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Within the referral centre

CERENEF

The referral centre has developed projects in the following research areas:

  • Therapeutic trials: Pierre Wolkenstein (Henri-Mondor Hospital) and Michel Kalamarides (Pitié-Salpêtrière Hospital).
  • Surgical techniques: Michel Kalamarides, Laurent Lantieri (Georges Pompidou European Hospital) and Philippe Decq (Beaujon Hospital).
  • Animal models: Pierre Wolkenstein, Piotr Topilko (Henri-Mondor Hospital), Michel Kalamarides and Marcello Giovannini (San Paolo Hospital, Milan).
  • Molecular biology: Benoît Funalot from the Genetics Department (Henri-Mondor Hospital) as well as Michel Vidaud, Éric Pasmant, and Dominique Vidaud from the Cochin Institute, Inserm team (genomics and epigenetics of rare tumours).
  • Clinical epidemiology: Pierre Wolkenstein and Émilie Sbidian (Henri-Mondor Hospital).

Epidemiologic research

The referral centre works in collaboration with the EpiDermE team.

Led by Pr. Émilie Sbidian, EpiDermE (Epidemiology in Dermatology and Evaluation of therapeutics), is a pharmaco-epidemiology research team whose two main axes are:

  • The benefit/risk assessment of the therapeutics used in chronic inflammatory pathologies.
  • Medication errors and serious skin adverse effects of therapeutics.

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If you are being followed for neurofibromatosis type 1, you can participate in epidemiological research. Your experience and testimonial are of crucial importance to enable researchers and doctors to improve your quality of life and your treatments.

By sharing your experience, you will help to accelerate medical research on neurofibromatosis type 1. Similar to other patients with different chronic diseases, you can then participate in the ComPaRe online cohort.

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Fundamental research

Neurofibromatosis type 1 (NF1), one of the most common genodermatosis, is defined as the association of pigmented lesions ("café-au-lait" macules [CALMs] and lentigines), neurofibromas (cutaneous [NFc] and plexiform [NFp]), and ophthalmological and bone abnormalities: NF1 diagnostic criteria.

It is linked to a mono-allelic mutation in the NF1 gene and the loss of heterozygosity due to its complications. Several animal models have allowed to explore its pathophysiology without ever reproducing its overall phenotype.

Professor Piotr Topilko's Inserm team has developed a unique murine model that reproduces the human one.

The mutant murine line (Nf1-KO) was obtained by bi-allelic inactivation of NF1 in cells that express the Prss56 gene. In the peripheral nervous system, the expression of Prss56 is limited to the frontier capsule (Fc) cells present during embryonic development at the entry and exit points of sensory and motor nerves.

We have shown that Fc cells give rise to Schwann cells that colonise the roots of nerves and then migrate along nerves into cutaneous nerve endings, which are the regions where patients' neurofibromas (NF) are located. Prss56 is also expressed in other structures affected by NF1: appendicular skeletal bone, eye, and brain.

Heterozygous NF1 bats have no symptoms. The loss of heterozygosity in NF1-KO results in a phenotype comparable to that of humans.

All mice develop paraspinal and subcutaneous NFc (100% at 1 year) and most of them NFp (60% at 5 months). The cellular composition of murine NF reproduces that of human NF. In addition, 70% of NFp spontaneously turns into malignant tumours of the nerve sheaths.

Finally, as in humans, mice systematically develop the following disorders either spontaneously or induced: CALMs, bone lesions (pseudarthrosis, spinal or craniofacial deformities), eye lesions (hamartomas), and abnormal oligodendrogenesis. The latter could be at the origin of the learning difficulties observed in children with NF1.

To our knowledge, this is the only animal model with the majority of manifestations associated with NF1 and thus meeting the diagnostic criteria for NF1.

Its exploration allows us:

  • Study the mechanisms that govern the development of NF and their malignant transformation.
  • Initiate therapeutic trials to prevent or block their development in mice.

These advances provide a robust and necessary basis for the future trials to develop innovative treatments for patients with NF.

Piotr Topilko et son équipe Inserm

Professor Piotr Topilko and his Inserm team

Topical delivery of MEK inhibitor binimetinib prevents the development of cutaneous neurofibromas in Neurofibromatosis type 1 mutant mice
Coulpier F, Pulh P, Oubrou L, Naudet J, Fertitta L, Gregoire JM, Bocquet A, Schmitt AM, Wolkenstein P, Radomska KJ, Topilko P.
Transl Res. 2023 Jun 16:S1931-5244(23)00105-6. doi: 10.1016/j.trsl.2023.06.003. Online ahead of print.
PMID: 37331503

Cellular Origin, Tumor Progression, and Pathogenic Mechanisms of Cutaneous Neurofibromas Revealed by Mice with Nf1 Knockout in Boundary Cap Cells
Radomska KJ, Coulpier F, Gresset A, Schmitt A, Debbiche A, Lemoine S, Wolkenstein P, Vallat JM, Charnay P, Topilko P.
Cancer Discov. 2019 Jan;9(1):130-147. doi: 10.1158/2159-8290.CD-18-0156. Epub 2018 Oct 22.
PMID: 30348676

Boundary cap cells in development and disease
Radomska KJ, Topilko P.
Curr Opin Neurobiol. 2017 Dec;47:209-215. doi: 10.1016/j.conb.2017.11.003. Epub 2017 Nov 22.
PMID: 29174469 Review.

