Cronkhite Canada syndrome

Cronkhite-Canada syndrome also called Canada-Cronkhite disease, is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems ¹. Worldwide, over 500 Cronkhite-Canada syndrome cases have been reported in the past 50 years, primarily in Japan but also in the United States and other countries ². Based on the large Japanese series, the estimated incidence of Cronkhite-Canada syndrome is about 1 case per million population ². Cronkhite-Canada syndrome is difficult to treat because of malabsorption that accompanies the polyps. Cronkhite-Canada syndrome occurs primarily in the older population (average age 59 with a range of 31 to 86 years) and predominantly occurs in males. The ratio seems to be approximately 3 males to 2 females ³. The reported cases of infantile Cronkhite-Canada syndrome are scant (< 10) ⁴. Cronkhite-Canada syndrome is considered to be an acquired, not hereditary disease.

Cronkhite-Canada syndrome treatment is based on controlling symptoms and providing support. The primary goal of treatment is to correct fluid, electrolyte and protein loss by nutritional supplementation or a nutritionally balanced liquid diet. Corticosteroids (i.e., prednisone) may be given occasionally to help reduce intestinal inflammation. Bacterial overgrowth in the intestines, which can cause malabsorption, may be treated with antibiotics. In rare cases, symptoms have resolved for no apparent reason (spontaneous remission).

Surgical removal of polyps may help to relieve some of the symptoms of Cronkhite-Canada syndrome. However, they may recur or be too numerous to remove individually. If necessary, severely affected portions of the colon may be removed. Case reports have suggested the use of immunosuppressive treatment, including aziathioprin and ciclosporin, if other treatments are not effective.

Figure 1. Cronkhite Canada disease

Cronkhite Canada syndrome causes

The exact cause of Cronkhite-Canada syndrome is unknown. It seems to occur for no known reason (sporadically) and is not thought to be hereditary.

The possibilities of asymptomatic offspring or afflicted patients have not been excluded. Reports suggest immune dysregulation as the basis of Cronkhite-Canada syndrome ⁵. Many patients with Cronkhite-Canada syndrome have positive antinuclear antibodies (ANA) as well as a variety of autoimmune diseases such as systemic lupus erythematous (SLE), rheumatoid arthritis, scleroderma, polymyalgia rheumatica, or hypothyroidism ⁶. Cronkhite-Canada syndrome patients have also been found to have elevated serum IgG4 levels. Positive results for immune staining of IgG4 plasma cells in stomach and colonic polyps have been also reported from patients with Cronkhite-Canada syndrome ⁷. The autoimmune etiology is further supported by the excellent clinical response to systemic steroids and azathioprine ⁸.

Negoro et al ⁹ 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 (Cowden disease), is not detected in persons with Cronkhite-Canada syndrome. Boland et al ¹⁰ performed whole exome sequencing on germline DNA from blood samples and polyp tissue from a gastric and a colonic polyp. The polyps did not share common nonsilent somatic mutations, suggesting distinct origin without a common molecular pathway. On germline analysis, they identified a rare variant affecting PRKDC, protein kinase DNA-activated catalytic polypeptide (DNA-PKcs).

Senesse et al ¹¹ described Cronkhite-Canada syndrome in association with arsenic poisoning.

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 syndrome. Clostridium difficile is isolated quite frequently in the stool. The exact cause of diarrhea is not clear. The symptom is 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 ¹². Elevated gastric acid secretion also was found in one reported case.

Ectodermal changes (ie, hyperpigmentation, alopecia, nail dystrophy) are believed to be due to protein loss and malabsorption; however, cutaneous manifestations preceded onset of diarrhea in many patients with Cronkhite-Canada syndrome. Authors suggest 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 ¹³. Moreover, based on the latest scalp biopsy histological findings, the hypothesis of an autoimmune causality for Cronkhite-Canada syndrome hair loss have been proposed ¹⁴. Regrowth of hair was noted after treatment, during spontaneous remission, and even during active disease. Hyperpigmentation also was noted to be reversible after and without any specific therapy.

Presence of edema correlates well to hypoalbuminemia.

Neurologic or psychotic symptoms occurred as a cause of hypocalcemia, hypomagnesemia, and hypokalemia.

