Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association

Abstract

Neurofibromatosis type 1 (NF1) is a common disorder that arises secondary to mutations in the tumor suppressor gene NF1. Glomus tumors are small, benign but painful tumors that originate from the glomus body, a thermoregulatory shunt concentrated in the fingers and toes. We report 11 individuals with NF1 who harbored 20 glomus tumors of the fingers and 1 in the toe; 5 individuals had multiple glomus tumors. We hypothesized that biallelic inactivation of NF1 underlies the pathogenesis of these tumors. In 12 NF1-associated glomus tumors, we used cell culture and laser capture microdissection to isolate DNA. We also analyzed two sporadic (not NF1-associated) glomus tumors. Genetic analysis showed germ line and somatic NF1 mutations in seven tumors. RAS mitogenactivated protein kinase hyperactivation was observed in cultured NF1 À/À glomus cells, reflecting a lack of inhibition of the pathway by functional neurofibromin, the protein product of NF1. No abnormalities in NF1 or RAS mitogen-activated protein kinase activation were found in sporadic glomus tumors. By comparative genomic hybridization, we observed amplification of the 3 ¶-end of CRTAC1 and a deletion of the 5 ¶-end of WASF1 in two NF1-associated glomus tumors. For the first time, we show that loss of neurofibromin function is crucial in the pathogenesis of glomus tumors in NF1. Glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1.

The Pathoetiology of Neurofibromatosis 1

“…The tumors arise from the glomus body, a highly innervated thermoregulatory shunt containing concentric layers of contractile ␣-actin-positive glomus cells, which harbor bi-allelic inactivation of the NF1 gene. 74 Glomus tumors may affect up to 5% of the adult NF1 patient population. 75 Neurofibromas are lesions characterized by bi-allelic inactivation of the NF1 gene in a subpopulation of Schwann cells.…”

Glomus tumours in the long finger and in the thumb of a young patient with neurofibromatosis-1 (Nf-1)

“…RAS mitogen-activated protein kinase (MAPK) hyperactivity was found in cultured glomus cells, which lack Nf-1 -/-. The cells from the glomus tumours in the report by Brems et al [8] showed increased activation of extracellular-regulated kinases 1 and 2 (ERK1/2) phosphorylation (p-ERK1/2) after stimulation with acidic fibroblast growth factor (aFGF) in the Nf-1-associated glomus tumour-erived glomus cells. An increased p-ERK:ERK ratio was therefore detected.…”

“…In a previous report, eight of the 11 patients were women aged 26-59 years, and a girl of 11 years [8]. Recently, a case of a painful glomus tumour of the thumb in an 11-year-old boy, on whom initially a neurofibroma of the terminal sensory branch of the digital nerve had been suspected [10], was reported.…”

“…Interestingly, a meticulous analysis of 5 these tumours showed that loss of neurofibromin function may be crucial in the pathogenesis of glomus tumours in Nf-1. The neurofibromin, which is a protein product of Nf-1 (tumour suppression gene Nf-1), regulates RAS through its GTPase activity protein related domain [8]. RAS mitogen-activated protein kinase (MAPK) hyperactivity was found in cultured glomus cells, which lack Nf-1 -/-.…”

Manifestações Cutâneas das Rasopatias

“…28 A associação entre a NF1 e os tumores glómicos foi definitivamente confirmada quando se detetou a inativação do gene NF1 nas células destes tumores benignos. 29 A origem é vascular, derivando do corpo glómico, responsável pela regulação local do fluxo sanguíneo nos capilares. Localizam-se mais frequentemente nas regiões acrais, particularmente nos dedos, região periungueal ou subungueal.…”