A 20-year-old college student named Mary Ann Piazza has been happy with her job as a babysitter and college life, until she develops an unusual cough. It seems to be from minor ailments, but the cough proves to be incredibly persistent, and she becomes fatigued. Worse, Mary Annalso deals with shortness of breath, wheezing, constant weight loss, night sweats, and itchy skin. After being dismissed for three years, one doctor finally figures out that Mary Ann has been suffering from Hodgkin's lymphoma the whole time. Since young Danielle Barckett's parents have brought her home from the hospital, they have noticed she has problems. Danielle vomits every time she is fed, yet she manages to gain weight over time. She also has diarrhoea and a distended belly from ascites accumulating in her abdomen. It turns out that Danielle has a rare genetic disorder called tyrosinemia.

Every year, millions of Americans fall prey to real-life medical mysteries ailments that go undiagnosed or misdiagnosed for years. Their lives are thrown into turmoil as medical professionals struggle to understand their baffling conditions. Mystery diagnosis tells their stories. Through interviews and dramatic recreations, each medical mystery is recounted in vivid detail. Symptoms emerge, specialists are called in, but still the daily struggle continues. And then one day, because of a patients relentless pursuit of an accurate diagnosis, or a forward thinking doctor, the problem is solved and a true diagnosis given.

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