AJRCCM: What is pulmonary hypertension associated with neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disease with a prevalence of 1/3000 to 1/6000 and a birth rate of 1/2000 to 1 /3000, and almost completely exposed before 5 years old
.

The disease is caused by mutations in the NF1 (Neurofibrin 1) gene, which encodes a cytoplasmic protein called neurofibrin that is involved in tumor suppression

Basic information of patients selected for the study:

Basic information of patients selected for the study:

This study identified 49 PH-NF1 patients who were characterized by a dominant female (female/male ratio, 3.
9:1) and a median age of PH diagnosis of 62 (18-82) years
.

None of the patients have identified risk factors for PAH, such as anorexic exposure, PAH-related conditions (portal hypertension, HIV infection, connective tissue disease, or congenital heart disease), or chronic thromboembolic PH

Pulmonary function tests showed that most patients had normal or mildly abnormal airflow and lung volume measurements (27 patients were normal), the average FEV1 was 87% of the predicted value (29% of the predicted value), and the average FVC was 95% of the predicted value ( 26% of the predicted value)
.

Twelve patients had obstructive pulmonary disease, defined as FEV1/FVC ratio <0.

Chest CT diagnosis: 45 patients underwent chest HRCT imaging at the time of PH-NF1 diagnosis
.

Chest CT diagnosis: 45 patients underwent chest HRCT imaging at the time of PH-NF1 diagnosis
.

Genetic testing: 16 patients (33%) were screened for small mutations and large gene rearrangements in the NF1 gene
.

NF1 mutations include short deletions, nonsense and missense mutations, and complete deletions of genes

Genetic testing: 16 patients (33%) were screened for small mutations and large gene rearrangements in the NF1 gene

Treatment and response of PAH approved drugs:

At the time of PH-NF1 diagnosis, 30 (61%) patients received long-term oxygen therapy with a median oxygen flow of 3 (2-6) L/min, 32 (65%) patients received diuretics, 26 (53 %) received anticoagulants (18 for PH and 8 for other indications)
.

After the diagnosis of PH-NF1, 45 patients started using approved PAH drugs, including endothelin receptor antagonists, type 5 phosphodiesterase inhibitors, and prostacyclin derivatives

Long-term prognosis:

Long-term prognosis:

Although approved PAH drugs are widely used, the prognosis of NF1 patients is poor
.

Twenty-nine (59%) patients died during the follow-up period, and 4 received transplantation due to severe PH.

Although approved PAH drugs are widely used, the prognosis of NF1 patients is poor

Anatomical pathology analysis:

Three transplant patients can obtain lung tissue
.

Parenchymal abnormalities were found in all lung explants, including lung cysts, alveolar wall thickening, alveolar macrophage desquamation, and minimal interstitial fibrosis
.
The parenchymal cyst has a thin wall and is formed by the confluence of several airspaces
.
Two patients showed diffuse alveolar wall thickening, which was caused by chronic interstitial inflammation, interstitial fibrosis, and telangiectasia, without structural deformation
.

A collection of macrophages in the alveoli was observed throughout the lung parenchyma
.
These characteristics are consistent with non-specific interstitial pneumonia (NSIP)
.
In all patients, we observed severe pulmonary vascular remodeling, characterized by thickening of the arterial and venous walls
.
Arterial remodeling involves elastic and muscular pulmonary arteries
.
Its main feature is an increase in the inner membrane layer, which is composed of cellular connective tissue and mucus-like extracellular matrix
.
No plexiform lesions or thrombosis were observed
.
The septal veins also showed remodeling as the thickness of the collagen tissue wall increased
.

