title: Pulmonary hypertension in patients with neurofibromatosis type I.
abstract: Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH. We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor. In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.
authors.affiliation: From Faculté de Médecine, (DM, BG, CO, DSO, LS, XJ, OS, GS, MH), Université Paris-Sud, Kremlin-Bicêtre; Service de Pneumologie et Réanimation Respiratoire (DM, BG, CO, DSO, LS, XJ, OS, GS, MH), Centre de Référence de l'Hypertension Pulmonaire Sévère, Hôpital Antoine Béclère, AP-HP, Clamart; INSERM U999, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique (DM, BG, CO, DSO, LS, XJ, PD, OS, GS, MH), and Service d'Anatomie Pathologique (PD), Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson; Département de Génétique (FC, ME, CBC, FS), GH Pitié-Salpêtrière, UPMC, AP-HP, Paris; Service de Pneumologie et Centre Régional de Compétence de l'HTAP (EB, GZ), Caen University Hospital, Caen; ER3 INSERM (EB, GZ), Caen; Service de Pneumologie B et Transplantation Pulmonaire (HM, GB), Hôpital Bichat, AP-HP, Paris; Service de Chirurgie Thoracique (CD), and Service d'Anatomie Pathologique (HB), Hôpital du Haut Levesque, Bordeaux; Université Nice Sophia Antipolis (TH, CM), Service de Pneumologie, CHU de Nice, Nice; Groupe de Recherche sur la Thrombose (LB), Université de St-Etienne, St-Etienne; and UMR-S 956 UPMC-INSERM (FS), Paris; France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bergot
authors.forename: Hervé
authors.initials: H
authors.lastname: Mal
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Biondi
authors.forename: Claire
authors.initials: C
authors.lastname: Dromer
authors.forename: Thomas
authors.initials: T
authors.lastname: Hugues
authors.forename: Charles
authors.initials: C
authors.lastname: Marquette
authors.forename: Caroline
authors.initials: C
authors.lastname: O'Connell
authors.forename: Dermot S
authors.initials: DS
authors.lastname: O'Callaghan
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.forename: Laurent
authors.initials: L
authors.lastname: Bertoletti
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
mesh_terms: D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis
chemical_list: D025542:Neurofibromin 1; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II