A 25-year-old man with weight loss, abdominal pain, and a positive fecal occult blood (guaiac) test, whose mother and siblings have similar symptoms, what is the most likely diagnosis: Peutz–Jegers syndrome, familial adenomatous polyposis, ulcerative colitis, or Crohn disease?

Most Likely Diagnosis: Crohn Disease

Given the patient's age (25 years), presentation of weight loss, abdominal pain, bloody stools, positive fecal occult blood test, and strong family history with multiple affected relatives (mother and siblings), the most likely diagnosis is Crohn disease (Option D).

Clinical Reasoning Algorithm

Step 1: Evaluate the Family History Pattern

The key distinguishing feature in this case is the familial clustering with multiple affected family members across generations (mother and siblings with similar symptoms). This pattern helps differentiate between the diagnostic options:

• Crohn disease and ulcerative colitis: Both can have familial clustering, with family history conferring a 2-3 fold increased risk when first-degree relatives are affected 1, 2
• Familial adenomatous polyposis (FAP): Would present with hundreds of adenomatous polyps visible on endoscopy, typically manifesting in teenage years with a nearly 100% lifetime cancer risk if untreated 1, 2
• Peutz-Jeghers syndrome: Rare (1:50,000 to 1:200,000), would show characteristic mucocutaneous melanin pigmentation on lips and oral mucosa in over 90% of cases, with hamartomatous (not adenomatous) polyps 1, 3

Step 2: Analyze the Clinical Presentation

The triad of weight loss, abdominal pain, and bloody stools in a 25-year-old strongly suggests inflammatory bowel disease:

• Crohn disease: Classic presentation includes abdominal pain (often relieved by defecation), bloody diarrhea, weight loss, and can affect any part of the GI tract with transmural inflammation 1, 4
• Ulcerative colitis: Presents with bloody diarrhea with mucus, rectal urgency, tenesmus, and continuous mucosal inflammation extending from rectum proximally, with bimodal age distribution peaking in the 2nd-3rd decades 1, 4

Step 3: Consider What's Missing from the Examination

The unremarkable abdominal examination does not exclude inflammatory bowel disease, as symptoms correlate poorly with inflammation severity 1. However, the absence of certain findings helps narrow the diagnosis:

• No mention of mucocutaneous pigmentation: Makes Peutz-Jeghers syndrome unlikely, as pigmentation crosses the vermillion border and is present in >90% of cases 1
• No mention of hundreds of polyps on endoscopy: Would be expected in FAP, where patients develop numerous adenomatous polyps requiring prophylactic colectomy at age 20-25 years 1

Step 4: Distinguish Between Crohn Disease and Ulcerative Colitis

Both conditions present similarly in young adults with familial clustering, but several factors favor Crohn disease:

• Weight loss is more prominent in Crohn disease: Due to malabsorption from small bowel involvement and transmural inflammation 1
• Abdominal pain is a cardinal feature of Crohn disease: Often related to inflammation, strictures, or fistulas, whereas UC pain is typically relieved by defecation 4
• Family history pattern: Multiple siblings affected suggests autosomal dominant inheritance pattern more consistent with Crohn disease, though both IBD types show familial clustering 2

Why Other Options Are Less Likely

Peutz-Jeghers Syndrome (Option A)

• Would require mucocutaneous melanin pigmentation (absent in this case) 1
• Polyps are hamartomatous, not adenomatous, with characteristic branching smooth muscle pattern 1, 5
• Symptoms often arise from intussusception (15% by age 10,50% by age 20) rather than chronic inflammatory symptoms 1
• Much rarer than IBD (1:50,000 to 1:200,000 vs. IBD incidence of 1.2-20.3 per 100,000) 3, 4

Familial Adenomatous Polyposis (Option B)

• Requires hundreds of adenomatous polyps visible on endoscopy 1
• Symptoms typically include diarrhea from polyp burden, not primarily bloody stools 1
• Would show congenital hypertrophy of retinal pigmented epithelium (70-80%), epidermoid cysts (50%), or osteomas (50-90%) 1
• Screening begins at age 12-15 years with sigmoidoscopy, and diagnosis would likely have been made earlier 1

Ulcerative Colitis (Option C)

• Remains a close differential, but less likely given the prominence of weight loss and abdominal pain 4
• Classic presentation emphasizes bloody diarrhea with mucus, rectal urgency, and tenesmus more than weight loss 4
• Inflammation is continuous from rectum proximally, whereas Crohn disease shows skip lesions 4

Critical Next Steps

Definitive diagnosis requires ileocolonoscopy with biopsy to identify:

• Crohn disease findings: Cobblestoning, aphthous ulceration, skip lesions, non-caseating granulomas, transmural inflammation 1, 4
• Ulcerative colitis findings: Continuous inflammation from rectum, crypt architectural distortion, decreased crypt density, absence of granulomas 4

The positive fecal occult blood test confirms GI bleeding but is non-specific 1. Given the family history, genetic counseling should be offered as 35% of colon cancer cases arise from heritable factors, and family history of CRC in first-degree relatives confers 2-3 fold increased risk 2.