The Cronkhite-Canada syndrome (CCS) was a rare, non-hereditary disorder that was originally described in 1955 by Leonard W. Cronkhite, and Wilma J. Canada [1] . The syndrome is characterized by diffuse gastrointestinal (GI) hamartomatous polyps, a unique dermatologic triad of alopecia, skin hyperpigmentation, and onychodystrophy, along with clinical features of diarrhea, weight loss, protein-losing enteropathy, and malabsorptive syndrome.

An 81-year-old Caucasian female with past medical history of hypothyroidism (currently on synthroid) and colon adenocarcinoma status post right hemicolectomy (2006), presented to the GI office with new onset diarrhea and weight loss of 16 lbs over one month. The diarrhea was profuse, 7 - 8 watery stools every day, sometimes associated with fecal incontinence, but without blood, mucus, or abdominal pain. She also had loss of appetite and pruritic rash on the inner thighs. She initially went to ER for the diarrhea, but was found to have pneumonia and treated with levaquin. Her diarrhea continued. Her family history was significant for colon adenocarcinoma, affecting her father, maternal uncle, and two cousins. She lived alone, and denied alcohol, tobacco or illicit drug use. Her physical examination showed rashes on inner thighs, mild bilateral lower extremity edema, and guaiac positive brown stool.

Her blood work showed normal hemoglobin concentration with elevated MCV (107 fL), deceased serum potassium (K), total protein and albumin (K 3.1 mmol/L, serum albumin 2.4 g/dL, total protein 4.7 g/dL). Her other serum electrolytes, liver function tests (liver enzymes [ALT, AST], total bilirubin, and alkaline phosphatase), and 24-hr urine protein were all normal. Her vitamin B12 was low (128 pg/mL), TSH was elevated (8.65 uIU/mL). Her CEA was 5.3 ng/mL (nl < 5). Stool cultures, stool clostridium difficile toxin and celiac panel were all negative.

Computed tomography (CT) of the abdomen and pelvis showed gastric fold thickening, most prominent in the distal gastric body and gastric antrum (Figure 1). She underwent an esophagogastroduodenoscopy (EGD) which revealed prominent gastric folds in the entire stomach, with diffuse edematous mucosa and nodular swelling (Figure 2). Biopsy showed benign hyperplastic/inflammatory polypoid gastric mucosa with focal glandular dilation, and lamina propria expansion (Figure 3). H. pylori staining of the biopsy was positive.

She showed mild improvement after H. Pylori eradication treatment, and was started on B12 supplements. However, her diarrhea recurred again, resulting in a total of 25 lb weight loss, with hair thinning, loss of fingernails, and hyperpigmentation of the skin (Figure 4). Colonoscopy was performed, and showed similar features of edematous, nodular-appearing colonic mucosa (Figure 5). Biopsy reported colonic mucosa with glandular dilation, edema, congestion, chronic inflammation, with focal epithelial inflammatory atypia noted (Figure 6).

She subsequently had an upper GI with small bowel follow through (SBFT), which revealed diffusely thickened and nodular gastric folds and evidence of innumerable tiny nodules or polyps, particularly in the antrum with mild distal small bowel fold thickening (Figure 7). A diagnosis of Cronkhite-Canada syndrome (CCS) was made, and she was started on treatment with proton pump inhibitor (dexlansoprazole 30 mg once daily), medium chain triglyceride diet with ensure plus protein supplements, and steroid (prednisone 40 mg

once daily, tapered by 5 mg every 2 weeks). She was also given low dose Lasix for her peripheral edema, with potassium supplements.

The Cronkhite-Canada syndrome (CCS) is an uncommon, non-hereditary GI hamartomatous polyposis syndrome. Since its first description in 1955, there have been more than 500 cases reported in the literature. So far no germline mutation has been found, and there does not appear to have familial predisposition. It occurs most often in middle-aged or older adults, with a slight male predominance of male-to-female ratio of 3:2 [2] . European and Asian patients appear to be most frequently affected [3] , with 75% of cases being reported in Japan [4] .