In all patients, we observed severe pulmonary vascular remodeling, characterized by thickening of the arterial and venous walls
.
Arterial remodeling involves elastic and muscular pulmonary arteries
.
Its main feature is an increase in the inner membrane layer, which is composed of cellular connective tissue and mucus-like extracellular matrix
.
No plexiform lesions or thrombosis were observed
.
The septal veins also showed remodeling as the thickness of the collagen tissue wall increased
.
In all patients, we observed severe pulmonary vascular remodeling, characterized by thickening of the arterial and venous walls
.
Arterial remodeling involves elastic and muscular pulmonary arteries
.
Its main feature is an increase in the inner membrane layer, which is composed of cellular connective tissue and mucus-like extracellular matrix
.
No plexiform lesions or thrombosis were observed
.
The septal veins also showed remodeling as the thickness of the collagen tissue wall increased
.

PH is considered a rare but serious complication of NF1
.
This study reports the clinical, functional, radiological, histological, and hemodynamic characteristics and results of the largest PH patient population associated with NF1
.
We confirmed that PH-NF1 appeared in the late course of NF1, and women were predominant; HRCT scans at the time of diagnosis showed that lung parenchymal involvement was almost always present, mainly manifested as lung cysts and ground glass shadows
.
In addition, the PH at diagnosis is severe and is associated with limited response to PAH approved drugs and poor prognosis
.
Two-lung transplantation should be considered as an option in this population.
There are 4 patients in our cohort who underwent transplantation due to PH
.
Pathological evaluation finally showed that there is strong pulmonary vascular remodeling and interstitial remodeling in PH-NF1, with NSIP pattern
.

PH is considered a rare but serious complication of NF1
.
This study reports the clinical, functional, radiological, histological, and hemodynamic characteristics and results of the largest PH patient population associated with NF1
.
We confirmed that PH-NF1 appeared in the late course of NF1, and women were predominant; HRCT scans at the time of diagnosis showed that lung parenchymal involvement was almost always present, mainly manifested as lung cysts and ground glass shadows
.
In addition, the PH at diagnosis is severe and is associated with limited response to PAH approved drugs and poor prognosis
.
Two-lung transplantation should be considered as an option in this population.
There are 4 patients in our cohort who underwent transplantation due to PH
.
Pathological evaluation finally showed that there is strong pulmonary vascular remodeling and interstitial remodeling in PH-NF1, with NSIP pattern
.

Literature source:

Jutant EM, Jaïs X, Girerd B, Savale L, Ghigna MR, Perros F, Mignard X, Jevnikar M, Bourlier D, Prevot G, Tromeur C, Bauer F, Bergot E, Dauphin C, Favrolt N, Traclet J, Soumagne T , De Groote P, Chabanne C, Magro P, Bertoletti L, Gueffet JP, Chaouat A, Goupil F, Moceri P, Borie R, Fadel E, Wolkenstein P, Brillet PY, Simonneau G, Sitbon O, Humbert M, Montani D.
Phenotype and Outcomes of Pulmonary Hypertension Associated with Neurofibromatosis Type 1.
Am J Respir Crit Care Med.
2020 Sep 15;202(6):843-852.
doi: 10.
1164/rccm.
202001-0105OC.
PMID: 32437637.

Jutant EM, Jaïs X, Girerd B, Savale L, Ghigna MR, Perros F, Mignard X, Jevnikar M, Bourlier D, Prevot G, Tromeur C, Bauer F, Bergot E, Dauphin C, Favrolt N, Traclet J, Soumagne T , De Groote P, Chabanne C, Magro P, Bertoletti L, Gueffet JP, Chaouat A, Goupil F, Moceri P, Borie R, Fadel E, Wolkenstein P, Brillet PY, Simonneau G, Sitbon O, Humbert M, Montani D.
Phenotype and Outcomes of Pulmonary Hypertension Associated with Neurofibromatosis Type 1.
Am J Respir Crit Care Med.
2020 Sep 15;202(6):843-852.
doi: 10.
1164/rccm.
202001-0105OC.
PMID: 32437637.
Phenotype and Outcomes of Pulmonary Hypertension Associated with Neurofibromatosis Type 1.

 

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