Mild-to-moderate anemia is secondary to malabsorption (ie, iron, vitamin B-12, folate deficiency), blood loss, or both. A case of Cronkhite-Canada syndrome concomitant with myelodysplastic syndrome has been diagnosed ¹⁵.

Cataract progression likely is associated with hypoproteinemia and hypocalcemia. Low calcium levels in the aqueous humor were believed to promote changes in lens membrane permeability and subsequent membrane disruption. A flux of sodium ions was postulated to occur from the aqueous into the lens, resulting in overhydration and production of a cortical lens opacity.

The cause of macrocephaly, typically present in cases of the juvenile Cronkhite-Canada syndrome, is unknown. An increase of arachnoid cysts was demonstrated.

Cronkhite Canada syndrome pathophysiology

Gastrointestinal lesions in Cronkhite-Canada syndrome are hamartomatous polyps generally involving the entire gastrointestinal tract except for the esophagus ¹⁶. Histologically they reveal pseudopolypoid-inflammatory changes. One report describes an esophageal squamous cell papilloma ¹⁷.

Cutaneous symptoms are believed to be due to malabsorption; however, ectodermal changes did not appear to parallel the disease activity and improved despite gut dysfunction in some reported cases. Multiple brownish macules and patches also preceded the onset of gastrointestinal symptoms in one of the first reported cases of Cronkhite-Canada syndrome.

Infantile Cronkhite-Canada syndrome (similar to typical Cronkhite-Canada syndrome) includes juvenile gastrointestinal polyps, alopecia, nail changes, and macrocephaly. 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, parental consanguinity was not present in either described case. This raises the question of whether infantile Cronkhite-Canada syndrome may be a sporadic condition ⁴.

Cronkhite Canada syndrome symptoms

The symptoms of Cronkhite-Canada syndrome occur because of multiple polyps occurring in the stomach, small intestine, colon and, less frequently, the esophagus. These include chronic or recurring watery diarrhea, cramps, and abdominal discomfort. These people may also have abnormally low levels of protein in the blood (protein-losing enteropathy), causing a feeling of general ill health (cachexia), malnutrition, nausea and vomiting.

The earliest symptoms reported are changes in taste and loss of smell. Patients can even experience a profound loss of appetite, sometimes to the point of malnutrition, weight-loss and/or excess fluid accumulation in the arms and legs (peripheral edema). An imbalance of certain essential minerals (electrolytes) may occur because of chronic diarrhea. Some people with Cronkhite-Canada syndrome may also have large skin bruises (ecchymotic plaques) and/or impaired lung function. Other symptoms may include loss of hair (alopecia), large areas of dark spots on the skin (hyperpigmentation) and degenerative changes and, eventually, loss of the fingernails (onychodystrophy).

Patients with Cronkhite-Canada syndrome can also have coexisting autoimmune disorders, where the body develops antibodies against an organ, thereby attacking itself, e.g. hypothyroidism, rheumatoid arthritis, scleroderma, systemic lupus erythematous, etc.

Cronkhite Canada syndrome diagnosis

The diagnostic criteria for Cronkhite Canada Syndrome is based on symptoms and particular features; however, there is no specific diagnostic test for this syndrome. The mean age of onset is 60, ranging from 31 to 86 years old. There are usually large numbers of polyps in the digestive tract, most often sparing the esophagus. The polyps have hamartomatous features, meaning they contain mucus and are inflamed within an intact surface.

Besides the gastrointestinal tract, findings in the skin are also diagnostic for this disease. Patients experience alopecia (loss of hair), dark spots on the skin of the arms, legs and face (hyperpigmented macules) and have a loss of finger nails (onychodystrophy).

One test that can be positive with this syndrome is IgG4 plasma cells but a negative test does not rule out the syndrome. The most important aspects for a diagnosis of Cronkhite Canada Syndrome are the aforementioned physical presentations as there is no particular test to provide a definitive diagnosis of the syndrome.

