P4.034: When Back Pain is More Than it Seems: Rethinking Diagnosis and Embracing Genetic-guided Therapies for Spinal Arteriovenous malformations

Introduction: Arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that bypass the capillary network, resulting in abnormal blood flow. They can occur sporadically or as part of genetic syndromes, including Hereditary Hemorrhagic Telangiectasia. Spinal AVMs, although less common than intracranial AVMs, can lead to significant neurological deficits due to their potential to disrupt normal spinal cord function. In pediatric patients, AVMs are a major cause of hemorrhagic strokes, with hemorrhage occurring in approximately 85% of cases. Treatment options include endovascular embolization and surgical resection; however, results from endovascular treatments have been variable, and incomplete obliteration of lesions can lead to recurrent bleeding and deterioration. Molecular studies have linked AVMs to somatic mutations in genes such as KRAS and MAP2K1, which activate the RAS/MAPK pathway, contributing to abnormal cellular proliferation and angiogenesis. Recent advancements in therapy focus on targeting these underlying molecular mechanisms, with the MEK inhibitor trametinib showing promise in reducing blood flow to AVMs by over 75% in some patients after six months of treatment.

Case Description: This case involves a 14-year-old girl with a four-year history of night back and leg pain that suddenly worsened to acute paraplegia and urinary incontinence. Spinal MRI and angiography revealed an intraparenchymal hemorrhage and a type 2 spinal AVM. Despite partial embolization, the AVM recurred with persistent neurological deficits. Genetic testing of the resected tissue revealed a KRAS somatic mutation (c.35G>A, p.Gly12Asp), associated with mosaic RASopathies. The patient was treated with trametinib, a MEK inhibitor, resulting in partial sensory recovery and stabilization, with manageable acneiform rash as a side effect. Notably, the patient had no dermatological lesions initially, and no family history of AVMs was reported.

Discussion: The specific KRAS mutation identified in this case is a mosaic RASopathy, leading to the constitutive activation of the KRAS protein and the downstream activation of signaling pathways involved in cell proliferation and differentiation. This variant has been associated with segmental overgrowth of subcutaneous fatty tissue and vascular malformations. It can also contribute to tumorigenesis via persistent MAPK and PI3K pathway signaling, increasing the risk of cancers such as colorectal, pancreatic, and lung cancers. In this case, the mutation was somatic, meaning it was confined to specific tissues, leading to localized malformations. The first-line treatment for AVMs in patients with the KRAS c.35G>A mutation is typically endovascular embolization or surgical resection if embolization is not possible. Pharmacological management focuses on genotype-targeted therapies, such as trametinib, which inhibits MEK 1 and MEK 2, components of the RAS/RAF/MEK/ERK signaling pathway.

Conclusion: This case underscores the importance of considering spinal AVMs as a potential cause of back pain in pediatric patients and highlights the role of molecular genetic testing in identifying potential therapeutic targets, such as trametinib, for managing recurrent AVMs.