 variants, showed a more severe and complex phenotype than their relatives, suggesting a contribution of the second variant to the phenotype. A similar pattern has been described for family 17 by Paterra et al (2022).…”

“…It is worth noting that the two pairs of NF1 variants inherited in families 1 and 17, described by Paterra et al (2022), have different pathogenicity scores and different ΔΔGs calculated by an in-silico conformational analysis. In family 1, the NM_001042492.3: c.62T > A (p.Leu21His) missense variant was shared by the father, the proband, and his brother and seems to be associated to an SNF condition.…”

“…Based on a previously reported analysis by Paterra et al (2022) out of 106 classic NF1 and 75 SNF patients, three familial SNF patients, carrying two variants in the NF1 gene, were identified (Paterra et al, Table 3) by NGS (Paterra et al supplementary materials,file S1). The segregation analysis revealed that in family 1, the two NF1 variants were inherited in trans (Figure 1 and Paterra et al, Table 3).…”

“…The patient showed a severe phenotype, including paraparesis, spinal neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs) at spinal level, which the authors correlated to the p.Cys1016Arg. The other two patients have been recently described (Paterra et al, 2022). They are two unrelated familial SNF patients: family 1 proband carried the missense c.62T > A (p.Leu21His) and c.528T > A (p.Asp176Glu) variants, family 17 proband carried the splice variant c.3314 + 2T > C, and the missense variant c.7532C > T (p.Ala2511Val).…”

“…Additional reported cases of double variants identified in the NF1 gene are patients carrying variants in cis ; therefore, one of the two NF1 copies remains functional (Hernández‐Imaz et al., 2013; Paterra et al., 2022; Terzi et al., 2012).…”