Pulmonary Venoocclusive Disease 1, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that pulmonary venoocclusive disease-1 (PVOD1) is caused by heterozygous mutation in the BMPR2 gene (600799) on chromosome 2q33.

Description

Pulmonary venoocclusive disease primarily affects the postcapillary venous pulmonary vessels and may involve significant pulmonary capillary dilation and/or proliferation. PVOD is an uncommon cause of pulmonary artery hypertension (PPH; see 178600), a severe condition characterized by elevated pulmonary artery pressure leading to right heart failure and death. PVOD accounts for 5 to 10% of 'idiopathic' PPH and has an estimated incidence of 0.1 to 0.2 cases per million. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by fibrous tissue, with intimal thickening present in venules and small veins in lobular septa and, rarely, larger veins. Definitive diagnosis of PVOD requires histologic analysis of a lung sample, although surgical lung biopsy is often too invasive for these frail patients. Patients with PVOD respond poorly to available therapy, therefore it is crucial to distinguish PVOD from other forms of PPH. Radiologic characteristics suggestive of PVOD on high-resolution CT of the chest include nodular ground-glass opacities, septal lines, and lymph node enlargement. In addition, because PVOD mainly affects postcapillary vasculature, it causes chronic elevation of pulmonary capillary pressure and thus promotes occult alveolar hemorrhage, which may be a characteristic feature of PVOD (summary by Montani et al., 2008).

Genetic Heterogeneity of Pulmonary Venoocclusive Disease

See also PVOD2 (234810), caused by mutation in the EIF2AK4 gene (609280) on chromosome 15q15.

Clinical Features

Voordes et al. (1977) reported pulmonary venoocclusive disease in a male infant who died at the age of 3 months. Both intra- and extrapulmonary veins were involved. A brother had died at the age of 8 weeks of the same disease, limited to the intrapulmonary veins. They suggested that this may have occurred in 2 sibs reported by Rosenthal et al. (1973). They further suggested that the disease may be viral (not genetic), with the mother serving as carrier, and that some instances of isolated extraparenchymal pulmonary vein atresia or obstruction may be this disorder.

Runo et al. (2003) studied a family in which the proband had PVOD and her mother had severe primary pulmonary hypertension (see PPH1; 178600). The proband presented at 36 years of age with dyspnea, prominent pulmonary arteries on chest x-ray, and an elevated mean pulmonary artery pressure of 53 mm Hg. Her disease was initially thought to be PPH, but open lung biopsy revealed findings consistent with PVOD. The patient's mother had died of complications of right heart failure; she had a mean pulmonary artery pressure of 92 mm Hg on right heart catheterization, absence of thromboembolic disease by pulmonary angiography, and no evidence of secondary etiologies. Because lung biopsy and autopsy were not performed, it was unknown whether the mother's pulmonary hypertension was from PPH or PVOD.

Montani et al. (2008) retrospectively reviewed 48 cases of pulmonary artery hypertension, including 24 patients with biopsy-proven PVOD and 24 patients with no evidence of PVOD after meticulous evaluation of lung pathology. Compared to PPH, PVOD was characterized by a higher male-to-female ratio and higher tobacco exposure. Clinical presentation was similar except for a lower body mass index in PVOD patients. In addition, at baseline PVOD patients had significantly lower partial pressure of arterial oxygen, diffusing lung capacity of carbon monoxide per alveolar volume, and oxygen saturation nadir during a 6-minute walk test. Hemodynamic parameters showed a lower mean systemic arterial pressure and right atrial pressure, but no difference in pulmonary capillary wedge pressure. CT of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared to patients with PPH (p less than 0.05 for all). Seven (44%) of 16 PVOD patients who received PPH-specific therapy developed pulmonary edema, and clinical outcomes were worse for PVOD than PPH patients.

Molecular Genetics

In a family in which the proband had PVOD and her mother had pulmonary hypertension, Runo et al. (2003) analyzed the BMPR2 gene and identified heterozygosity for a 1-bp deletion (600799.0021) in the proband and her unaffected sister. DNA was not available from their mother, who died of right heart failure, or from the maternal grandparents.

In a patient with pulmonary arterial hypertension and PVOD, Machado et al. (2006) identified heterozygosity for a nonsense mutation (600799.0022) in the BMPR2 gene.

In a patient with primary pulmonary hypertension and histologic features of PVOD, Aldred et al. (2006) identified heterozygosity for a deletion of exon 2 of the BMPR2 gene (600799.0023). The patient had 3 affected relatives, all of whom were deceased. The same deletion was identified in an unrelated family with primary pulmonary hypertension and no known evidence of PVOD.

In a cohort of 48 patients with PPH, 24 of whom had histologic evidence of PVOD, Montani et al. (2008) identified mutations in the BMPR2 gene in 2 patients with PVOD (600799.0027 and 600799.0028) and in 4 patients with no evidence of PVOD.