Cronkhite–Canada syndrome

What is Cronkhite–Canada syndrome?

Cronkhite–Canada syndrome (CCS) is a rare, sporadic, non-inherited disorder characterised by gastrointestinal and dermatological symptoms.

It has a number of other names, including Canada–Cronkhite syndrome, Cronkhite–Canada polyposis, allergic granulomatous angiitis of Cronkhite–Canada, gastrointestinal multiple polyposis syndrome, and gastrointestinal polyposis and ectodermal changes. 

CCS was first described by Leonard Cronkhite and Wilma Canada in 1955.

Who gets Cronkhite–Canada syndrome?

CCS is extremely rare:

• There are around 500 reported cases in the medical literature, with an estimated prevalence of 1 in 1 million.
• While distribution is worldwide, it appears that Japanese and Europeans are slightly more likely to have this syndrome than other populations.
• It is sporadic with no prior family history in patients with CCS.
• There is are slightly more cases of CCS in men than in women.
• The average age of onset is 59 years.

What causes Cronkhite–Canada syndrome?

The exact cause of CCS is unknown: some researchers have attributed it to immune dysfunction, although in some studies, it has been linked to arsenic poisoning.

What are the clinical features of Cronkhite–Canada syndrome?

Gastrointestinal problems seen in CCS include:

• Nausea and vomiting, loss of appetite, and weight loss, often with cachexia (physical wasting and malnutrition)
• Upper abdominal pain, watery diarrhoea, and melaena (bleeding)
• Swelling and loss of papillae of the tongue, with an accompanying loss of taste
• Lactose intolerance
• Pancreatitis
• Hypoproteinaemia (protein deficiency in circulating blood) and malabsorption
• The formation of polyps throughout the gastrointestinal tract, which can lead to rectal or colon cancer in 10% of cases.

The ectodermal changes seen in CCS are thought to be due to malabsorption and malnutrition; these include:

• Patchy and diffuse, mild to severe hair loss on the scalp, face, and genitals
• Hyperpigmentation, especially on the limbs, neck, torso and body folds
• Hypopigmented macules or leukoderma on the palms, soles, upper limbs, chest
• Blisters
• Nail dystrophy (onycholysis, koilonychia) and onychomadesis (loss of nails)
• Dry mouth and loss of taste.

Other disorders found in CCS include:

• Loss of the sense of smell
• Swelling of the limbs
• Discoloured streaks in the retina
• Positive Chvostek sign (twitching of facial muscles in response to tapping over the facial nerve) and positive Trousseau sign (spasm of the hand caused by inflating a blood-pressure cuff to above systolic pressure for 3 minutes)
• Coagulation abnormalities
• Cardiac failure
• Neurological signs
• Other autoimmune diseases, including hypothyroidism, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.

How is Cronkhite–Canada syndrome diagnosed?

The diagnosis of CCS can be reached after a variety of tests are performed. These tests include:

• A full blood count (anaemia is common)
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (often elevated)
• Serum electrolyte levels
• Total protein, albumin (often lowered), and immunoglobulin levels (raised IgG4 is characteristic)
• Glucose and lipid concentrations
• Antinuclear factor (usually positive)
• Serum levels of gastrin- or histamine-fast achlorhydria (absence of stomach acid)
• Serum micronutrient levels (malabsorption leads to deficiencies)
• Occult blood testing and Sudan III testing for stools
• Tests for Helicobacter pylori
• Radiological examination of the gastrointestinal tract
• Biopsy of gastric, small bowel and colonic polyps (various morphologies are reported).

How is Cronkhite–Canada syndrome treated?

Because there is no cure for CCS, treatment is symptomatic. Treatment focusses on hydration, restoration of nutrients and electrolytes, and regularisation of bowel movements. Pain management may also be required. Regular colonoscopy to remove polyps and identify colon cancer should be undertaken.

Treatments of bowel symptoms may include:

• A combination of systemic corticosteroids, antiplasmin, immunomodulators, and anti-tumour necrosis factor (TNF)-α agents
• An elemental diet and supplemental nutrition
• Antibiotics for bacterial infections
• Blood transfusion in cases of anaemia
• Ranitidine for gastric reflux or ulceration
• Sulfasalazine and metronidazole
• Eradication of H. pylori, if present
• Polyp removal and/or the surgical correction of prolapse, obstruction or colon cancer.

What is the outlook for Cronkhite–Canada syndrome?

The outlook for CCS is poor, with mortality rates in the first 5 years after diagnosis of around 50%, even with treatment. This is usually due to colon cancer or portal vein thrombosis.