  1. Radomska K, Coulpier F, Gresset A, Schmitt A, Debbiche A, Wolkenstein P, Vallat J-M, Charnay P, Topilko P. Cellular origin, tumor progression and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knock out in boundary cap cells. Cancer Discovery 2019.
  2. Radomska KJ, Topilko P. Boundary cap cells in development and disease. Curr Opin Neurobiology 2017;47:209-215.
  3. Gresset A, Coulpier F, Gerschenfeld G, Jourdon A, Matesic G, Richard L, Vallat JM, Charnay P, Topilko P. Boundary Caps Give Rise to Neurogenic Stem Cells and Terminal Glia in the Skin. Stem Cell Reports. 2015;5(2):278–90.

Clinical research

Several clinical research activities are also carried out in collaboration with the Mondor GHU clinical investigation centre, including the realisation of the following Hospital Clinical Research Protocols (Protocoles Hospitaliers de Recherche Clinique, PHRC) and therapeutic trials:

Study of the expression of neurofibromatosis 1 with establishment of a phenotype/genotype database. Thus, 1017 patients were enrolled this multicentre study from March 2003 to March 2006.

Patients at risk of evolution during neurofibromatosis 1 with a comparative phenotypic, genotypic, and proteomic study within a cohort. Thus, 219 patients were enrolled in 3 centres from June 2007 to January 2008.

Study of the expression of neurofibromatosis 1 with identification of modifying genes. Thus, 475 patients were enrolled in this multicentre study from June 2012 to November 2013.

Multicentre, phase IIa, open-label trial evaluating RAD001 (everolimus) monotherapy during neurofibromatosis 1 for the treatment of inoperable internal plexiform neurofibromas. Inclusion of 23 patients across 3 centres from April 2011 to June 2014.

Predictive risk factors for osteoporosis in neurofibromatosis 1. Single-centre enrolment of 60 patients from November 2014 to March 2016.

  1. Sabbagh A, PasmantE, Laurendeau I, Parfait B, Barbarot S, Guillot B, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet. 2009;18(15):2768‑78.
  2. Wolkenstein P, Rodriguez D, Ferkal S, Gravier H, Buret V, Algans N, et al. Impact of neurofibromatosis 1 upon quality of life in childhood: a cross-sectional study of 79 cases. Br J Dermatol. 2009;160(4):844‑8.
  3. Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel M-J, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010;31(6):E1506-1518.
  4. Sbidian E, Wolkenstein P, Valeyrie-Allanore L, Rodriguez D, Hadj-Rabia S, Ferkal S, et al. NF-1Score: a prediction score for internal neurofibromas in neurofibromatosis-1. J Invest Dermatol. 2010;130(9):2173‑8.
  5. Sbidian E, Bastuji-Garin S, Valeyrie-Allanore L, Ferkal S, Lefaucheur JP, Drouet A, et al. At-risk phenotype of neurofibromatose-1 patients: a multicentre case-control study. Orphanet J Rare Dis. 2011;6:51.
  6. Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, et al. Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst. 2011;103(22):1713‑22.
  7. Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013;34(11):1510‑8.
  8. Imbard A, Pasmant E, Sabbagh A, Luscan A, Soares M, Goussard P, et al. NF1 single and multi-exons copy number variations in neurofibromatosis type 1. J Hum Genet. 2015;60(4):221‑4.
  9. Zehou O, Ferkal S, Brugieres P, Barbarot S, Bastuji-Garin S, Combemale P, et al. Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. J Invest Dermatol. 2019;139(3):718‑20.
  10. Pacot L, Vidaud D, Sabbagh A, Laurendeau I, Briand-Suleau A, Coustier A, et al. Severe Phenotype in Patients with Large Deletions of NF1. Cancers. 2021;13(12):2963.
  11. Jalabert M, Ferkal S, Souberbielle J-C, Sbidian E, Mageau A, Eymard F, et al. Bone Status According to Neurofibromatosis Type 1 Phenotype: A Descriptive Study of 60 Women in France. Calcif Tissue Int. 2021;108(6):738‑45.

In the dermatology field, learned societies and teachers' training colleges also contribute to the research in the rare diseases arena.

President: Pr. Marie-Aleth Richard.

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Coordinator: Pr. Christine Bodemer.

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President: Pr. Gaëlle Quéreux-Baumgartner

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