eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Cronkhite-Canada Syndrome

Author: Simon S Rabinowitz, MD, PhD, Professor of Clinical Pediatrics, New York Medical College; Chairman, Chief and Medical Administrator, Department of Pediatrics, Chief, Pediatric Gastroenterology and Nutrition, Richmond University Medical Center
Coauthor(s): Manoj Sheth, MD, Chief Resident, Department of Pediatrics, Richmond University Medical Center of Long Island
Contributor Information and Disclosures

Updated: Apr 1, 2008

Introduction

Background

Cronkhite-Canada syndrome (CCS) is a rare nonfamilial syndrome characterized by marked epithelial disturbances in the GI tract and epidermis. The GI changes are generalized hamartomatous polyposis with abnormal intervening mucosa. The mucosal proliferation leads to fluid and electrolyte abnormalities, malabsorption, malnutrition, GI bleeding, and surgical complications. The prevalence of GI malignancy in CCS patients is about 10%. Epidermal manifestations include alopecia, onychodystrophy, and hyperpigmentation. Approximately two thirds of all cases occur in individuals of Japanese descent. A few case reports have described an infantile form of this syndrome associated with a poor prognosis.¹

Cronkhite and Canada described the first 2 cases in 1955. Many case reports and several accumulated series bring the total cases reported in the medical literature to more than 400. Current understanding of the disease is based on small series and anecdotal reports. The etiology, the factors leading to progression or spontaneous remission, and the optimal treatment have not been established. In particular, the coordination of profound disturbances in 2 discrete epithelia, either concurrently or sequentially, is a provocative but unexplained phenomenon.

Pathophysiology

The characteristic features are GI polyposis and ectodermal changes. The polyps are part of a generalized GI mucosal disturbance that results in malabsorption and protein-losing enteropathy. These changes lead to the clinical symptoms, including diarrhea, abdominal pain, and profound malnutrition.

Dermatologic signs accompany the GI symptoms. The vast majority of affected individuals have alopecia and alterations in the nail beds and skin pigmentation. Although data from most cases support the belief that ectodermal features are the result of profound malnutrition, many symptoms and signs appear or remit in a manner inconsistent with this theory.

Diarrhea is multifactorial. Dilated glands in the GI mucosa release protein-enriched secretions into the lumen of the gut. The disrupted mucosa cannot digest disaccharides or absorb carbohydrates and lipids. The beneficial affects of antibiotics are attributed to small-bowel overgrowth. Steroids are most likely effective as anti-inflammatory agents. Polyps are believed to contribute to diarrhea. However, some therapeutic modalities and spontaneous remissions have improved diarrhea without affecting the number of polyps.

The disease usually evolves rapidly over several months. Mild GI and nutritional symptoms progress to substantial weight loss and edema. Ectodermal changes are usually observed several weeks or months after GI symptoms begin. Aside from the consequences of malnutrition, which can become life-threatening, most of the complications encountered are manifestations of the polyposis. Some patients with CCS have been diagnosed after presenting initially with other gastrointestinal conditions including Helicobacter pylori gastritis, eosinophilic gastroenteritis, and intestinal candidiasis.  

Juvenile GI polyposis is a syndrome described in infants who present with hamartomatous polyposis, macrocephaly, alopecia, nail dystrophy, clubbing of fingers and toes, hypotonia, hepatosplenomegaly, anemia, and hypoproteinemia due to protein-losing enteropathy. Although some authors consider this syndrome a form of CCS, others think it is a different entity. The prognosis is usually very poor. 

With the increasing observation of gastric and colorectal cancer in patients with CCS, various authors have attempted to hypothesize about this association. A group from Japan found a 40% prevalence of serrated adenomatous polyps in patients with CCS compared with a 1% incidence of this histology in all GI polyps.² Furthermore, this same group described a patient with microsatellite instability and overexpression of the p53 protein in the cancer and serrated adenoma. They proposed the possibility of a serrated adenoma-carcinoma sequence underlying some CCS GI malignancy.

Frequency

United States

As of 1995, only 15 authenticated cases were reported in American literature. As the number of cases reported has increased over the last decade, this has increased.

International

Two thirds of the 400 or so reported cases come from Japan.³ An old estimate is an incidence of 1 case in 1 million population.

Mortality/Morbidity

About one half of reported cases have resulted in long-term survival; however, many patients die from unrelated causes because of their advanced age. The grave prognosis has been modified with the identification of long-term survivors.

• Malnutrition: Acute fluid and electrolyte disturbances can follow long-term nutrient depletion and can be exacerbated by enteral losses of serum proteins. These disturbances result in anasarca, congestive heart failure, and immunologic deficiencies.
• Anemia: Acute and chronic GI blood losses secondary to gastroduodenal ulceration and erosions of colorectal polyp epithelium compound nutritional deficiencies of iron, folate, and, possibly, vitamin B-12 and reticulocytopenia found in chronic disease. Packed RBC transfusions may be required. Patients may die from severe GI hemorrhage.
• Surgery: In the early literature, bowel resection was performed to make a diagnosis. It is now mainly reserved for emergency complications. A compromised preoperative state contributes to the high surgical mortality rate.

Race

• The cause of the frequent case reports from Japan is unclear. The author of the largest series postulates that mental and physical stresses are contributory factors.³ Evidence does not suggest a genetic or specific infectious basis.
• After Japanese patients, most patients are Caucasians from North America and western Europe.

Sex

In Japan, the male-to-female ratio is 2:1. Outside Japan, the small number of cases has no sexual predilection.

