Multidisciplinary team approach for Klippel-Trenaunay syndrome: A case series.

Klippel-Trenaunay syndrome (KTS) is a rare vascular malformation syndrome characterized by the proliferation of capillary, venous, and lymphatic vessels associated with cutaneous staining and hypertrophy of the affected limb.1Alwalid O. Makamure J. Cheng Q.G. Wu W.J. Yang C. Samran E. et al.Radiological aspect of klippel-Trénaunay syndrome: a case Series with Review of literature.Curr Med Sci. 2018; 38: 925-931Crossref PubMed Scopus (15) Google Scholar,2International Society for the Study of Vascular Anomalies, ISSVA classification of vascular anomalies. Classification and appendix 5, Available at https://www.issva.org/classification. Accessed July 31, 2022.Google Scholar KTS has been associated with somatic overactivation of the phosphoinositide 3-kinase (PI3K) pathway.2International Society for the Study of Vascular Anomalies, ISSVA classification of vascular anomalies. Classification and appendix 5, Available at https://www.issva.org/classification. Accessed July 31, 2022.Google Scholar Sirolimus is an mammalian target of rapamycin (mTOR) inhibitor that downregulates PIK3CA and inhibits angiogenesis and endothelial cell overgrowth.3Venot Q. Blanc T. Rabia S.H. Berteloot L. Ladraa S. Duong J.P. et al.Targeted therapy in patients with PIK3CA-related overgrowth syndrome.Nature. 2018; 558: 540-546Crossref PubMed Scopus (299) Google Scholar Sirolimus reduces the size of vascular malformations and the frequency of complications.4Hammer J. Seront E. Duez S. Dupont S. Van Damme A. Schmitz S. et al.Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study.Orphanet J Rare Dis. 2018; 13: 191Crossref PubMed Scopus (126) Google Scholar We present the clinical challenges and the importance of multidisciplinary team care for patients with KTS (Table S1). The study was approved by the Joint Institutional Review Board of Taipei Medical University (TMU-JIRB No.N202207019). An 8-year-old girl has KTS of the left lower limb with pelvic invasion (Fig. 1A–C), mild anemia with hemoglobin levels (10.5–11.1 mg/dL) associated with intralesional bleeding, and gait disturbance. Between the ages of 5 and 8 years, she received four courses of intralesional LASER therapy. At 8 years of age, she developed cellulitis of the left buttock and lower limb with septic shock, intralesional hematomas, and bleeding with coagulopathy. After wound debridement and infection control, treatment comprising sirolimus, propranolol (due to a component of capillary hemangioma), and aspirin was initiated, in addition to the use of elastic socks and a rehabilitation program.5Cho Y.J. Kwon H. Kwon Y.J. Kim S.C. Kim D.Y. Namgoong J.M. Effects of sirolimus in the treatment of unresectable infantile hemangioma and vascular malformations in children: a single-center experience.J Vasc Surg Venous Lymphat Disord. 2021; 9: 1488-1494Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The patient was bedridden for 2 months. Her ambulatory function gradually improved with supportive care and rehabilitation: she could walk with assistance at 6 weeks after initiation of pharmacotherapy and walk independently 7 months later. Follow-up MRI after initiation of sirolimus showed shrinkage of the vascular lesions (Fig. 1D–F). Three drugs were simultaneously initiated. Propranolol was stopped after 1 year and aspirin 4 months later (Supplemental Table S2). After treatment for KTS, the patient's hemoglobin level was maintained at 12.5 mg/dL. No side effects were noted, except for occasional episodes of grade 1 oral ulcers. However, the patient subsequently suffered from a fall with multiple new, intralesional hematomas, complicated by cellulitis with septic shock, which was successfully treated with antibiotics and supportive care. Six months after the fall, imaging showed that the size of the blood-filled cyst decreased. During follow-up, slow progressive leg length asymmetry due to left leg hypertrophy was noted, and thus an orthopedic intervention was planned. A 34-year-old woman was diagnosed with KTS of the left lower limb at early childhood. At 21 years of age, she underwent left above-knee amputation due to blood sequestration and severe thrombosis and anemia. Imaging during follow-up evaluations revealed vascular malformations invading the uterus, liver, and