Survival outcomes in EIF2AK4 mutation-associated pulmonary arterial hypertension: seeking clarity in contrast.

Background: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary arterial hypertension (PAH) characterized by widespread fibrous intimal proliferation of pre-septal pulmonary venules and a lower lung diffusion capacity for carbon monoxide when compared to classical PAH. Mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene have been linked to the development of PVOD, with the worst prognosis seen in homozygous mutation carriers. Case summary: We describe two patients with homozygous EIF2AK4-associated PVOD, who despite typical clinical features at presentation have demonstrated a remarkable response to pulmonary vasodilator therapy and comparatively benign clinical courses. Intrapulmonary shunt (IPS) was evident on resting contrast transthoracic echocardiography (CTTE) in both patients undertaken 4 and 36 months following diagnosis. At 2 and 10 years of follow-up, respectively, both patients retain preserved right heart function and remain in the World Health Organization functional class II. This case series contrasts strikingly with prior reports of patients with classical PAH where IPS that develops in response to pulmonary vasodilator treatment has been associated with dramatic reduction in systemic oxygen saturations, necessitating withdrawal of therapy. Discussion: In two patients with PVOD associated with homozygous EIF2AK4 mutations, IPS may act to offload the right ventricle with relative preservation of systemic exercise saturations and a more favourable prognosis. Greater use of CTTE in patients with PVOD as well as PAH with lower lung diffusion capacity may lend insight into the clinical and prognostic relevance of IPS in these patient subgroups with otherwise poor prognosis.