Francesca Dughera, Sara Baino
Introduction
Cronkhite-Canada syndrome (CCS) is a rare noninherited disorder reported for the first time in 1955 by Leonard W. Cronkhite Jr, and Wilma J. Canada as a new distinct clinical entity in 2 female patients with generalized gastrointestinal polyps, cutaneous pigmentation, alopecia, and onychodystrophy.
It is sporadic and it is currently considered acquired and idiopathic.
Cronkhite-Canada syndrome has a worldwide distribution and 75% of reports come from Japan. It is a rare disorder in fact at the end of 2002, only 467 cases have been reported in the world literature, 354 of which were reported by Japanese groups. Cronkhite-Canada syndrome seems to affect both sexes almost equally. The male-to-female ratio is approximately 1.5-1.3:1.
The typical onset of Cronkhite-Canada syndrome is during middle or old age. The average age is 55 years; the range is 31-86 years. Vernia et al have suggested that the disease may remain asymptomatic, thus not being diagnosed for a long time. Most patients are older than 50 years at the time of presentation.
Cronkhite-Canada syndrome:Wikipedia, February 2014
Symptoms
Cronkhite-Canada syndrome is characterized by the association through gastrointestinal polyposis and dermatologic triad: hyperpigmentation, hair loss, and dystrophic changes in the fingernails.
- as far as gastrointestinal symptomps are concerned patients' principal complaints start with a constant or episodic pain in the lower or upper abdomen. Intensity varies from mild and localized to severe and generalized. Pain is accompanied by chronic or recurrent watery diarrhea, sometimes melena. Watery bowel movements may occur 5-7 times per day, and stool volume as high as 4-6 L/d. Progressive weight loss follows the diarrhea and most patients lose more than 20 kg during the course of the disease. Chronic diarrhea and protein-losing enteropathy are often observed but the exact etiology of diarrhea is not clear.
Change in taste sensation and loss of smell, with or without hypogeusia, is an early symptom and it leads to anorexia. Other gastrointestinal symptoms are nausea and vomiting, apparently more frequent in female patients, and also swallowing difficulties.
Polyps are presented in the entire alimentary tract except the esophagus, because of that it is named “carpetlike” polyposis, The polyps are multiple sessile or semipedunculated and they range from 0.5-2 cm in diameter. Stomach mucosa changes into a rough granular shape with edematous giant rugae. The polyp-like samples of mucosa, hyperplasia, and adenoma is characterized by acute or chronic inflammation.
The principal gastrointestinal symptoms, weight loss, and weakness probably are due to altered digestive, motive, absorptive, and secretory functions of the gut and bacterial overgrowth. Clostridium difficile is isolated quite frequently in the stool. The symptoms are likely related to the presence of polyps; however, the impaired bowel motility may cease without alteration of the size and number of polyps. Gastric polyps have been found to be infected with Helicobacter pylori.
Almost 40 cases of colorectal cancer have been reported in association with Cronkhite-Canada syndrome, adenocarcinoma arise from the mucosal hyperplasia. These cases include patients with polyps containing serrated adenoma lesions.
- In the matter of dermatologic symptoms they are caused by malnutrition as a result of protein-losing enteropathy. Recent findings have called this hypothesis into question; specifically, the hair and nail changes may not improve with improved nutrition. However, cutaneous manifestation precedes onset of diarrhea in some patients with Cronkhite-Canada syndrome. It suggests that ectodermal changes are an inherent part of the syndrome, not secondary to malabsorption, because similar ectodermal lesions do not appear in other protein-losing gastroenteropathies. Patients typically experience:
1) Alopecia that occurs rapidly and total hair loss happens in a few days. In most patients, it takes place simultaneously from the scalp, eyebrows, face, axillae, pubic areas, and extremities.
2) Ectodermal lesions: skin-spotty with lentigolike macules ranging from a few millimeters to 10 cm in diameter, and diffuse hyperpigmentation. This is notably localized on the dorsal surface of the hands, palms, arms, neck, face, scalp, anterior chest region, and body folds. Moreover patients may present ill-defined brown patches on the perioral and buccal areas with swollen tongue and loss of papillae, and patchy vitiligo.
3) Fingernails and toenails show discoloration, proximal nail plate separation and shedding, onychoschizia, splitting of nails into layers, and onychomadesis, nail shedding staring at the base and extending forward. All of these lead to onycholysis, which means detachment of the nail from the nail bed, starting at its distal and/or lateral attachment.
- The disease may include also some neurological symptoms such as sensory neuropathy, seizures, syncope, and/or vestibular disturbances such as gaze-evoked nystagmus, dysequilibrium. Neurologic or psychotic symptoms occurre as a cause of hypocalcemia, hypomagnesemia, and hypokalemia.
In two cases, Cronkhite-Canada syndrome was preceded by a blistering episode: one case described subepidermal blisters and antibasement membrane zone antibodies in direct immunofluorescence, suggesting epidermolysis bullosa acquisita. The second case reported blistering eruption as a form of drug-induced erythema multiforme.
In another reported case, the characteristic changes of Cronkhite-Canada syndrome developed two months after hemicolectomy of the descending colon for a carcinoma and three neighboring polyps, followed by four weeks of chemotherapy.
