Cronkhite-Canada syndrome (ORPHA:2930)
Cronkhite-Canada syndrome (CCS) is a rare gastrointestinal (GI) polyposis syndrome characterized by the association of non-hereditary GI polyposis with the cutaneous triad of alopecia, nail changes and hyperpigmentation.
Epidemiology
To date, there have been more than 500 cases reported worldwide. Individuals of European and Asian descent are most often affected, with most case reports emerging from Japan. A slight male predominance has been reported.
Clinical description
The mean age of onset is 59 years, but the age at presentation may vary from 31 to 85 years. Presenting symptoms include watery diarrhea with stool volumes of 4-6 L (steatorrhea and melena may also occur), dysgeusia, dry mouth, partial or total lack of appetite, weight loss (often >10 kg), constant or episodic abdominal pain, and weakness. Diarrhea is usually followed by a variable sequence of onychodystrophy (including onycholysis, thinning of the nail plate, onychoschizia and onychomadesis), alopecia (initially patchy, rapidly leading to complete hair loss), and hyperpigmentation (diffuse light-to-dark brownish macules and plaques, and patchy vitiligo) distributed on the palms and soles, upper extremities, face, and chest. More than 10% of CCS patients develop GI cancer (mostly in the sigmoid colon and rectum). Neurologic symptoms (numbness and tingling in the extremities, dysphagia and convulsions) and autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, scleroderma (see these terms), hypothyroidism and membranous glomerulopathy) have been reported in some patients. The GI lesions are usually generalized. The stomach and colon almost always contain polyps and the small bowel is affected in more than 50% of cases. The esophagus is less frequently involved. Common complications include GI bleeding, malabsorption, malnutrition, and infection.
Etiology
The pathogenesis of CCS is still elusive but an immune-mediated process has been proposed and this hypothesis is supported by the increased systemic levels of immunoglobulin G4 and antinuclear antibody found in CCS patients as well as the higher frequency of autoimmune disorders associated with CCS. The cutaneous manifestations of CCS have been attributed to malabsorption and malnutrition caused by the GI pathology. Dysgeusia and dry mouth might result from mucositis or oral infections secondary to malnutrition but other mechanisms may be involved.
Diagnostic methods
Diagnosis relies on clinico-pathological features with the correlating cutaneous, radiological, endoscopic and pathological findings. Endoscopic evaluation may reveal multiple sessile polyps in the stomach, small bowel, colon and rectum. Histopathological examination of biopsies may show different types of polyps (hyperplastic or adenomatous (with malignant potential), juvenile, hamartomatous and inflammatory) in the same patient, necessitating resection and/or surveillance. Laboratory parameters reveal normocytic, normochromic anemia, vitamin deficiency, hypoproteinemia and hypoalbuminemia.
Differential diagnosis
Differential diagnosis includes familial adenomatous polyposis, hyperplastic polyposis syndrome, cap polyposis, juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome (see these terms), as well as lipomatous polyposis, inflammatory polyposis and lymphomatous polyposis.
Genetic counseling
CCS occurs sporadically so there is no risk of intrafamilial transmission.
Management and treatment
Current treatments, which can be used individually or in combination, include steroids, nutritional therapy (fluid, electrolyte, protein and vitamin supplementation and, if necessary, an elemental diet or parenteral nutrition), 5-aminosalicylate acid, histamine H2 receptor antagonists, anti-tumor necrosis factor alpha agents, immunomodulators, and eradication of Helicobacter pylori. Regular surveillance for GI malignancy is recommended as development of colorectal or gastric cancer has been reported in 10 to 15% of cases.
Prognosis
The clinical course of CCS is progressive with occasional spontaneous remissions and frequent relapses, and with rare progression to malignancy. The 5-year mortality rate of CCS can be as high as 50 % (mainly due to GI malignancy or portal vein thrombosis, infection and membranous glomerulonephritis), even with treatment.

                            Last update: 
                            May 2016


                            - Expert reviewer(s): 
                            Pr Jean-Alain CHAYVIALLE  - Pr Jean-Christophe SAURIN