Age

The age distribution of published cases ranges from 31-85 years, with onset of disease occurring most commonly in patients aged 50-60 years. Similar to the experience of one author presented in abstract form, an Italian group has described a case of a 17-year-old with clinical features consistent with CCS.⁴  

Clinical

History

• At the time of presentation and throughout the course of Cronkhite-Canada syndrome (CCS), the symptoms are manifestations of the degree of GI mucosal disease. The duration from onset of symptoms to diagnosis is less than 3 months in about 50% of patients.
• Several recognized patterns of disease evolution include either diarrhea or hypogeusia (taste disturbances) as the initial symptom. Diarrhea usually occurs, followed by a variable sequence of the triad that includes nail dystrophy, alopecia, and hyperpigmentation (see Staging).
• The etiology of hypogeusia is uncertain; it may result from disturbances of zinc absorption, possibly secondary to diarrhea or mucosal changes. In some individuals, xerostomia (unusual oropharyngeal sensation) precedes diarrhea or ectodermal changes. Another pattern in which ectodermal changes precede diarrhea is less common but well described.
• Diarrhea is multifactorial and is observed in 90% of patients. Patients typically have 5-7 loose, watery bowel movements each day, with stool volumes as much as 4-6 L. Hematochezia and steatorrhea both occur. Abdominal pain, anorexia, emesis, weakness, and weight loss often greater than 10 kg accompany the diarrhea. Weakness can be related to caloric deprivation, muscle wasting, dehydration, and fecal electrolyte losses, including calcium, magnesium, potassium, and zinc.
• A few patients have neurologic symptoms. These include numbness and tingling in the extremities, dysphagia, and seizures. Convulsions are often secondary to electrolyte imbalance. Whether recent reports of CCS in patients with psychiatric illness has any significance besides coincidence is unclear.

Physical

Physical examination reveals characteristic ectodermal changes starting several weeks or months after the initial GI symptoms in almost all patients. Most patients have 2 or more of the cutaneous triad that consists of alopecia, nail changes, and hyperpigmentation.

• Alopecia
  • The alopecia is initially patchy; however, it rapidly progresses and leads to complete hair loss.
  • Hair loss typically involves the scalp, eyebrows, face, axillae, pubic areas, and extremities; however, loss of only scalp hair has also been described.
  • Regrowth is noted after treatment, during spontaneous remissions, and despite ongoing active disease.
• Onychodystrophy (nail changes)
  • Nail changes involve thinning, splitting, and color changes in all fingernails and toenails.
  • Onycholysis (partial separation of the nail from its bed) leads to a unique pattern of an inverted triangle of normal nail bordered by a dystrophic nail.
  • Onychomadesis (the loss of all finger and toenails) occurs over several weeks.
  • Partial or total regeneration of nails occurs spontaneously in spite of active disease or remission.
• Hyperpigmentation
  • Hyperpigmented light-to-dark brownish macules and plaques are diffusely distributed. Although they are most commonly found on the hands and arms, they are also found on the legs, face, palms, soles, neck, trunk, and elsewhere.
  • They may coalesce and range from a few millimeters to 10 cm in diameter.
  • Patchy vitiligo is relatively common.
  • Similar to the other ectodermal changes, pigmentation can persist or resolve after medical therapy, surgical treatment, or no therapy.
• Other signs
  • Other signs are often secondary to long-standing protein, vitamin, and mineral depletion.
  • Findings include Chvostek and Trousseau signs, glossitis, edema that can range from mild peripheral findings to anasarca, and vestibular disturbances.

Causes

• At this time, speculation on the etiology is limited to anecdotal associations. The author of the largest series described mental stress, such as mental suffering or family problems, and physical fatigue as the most frequent precipitating factors for Japanese patients.³ Unlike many other GI polyposis syndromes, familial patterns of inheritance have not been identified. In particular, mutations in PTEN, which are responsible for Cowden disease, have not been found in patients with CCS.
• The unique involvement of 2 epithelial tissues in CCS suggests that potentially reversible derangements in epithelial cell-to-cell signaling or maturation may play a pivotal role in initiating the syndrome. Although no experimental evidence has validated this hypothesis, the observation that sulindac administration led to regression of CCS polyps may be interpreted as consistent with this mechanism.⁵ Nonsteroidal anti-inflammatory drugs (NSAIDs) are felt to inhibit cellular proliferation through various methods, including influencing cell-cycle regulatory proteins.
• Although the efficacy of corticosteroids provides the strongest evidence to suggest an inflammatory cause for CCS, additional reports could support this theory. Patients with CCS have been described with coexisting autoimmune conditions such as type 1 diabetes mellitus, hypothyroidism, membranous glomerulopathy, and high titers of antinuclear antibody.
• A recent provocative report described the infiltration of immunoglobulin G4 (IgG4)–producing plasma cells in half of the CCS polyps studied in 7 affected individuals.⁶ This histochemical finding is the criteria for IgG4–related autoimmune disease (IRAD), which includes autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis. The authors of this report speculate that CCS is an intestinal manifestation of IRAD.
• As detailed above, many signs and symptoms are secondary to the changes in the GI mucosa and the consequential malabsorption of nutrients.

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• Cronkhite-Canada Syndrome (Dermatology)
• Dermatologic Manifestations of Gastrointestinal Disease (Dermatology)
• Intestinal Polyposis Syndromes (Pediatrics: General Medicine)
• Colorectal Tumors (Pediatrics: General Medicine)