Laboratory studies

Various laboratory studies may include the following:

• Electrolyte and micronutrient determination – Hypokalemia; hypocalcemia; depressed serum levels of zinc, iron, copper, and magnesium; and vitamin B-12
• Hematology – Depressed white blood cell count, hemoglobin, red blood cell count, and hematocrit
• 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.
• Biochemical and hematologic tests – Total protein level; albumin level; glucose and lipids concentration; iron, magnesium, zinc, calcium, sodium, potassium, and copper concentrations; ESR; CRP
• Decreased cholinesterase activity
• Stool examination – Occult blood and Sudan III staining
• Helicobacter pylori infection test

Imaging studies

Endoscopic also wireless capsule endoscopy) procedures (ie, panendoscopy, gastroscopy, colonoscopy, sigmoidoscopy) reveal polyp lesions of the sessile or semipedunculated type throughout the stomach, duodenum, ileum, and colon, sparing the esophagus ¹⁸. Ikeda et al ¹⁹ found pedunculated polyps in patients with Cronkhite-Canada syndrome. A few reports have described selective sparing of the stomach, small intestine, and/or the colorectum. Lesion size has varied from a few millimeters to 2 cm in diameter ²⁰. Endoscopic findings in the stomach also include reddish and edematous granular lesions with mucoid exudate and giant folds.

Murata et al ²¹ applied a prototype of a magnifying single-balloon enteroscope to observe the entire small bowel intestine in a patient with Cronkhite-Canada syndrome. Further analysis should be done to investigate its usefulness as a diagnostic tool.

Abdominal CT scanning may reveal thickened gastric folds.

Regarding radiography, a barium enema and small intestine double-contrast radiology examination show polypoid lesions.

A CT endoscopy using a multidetector-row CT scan with 3-dimensional reconstruction has been shown to be useful for the detection of Cronkhite-Canada syndrome polyps and for the monitoring of effects of therapy ²².

Magnified chromoendoscopy with crystal violet reveals sparsely distributed crypt openings with widening of the pericryptal space on the surface of the polyps and the intervening colonic mucosa ²³.

Fluoroscopic examination of the stomach may show rough granular changes of the mucosa with edematous giant rugae and polypoid lesions.

Scintigraphy using technetium Tc 99m–labeled human albumin may result in leakage to the gastrointestinal tract.

Consider intraoperative or postoperative examination of p55 immunoreactivity accumulation in the tissue suspected of having a carcinomatous component.

Other tests

Other tests may include the following:

• Presence of antinuclear antibodies, usually with a nucleolar pattern
• Malignancy markers (carcinoembryonic antigen, alpha-fetoprotein)
• D-xylose absorption test (impaired)
• Glucose tolerance test (may be impaired)
• Fecal fat excretion (increased)
• Gastrointestinal clearance of alpha-1 antitrypsin (usually elevated)
• Culture of nail scrapings for fungi (for differential diagnosis)
• HIV testing (possibly)
• Stool culture for C difficile, Salmonella, Shigella, Yersinia, and Campylobacter species and for parasites
• 14C-xylose breath test – Bacterial overgrowth syndrome, small intestinal bacterial overgrowth ⁶

pathology

Hyperpigmentation is related to an increase in melanin within the basal layer with or without the melanocyte proliferation, pigment incontinence, hyperkeratosis, and nonspecific perivascular inflammation ²⁴.

Ong et al ²⁵ reported an increased number of telogen hair follicles, hair follicle miniaturization, presence of pigment casts and peribulbar lymphoid cell infiltrate. These findings point to alopecia areata incognito as the probable cause of hair loss in Cronkhite-Canada syndrome (Cronkhite-Canada syndrome). This variant of alopecia areata is characterized by acute diffuse hair thinning.

Such results contrast those formerly reported by Watanabe-Okada et al ²⁶ in two patients with Cronkhite-Canada syndrome. They described a diffuse anagen-telogen conversion with increased telogen hair follicles in the absence of miniaturization or hair follicle inflammation, previously suggesting that acute telogen effluvium triggered by malnutrition was the preceding factor inducing hair loss in Cronkhite-Canada syndrome. Given the complex spectrum of the syndrome, further research on scalp biopsies is required.

A case report presented the histologic evaluation of a nail matrix biopsy showing hypergranulosis. Matrix hypergranulosis is a common finding in numerous inflammatory nail diseases, suggesting that nail changes found in Cronkhite-Canada syndrome could be an inflammatory reaction, rather than a consequence of malnutrition as previously believed ²⁷.

