Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension.

References 1. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus conventional my-eloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. et al. Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study. et al. Reduced-intensity conditioning followed by peripheral blood stem cell transplantation for adult patients with high-risk acute lymphoblastic leukemia. The outcome of full intensity and reduced intensity conditioning matched sibling or unrelated donor (URD) transplantation in adults with Philadelphia chromosome negative acute lymphoblastic leukemia (PH-ALL) in first and second complete remission (CR1 and CR2). Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension Hereditary erythrocytosis can be caused by mutations in genes involved in the hypoxia-inducible factor (HIF) pathway. 1-3 For example, Chuvash polycythemia is caused by an R200W substitution in the von Hippel–Lindau protein (VHL). 1 There is increasing evidence linking VHL-HIF dysregulation to altered vascular physiology , and a mouse model of Chuvash polycythemia develops pulmonary arterial hypertension (PAH). 4-6 Recently, we reported an autosomal dominant erythrocytosis associated with an activating EPAS-1 (HIF-2A) mutation in which there was late-onset PAH in some family members. 7 We now report a patient with severe erythropoietic dysregulation and PAH who is a compound heterozy-gote for novel VHL mutations. A 2-month-old boy presented with increasing dyspnea and hypoxia requiring emergency ventilation and inotropic support. Echocardiography showed right ventricular dysfunction and hyper-trophy. Severe PAH was confirmed by cardiac catheterization. Pulmonary artery systolic pressure was 91 mm Hg (approximately twice systemic values). Infusions of nitric oxide, prostacyclin, and sildenafil were required to allow discontinuation of ventilation. Treatment with vasodilators, diuretics, and bosentan was continued on eventual discharge from hospital. Consistently raised hemoglobin (Hb) concentrations (Ͼ 21 g/dL) prompted further investigation. Serum erythropoietin (EPO) concentration was grossly elevated at 4120 IU/L. Diagnostic imaging and selective venous sampling provided no evidence of an EPO-secreting lesion. We hypothesized that this unusual phenotype was explicable by congenital dysregulation of the HIF pathway. Gene sequencing revealed heterozygous mutations in exon 2 (376 GϾA) and exon 3 (548 CϾT) of VHL (Figure 1A), predicting the amino acid changes Asp126Asn (D126N) and Ser183Leu (S183L), respectively. To examine the functional consequences of the mutations, VHL-null renal carcinoma cells were …