1. Introduction

Pulmonary arteriovenous malformation (PAVM) is characterized by abnormally dilated blood vessels where arterial blood, not oxygenated by capillaries, directly enters the veins, creating a right‐to‐left shunt between the pulmonary artery and venous circulation [1]. The clinical manifestations of children diagnosed with PAVM are diverse, mainly including symptoms and signs such as cyanosis, difficulty breathing, clubbing of fingers, dizziness, fatigue, and decreased blood oxygen saturation [2]. The diagnosis of PAVM primarily relies on imaging examinations. Chest computed tomography (CT) scanner examination, computed tomography angiography (CTA), and digital subtraction angiography (DSA) are the main tools. CT scanning is considered the preferred imaging modality for diagnosis and plays a crucial role in diagnosis, treatment planning, and follow‐up [3]. With the advancement of catheter embolization techniques, percutaneous embolization has become the preferred treatment method for PAVM [4, 5].

The most common cause of PAVMs is hereditary hemorrhagic telangiectasia (HHT), a vascular malformation disease inherited in an autosomal dominant pattern [6, 7]. The ENG gene is located at the 9q34.11 region [8]. Variations in the ENG gene (encoding endoglin [ENG]) and the ACVRL1 gene (encoding the activin receptor‐like kinase 1 [ALK1]) cause HHT1 (OMIM #187300) and HHT2 (OMIM #600376), respectively [8, 9]. The ENG and ACVRL1 genes encode proteins of the TGF‐β receptor. ENG is a transmembrane glycoprotein found on endothelial cells that serves as a coreceptor for various ligands of the transforming growth factor‐beta (TGF‐β) family. The TGF‐β signaling pathway plays a crucial role in regulating processes such as cell proliferation, differentiation, adhesion, and migration, ultimately affecting the structure and function of blood vessels [10].

The main clinical manifestations of HHT include the following four aspects: (1) recurrent and refractory epistaxis (nosebleeds); (2) cutaneous and mucosal telangiectasia; (3) visceral arteriovenous malformations (AVMs), with the most commonly affected organs being the lungs, liver, gastrointestinal tract, and brain; and (4) family history. The currently accepted clinical diagnostic criteria for HHT are the Curaçao Criteria established in 1999 [11]: A definite diagnosis is made if three or more of the above four criteria are met; a suspected diagnosis is considered if only two of the four criteria are met; if only one of the above criteria is met, HHT is generally not diagnosed.

In this study, we reported four families with patients diagnosed with PAVMs, whose clinical manifestations are consistent with HHT. Through whole exome sequencing (WES), variations in the ENG gene were identified in all four families. This includes previously unreported variants (c.1428 + 2 T > C, c.1498dup, and c.322del), thereby expanding the variation spectrum of the ENG gene. In addition, we performed in silico analysis to explore the possible molecular pathogenesis of HHT in these families.