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Original Research: PULMONARY HYPERTENSION |

Is Pulmonary Arterial Hypertension in Neurofibromatosis Type 1 Secondary to a Plexogenic Arteriopathy?*

Douglas R. Stewart, MD; Joy D. Cogan, PhD; Mordechai R. Kramer, MD, FCCP; Wallace T. Miller, Jr, MD; Leif E. Christiansen, DO; Michael W. Pauciulo, MBA; Ludwine M. Messiaen, PhD; George S. Tu, MD, FCCP; William H. Thompson, MD, FCCP; Reed E. Pyeritz, MD, PhD; Jay H. Ryu, MD, FCCP; William C. Nichols, PhD; Makoto Kodama, MD; Barbara O. Meyrick, PhD; David J. Ross, MD
Author and Funding Information

*From the National Human Genome Research Institute (Dr. Stewart), National Institutes of Health, Bethesda, MD; the Department of Pediatrics (Dr. Cogan), Vanderbilt University Medical Center, Nashville, TN; Institute of Pulmonary Medicine (Dr. Kramer), Rabin Medical Center, Petach Tikva, Israel; the Departments of Radiology (Dr. Miller) and Medicine (Dr. Pyeritz), University of Pennsylvania School of Medicine, Philadelphia, PA; St. Joseph’s Hospital (Dr. Christiansen), Reading PA; Cincinnati Children’s Hospital Medical Center (Mr. Pauciulo and Dr. Nichols), Cincinnati, OH; the Department of Genetics (Dr. Messiaen), University of Alabama at Birmingham, Birmingham, AL; Lung Center of Nevada (Dr. Tu), Las Vegas, NV; the Division of Pulmonary and Critical Care Medicine (Dr. Thompson), University of Washington, Seattle, WA; the Division of Pulmonary and Critical Care Medicine (Dr. Ryu), Mayo Clinic, Rochester, MN; the First Department of Internal Medicine (Dr. Kodama), Niigata University School of Medicine, Niigata, Japan; the Department of Pathology and Medicine (Dr. Meyrick), Vanderbilt University Medical Center, Nashville, TN; and the Department of Pulmonary and Critical Care Medicine and Hospitalists (Dr. Ross), David Geffen School of Medicine, University of California, Los Angeles, CA.

Correspondence to: Douglas R. Stewart, MD, National Human Genome Research Institute, National Institutes of Health, 49 Convent Dr, Building 49, Room 4A62, Bethesda, MD 20892; e-mail: drstewart@mail.nih.gov



Chest. 2007;132(3):798-808. doi:10.1378/chest.06-3017
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Background: Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1. Pulmonary arterial hypertension (PAH) in patients with NF1 is hypothesized to be secondary to an underlying vasculopathy.

Methods: We describe the entity we term NF1-associated PAH (NF1-PAH) in four new patients and update the data on four previously published reports of patients with PAH and NF1. We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which is mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH. We report, for the first time, pathologic findings in the autopsy-obtained lung of one patient with NF1-PAH.

Results: Patients with NF1-PAH have a generally poor long-term prognosis. In four patients, we observed the mosaic pattern of lung attenuation on a CT scan of the chest, a radiographic finding that can be consistent with an underlying vasculopathy. No mutations or rearrangements in the BMPR2 gene were found. We observed complex plexiform lesions in the one available autopsy specimen. Similar lesions are a hallmark of plexogenic pulmonary arteriopathy and are associated with several severe types of PAH. (Plexiform lesions should not be confused with plexiform neurofibromas, which are distinctive tumors seen in NF1.)

Conclusions: Our findings suggest that NF1 should be considered as being “associated with PAH” as outlined in the Revised Clinical Classification of Pulmonary Hypertension. Understanding the mechanism of PAH in NF1 may inform the pathogenesis of PAH, NF1-PAH itself, and other NF1-associated vasculopathies. The pulmonary vasculature should now be included among the arterial beds affected by NF1 vasculopathy.

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