Pediatric Cronkhite-Canada Syndrome

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. 

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.

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]

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] .  

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. 

At the time of presentation and throughout the course of Cronkhite-Canada syndrome the symptoms are manifestations of the degree of dermatologic and GI mucosal disease. The duration from onset of symptoms to diagnosis is less than 3 months in about 50% of patients. The most common symptoms at presentation noted in Japan were diarrhea (70%), dysgeusia, disordered sense of taste (65%), alopecia (49%), onychodystrophy, changes in nail morphology (64%), and hyperpigmentation (49%).[2]

Several recognized patterns of disease evolution include either diarrhea or dysgeusia 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 dysgeusia is uncertain. It has been noted in other clinical settings with zinc deficiency, possibly secondary to diarrhea or mucosal changes. In some individuals, xerostomia (dry mouth with or without 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 80% of patients. Patients can 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 may have neurologic symptoms, including numbness and tingling in the extremities, dysphagia, anosmia, vestibular disturbances, 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.[10, 11, 12]

Other manifestations include cataracts, thrombosis and coagulation disorders, cardiac failure, recurrent acute pancreatitis, and psychiatric disorders.[12]

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 palms, soles, hands, and arms, they are also found on the legs, face, 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, vestibular disturbances, and evidence of osteoporosis and osteopenia, including rib fractures.[13]

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 myelodysplastic syndrome.[14]  High titers of antinuclear antibody were found in 28% of the Japanese patients, and individuals refractory to steroids have responded to calcineurin inhibitors, azathioprine, and anti-TNF agents.[2]

Two recent groups provided documentation of immunoglobulin G4 (IgG4)–producing plasma cells infiltrating CCS polyps. Both described this finding in half of the CCS polyps removed from 7[15]  and 14[16]  patients studied. One group found only 12% positive immunostaining in juvenile polyposis syndrome polyps and no staining in control tissue.[16]  This histochemical finding is the criteria for IgG4–related autoimmune disease (IRAD), which includes autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis. The authors of the first report speculated that CCS is an intestinal manifestation of IRAD.[15]

The author of a large series described mental stress, such as mental suffering or family problems, and physical fatigue as the most frequent precipitating factors for Japanese patients.[6]  Onset of symptoms following a fracture was reported in one case.[17]

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 Cronkhite-Canada syndrome.

The unique involvement of two 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.[18] Nonsteroidal anti-inflammatory drugs (NSAIDs) are felt to inhibit cellular proliferation through various methods, including influencing cell-cycle regulatory proteins.

Characteristic changes in the ectoderm (hair loss, nail dystrophy, hyperpigmentation) are usually the initial findings that suggest CCS.

Besides intractable diarrhea leading to malnutrition, various vitamin deficiencies, weight loss, and hypoalbuminemia, and the ectodermal changes, the most significant issue is GI cancer arising in one of the many polyps. Rarely, GI bleeding occurs. 

A case report described a large gastric adenocarcinoma that was limited to the mucosa, which resembled the hyperplasia seen in CCS polyps. These investigators determined that the phenotypic expression of the mucins was MUC2(-) and MUC5AC(+) typical of a gastric type well differentiated adenocarcinoma. Their literature search confirmed that previous reports on 32 gastric carcinomas in CCS patients were also most limited to within the submucosa despite their huge size.[19]

A handful of histopathologic studies have provided evidence that suggests that carcinogenesis in CCS patients does not universally follow the adenoma to adenocarcinoma.[3]

Carcinomas of the colorectum (most often distal) and stomach have been documented in 15-25% of patients with Cronkhite-Canada Syndrome at diagnosis and may be multiple.[12]

Because the diagnosis of CCS is clinical, relatively little effort is made to comprehensively categorize laboratory data in affected patients.

A Japanese survey revealed that hemoglobin levels at initial diagnosis were in the normal range and after initial treatment remained unchanged. However, total protein, albumin, and total cholesterol were all decreased and improved with treatment. Conversely, treatment resulted in a decrease in C-reactive protein. Other laboratory findings included a positive ANA (28% prevalence), elevated fecal alpha-1-antitrypsin (93%), and 54% positive Helicobacter pylori (through various testing).[2] Testing is necessary to identify and monitor complications of the disease.

Baseline blood testing: Important baseline blood results include serum electrolyte (eg, calcium, magnesium, potassium, zinc), BUN, creatinine, albumin, and total protein levels, as well as the prothrombin time (PT) and/or the activated partial thromboplastin time (aPTT) and CBC count.