spleen (Figure S1). Warfarin, tranexamic acid, leuprorelin acetate, and ergometrine were taken for more than 4 years to control uterine bleeding and coagulopathy. The patient was frequently hospitalized for blood transfusion and recurrent infections for 2 years (including two episodes of urinary tract infection due to Escherichia coli and one episode of bacteremia of Bacteroides fragilis). Discontinuation of warfarin followed by low-molecular-weight heparin had a transient effect on bleeding episodes. The patient began sirolimus therapy for tumor progression and worsening symptoms, including low abdominal pain, diarrhea, and urinary frequency.4Hammer J. Seront E. Duez S. Dupont S. Van Damme A. Schmitz S. et al.Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study.Orphanet J Rare Dis. 2018; 13: 191Crossref PubMed Scopus (126) Google Scholar Her severe vaginal and rectal bleeding significantly improved after receiving radiotherapy to the uterus and rectum of 3000 cGy/15 fractions.6Yildiz F. Yilmaz M. Cengiz M. Gürkaynak M. Cila A.N. Doğan A.I. et al.Radiotherapy in the management of Klippel-Trénaunay-Weber syndrome: report of two cases.Ann Vasc Surg. 2005; 19: 566-571Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Two months after therapy, the frequency of uterine bleeding, diarrhea, and infection was reduced. Follow-up computed tomography showed partial response of the vascular tumors within and outside of the radiotherapy field (Figure S1B). Grade 2 lymphopenia was noted during treatment. The patient suddenly died at home at 36 years of age, after an episode of fever, vomiting, and diarrhea 9 days after the second dose of BioNTech COVID-19 vaccine (BNT162b2). The precise cause of death was uncertain. An autopsy was not performed. To the best of our knowledge, vascular malformations have not been associated with death following COVID-19 vaccination. A 3-year-old girl with KTS of the buttocks and left lower limb presented with a fistula between her vascular malformation and intestine at the age of 9 months (Figure S2). A biopsy of the left lower leg confirmed KTS. The patient was frequently hospitalized due to buttock cellulitis and sepsis. After treatment with propranolol (due to a component of capillary hemangioma) and sirolimus, the frequency of infections and bleeding was reduced. Sirolimus was stopped during episodes of cellulitis and during the COVID-19 pandemic. The patient continues to undergo careful follow-up evaluations by pediatric and orthopedic surgeons. The major complications of KTS include thrombosis, hemorrhage, infections, leg length inequality, and even life-threatening sepsis, bleeding, and vital organ compression. The size of vascular malformations may enlarge as the child grows older, which complicates the assessment of their response. The distortion of the vascular bed in KTS results in venous stasis, which may lead to thrombosis and consumptive coagulopathy; the coagulopathy may worsen after trauma or surgery. Tufted angioma and kaposiform hemangioendothelioma are vascular tumors that also result in platelet trapping and destruction, causing consumptive coagulopathy known as Kasabach-Merritt syndrome.7Mazoyer E. Enjolras O. Laurian C. Houdart E. Drouet L. Coagulation abnormalities associated with extensive venous malformations of the limbs: differentiation from Kasabach-Merritt syndrome.Clin Lab Haematol. 2002; 24: 243-251Crossref PubMed Scopus (171) Google Scholar Cases 1 and 2 had severe manifestations of KTS that required anticoagulation. Cases 1 and 3 had a capillary hemangioma component that required a combination of propranolol and sirolimus. We believe that sirolimus can serve as the backbone treatment for most cases of complicated KTS, supplemented by treatment for thrombosis and capillary hemangioma (Supplemental Table S3). In summary, some patients with KTS may require treatment that includes LASER therapy for local control of the disease, targeted therapy using sirolimus, radiotherapy for severe visceral involvement, and rehabilitation to improve ambulatory function. Combining therapies optimally requires precise evaluation and long-term follow-up. Essentially, care for patients with KTS requires a multidisciplinary approach. This work was financially supported of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.