The first case of a compound heterozygous association of von Hippel-Lindau (VHL) mutations with severe, early-onset pulmonary arterial hypertension (PAH) was recently reported in Belgium and published in Pulmonary Circulation.

An 18-month old boy with learning, walking, and feeding difficulties was admitted to the hospital due to an infection. The estimated systolic pulmonary arterial pressure was 70 mmHg, and the boy had right ventricular hypertrophy and dilatation, as well as a small interatrial communication with right-to-left shunting and pericardial effusion.

Additional examination showed congestive hepatopathy and homogeneous splenomegaly. No signs of vascular malformations or pulmonary embolism were detected.

Continue Reading

He failed to respond to pulmonary vasodilator testing using inhaled nitric oxide. Also, he presented with polycythemia, which was thought to be associated with his lung disease. The first diagnosis was precapillary pulmonary hypertension.

Read more about PAH diagnosis

“PAH due to congenital heart disease was excluded because the severity of the patient’s hemodynamics could not be explained by the very small interatrial communication initially observed on transthoracic echocardiogram, which could also be a patent foramen ovale,” the authors explained.

Sequencing studies revealed compound heterozygous mutations in the VHL gene: c.162G>C(p.Met54Ile), inherited from the mother, and c.376G>A (p.Asp126Asn), inherited from the father. Both mutations have been linked to polycythemia with elevated erythropoietin (EPO) levels and PAH. Accordingly, the levels of circulating EPO were elevated in the patient.

At the time of publication, the boy was being treated with sildenafil and bosentan for 5 years. His last follow-up visit confirmed moderate dilatation with mild hypertrophy and preserved function of the right ventricle, dilated right atrium, and absence of pericardial effusion.


Chomette L, Migeotte, Dewachter C, Vachiéry J, Smits G, Bondue A. Early‐onset and severe pulmonary arterial hypertension due to a novel compound heterozygous association of rare VHL mutations: a case report and review of existing data. Pulm Circ. Published online February 16, 2022. doi:10.1002/pul2.12052