Diagnosis Challenge: Can You Solve These Bizarre Medical Mysteries?

In medicine, no two patients are alike—and sometimes, the body presents a mystery that even experienced clinicians can’t solve at first glance. These are the “zebra” cases, the diagnostic curveballs, the stories that haunt doctors for weeks and then make for legends in hospital corridors.

Whether it's a rash with no cause, a seizure without a trigger, or fatigue that spirals into multi-organ dysfunction, strange symptom stories challenge even the most seasoned diagnosticians. They test our knowledge, instincts, and humility.

In this article, we present a series of realistic, case-based medical puzzles—each rooted in actual diagnostic patterns, designed to challenge your clinical reasoning. For doctors, medical students, and curious readers alike:

Can you diagnose before the final reveal?

Case 1: The Twitching Teacher
Patient: 34-year-old female
Occupation: High school language teacher
Chief Complaint: Involuntary facial twitching and tongue movements for 2 weeks

History:

• Symptoms started subtly, progressed to noticeable spasms during speaking
  
  
• Mild fatigue, but no fever, weight loss, or trauma
  
  
• Denies drug or alcohol use
  
  
• No history of seizures
  

Vitals: Normal
Neurologic exam: Unremarkable except for facial myokymia
Bloodwork: Normal CBC, electrolytes, thyroid function
MRI Brain: Normal
EMG: Fasciculations in facial nerve distribution

Your Clues: Recent respiratory illness, mild hoarseness, and a coworker who was recently sick.
Diagnosis?

Answer: Paraneoplastic brainstem encephalitis from thymoma (associated with myasthenia gravis)
The subtle neuromuscular signs, especially in a younger woman with prior respiratory symptoms, hint at an autoimmune paraneoplastic process—often missed without imaging the chest for thymoma.

Case 2: The Yellow Marathon Runner
Patient: 28-year-old male
Occupation: Software developer and weekend triathlete
Chief Complaint: Jaundice and dark urine after marathon training

History:

• Training for first Ironman
  
  
• No alcohol, no medications, no recent illness
  
  
• No family history of liver disease
  
  
• Noted tea-colored urine and yellowing eyes post-run
  

Labs:

• Bilirubin: Elevated (indirect > direct)
  
  
• ALT/AST: Normal
  
  
• Hemoglobin: Slightly low
  
  
• Reticulocyte count: High
  
  
• LDH: Elevated
  
  
• Coombs test: Negative
  

What do you suspect?

Answer: Gilbert’s Syndrome with exertional hemolysis
In endurance athletes, hemolysis from repetitive impact (e.g., footstrike hemolysis) plus Gilbert’s Syndrome (a benign disorder of bilirubin conjugation) leads to exercise-induced jaundice. A red herring if you’re not thinking hematology + exertion.

Case 3: The Cough That Made Her Collapse
Patient: 46-year-old woman
Occupation: Professional singer
Chief Complaint: Coughing spells leading to brief fainting episodes

History:

• Sudden-onset paroxysmal coughing 2 weeks ago
  
  
• No recent fever or upper respiratory symptoms
  
  
• Fainting only occurs after severe coughing
  
  
• No chest pain, palpitations, or seizure activity
  

Vitals: Mild tachycardia, otherwise stable
Chest X-ray: Normal
EKG and Holter Monitor: No arrhythmias
CT Neck: Shows subtle soft tissue thickening
Pertussis titer: Pending

What’s behind the syncopal episodes?

Answer: Pertussis (Whooping Cough) in an adult
Though classically pediatric, pertussis in adults often presents with post-tussive syncope. Misdiagnosed as asthma, reflux, or even anxiety—until you look at the epidemiological resurgence and cough timing.

Case 4: The Man Who Forgot How to Walk
Patient: 59-year-old male
Occupation: Retired postal worker
Chief Complaint: Progressive difficulty walking over 3 months

History:

• Trouble with balance, tripping, dragging feet
  
  
• No pain, no numbness
  
  
• No trauma or fever
  
  
• Recently started taking nitrous oxide recreationally
  

Neuro Exam: Positive Romberg, loss of proprioception
MRI Spine: Inverted “V” sign in cervical cord
Labs: B12 borderline low, methylmalonic acid elevated

Diagnosis?

Answer: Subacute combined degeneration from B12 deficiency (Nitrous oxide abuse)
Recreational nitrous oxide inactivates B12, leading to posterior column and corticospinal tract degeneration. A classic neurology board question, but very real in today’s party culture.

Case 5: The Child Who Smells Like Maple Syrup
Patient: 3-day-old newborn
Chief Complaint: Poor feeding, lethargy, seizures

History:

• Term delivery, uncomplicated pregnancy
  
  
• No fever, no birth trauma
  
  
• Family reports urine has “sweet smell”
  
  
• Family history includes two early childhood deaths
  

Labs: Severe metabolic acidosis, hypoglycemia, elevated branched-chain amino acids

Diagnosis?

Answer: Maple Syrup Urine Disease (MSUD)
A classic metabolic disorder that must be caught early. The sweet-smelling urine, combined with metabolic derangement and neonatal symptoms, are key clues.

Case 6: The Night Sweats That Didn’t Match the Labs
Patient: 38-year-old male
Occupation: Architect
Chief Complaint: 3 months of night sweats, weight loss, and low-grade fevers

History:

• No cough or respiratory symptoms
  
  
• Travel to Asia 6 months ago
  
  
• PPD negative
  
  
• HIV negative
  
  
• Multiple inconclusive biopsies
  

CT Scan: Retroperitoneal lymphadenopathy
Serum ACE: Elevated
Calcium: Elevated
PET-CT: “Hot” but biopsy-negative lymph nodes

Diagnosis?

Answer: Sarcoidosis
While lymphoma is often suspected with B symptoms and PET-avid nodes, sarcoidosis can mimic malignancy but have negative biopsies due to non-caseating granulomas. ACE and hypercalcemia are subtle supporting clues.

Case 7: The Woman with the Flu That Never Ended
Patient: 42-year-old female
Occupation: Lawyer
Chief Complaint: Ongoing fatigue, low-grade fever, and muscle aches for 3 months

History:

• Started as flu-like symptoms
  
  
• Negative for COVID, influenza, mono
  
  
• Has Hashimoto’s thyroiditis
  
  
• “Brain fog,” lightheaded when standing, palpitations
  

Vitals: Orthostatic hypotension
TILT table test: Positive
ANA: Negative

What’s going on here?

Answer: Post-viral autonomic dysfunction / POTS (Postural Orthostatic Tachycardia Syndrome)
Often seen after viral illnesses or in patients with autoimmune predispositions. Still frequently dismissed or misdiagnosed, POTS causes significant disability, especially in younger women.

Why These Cases Matter
These strange symptom stories serve more than entertainment—they:

• Sharpen diagnostic reasoning
  
  
• Remind clinicians to think beyond the obvious
  
  
• Showcase zebras hiding among horses
  
  
• Emphasize patient stories over pattern recognition
  
  
• Highlight rare but real conditions clinicians must keep on the radar
  

Medical mysteries may frustrate at first—but solving them is what defines good clinical medicine.