The 18-year-old was one of two South African girls living with a rare genetic disorder. Progeria causes rapid aging.
Her doctors predicted that she would only survive until her 14th birthday. But she went on to spend 4 more years.
Last month, President Jacob Zuma fulfilled her wish to meet him.
The Phalatse family has released a statement, saying Ontlametse was surrounded by her mother, brother, family members and friends.
"It is with great sadness to inform you of the passing of our first lady, Ontlametse Ntlami Phalatse," read the statement.
"Our hearts are filled with pain and sadness but Ontlametse, as we know her would want us to carry on with her courageous spirit."