A novel SMAD9 nonsense variant in an 11-year-old Japanese patient with diffuse pulmonary arteriovenous malformation: A case report

Abstract

Most cases of pulmonary arteriovenous malformation (PAVM) are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is typically caused by loss-of-function gene mutations in the genes ENG, ACVRL1, or SMAD4, all participating in transforming growth factor β (TGF-β) family signaling pathways. We describe the case of an 11-year-old Japanese girl with PAVM, with no known family history of HHT or similar disease. She was found to carry a novel nonsense variant in SMAD9 (SMAD9-p. T267*), which we speculate contributed to her disease, because SMAD9 also participates in TGF-β family signaling pathways. SMAD9 mutations have been linked with pulmonary arterial hypertension (PAH), and, hence, mutations in SMAD9—as for ENG, ACVRL1, and SMAD4—may predispose to both PAH and HHT(−characteristic) disease features. The PAVM in our patient spread diffusely inside the lower lobe of the left lung, and coil embolization was considered difficult. Therefore, after feasibility assessment by performing a balloon occlusion test during cardiac catheterization, left lower lobectomy was performed. The patient's dyspnea recovered well postoperatively, and two years later an increase in left lung volume was observed and disease symptoms had not recurred. Thus, if PAVM spreads diffusely in a certain lung area, surgical treatment can be a viable option.

Learning objective

SMAD9 gene mutations have been linked to pulmonary arterial hypertension (PAH). However, their associations with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arteriovenous malformation (PAVM), which usually is HHT-associated, have not been reported previously. Our PAVM patient carrying a SMAD9 variant suggests that mutations in this gene, like in others participating in TGF-β family signaling pathways (like ENG, ACVRL1, and SMAD4), predispose to both PAH and HHT(−characteristic) disease features. Diffuse PAVM confined to a lung area may be treated by lobectomy.