Pulmonary arterial hypertension in hereditary hemorrhagic telangiectasia associated with ACVRL1 mutation: a case report

Abstract

Introduction Hereditary hemorrhagic telangiectasia is an autosomal dominant condition with an estimated prevalence of 1 in 5000. It is characterized by the presence of abnormalities of vascular structures, and may affect many organ systems, including the lungs, brain, spinal cord, gastrointestinal tract, and liver. A causative mutation is identified in approximately 97% of patients with definite hereditary hemorrhagic telangiectasia in one of three genes including a mutation in endoglin, a mutation in a locus mapped to chromosome 5, and an activin receptor-like kinase-1 (ACVRL1) mutation that is associated with an increased incidence of primary pulmonary hypertension. Pulmonary arterial hypertension is a rare (15–25 cases per million people) but severe vascular disorder. Heritable pulmonary arterial hypertension is associated with several gene mutations, with 75% having a mutation in the bone morphogenetic protein receptor 2 (BMPR2). However, the remaining 25% of patients have other associated genetic mutations including ACVLR1, which is also associated with hereditary hemorrhagic telangiectasia. Pulmonary arterial hypertension is a rare complication in patients with hereditary hemorrhagic telangiectasia (< 1% of the hereditary hemorrhagic telangiectasia population). We describe a case report with this rare occurrence. Case presentation A 70-year-old white/caucasian Irish male presented for screening for hereditary hemorrhagic telangiectasia due to a history of recurrent epistaxis (once/week) and a family history suggestive of pulmonary hypertension. Genetic testing confirmed an ACVRL1 mutation, while an echocardiogram and right heart catheterization confirmed pulmonary arterial hypertension. On examination, he had several mucocutaneous telangiectasia across his face. He was commenced on tadalafil and macitentan. However, this led to increased iron deficiency anemia and pedal edema. Selexipag was also added to his drug regime. He continues to require intermittent admissions for diuresis and blood transfusions. Conclusion The association of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension is rare (< 1%). Here we describe a case of hereditary hemorrhagic telangiectasia complicated with pulmonary arterial hypertension as a result of an ACVRL1 mutation. We also describe the clinical challenges of treating these two conditions together, as treatment options for pulmonary arterial hypertension tend to worsen hereditary hemorrhagic telangiectasia symptoms.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

“…Variant p.Arg484Gln impacts a conserved surface-exposed residue located in helix αI of the kinase C-lobe, and encodes a catalytically inactive ALK1 mutant 86 . Mutations in this region are associated with HHT2, an increased incidence of pulmonary arterial hypertension [87][88][89] , and with other ALK family-associated diseases such as brachydactyly type A2 (ALK6) 90,91 and Loeys-Dietz syndrome (ALK5) 92,93 . ACVRL1 p.Arg484Gln has also been identified in HHT2 94 and in childhood-onset pulmonary arterial hypertension 95 .…”

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

“…Beyond supportive therapy (e.g., oxygen supplementation, diuretics, and iron replacement), the treatment of PAH in patients with HHT currently involves the use of standard PAH vasodilator therapies, including endothelin receptor antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, and prostanoids. Individual studies have reported success, either in normalization of hemodynamic parameters or improvement of functional status, with the use of bosentan, sildenafil, selexipag, epoprostenol, treprostinil, and iloprost 81–87 . One investigation included a cohort of five patients as well as an analysis of 32 subjects across 21 studies, all of whom were patients with HHT and PAH treated with oral or intravenous prostanoids 87 .…”

“…Individual studies have reported success, either in normalization of hemodynamic parameters or improvement of functional status, with the use of bosentan, sildenafil, selexipag, epoprostenol, treprostinil, and iloprost. 81 , 82 , 83 , 84 , 85 , 86 , 87 One investigation included a cohort of five patients as well as an analysis of 32 subjects across 21 studies, all of whom were patients with HHT and PAH treated with oral or intravenous prostanoids. 87 Results showed significant improvement in mPAP (65 ± 19 pretreatment vs. 51 ± 16 mmHg posttreatment; p = 0.04) and PVR (12 ± 6 pretreatment vs. 8 ± 4 WUs posttreatment; p = 0.01) following therapy, with no significant difference in survival between those who received oral or intravenous medication.…”

Human iPSCs as Model Systems for BMP-Related Rare Diseases

“…Interestingly, a few HHT individuals carrying ACVRL1 mutations are predisposed to the development of PAH [227]. Currently, in those ACVR1L mutant affected HHT2 patients, PAH is seen as an extremely rare complication [228]. Similarly, GDF2 mutations cause a vascular-anomaly syndrome somehow overlapping with HHT [205], and some BMPR2 variants increase the risk of developing pulmonary AVMs reminiscent of an HHT-like condition [229].…”