PTEN HAMARTOMA TUMOR SYNDROME PRESENTING WITH EXTENSIVE VASCULAR MALFORMATIONS AND HIGH-OUTPUT HEART FAILURE: ROLE OF MTOR INHIBITION

PTEN Hamartoma Tumor Syndrome (PHTS) encompasses a spectrum of rare autosomal dominant disorders caused by germline mutations in the PTEN gene. This syndrome includes Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome (BRRS), characterized by macrocephaly, mucocutaneous lesions, hamartomatous polyps, vascular anomalies, and increased cancer susceptibility. Vascular malformations in PHTS can manifest as Fast-Fow Vascular Malformations (FFVMs), leading to severe complications, including high-output cardiac failure. Management is complex, requiring multidisciplinary care. While serial embolizations are the mainstay of symptom control, mTOR inhibitors such as sirolimus and everolimus have emerged as potential therapeutic strategies, though evidence remains limited. We report a 29-year-old male presenting with macrocephaly, tall stature, multiple hyperpigmented macules on the glans penis, and extensive Arteriovenous Malformations (AVMs) of the left lower extremity. The clinical phenotype was suggestive of Bannayan-Riley-Ruvalcaba Syndrome. Genetic testing revealed a pathogenic heterozygous deletion involving exons 8‒9 of the PTEN gene [NM_000314.4]. The patient experienced progressive enlargement of AVMs in the left thigh and inguinal regions, resulting in venous aneurysms and arteriovenous shunting. Over the course of four years, he underwent 12 embolization procedures, which provided temporary symptom relief. Despite these interventions, the patient developed high-output heart failure, with clinical and echocardiographic findings demonstrating biatrial dilatation, right ventricular enlargement, and elevated pulmonary artery pressures. Additionally, atrial flutter ensued, necessitating catheter ablation and chronic antiarrhythmic therapy. Magnetic resonance imaging of the brain revealed a stable cerebellar cavernoma. Given the progression of vascular anomalies and the development of high-output heart failure despite serial embolizations, systemic therapy with the mTOR inhibitor everolimus was initiated. Preliminary evidence from small studies suggests that mTOR inhibitors may contribute to the stabilization of vascular malformations and improve symptoms in PHTS patients, though its efficacy in fast-flow lesions remains to be fully established. This case illustrates the severe clinical burden of PHTS with extensive vascular anomalies leading to high-output cardiac failure. Serial embolizations play a central role in palliation but are insufficient to alter disease progression. mTOR inhibitors represent a promising therapeutic adjunct, with preliminary evidence suggesting benefits in vascular anomalies associated with PTEN mutations. Further clinical studies are essential to elucidate their role, particularly in patients with FFVMs. The management of PHTS requires a coordinated, multidisciplinary approach, emphasizing the need for early diagnosis and comprehensive long-term follow-up.