Erythrocyte sedimentation rate (ESR) testing: In the early stages of the syndrome, blood obtained for ESR testing and stools obtained for cultures and evaluation for ova, parasites, and leukocytes are helpful in ruling out other causes of diarrhea.

Serial evaluations

Results of serial evaluations may guide therapy and minimize morbidity.

Evaluations help in identifying treatable causes of anemia (eg, iron, folate, and vitamin B-12 deficiency); the Schilling test is occasionally used.

Evaluations are performed to characterize malabsorption by using the serum xylose, carotene, hydrogen breath, fecal alpha-1-antitrypsin, and fat excretion tests.

Evaluations elucidate secondary immunologic deficiencies by measuring serum globulins.

Nuclear medicine studies based on technetium-labeled human serum albumin can be used to localize the site of protein-losing enteropathy and to direct surgical resection.

Other tests

Previous investigators determined that Cronkhite-Canada syndrome is not primarily associated with pituitary, adrenal, pancreatic, renal, or liver abnormalities.

A small number of patients have hypothyroidism.[20] The nature of this association is unknown.

Plain radiography and contrast-enhanced studies of the abdomen are used to diagnose complications that require surgical intervention, such as ulcer perforation and intussusception.

Upper GI series, along with small-bowel follow-through, is used to evaluate polyps in the stomach and small bowel, especially those beyond the ligament of Treitz.

Although the esophagus is rarely involved, the stomach and colon almost always contain polyps. Polyps are noted in the small bowel in approximately one half of all patients, most often in the duodenum and terminal ileum.[21] Although most polyps are sessile, pedunculated lesions are frequently encountered.

Gastric folds can enlarge[22] and create the appearance of Menetrier syndrome.

Barium enema with reflux into the terminal ileum can be used to investigate colonic and distal small-bowel polyps if colonoscopy is unavailable.

Newer higher-resolution CT scanning is able to provide greater definition to lesions and has been able to demonstrate a multiple lobular mass in the stomach, which was then biopsied endoscopically to diagnose the syndrome.[23]

Wireless capsule endoscopy has allowed for visualization of abnormal mucosal appearance throughout the small bowel.[24] This noninvasive technique may allow for sequential studies, which can enhance the understanding of the temporal relationships between mucosal changes and the development of malabsorption and clinical symptoms. It may also have a role in evaluating the early response of patients with Cronkhite-Canada syndrome to various treatment modalities. Newer generations of machines continue to provide additional clarity.[25]

Diagnostic endoscopy, which is superior to radiographic imaging, allows direct visualization and biopsy of the GI mucosa. Abnormal intervening mucosa distinguishes Cronkhite-Canada syndrome from the generalized polyposis syndromes prior to the ectodermal changes. Compared with the hamartomas seen in patients with juvenile colonic polyposis, colonic CCS polyps generally have a broader sessile base. The recent comprehensive Japanese survey provides the most comprehensive description of the polyposis.[2]

• Distribution: The prevalence of confluent polyps in the stomach (82%) is greater than in the colon (55%). Less than one fourth of the patients had confluent polyps in their small intestine. However, 12% of the endoscopies revealed esophageal involvement.

• Size: Gastric polyps were smaller (51% were 5-10 mm and 18% were >15 mm) than those in the colon (30% were >15 mm and 45% were 5-10 mm). Almost half of the small intestine polyps were less than 5mm, and most of the others were 5-10 mm.

• Appearance: About half of the polyps in the stomach and colon were engorged, and most of the others were classified as edematous (the major appearance of polyps noted in the small bowel). An edematous, reddish coarser mucosa was seen between the polyps in 74% of the stomachs and 58% of the colons.  

Atypical endoscopic features include selective sparing of the stomach, small intestine or colorectum; elongated villiform polyps, diffuse thickening of the mucosa with hypertrophic rugae and duodenal folds; and mucosal atrophy.[12]

Therapeutic endoscopy is used to identify and treat sources of GI bleeding and to remove polyps with suspected dysplasia and carcinoma.

Advanced endoscopic techniques are being used to improve diagnosis and treatment of CCS patients. Magnified narrow-band imaging (NBI) has enabled a Japanese group to identify a single 7-mm discolored polyp with an irregular microvascular pattern as potentially neoplastic. The lesion was removed with endoscopic submucosal dissection. Histopathology revealed a well-differentiated tubular adenocarcinoma without lymphatic or venous infiltration, and with tumor free margins.[19] Since one hypothesis has GI malignancies arising in a select few of the hundreds of polyps, this approach holds promise as a method of screening for early detection and treatment of this complication.

