Pulmonary Venoocclusive Disease 2, Autosomal Recessive

A number sign (#) is used with this entry because pulmonary venoocclusive disease-2 (PVOD2) is caused by homozygous or compound heterozygous mutation in the EIF2AK4 gene (609280) on chromosome 15q15.

Description

Pulmonary venoocclusive disease-2 is an autosomal recessive subtype of primary pulmonary hypertension (PPH; see 178600). It is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules, and is frequently associated with pulmonary capillary dilatation and proliferation. The disorder can cause occult alveolar hemorrhage. High-resolution CT imaging of the chest shows patchy centrilobular ground-glass opacities, septal lines, and lymph node enlargement (summary by Eyries et al., 2014).

For a discussion of genetic heterogeneity of pulmonary venoocclusive disease, see PVOD1 (265450).

Clinical Features

Langleben et al. (1988) reported cases of familial pulmonary capillary hemangiomatosis. They described 3 sibs, 2 brothers and a sister in a French Canadian family, who died from primary pulmonary hypertension. Lung specimens obtained in 2 of the sibs showed extensive pulmonary capillary hemangiomatosis, with normal capillaries proliferating in the veins and the alveoli. Of their 3 cases and 6 nonfamilial cases in the literature, 4 had the presenting clinical picture of primary pulmonary hypertension.

Eyries et al. (2014) identified 13 families with pulmonary hypertension due to PVOD2 in a French referral center. Many of the families originated from North Africa. All families contained at least 2 affected sibs and unaffected parents, consistent with autosomal recessive inheritance. PVOD was confirmed histologically after lung transplantation or by lung biopsy in members from 8 of these families. Findings included intimal fibrosis of septal veins, intimal remodeling of pulmonary arteries, and patch-like foci of pulmonary capillary hemangiomatosis. Five additional patients with sporadic disease were subsequently identified. Among all patients, the age at diagnosis ranged between 11 and 50 years, although most patients were diagnosed in their twenties. Virtually all patients underwent lung transplantation or died.

Best et al. (2014) reported 2 brothers with pulmonary capillary hemangiomatosis. They presented in young adulthood with marked dyspnea, cough, and fatigue. Pulmonary function studies showed severe reduction of carbon monoxide diffusion capacity, and lung CT scans showed bilateral diffuse nodular opacities. Cardiac catheterization showed pulmonary hypertension. Analysis of explanted diseased lungs showed extensive proliferation of pulmonary capillaries and alveolar thickening, consistent with the diagnosis. Two additional unrelated patients with apparently sporadic disease and similar clinical features were also reported.

Inheritance

The transmission pattern of PVOD2 in the families reported by Eyries et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 13 unrelated families with autosomal recessive pulmonary venoocclusive disease-2, Eyries et al. (2014) identified homozygous or compound heterozygous mutations in the EIF2AK4 gene (see, e.g., 609280.0001-609280.0006). The initial mutations were found using linkage analysis and whole-exome sequencing; subsequent mutations were found by direct Sanger sequencing of the EIF2AK4 gene. Biallelic mutations were also found in 5 (25%) of 20 additional patients with apparently sporadic disease. In all, 22 different mutations were identified. Most were truncating or insertion/deletion mutations that disrupted the function of the gene. Detectable EIF2AK4 was found in lung tissue from a patient with a homozygous truncating mutation, consistent with a loss of function. There were no apparent genotype/phenotype correlations to explain the range in age at onset.

In 2 brothers with PVOD2, Best et al. (2014) identified compound heterozygous mutations in the EIF2AK4 gene (609280.0007 and 609280.0008). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Screening of this gene in 11 additional probands with the disorder identified biallelic mutations in 2 patients (609280.0001 and 609280.0009-609280.0010). All mutations were predicted to result in a truncated protein, but functional studies were not performed. Best et al. (2014) noted that the EIF2AK4 gene belongs to a family of kinases that regulate angiogenesis.