Ferdinand and Isabella, the Catholic Monarchs, had one son who survived into young adulthood named John (or Juan, as the case may be). In OTL he died of tuberculosis at age 19 and his wife Margaret gave birth to a stillborn daughter, which meant the Castilian succession ran through Isabella's daughter Joanna, which paved the way for the House of Habsburg to inherit the eventually sprawling Spanish Empire.
So, what if John was a little healthier?