In children the disease lead to a symmetric desquamating rash on the lower back, buttocks, genital area, lips, and perioral region, similar to skin lesions in acrodermatitis enteropathica (zinc deficiency). Macrocephaly is also a typical sign of infantile Cronkhite-Canada syndrome. The cause of it is unknown. An increase of arachnoid cysts was demonstrated. Infantile Cronkhite-Canada syndrome is believed to be a special variant of juvenile gastrointestinal polyposis. Its mode of inheritance is assumed to be autosomal recessive; however, paternal consanguinity is not present in either described case. This raises the question of whether infantile Cronkhite-Canada syndrome may be a sporadic condition.
All the symptoms described until now may refer to the symptoms of a lead poisoning and a block of the heme synthesis.
As far as lead poisoning is concerned, the typical signs are gastrointestinal, neuromuscular, on the central nervous system, renal and haematological. The gastrointestinal syndrome is more frequent in adults and it has the same features as Chronkite-Canda, such diarrhoea, vomiting, abdominal pain, lack of appetite and anorexia. On the other hand the nervous manifestation is more common in children and it include: headache, dizziness, insomnia, restlessness and all the other symptoms that characterize also Cronkite-Canada syndrome. In conclusion the more interesting matching through these diseases is the rule of heme. The lead poisoning cause a microcytic hipocromic anemia, that is similar to the one due to lack of iron. This has two different causes: the reduced life of the erythrocytes and the block of heme synthesis. The inhibition is on two enzymes of the biosynthetic pathway: delta-ala-dehydratase and iron.caralase, which include iron in the protoporphirin. Because of the polyposis Chronkite-Canada syndrome has iron maladsorption and it confirms heme block. Finally that is evident also in dermatological symptoms, especially alopecia and the ones on fingernails and toenails, which are related to vitamin D,that need heme to be activated.
Cronkhite-Canada Syndrome:Review of the Literature, November 2013
Pathophisiology
The etiology of the disease is unknown and there is no evidence exists to suggest a familial predisposition. The possibilities of asymptomatic offspring or afflicted patients have not been excluded. Mental and physical stress have been postulated as the most important risk factors for Cronkhite-Canada syndrome. The stress acts on the gastrointestinal mucosa, inducing a local inflammatory reaction. One patient with Cronkhite-Canada syndrome developed typical ectodermal lesions two weeks after starting oral thyroxine, and the cutaneous signs improved following cessation of the treatment.Cronkhite-Canada syndrome is considered a relentlessly progressive disease with a variable course and poor prognosis depending mainly on control of protein and electrolyte balance. Mortality rate exceeds 50% regardless of therapy and the prognosis in children is believed to be generally less optimistic than in adults. The first 2 described patients with Cronkhite-Canada syndrome died of starvation 7 and 8 months after the onset of symptoms but cases of spontaneous remission after nutritional support have been reported. As reported in cases of Cronkhite-Canada syndrome, coexistent malignant changes in the polyps, gastrointestinal bleeding, and the possibility of intussusception or prolapse of gastric polyp-bearing mucosa increase the mortality.
There are different theories about the disease’ etiology which have been found by different teams:
- Negoro et al demonstrated that germlike mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue), located at 10q23.3, which is responsible for another gastrointestinal polyposis syndrome named Cowden disease is not detected in persons with Cronkhite-Canada syndrome.
- Senesse et al described Cronkhite-Canada syndrome in association with arsenic poisoning.
- Murata et al suggested the possible role of an autoimmune response in the pathogenesis of
Cronkhite-Canada syndrome because of the presence of antinuclear antibodies in a serum of a patient with Cronkhite-Canada syndrome who had a history of chronic pityriasis lichenoides. The effectiveness of corticosteroid therapy in many cases of Cronkhite-Canada syndrome seems to support the involvement of the immune system in the pathogenesis of Cronkhite-Canada syndrome.
Cronkhite-Canada Syndrome, January 2014
Diagnosis
Cronkhite-canada syndrome often has characteristic features. Usually, it is not difficult to distinguish CCS from other polyposis syndromes, as each exhibits its own characteristic clinicopathology. Other conditions consisting of multiple hamartomatous polyps of the digestive tract include Peutz-Jeghers syndrome, juvenile polyposis, familial adenomatous polyposis, hyperplastic polyposis, and Cowden disease.
Diagnosis is based on history, physical examination, endoscopy with finding of gastrointestinal polyposis, and histology.
Laboratories studies include:
- biological and haematological tests that show:
- electrolyte and micronutrient determination: hypokalemia, hypocalcemia and depressed serum levels of zinc, iron, copper, magnesium and vitamin B-12.
- Hematology: depressed white blood cell count, hemoglobin, red blood cell count, and hematocrit. Mild-to-moderate anemia is secondary to malabsorption (ie, iron, vitamin B-12, folate deficiency)
- Serum proteins: Hypoproteinemia with hypoalbuminemia; increased in alpha1 globulin level
- Raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
- Elevated serum levels of gastrin, histamine-fast achlorhydria, hypochlorhydria.