Small-bowel polyposis beyond the ligament of Treitz has been mainly confirmed by radiological findings and rarely in endoscopic studies. Video capsule endoscopy in a patient presenting with severe watery diarrhea and alopecia confirmed excessively elongated villi, as well as multiple polyps with strawberylike central spots of the intestinal mucosa. This case points out that close follow-up with small-bowel endoscopy may be warranted due to an increased risk of the development of small bowel carcinomas.[26]

A case report describes a 66-year-old male with dysgeusia, oncodystrophy, and alopecia who had no GI polyps noted during endoscopy. Biopsies of the stomach and duodenum revealed severe atrophy and diffuse, marked edema of stomach mucosa and duodenum.[3]  

A small series describing initial clinical presentations and upper GI endoscopic appearances surprisingly reported antral malignancy and gastric infection with no gastroduodenal polyposis.[27]

The universal finding is hamartomatous polyps of the juvenile (retention) type throughout the GI tract with rare involvement of the esophagus. In addition, tubular adenomas and inflammatory polyps are typically encountered. Mucosal changes are characterized by intact surface epithelium, edematous chronically inflamed lamina propria, and proliferated tortuous glands, some of which are cystically dilated and filled with proteinaceous fluid or inspissated mucus. The mucosa often contains engorged vascular channels, surface erosions, and prominent eosinophilic infiltration.

Upper GI endoscopic biopsies typically have prominent mucosal edema, a mixed inflammatory infiltrate rich in eosinophils, and architectural changes with gland infiltration. Duodenal mucosa demonstrated total or subtotal villous atrophy, inflammation, crypt distortion, and increased apoptotic bodies. Histologic features are often those commonly found in other immune disorders of the GI tract. In the appropriate clinical setting, this helps establish that the diagnosis is consistent with Cronkhite-Canada syndrome as an immune dysregulation syndrome, different from IgG4-related disease.[27]

In CCS, but not in generalized juvenile polyposis coli, the mucosa between polyps is also abnormal, with edema, congestion, and a mixed inflammatory infiltrate in the lamina propria along with focal glandular ectasia. Impaired architecture of crypts and subtotal or total atrophy of villi is also noted. The inflammatory cells include lymphocytes, plasma cells, and eosinophils with scattered neutrophils. 

Adenomatous changes and carcinoma occur in, or in close proximity to, hamartomatous polyps in almost 15% of affected patients. As indicated above, future work may corroborate the importance of serrated adenoma as a premalignant lesion.

A case with innumerable hamartomatous colonic polyps had extensive adenomatous changes limited to the superficial regions of every polyp removed.[28]

Atypical histologic findings include paucicellular stroma, submucosal gland/crypt invagination, and prominent epithelial apoptosis. Prominence of specific inflammatory cell infiltration can mimic other inflammatory conditions: neutrophils, sometimes with microabscesses, as in Ulcerative Colitis; eosinophils as in eosinophilic gastroenteritis; and mast cells and IgG4 plasma cells.[12]

A histologic analysis on alopecic lesions in two Japanese women with CCS revealed a conversion from anagen (rapidly growing) to telogen (quiescent) hair follicles without any loss, atrophy, or destruction of the follicles. In addition, although severe inflammation was noted in the GI tracts, none was noted in the hair follicles, consistent with hair loss being a reversible event.[29] .

No staging system is available for this rare entity. However, Goto et al have divided the clinical presentation into 5 categories; this may assist clinicians considering this diagnosis.25 The categories, based on initial presenting symptoms followed by the subsequent clinical course, are listed below:

• Type I- Diarrhea (35%)

  • Skin hyperpigmentation and nail dystrophy (56%)

  • Hypogeusia, alopecia, skin hyperpigmentation, and nail dystrophy (28.2%)

  • Nail dystrophy, alopecia, skin hyperpigmentation, and hypogeusia (15.4%)

• Type II -Hypogeusia (40.9%)

  • Diarrhea, alopecia, hyperpigmentation of skin, and nail dystrophy (71.1%)

  • Nail dystrophy, alopecia, skin hyperpigmentation, and diarrhea (22.2%)

  • Nail dystrophy and alopecia (13.3%)

• Type III- Xerostomia (6.4%) - Diarrhea, alopecia, skin hyperpigmentation, and nail dystrophy

• Type IV- Abdominal discomfort (9.1%) - Alopecia, hyperpigmentation of skin, nail dystrophy, and diarrhea

• Type V- Alopecia (8.2%)

  • Diarrhea, nail dystrophy, skin hyperpigmentation, and hypogeusia (55.6%)

  • Skin hyperpigmentation, diarrhea, and hypogeusia (44.4%)

Cronkhite-Canada syndrome is a unique condition that affects the GI tract and the skin, nails, and hair. The morbidity is related to malabsorption and the potential for GI malignancy. The vast majority of patients are middle-aged Asian adults with few reports in younger patients.

