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SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype
  1. Eric Pasmant (eric.pasmant{at}gmail.com)
  1. UMR745 INSERM, France
    1. Audrey Sabbagh
    1. UMR745 INSERM, France
      1. Nadine Hanna
      1. UMR745 INSERM, France
        1. Julien Masliah-Planchon
        1. Hôpital Beaujon, AP-HP, France
          1. Emilie Jolly
          1. Hôpital Beaujon, AP-HP, France
            1. Philippe Goussard
            1. Hôpital Beaujon, AP-HP, France
              1. Paola Ballerini
              1. Hôpital Armand Trousseau, AP-HP, France
                1. François Cartault
                1. Centre hospitalier Félix Guyon, Bellepierre, France
                  1. Sébastien Barbarot
                  1. Hôpital Hôtel Dieu, Nantes, France
                    1. Judith Landman-Parker
                    1. Hôpital Armand Trousseau, AP-HP, France
                      1. Nadem Soufir
                      1. Hôpital Bichat Claude-Bernard, AP-HP, France
                        1. Béatrice Parfait
                        1. UMR745 INSERM, France
                          1. Michel Vidaud
                          1. UMR745 INSERM, France
                            1. Pierre Wolkenstein
                            1. Hôpital Henri Mondor-AP-HP, Université Paris 12, France
                              1. Dominique Vidaud
                              1. UMR745 INSERM, France

                                Abstract

                                Objective: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome.

                                Methods: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation.

                                Results: We described one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterized by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia.

                                Conclusions: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying a NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterized. NIH diagnostic criteria for NF1 must be revised in view of this newly characterized Legius syndrome in order to establish a specific genetic counselling.

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