RESUMEN
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.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Síndrome de Klippel-Trenaunay-Weber/genética , Lipoma/genética , Anomalías Musculoesqueléticas/genética , Nevo/genética , Malformaciones Vasculares/genética , Tumor de Wilms/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , ADN/genética , ADN/orina , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Síndrome de Klippel-Trenaunay-Weber/patología , Síndrome de Klippel-Trenaunay-Weber/orina , Lipoma/patología , Lipoma/orina , Masculino , Persona de Mediana Edad , Anomalías Musculoesqueléticas/patología , Anomalías Musculoesqueléticas/orina , Mutación , Nevo/patología , Nevo/orina , Fenotipo , Malformaciones Vasculares/patología , Malformaciones Vasculares/orina , Tumor de Wilms/patología , Tumor de Wilms/orinaRESUMEN
The temporomandibular joint (TMJ) is a specialized synovial joint essential for the function of the mammalian jaw. The main components of the TMJ are the mandibular condyle, the glenoid fossa of the temporal bone, and a fibrocartilagenous disc interposed between them. The genetic program for the development of the TMJ remains poorly understood. Here we show the crucial role of sprouty (Spry) genes in TMJ development. Sprouty genes encode intracellular inhibitors of receptor tyrosine kinase (RTK) signaling pathways, including those triggered by fibroblast growth factors (Fgfs). Using in situ hybridization, we show that Spry1 and Spry2 are highly expressed in muscles attached to the TMJ, including the lateral pterygoid and temporalis muscles. The combined inactivation of Spry1 and Spry2 results in overgrowth of these muscles, which disrupts normal development of the glenoid fossa. Remarkably, condyle and disc formation are not affected in these mutants, demonstrating that the glenoid fossa is not required for development of these structures. Our findings demonstrate the importance of regulated RTK signaling during TMJ development and suggest multiple skeletal origins for the fossa. Notably, our work provides the evidence that the TMJ condyle and disc develop independently of the mandibular fossa.