Pediatric Cronkhite-Canada Syndrome Workup

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%)