The etiopathogenesis of CCS is still unclear. In the past, mental and physical stresses were reported as precipitating factors [4] . Recently, however, there has been increasing evidence of autoimmune mechanism being involved in the process. For example, it was reported that positive immune staining for IgG4 plasma cells are increased in the CCS polyps [5] [6] . There has been associations between CCS and elevated antinuclear antibodies (ANA), as well as some autoimmune diseases (systemic lupus erythematous, membranous glomerulonephritis, rheumatoid arthritis, hypothyroidism, or scleroderma, etc.) [7] [8] . Treatment responses to corticosteroids or azathioprine also suggest possible underlying autoimmune mechanism. H. pylori infection was also reported to be related, and eradication of H. pylori seems to improve symptoms in some cases [9] [10] .

Patients typically present with diarrhea, weight loss, hematochezia, or abdominal pain. The diarrhea is usually 5 - 7 bowel movements a day, and the volume can be as high as 4 - 6 L/day. Hypogeusia or dysgeusia, progressive anorexia, xerostomia, or neurologic symptoms (such as seizures) has also been reported [3] , although our patient did not have these symptoms.

The unique ectodermal abnormalities of CCS include alopecia, onychodystrophy and diffuse skin hyperpigmentation. Alopecia can involve scalp, eyebrows, axillae, pubic areas, and extremities, and eventually complete hair loss in some patients. Onychodystrophic changes include thinning, splitting, spongy change, onycholysis (partial separation of nail from bed), and onychomadesis (loss of fingernails and toenails). The skin hyperpigmentation is usually manifested in the form of brown macules and plaques on the dorsal surface of the hands, palms, face, neck, and soles. This special dermatological triad is an important feature to distinguish CCS from the other hamartomatous polyposis syndromes (see below).

Radiographically or endoscopically, multiple hamartomatous polyps (varies from 5 to innumerable) are diffusely distributed throughout the GI tract, only sparing the esophagus. Histologically, they can be indistinguishable from juvenile polyposis, characterized by cystic gland dilatation, expanded edematous lamina propria, hyperplasia of foveolar epithelium and mild infiltration of inflammatory cells including eosinophils. Most of the polyps in CCS are non-neoplastic, however, it has been reports that serrated adenomas and carcinomas can arise from the CCS polyps, mostly gastric or colonic (sigmoid or rectum more common) [11] - [14] . Due to the rarity of the disease, optimal screening protocol has not been developed, although endoscopic surveillance is suggested.

Our patient presented in the paper had both upper and lower GI polyposis. Her physical examination, endoscopic findings, pathological features, and anatomic distribution of her polyps are all typical for CCS.

The disease course is usually progressive, leading to anemia, electrolyte disturbances, hypoalbuminemia, hypoproteinemia and vitamin deficiencies due to malabsorption and GI losses. The 5-year mortality rate of CCS has been reported to be 55% [4] . Complications of the polyposis can include gastrointestinal bleeding, intussusception and rectal prolapse. However, there have been reported long-term survivors and spontaneous remissions.

The optimal treatment of CCS has not been established because of the rarity of the disorder and the poor understanding of the etiology. Current literature favors a combination therapy including nutritional support, H2 receptor antagonist or proton pump inhibitors (PPIs), immune suppression (corticosteroids, azathioprine and cyclosporine), antibiotics, cromolyn sodium, or surgery [15] . Nutritional therapy and corticosteroids are currently recommended as the mainstay of treatment. Our patient was treated with medium chain triglyceride diet with ensure plus protein supplements, dexlansoprazole, and prednisone.

The differential diagnosis includes a number of gastrointestinal polyposis syndromes (Table 1), which can be classified into 4 groups based on the polyp type: hamartomatous, adenomatous, hyperplastic, and inflammatory. These are distinguished based on the polyp histology, polyp distribution, clinical presentations, family history, and molecular genetic testing.

I declare there are no conflicts of interest.