6 Tough-to-Diagnose Diseases

6 Tough-to-Diagnose Diseases

Despite all of the modern medical tools at our disposal, some diseases remain mysterious. They’re difficult to diagnose for a variety of reasons — whether they’re good at hiding within the body or cause ambiguous symptoms.

No matter the disease, Reem Jan, MD, rheumatologist and assistant professor of medicine at University of Chicago Medicine, says, “When someone has a severe case, it’s not difficult to come to a diagnosis. But if symptoms are mild or vague, you can run into trouble.”

For the people behind the symptoms, an evasive diagnosis can make them feel alone, scared, or cause them to question their own experience. But if you don’t feel right, trust your gut, and keep pushing for answers. 

Here are six common illnesses that may get missed.


Not fully understood, fibromyalgia can cause a range of symptoms: musculoskeletal pain, severe fatigue, and more — many of which mimic other conditions. Fibromyalgia doesn’t show up via blood tests or imaging studies (though doctors will use the tests to rule out other conditions). Providers must make a clinical diagnosis based on physical exam, history, and exclusion of diseases that mimic fibromyalgia, such as rheumatic disorders.

Lyme disease

Bacteria-carrying deer ticks cause this infection, but many people aren’t even aware they’ve had a tick bite because the insect is so small. If people have a fever, brain fog, or joint pain, but not the characteristic target-like rash, it may take weeks or months before they connect the illness to an outdoor experience. Fortunately, blood tests generally catch Lyme disease once providers look for it.

Celiac disease 

Often hereditary, this autoimmune disease, which causes a reaction to eating gluten, can strike at any age. Symptoms include bloating, diarrhea, anemia, and general discomfort. People who lose weight and can’t absorb nutrients get tested for celiac, but “patients with milder symptoms can go months or years without a proper diagnosis,” Jan says. The good news: A blood test can bring answers; however, people avoiding gluten will test normal. “You need exposure [to gluten] for the test to come back positive,” Jan says. Gold standard testing still involves a small bowel biopsy via endoscopy.

Sleep apnea 

Left untreated, this common sleep disorder can lead to hypertension, leg swelling, and heart and lung strain — not to mention chronic sleepiness. It can be tough to diagnose because “most people are tired,” Jan says. Plus, headaches and fatigue are vague symptoms. If people have no one to witness their snoring or notice that they stop breathing briefly at night, they may not be aware of these signs. And if people mention to their provider only headaches and lack of concentration — not feeling fatigued or irritable — providers may not think of apnea.


In this potentially lethal condition, the body’s response to infection damages its own tissues, including key organs, if left untreated. “Sepsis is a very broad term,” Jan says. Providers rarely miss it when people have the usual high fever, but if temperature is normal, the provider may not consider sepsis at first. 

Pulmonary embolism (PE)

A traveling blood clot blocks a lung artery, which can be fatal depending on the size of the clot and where it goes. People experiencing PE may have chest pain, shortness of breath, or no symptoms at all. If the clot is very small, causing subtle symptoms, doctors may not think to look for it. However, a blood test can show elevated levels of a protein that indicates clotting. Imaging will reveal clots and whether they have damaged the heart or lungs.

Originally published in the Spring/Summer 2023 print issue.