Neither evidence-based medicine nor systematic investigations of medical or surgical interventions are available.[30] Reported therapies are based on small nonrandomized series, retrospective surveys and expert opinions. These include supportive care, hyperalimentation, antibiotics, corticosteroids, acid suppression, cromolyn, anabolic steroids, surgery, and combinations of these therapies. Isolated anecdotal reports have described administration of zinc other immune suppressives, and eradication of H pylori. Each approach has been reported to be successful in some cases. A short communication has described the successful use of NSAIDs to regress CCS polyps, as has been described in patients with hereditary polyposis adenoma-to-carcinoma syndromes.[18]

A published expert opinion described successful management recommendations that included treating GI symptoms, aggressive nutritional support, and vigilant monitoring for complications requiring emergent surgery. Many anecdotal reports and a recent review support the use of corticosteroids, immunosuppressives,[16] and, less commonly, anabolic steroids if deterioration continues. A multicenter comprehensive study indicated that about 90% of the Japanese patients received corticosteroids and that 80% of those had a good early response 30-49 mg/d). Most nonresponders were able to have a good response to other agents, such as calcineurin inhibitors, octreotide, azathioprine, and anti-TNF alpha agents.[2]

In a case series, two patients had no clinical response to steroids but marked improvement in both clinical symptoms and polyposis after beginning cyclosporine. The authors, in their analysis of medical literature, found that out of 57 patients for which outcomes have been described, 48 patients (84%) responded to steroids whereas 9 patients (16%) did not. Out of these 9 cases, 5 achieved remission with immunosuppresive therapy (calcineurin inhibitors for 4 patients and infliximab for 1).[31]

Antibiotics are indicated for sepsis, peritonitis, and possible small-bowel overgrowth.

Abdominal pain, anorexia, and Hemoccult-positive stools may be related to gastroduodenal mucosal erosions that respond to acid suppression and sucralfate. Flatulence of abdominal pain secondary to distension is addressed by restricting disaccharides, especially lactose, and decreasing small-bowel flora. Dramatic increases in abdominal pain are secondary to perforation or intussusception.

The degree of malabsorption present dictates the form of nutritional therapy. Elimination diets or antiperistaltic agents attenuate diarrhea. Mild malnutrition is reversed with replacement of nutrients, the above measures, and treatment of small bowel overgrowth. Specific antibiotic regimens are not suggested. Elemental diets and parenteral hyperalimentation are required with progressive compromise.

One report suggest that after medical therapy has been initiated, remission of diarrhea usually occurs first (51 d), followed by reversal of dysgeusia (84 d), and then the ectodermal changes (97 d). Decrease in size and number of polyps takes considerably longer (almost 250 d).[2]  The attenuation of polyps often results in a nodular mucosa with a cobblestone appearance.[12]

Some patients were diagnosed only after surgical resection and others have achieved symptomatic remission after the polypoid tissue was removed. Because of the generalized nature of Cronkhite-Canada syndrome and the possibility of operative complications in an elderly and compromised patient population, surgery is usually reserved to treat complications (eg, bleeding ulcers, perforation, intussusception, malignancy).

Among 36 Japanese patients, 37 operations were performed. The indications were for 19 colon cancers, 7 gastric cancers, 3 gastroduodenal adenomas, 4 intussusception cases, 2 GI bleeding cases, 1 gastric gastrointestinal stromal tumor, and 1 severe enteric protein loss case. No mortalities were reported in this series, and the mean duration of posttreatment survival was 5 years (range of 0-14 years).[2]  

Newer imaging techniques such as the capsule endoscopy and technetium Tc 99m–labeled human serum albumin nuclear medicine scans can enable surgeons to identify specific regions of the bowel that have either suspicious lesions or more active malabsorption. These hold promise for directing limited resections and improving overall outcomes.

The team that successfully cares for a patient with Cronkhite-Canada syndrome includes a nutritional support group, a surgeon, and a gastroenterologist able to perform diagnostic and therapeutic endoscopy.

Parenteral or enteral nutritional therapy has been used in about half of the Japanese patients who received corticosteroids. No difference was reported in early response between patients receiving this form of therapy and those who did not.[2]

As outlined above, dietary requirements evolve as the mucosal involvement varies. Preservation of an adequate nutritional status is essential to minimize morbidity.

The overall clinical condition of the patient determines the level of physical activity. Prophylactic dietary or activity modifications are not recommended as prevention for Cronkhite-Canada syndrome.