- Decreased cholinesterase activity
- Stool examination - Occult blood and Sudan III staining and H pylori infection test
Imaging studies incude:
- Endoscopic procedures, also wireless capsule endoscopy, such as gastroscopy, colonoscopy, sigmoidoscopy. They reveal polyp lesions of the sessile or semipedunculated type throughout the stomach, duodenum, ileum, and colon, sparing the esophagus. Their size varied from a few millimeters to 2 cm in diameter.
Endoscopic findings in the stomach also include reddish and edematous granular lesions with mucoid exudate and giant folds.
- Abdominal CT scanning: may reveal thickened gastric folds.
- Regarding radiography, a barium enema and small intestine double-contrast radiology examination show polypoid lesions.
- CT endoscopy using a multidetector-row CT scan with 3-dimensional reconstruction: it’s useful for the detection of Cronkhite-Canada syndrome polyps and for the monitoring of effects of therapy.
- Magnified chromoendoscopy with crystal violet: it reveals sparsely distributed crypt openings with widening of the pericryptal space on the surface of the polyps and the intervening colonic mucosa.
- Fluoroscopic examination of the stomach: it may show rough granular changes of the mucosa with edematous giant rugae and polypoid lesions.
- Scintigraphy using technetium Tc 99m–labeled human albumin:it may result in leakage to the gastrointestinal tract.
Histologic findings show:
- Hyperpigmentation is related to an increase in melanin within the basal layer without the melanocyte proliferation.
- Scalp biopsy shows a marked noninflammatory loss of follicular units, miniaturization of the hair shafts, markedly dilated follicles, and a heavy deposition of glycosaminoglycans in the reticular dermis.
- polyps in patients with Cronkhite-Canada syndrome are pseudopolypoid-inflammatory changes with cystic dilatation.
Cronkhite-Canada syndrome polyps are characterized by their broad sessile base, expanded edematous lamina propria, and cystic glands. The only reliable distinction between Cronkhite-Canada syndrome and colonic juvenile polyposis is the pedunculated growth of the latter, with the exception of the gastric polyps. Gastric polyps in Cronkhite-Canada syndrome are sessile and composed of focally dilated irregular foveolar glands within a lamina propria expanded by edema and often an inflammatory infiltrate.
Most polyps contain smooth muscle fibers in the lamina propria, and mild infiltration of inflammatory cells including eosinophils, massive submucosal edema mostly located in the lamina propria, hyperplasia of the foveolar epithelium, focal hyperplastic features, and cystic dilation of the mucosal glands. In approximately half of the patients, some polyps reveal adenomatous changes with stromal edema and dilated glands.
Microscopic examinations reveal a significant mucosal alteration in all nonpolypoid biopsies, which are more pronounced in small bowel samples. In general, it comprises impaired architecture of crypts, including dilation and branching, edema, and presence of mixed inflammatory infiltrate. The latter is composed mainly of lymphocytes, plasma cells, and eosinophils, with scattered neutrophils. Interestingly, the surface of duodenal, jejunal, and ileal mucosa is rather flat due to subtotal and/or total atrophy of villi.
The challenging diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract: a series of 7 cases with clinical follow-up, February 2014
Treatment
Because of the unknown etiology, treatment remains predominantly symptomatic. Controlled therapeutic trials have not been possible because of the rarity of the disease. Remissions may occur spontaneously. The current literature favours combined therapy based on parenteral nutrition, antibiotics, and corticosteroids. The indication for corticosteroids is gastrointestinal inflammation, however, its origin is not clear.
The primary goal of the treatment is to correct fluid, electrolyte, and protein loss, and to regulate stool frequency. These measures help improve the patient's general condition, but can rarerly lead to complete remission.
Most patients need symptomatic treatment for abdominal pain.
The most effective treatment is combination therapy composed of systemic corticosteroids together with an antiplasmin, an elemental diet, and hyperalimentation. This is nutritional supplementation which comprises oral and/or intravenous fluids, electrolytes, vitamins, minerals, amino acids, albumins, and lipids. Total parenteral nutrition is preferred to enteral nutrition because of the supposed effect of bowel rest.
Antibiotics such as tetracycline and metronidazole are used to correct intestinal bacterial overgrowth. Transfusions because of severe anemia or acute blood loss sometimes are required. Other medications used are sulfasalazine and metronidazole.
Other therapies such as antihistamine receptor agonist agents and cromolyn sodium have also been used as a supplementary therapy in patients where degranulating eosinophils and mast cells are found in biopsies. Because of the apparent autoimmune features of the disease, azathioprine and tacrolimus were given to the patients in some cases. Most studies recommend treatment with proton pump inhibitors or H2 receptor antagonists.
At present, surgery is available only for complications of Cronkhite-Canada syndrome, such us prolapse, bowel obstruction, and malignancy. Moreover, intervention should also be reserved for patients who are not responsive to conservative methods.
Eradication of Helicobacter pylori with clarithromycin, amoxicillin, and lansoprazole is recommended if he patient results positive at the test.
Acute brain syndrome requires psychiatrist consultation.
Cronkhite-Canada Syndrome Clinical Presentation, January 2012
