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Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome.

ABSTRACT: Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum (PROS), including Klippel-Trenaunay syndrome and CLOVES syndrome. PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K/AKT gene signaling pathway. PS is caused by a single somatic activating AKT1 c.49G > A p.E17K variant while PROS can be caused one of multiple variants in PIK3CA. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram/ venography (MRA/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D-dimers (0.60-2.0 mcg/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E-selectin, and P-selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of AKT1 and PIK3CA variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.

SUBMITTER: Keppler-Noreuil KM

PROVIDER: S-EPMC8513083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPROS disorders are driven by somatic, gain-of-function mutations in PIK3CA that result in hyperactivation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PROS encompasses a broad spectrum of overlapping phenotypes (including overgrowth and vascular malformations) that vary significantly in their severity; every case is unique, leading to different, complex experiences. Here, we aim to describe the PROS experience from the patients' and caregivers' points of view, from onset to diagnosis to treatment and support.ResultsThe PROS patient journey was developed using a literature review, an ethnography study, health care professional (HCP) research, and social listening. It was then validated with patients, caregivers, and patient advocates. Physician research included 94 PROS centers and other vascular anomaly centers throughout the United States and Europe. Ethnographic research included 24 patients, caregivers, and/or advocates; selected data from 223 patients were reviewed. Key priority areas of need were identified, along with barriers to and potential enablers of quality care. Visual mapping of the PROS patient and family journey was developed to identify key personal health and system issues, and opportunities for improvements throughout patients' lifespans. Maps were also developed for 3 specific conditions: Klippel-Trénaunay syndrome (K-T); congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal anomalies (CLOVES) syndrome; and megalencephaly-capillary malformation syndrome (M-CM). Overall, most patients with PROS conditions and their families struggle with a long path to diagnosis, access to genetic testing, and finding qualified specialists. Following diagnosis, patients and families are frequently challenged with major medical events, comorbidities, unpredictability, frequent hospitalization, impact on school and work, the need for multidisciplinary care, unwanted attention, adverse impact on mental and emotional health, and financial pressures. Lack of effective pain management emerged as a substantial issue. Challenges and barriers to quality care shift throughout patients' lifespans; transition from pediatric to adult care can be especially difficult.ConclusionsThis patient journey in PROS was created in collaboration with patients, caregivers, and advocates as key partners. This novel methodology, which could be applied elsewhere, can more accurately identify areas of unmet need, barriers to care, education topics, and assist HCPs to understand the patient and family perspective.

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Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome.

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