The goals of therapy are to restore nutritional adequacy and prevent complications. The most significant problem to avoid is CCS-related cancer. The experience in Japan has demonstrated that sustained improvement demonstrated by serial endoscopies correlated with a decreased risk of cancer and mortality. Among 66 patients with sustained endoscopic remission, only one new case of cancer was reported. However, among 42 patients who did not achieve long-term response, the risk of cancer was 40%, and the risk of CCS-related death was 16% risk.[2]

A generalized algorithm for treating CCS, such as one that addresses the use of any specific pharmacologic agent or nonstandard dosages, has not been established. Therapy is always supportive and includes vigorous fluid and electrolyte replacement and maintenance of macronutrient and micronutrient requirements. Antibiotics are given orally to treat small-bowel overgrowth or parenterally to treat systemic infections. Broad-spectrum coverage should be provided to patients with immunocompromise. Corticosteroids (30-49 mg prednisolone/day) have been widely used in Japan and have proven to be effective in about 80% of patients. Care should be used to document endoscopic remission of polyposis to avoid early relapse.[2] Other immunosuppressive agents (calcineurin inhibitors, azathioprine, anti-TNG-alpha agents) have been used as steroid-sparing agents or in steroid-refractory patients.

Class Summary

These drugs are presumably used for their anti-inflammatory effect. They elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Hydrocortisone (Solu-Cortef)

Decreases inflammation by suppressing migration of polymorphonuclear (PMN) leukocytes and reversing increased capillary permeability. Data to support use sparse and anecdotal. Corticosteroids often used in combination with other agents. Documentation of spontaneous remissions further obscures picture. Standard corticosteroid dosage, as in other GI inflammatory conditions, is empiric but prudent starting point.

Prednisone (Deltasone, Orasone)

Used for immunosuppression and anti-inflammatory effects. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Data to support use sparse and anecdotal. Corticosteroids often used in combination with other agents. Documentation of spontaneous remissions further obscures picture. Standard corticosteroid dosage, as in other GI inflammatory conditions, is empiric but prudent starting point.

Although remissions may persist for longer than 10 years, patients must be monitored for nutritional deficiencies.

Patients should  also regularly undergo upper endoscopy and colonoscopy because 10% of patients with Cronkhite-Canada syndrome develop GI (stomach, colon) cancer. Guidelines for colorectal cancer screening have been established by the American College of Gastroenterology.[32] . The authors of a large multicenter Japanese studying describing over 200 patients suggest annual surveillance colonoscopy.[2]

Steroid therapy, which is expected to diminish the inflammatory polyp burden, should precede endoscopic surveillance to assist in the identification of malignancy. Advanced endoscopic techniques, including narrow-band imaging, magnifying endoscopy, and dye-based contrast-enhanced techniques, have been used to improve sensitivity.[2]

Hyperalimentation, including electrolytes, minerals, protein, vitamins, dextrose, and lipids, are indicated in the face of clinically significant losses of nutrients and fluid from the GI tract.

Monitor the patient for impending surgical complications.

The literature does not support prophylactic therapy.

All therapy should be individualized for the patient's specific symptoms and complications.

Consider transferring the patient to an intensive care unit for surgical intervention, diagnostic and therapeutic GI endoscopy, and parenteral hyperalimentation.

Specific recommendations are not available.

Epidemiologic data do not suggest specific infectious etiology.

Maintenace of adequate nutritional status, including normal levels of vitamins, is essential to minimize complications.

Complications include the following:

• Dehydration, electrolyte abnormalities, and shock

• Kwashiorkor and various nutritional deficiencies

• Small bowel overgrowth, systemic infections, and sepsis

• Anemia related to GI blood losses and deficiencies

• Edema, anasarca, and congestive heart failure

• Thromboembolic phenomena

• Reportedly high rates of surgical complications

• Secondary immune deficiencies

• Malignant transformation: After diffuse inflammatory polyps have responded to steroid therapy, other existing adenomas require endoscopic treatments, which can decrease the possibility of neoplastic transformation.[17]

Early reports indicated a grave prognosis. Large series have shown that more than one half of affected patients have a remission; long-term survivors are reported.

Survival largely depends on adequate and sometimes prolonged intensive care.

Although the diagnosis depends on alopecia, nail dystrophy, or pigmentation changes, the prognosis is related to only the GI mucosal pathology.

Patients who go into remission should promptly report any change in GI symptoms or weight loss to their physicians.

Regular surveillance endoscopy is important for long-term survivors.

Patients should be reassured that Cronkhite-Canada syndrome is neither contagious nor familial.