Is pulmonary arterial hypertension in neurofibromatosis type 1 secondary to a plexogenic arteriopathy?
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 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.
Stewart
Douglas R
DR
National Human Genome Research Institute, National Institutes of Health, 49 Convent Dr, Building 49, Room 4A62, Bethesda, MD 20892, USA. drstewart@mail.nih.gov
Cogan
Joy D
JD
Kramer
Mordechai R
MR
Miller
Wallace T
WT
Christiansen
Leif E
LE
Pauciulo
Michael W
MW
Messiaen
Ludwine M
LM
Tu
George S
GS
Thompson
William H
WH
Pyeritz
Reed E
RE
Ryu
Jay H
JH
Nichols
William C
WC
Kodama
Makoto
M
Meyrick
Barbara O
BO
Ross
David J
DJ
D000328:Adult; D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D005260:Female; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000235:genetics / Q000473:pathology; D011859:Radiography
C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II