Pediatric Cronkhite-Canada Syndrome

Updated: Oct 20, 2017
  • Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: Carmen Cuffari, MD  more...
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Overview

Background

Cronkhite-Canada syndrome (CCS) is a rare nonfamilial syndrome characterized by marked epithelial disturbances in the GI tract and epidermis that was first described in 1955. 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 patients with CCS 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]

Many case reports and several accumulated series bring the total cases reported in the medical literature to more than 400. Until recently, the understanding of the disease was based on small series and anecdotal reports. However, a Japanese survey that included 200 patients provided the most comprehensive characterization of this unique syndrome. [2] Although this survey includes the most detailed description of the clinical features, the impact of the various therapeutic options and the prognosis, the etiology, and the factors leading to disease progression or spontaneous remission have still not been established. In particular, the coordination of profound disturbances in two discrete epithelia, either concurrently or sequentially, is a provocative but unexplained phenomenon. Presently, the most common postulated pathogenesis factors include an autoimmune and/or an infectious trigger for the symptoms. 

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Pathophysiology

The characteristic features are GI polyposis and ectodermal changes. The polyps are part of a generalized GI mucosal disturbance that presents with malabsorption and protein-losing enteropathy. These changes lead to the clinical symptoms, including diarrhea, abdominal pain, and profound malnutrition. Ultimately, the polyps can become malignant, necessitating the need for ongoing surveillance. [3]  

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 secondary to chronic inflammation in the GI tract and 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 effects 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. Untreated, the disease progresses, with occasional spontaneous remissions and frequent relapses and rare progression to malignancy. [2] The most common agent employed to successfully treat CCS patients is corticosteroids, which has suggested an autoimmune basis. The concurrence of gastrointestinal infections such as Helicobacter pylori and Candida have suggested an infectious etiology. One case report describes a woman who showed complete regression of CCS lesions following abdominal colectomy and eradication of Helicobacter pylori infection. [4]  The observation of CCS in a patient with eosinophilic gastroenteritis suggests the possibility of an allergic etiology. [5]  

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. [6] 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.

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Epidemiology

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 450 or so reported cases come from Japan. [7] An old estimate is a prevalence of 1 case in 1 million population. In Japan, which has a population of approximately 125 million and over 250 cases, the prevalence is thus approximately 1 case per 500,000. 

Mortality/Morbidity

Earlier, the mortality had been reported to be up to 50% but that cohort was untreated, inadequately treated, or had treatment delay. The recent Japanese survey reported that 15.7% of those diagnosed had died, but only about one third (10/33) were related to CCS. Of these 10, 3 died of gastric cancer, 3 died of colon cancer, and 4 died of sepsis secondary to colitis and pancreatitis. The other deaths were secondary to unrelated causes because of their advanced age. [2]

  • Malnutrition: Acute fluid and electrolyte disturbances can follow long-term nutrient depletion, including vitamin 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. The recent Japanese survey also reported 30% prevalence of carcinomas (19 gastric, 41 colon, and none in the stomach or small bowel). Carcinomas were found throughout the colon. [2]  

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. [7] Evidence does not suggest a genetic or specific infectious basis. A single case report describes the disease in a 50-year-old Indian man and his 22-year-old son. [8] 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 Cronkhite-Canada syndrome. [9]

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Prognosis

Although early publications predicted a guarded prognosis, a Japanese epidemiologic survey confirms that aggressive glucocorticoid and possibly added nutritional therapy can result in good short-term improvement in the nutritional parameters. This yields a resolution of the protein-losing enteropathy/hypoalbuminemia, the ectodermal changes seen in the nails, alopecia, and dysgeusia. Persistence of polyps then becomes the focus with endoscopic decrease a therapeutic end point. This will often require a much more prolonged course of therapy. Subsequently, steroids should be weaned slowly. Decreasing the long-term mortality is then centered around detecting and removing malignant polyps. Thus, ongoing surveillance for gastric and colonic cancer is recommended [2] .  

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Patient Education

Patients should be familiarized with the spectrum of ectodermal changes that are seen in the syndrome. Any aberrant gastrointestinal syndromes and weight loss should be brought to the attention of their gastroenterologists. Even if a patient achieves a resolution of symptoms, he or she remains at risk for GI malignancy and should continue to have annual surveillance endoscopies and colonoscopies or at a schedule determined in conjunction with their gastroenterologist. 

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