The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin

Abstract

In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown. First, we conducted a comprehensive, multi-molecular, immunofluorescence (IF) analyses on 3mm punch biopsies from three separate locations in normal appearing, cNF-free skin in 19 NF1 patients and skin of 16 normal subjects. At least one biopsy in 17 NF1 patients had previously undescribed micro-lesions consisting of a small, dense cluster of nonpeptidergic C-fiber endings and the affiliated nSC consistently adjoining adnexal structures—dermal papillae, hair follicles, sweat glands, sweat ducts, and arterioles—where C-fiber endings normally terminate. Similar micro-lesions were detected in hind paw skin of mice with conditionally-induced SC Nf1 -/- mutations. Hypothesizing that these microlesions were pre-cNF origins of cNF, we subsequently analyzed numerous overt, small cNF (s-cNF, 3–6 mm) and discovered that each had an adnexal structure at the epicenter of vastly increased nonpeptidergic C-fiber terminals, accompanied by excessive nSC. The IF and functional genomics assays indicated that neurturin (NTRN) and artemin (ARTN) signaling through cRET kinase and GFRα2 and GFRα3 co-receptors on the aberrant C-fiber endings and nSC may mutually promote the onset of pre-cNF and their evolution to s-cNF. Moreover, TrpA1 and TrpV1 receptors may, respectively, mediate symptoms of chronic itch and pain. These newly discovered molecular characteristics might be targeted to suppress the development of cNF and to treat chronic itch and pain symptoms in NF1 patients.

Congenital cutaneous neurofibromas in neurofibromatosis type 1: Clinicopathological features in early infancy

“…Recently, the migration of stem cells located in the "boundary cap" of dorsal nerve roots with the ability to potentially differentiate into Schwann cells, melanocytes, macrophages and fibroblasts which migrate along peripheral nerves until reaching the skin has been characterized in human and murine models [39,49,50]. According to these models these cells could migrate to the skin using the nerve branches and terminations that innerve it and which accompany the annexes and vascular cutaneous plexus during development [51]. This process of migration and skin colonization would account for the interstitial and periadnexal distribution of the fusiform and pigmented S100-protein + , CD68 + and Melan-A + cells observed in our series.…”

Angeborene kutane Neurofibrome bei Neurofibromatose Typ 1: Klinisch‐pathologische Merkmale in der frühen Kindheit

“…Diese Stammzellen können sich potentiell in Schwann-Zellen, Melanozyten, Makrophagen oder Fibroblasten differenzieren [39,49,50]. Gemäß diesen Modellen könnten die Zellen in die Haut migrieren und dabei Nervenäste und Nervenenden nutzen, die die Haut innervieren und die während der Entwicklung die Hautanhangsgebilde und die Gefäßgeflechte der Haut begleiten [51]. Dieser Prozess der Migration und Kolonisierung der Haut würde die interstitielle und periadnexale Verteilung der pigmentierten, S100-Protein-positiven, CD68+-positiven und Melan-A-positiven Spindelzellen erklären, die wir in unserer Fallserie beobachtet haben.…”

Hypohidrosis in the macules in tuberous sclerosis complex and neurofibromatosis

“…mTOR signaling is also activated in NF1; however, another mechanism may exist in NF1 considering its hyperpigmentation. For instance, not only in the blood 5 but also in the cutaneous biopsy specimens of NF1, the mRNA expression level of transforming growth factor (TGF)‐β1 was high, 6 although the report was not melanocyte‐specific. TGF‐β1 also shifts GSK3β from an inactivating to activating state, 7 which may result in reduced perspiration in the hyperpigmentation in NF1 (Fig.…”