The study will enroll participants 2 months of age up to 30 years of age. The purpose of this study is to assess the effectiveness and safety of Alpelisib (the "Study Drug") in patients with PIK3CA/TIE-2/TEK pathway driven vascular anomalies (VA). Alpelisib has been approved by the U.S. Food and Drug Administration (FDA) for treating adults and children with certain types of breast cancer. Its use in this study is considered experimental because FDA has not approved the study drug for treating people with VAs.

Study participation will last for up to 3 years and will involve regular study visits to Children's Hospital of Philadelphia (CHOP)'s Philadelphia Campus. Participants will need to take the study drug Alpelisib for at least 2 years, or up to 3 years in total if there is a positive response. Participating in this research means you will attend up to 16 clinic visits for the purposes of the study. Most visits will take approximately 30 minutes, but some visits will take approximately 2 hours, because you will be asked to complete questionnaires about your experience. Participating in this research also means taking the study drug, having pictures taken, and completing study drug diaries. There is also an optional portion to this study that involves collecting blood for biomarker testing.

Inclusion Criteria:

1. Signed informed consent and assent (when applicable)
2. Males or females age ≥ 2 years to <=30 years at the time of informed consent.
3. Have a documented PIK3CA or somatic TIE2/TEK variant.
4. Have a symptomatic vascular anomaly in need of medical therapy.
5. Have a disease-related lesion or lesions which can be measured
6. Have a Lansky or Karnofsky performance status score of ≥ 50.
7. Have acceptable organ function
8. (For persons who can get pregnant) Have a negative serum or urine pregnancy test within 7 days prior to starting study medication.
9. Must agree to the use an acceptable method of contraception
10. Subjects that have received alpelisib previously either via Managed Access Program from Novartis or commercial supply are eligible to enroll IF they have been off alpelisib for at least 7 days and there is clinical progression/worsening while off treatment

Exclusion Criteria:

1. Subject with only epidermal nevus/nevi in the absence of other PIK3CA vascular anomaly/overgrowth
2. Debulking or other major surgery performed within 30 days, at time of informed consent
3. Clinically meaningful bleeding related to VA: Grade 2 within 14 days or Grade 3 and more within 28 days before study treatment start as per CTCAE v. 5.0
4. Sclerotherapy/embolization for vascular complications performed within 14 days before informed consent.
5. Prior medications that are not allowable per the study protocol
6. Participation in any other prior investigational study within 4 weeks prior to study treatment start and within 5 half-lives of the investigational product, whichever is longer
7. Supportive care use of anticoagulants and compression garments is allowed. Subjects must have been using these interventions in an unchanged manner for 30 days before study enrollment.
8. History of prior and or ongoing malignancy, or ongoing investigations or treatment for malignancy at time of informed consent.
9. Clinically significant heart disease not due to VA
10. Documented pneumonitis or interstitial lung disease not due to VA
11. History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis
12. Subjects with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus
13. Impaired gastrointestinal (GI) function that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
14. History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib
15. Known history of Steven Johnson's syndrome, erythema multiform or toxic epidermal necrolysis
16. History of seizures or epilepsy on enzyme inducing antiepileptic drug(s); uncontrolled seizures are only allowed if due to PIK3CA variation
17. Concurrent severe and/or uncontrolled medical conditions not due to PIK3CA variation. Resolution of symptoms for at least 28 days must have occurred before consent
18. Subject may not be pregnant or breast feeding.
19. Female subjects of childbearing age and male subjects who do not agree to abstinence or to a highly effective method of contraception (condoms and/or oral, injected or implanted hormonal methods of contraception, or placement of an intrauterine device or intrauterine system, or surgical sterilization for the duration of the study and for one week following discontinuation of alpelisib, or non-heterosexual partnerships)
20. Human Immunodeficiency Virus (HIV) infection by history or by eligibility testing
21. Concomitant treatment with Strong inducers of CYP3A4
22. Subjects not able to understand and to comply with study instructions and requirements (in patients, legally authorized representatives, or guardians as applicable) at time of informed consent.