Cronkhite-Canada Syndrome: Its Causes, Symptoms, and Treatment

Introduction

Cronkhite-Canada syndrome (CCS) is a rare, sporadic condition that primarily affects the skin and the gastrointestinal tract. It was first described in 1955 by Leonard Cronkhite and Wilma Canada; however, the term was coined in 1966 by Jarnum and Jensen. To date, roughly 500 cases have been reported worldwide, most of them being reported in Japan. The etiopathogenesis is obscure; however, it is not a hereditary condition. Generalized polyps throughout the gastrointestinal tract, except the esophagus, are their characteristic feature. Malabsorption is a common complication associated with CCS. However, quite a few reports are presented with malignant co-morbidities, including esophageal carcinoma, colon carcinoma, gastric carcinoma, and cholangiocarcinoma.

CCS is known by other terms such as:

• Canada-Cronkhite disease (CCD).

• Allergic granulomatous angiitis of Cronkhite-Canada.

• Gastrointestinal polyposis and ectodermal changes.

What Causes Cronkhite-Canada Syndrome?

The exact cause remains unknown. However, no evidence suggests a hereditary source. Several reports indicate the possibility of autoimmune or immune dysregulation as a probable reason for CCS. Certain facts supporting the autoimmune theory are:

• CCS patients have tested positive for antinuclear antibodies and are associated with other autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and polymyalgia.

• CCS patients have elevated serum immunoglobulin G4 (IgG4) levels. Serum IgG4 is a reliable marker for autoimmune or primary immune-deficiency diseases.

• Positive IgG4 immunostaining is noticed with gastrointestinal polyps.

Other possible causes include the following:

• In a few cases, Helicobacter pylori infection was involved in the pathogenesis.

• A PRKDC gene mutation thus indicates that familial predisposition cannot be entirely ruled out.

• Drug-induced allergic reaction.

• Arsenic poisoning.

• Physical and psychological stress.

What Are the Signs and Symptoms of Cronkhite-Canada Syndrome?

CCS can occur in all ethnic groups though most of it is reported in the Japanese population, with an increasing male predominance. It is characterized by gastrointestinal and dermatological symptoms. The average age of onset is roughly around the fifth or sixth decade. The most common symptoms are:

• Diarrhea.

• Dysgeusia (impaired taste sensation).

• Alopecia (hair loss).

• Skin hyperpigmentation.

• Onychodystrophy (abnormal nails).

The mucocutaneous features are:

• Alopecia: The hair loss may be patchy or diffuse with varying severity. It may involve the scalp, eyelashes, eyebrows, or beard.

• Onychodystrophy: Nail dystrophy may present in the form of abnormal shape, size, or texture of the nails. The most commonly associated nail abnormalities are onycholysis (nail separation), koilonychia (spoon-shaped nails), and onychomadesis (idiopathic shedding of the proximal end of nails.)

• Hyperpigmentation: The appearance of diffuse or well-defined brown flat pigments is a classic feature of CCS. This hyperpigmentation may be seen on the palms, soles, face, chest, and upper limbs.

The gastrointestinal features Are:

• Diarrhea.

• Altered taste.

• Nausea and vomiting.

• Upper abdominal pain.

• Loss of appetite.

• Weight loss.

• Possibility of cachexia.

• Blood in the stools.

• Lactose intolerance.

• Polyps throughout the gastrointestinal tract except for the esophagus.

What Are the Chances of Malignant Transformation?

Several studies have emphasized the risk of malignant transformation of the polyps. Reports have also suggested the contemporary occurrence of malignant comorbidities such as gastric carcinoma, esophageal carcinoma, and colon carcinoma in CCS. It is indicated that adenomatous polyps may have an increased predilection to develop colorectal cancer as they are the precursor for colorectal neoplasia. The colon and rectum are the most common sites of malignancy. Though the exact mechanism of malignant transformation is unknown, periodic screening and endoscopy should be advised to rule out malignancy, considering the increased risk.

How Is Cronkhite-Canada Syndrome Diagnosed?

A diagnosis of CCS should be ascertained if the patient presents gastrointestinal symptoms along with dermatological issues. The diagnostic workup is as given below:

• Physical Signs and Symptoms: The characteristic gastrointestinal features with a dermatological triad of nail dystrophy, hair loss, and hyperpigmentation indicate CCS. However, further diagnostic tests are required to confirm and rule out the differentials.

• Endoscopy: Endoscopy is an invasive diagnostic test in which a flexible tube with a camera and light attached to either end is inserted through the mouth into the gastrointestinal tract. In CCS, diffuse, non-neoplastic polyps are observed throughout the gastrointestinal tract except the esophagus.

• Blood Test: Blood tests though not conclusive, may be suggestive of the severity of the condition by indicating the complications. Anemia, nutritional deficiencies, electrolyte disturbances, and positive autoimmune antibodies.

• Endoscopy-Guided Biopsy: An endoscopic-guided biopsy of the polyps may reveal dilated mucosal glands, inflammatory infiltrate (predominantly eosinophils), and edema.

What Are the Differential Diagnoses of Cronkhite-Canada Syndrome?

Gastrointestinal polyps are seen in a few other conditions, such as:

• Cowden disease.

• Peutz-Jeghers syndrome.

• Familial polyposis.

• Juvenile polyposis.

How Is Cronkhite-Canada Syndrome Treated?

Considering CCS to be a rare entity, a standard therapeutic guideline has not been developed. Based on the literature reviews, the treatment plan can be outlined below:

• Systemic corticosteroids are the first line of treatment.

• Non-steroidal anti-inflammatory drugs can be used to suppress the polyps.

• Proton pump inhibitors for acid reflux.

• Nutritional support.

• Immune-modulating drugs can be used if the patient does not respond or improve with steroids.

What Is the Prognosis of Cronkhite-Canada Syndrome?

When first reported, CCS was associated with poor prognosis and a mortality rate of 50 percent within the first five years. However, with aggressive corticosteroid therapy and other diagnostic advances, prognosis, and survival rate have significantly improved. Complete remission of the signs and symptoms is seen in two to four months of therapy. Steroid dose reduction should be done gradually to prevent rebound flare.

What Are the Complications Associated With Cronkhite-Canada Syndrome?

• Malnutrition.

• Anemia.

• Hypoproteinemia.

• Rectal prolapse and intussusception.

• Pancreatitis.

• Gastrointestinal malignancy.

• Membrane glomerulonephritis.

• Portal vein thrombosis.

• Myelodysplastic syndrome.

Conclusion

CCS is a rare yet grave condition with an unexplained mortality rate. Prompt diagnosis and treatment can help prevent complications and other fatalities. Malabsorption is one of the prime reasons for morbidity. The rarity of this condition and non-familiarity are the reasons for a delay in diagnosis. CCS should be considered in patients presenting with concomitant dermatological and gastrointestinal symptoms. With the debatable malignant transformation or association with malignant co-morbidities, a set of defined screening and therapeutic criteria may greatly benefit the diagnosis and prognosis associated with this condition. Endoscopy and biopsy are vital tools that can be used to validate the diagnosis.