ABSTRACT
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Klippel-Trenaunay-Weber Syndrome/genetics , Lipoma/genetics , Musculoskeletal Abnormalities/genetics , Nevus/genetics , Vascular Malformations/genetics , Wilms Tumor/genetics , Adolescent , Adult , Alleles , Child , Child, Preschool , DNA/genetics , DNA/urine , Female , Genetic Predisposition to Disease , Humans , Infant , Klippel-Trenaunay-Weber Syndrome/pathology , Klippel-Trenaunay-Weber Syndrome/urine , Lipoma/pathology , Lipoma/urine , Male , Middle Aged , Musculoskeletal Abnormalities/pathology , Musculoskeletal Abnormalities/urine , Mutation , Nevus/pathology , Nevus/urine , Phenotype , Vascular Malformations/pathology , Vascular Malformations/urine , Wilms Tumor/pathology , Wilms Tumor/urineABSTRACT
OBJECTIVES: Dysregulation of angiogenesis has been proposed to play a central role in hemangioma pathogenesis. The aim of the study was to determine the peripheral and local serum levels of bFGF in patients with hemangiomas and vascular malformations (VM). DESIGN AND METHODS: The study group consisted of 52 children with infantile hemangioma, 14 with VM and 36 healthy patients. bFGF serum levels were analyzed by an ELISA assay. Urinary bFGF was determined in 11 individuals with hemangioma. RESULTS: The serum peripheral bFGF concentrations in children with proliferating hemangiomas were lower than in healthy controls (p=0,03). There was no correlation between the measured cytokine level and hemangioma size, as well as patients' age. The serum local bFGF levels in 29 children with hemangiomas were higher than in the peripheral blood (p=0.022). Urinary bFGF in hemangioma patients did not differ statistically from healthy controls. CONCLUSIONS: (1) Determination of bFGF serum levels is not helpful in differentiating the phases of hemangioma growth and distinguishing hemangiomas from VM; (2) serum levels of bFGF cannot distinguish between extrinsic and intrinsic theories of endothelial cell proliferation in hemangiomas.
