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.

Congenital infiltrating lipomatosis of the face with lingual mucosal neuromas associated with a PIK3CA mutation

“…Unique surgical risks that should be disclosed to patients prior to surgery include anesthetic complications due to possible hypertrophy of palatine tonsils and an increased risk of thromboembolism. Predisposition to thrombosis in PROS is multifactorial: vascular endothelial dysfunction caused by somatic PIK3CA variants, platelet dysfunction, chronic stasis in the case of vascular malformations and impaired mobility after surgery 12 . Furthermore, although there have been no reports of malignancy in association with CILF, some cases of pediatric renal cancer have been described in children with PROS, and thus, it is recommended that serial abdominal ultrasonography every 4 months until age 8 years be considered in children with somatic PIK3CA mutations 11 …”

Immature Teratoma in an Adolescent with Proteus Syndrome; A Novel Association.

“…The left ovarian mass measured 14 x 11 x 5 cm and weighed 380 mg. The patient tolerated the procedure well and had an unremarkable post-operative course, during which she was placed on prophylactic enoxaparin given the increased risk of venous thromboembolism in Proteus syndrome (Keppler-Noreuil et al, 2019). She was discharged after four days and evaluated one month later in oncology clinic, where repeat CT abdomen/pelvis showed no residual disease.…”

Immature teratoma in an adolescent with Proteus syndrome: A novel association

“…The left ovarian mass measured 14 × 11 × 5 cm and weighed 380 mg. The patient tolerated the procedure well and had an unremarkable postoperative course, during which she was placed on prophylactic enoxaparin given the increased risk of venous thromboembolism in Proteus syndrome 2 . She was discharged after four days and evaluated one month later in oncology clinic, where repeat CT abdomen/pelvis showed no residual disease.…”