A Case of High Pressure and High Stakes: Pulmonary Arterial Hypertension Emergence in an Infant With Hereditary Hemorrhagic Telangiectasia

Amal Ahmed, Anna M. Brown, Samantha J. Eagle, Evan L. Brittain, Anna R. Hemnes, Rachel T. Sullivan, Eric D. Austin

https://doi.org/10.1002/pul2.70375 

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal‑dominant vascular disease characterized by telangiectasias and visceral arteriovenous malformations (AVMs), commonly in the lungs, liver, and brain. HHT is linked to mutations in the genes Activin A Receptor Like Type 1 (ACVRL1), Endoglin (ENG), and SMAD Family Member 4 (SMAD4). The ACVRL1 gene encodes the receptor ACVRL1 (Activin A Receptor Like Type 1), also known as ALK1 (Activin Receptor-Like Kinase 1), and belongs to the Transforming Growth Factor-Beta (TGFβ) Superfamily of receptors. Approximately 20% of patients with ACVRL1-associated HHT develop pulmonary arterial hypertension (PAH). [1] In pediatric PAH cohorts, ACVRL1 mutations account for nearly 10% of identified genetic variants. [2] The reduced penetrance of PAH among ACVRL1 mutation carriers suggests that additional modifiers account for PAH development. [3]. Given the relevance of the bone‑morphogenetic‑protein (BMP) pathway to the pathogenesis of PAH, and the intimate relationship of TGFβ superfamily signaling partners including ACVRL1 and BMPR2, genes which modify BMP-TGFβ signaling balance may contribute to PAH development in children with ACVRL1‑positive HHT. One such gene is SMAD9 (Receptor Regulated SMAD 9); the protein product of SMAD 9 (SMAD8) which mediates downstream TGFβ signaling. Herein, we report what we believe to be the youngest reported case of PAH in ACVRL1‑mediated HHT, in a patient who co‑harbors a SMAD9 mutation.

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