Histologically, polyps in patients with Cronkhite-Canada syndrome are pseudopolypoid-inflammatory changes with cystic dilatation. Ikeda et al ¹⁹ found that some of the colon polyps presented a histologic pattern of a tubulovillous adenoma and others exhibited that of a juvenile-type polyp. The latter polyps were characterized by the presence of elongated and/or tortuous crypts with microcystic dilatation and inflamed edematous wide stroma. The areas of focal intestinal metaplasia were present. Even though cellular atypia was present, the adenomatous polyps showed histologic similarity to juvenile polyps with inflamed edematous stroma and occasional cystic glands. Extensive diffuse mucosal thickening has been reported instead of individual polyp growth. Often, this diffuse thickening, possibly an early active stage of disease, is seen in the upper gastrointestinal tract, leading to giant gastric and/or duodenal rugal folds ²⁸. Although rare, flat or atrophic mucosa has also been described in patients with Cronkhite-Canada syndrome ²⁰.

According to Burke and Sobin ²⁹, 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 a minority has surface erosions. Gastric Cronkhite-Canada syndrome polyps are quite similar to juvenile or hyperplastic polyps. Prominent mast cells, eosinophils, and IgG4 plasma cell infiltration have all been reported as well ³⁰.

The most constant features of Cronkhite-Canada syndrome polyps are a sessile base, an expanded edematous lamina propria, and dilated glands. Other features, including inflammation, a small number of smooth muscle fibers, and a complex contour, are variable.

Cronkhite Canada syndrome treatment

Because of the unknown cause, treatment for Cronkhite-Canada syndrome remains predominantly symptomatic. Controlled therapeutic trials have not been possible because of the rarity of the disease. Remissions may occur spontaneously.

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. 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 (nutritional supplements). Antibiotics are used to correct intestinal bacterial overgrowth syndrome. The indication for corticosteroids is gastrointestinal inflammation; however, its origin is not clear. Yamakawa et al ¹⁵ reported two cases of steroid-resistant Cronkhite-Canada syndrome that were effectively treated with cyclosporine. Dramatic improvement of clinical symptoms and endoscopic findings were observed in both cases. Another case in which multiple treatments, including steroids, azathioprine, adalimumab, and cyclosporine, failed was treated with sirolimus, with apparent clinical and endoscopic remission of the disease ³¹. One case has been reported to be treated with rituximab ³².

Reports describe clinical response in Cronkhite-Canada syndrome to tumor necrosis factor (TNF) inhibitors, with improvement of symptoms, weight gain, and polyp regression. These findings reinforce the theory of this syndrome’s inflammatory etiology ³³. Immunosuppression in Cronkhite-Canada syndrome patients should be cautiously performed, owing to the potential accelerated malignancy risk.

Nutritional supplementation includes oral and/or intravenous fluids, electrolytes, vitamins, minerals, amino acids, albumins, and lipids.

Transfusions are sometimes required for severe anemia or acute blood loss.

In one reported case with elevated gastric acid secretion, the patient responded very well to ranitidine therapy ³⁴. Other medications used are sulfasalazine and metronidazole.

After Helicobacter pylori eradication, gastric polypectomy can be of value ¹².

Emergent re-admission of patients with Cronkhite-Canada syndrome may occur because of significant diarrhea, gastrointestinal bleeding, intussusception, prolapse of gastric polyp-bearing mucosa, and thromboembolic episodes due to dehydration.

Surgical care

At present, surgery is needed only for complications of Cronkhite-Canada syndrome, such us prolapse, bowel obstruction, and malignancy. Other authors suggest that surgical intervention should also be reserved for patients who are not responsive to conservative methods.

Surgical intervention carries a significant risk in weakened patients with Cronkhite-Canada syndrome. Careful consideration must be given to the clinical course of Cronkhite-Canada syndrome before administration of systemic corticosteroids.

Long-term monitoring

Some Cronkhite-Canada syndrome patients remain asymptomatic after the hospital treatment and do not require further therapy. Prolonged corticosteroid therapy is necessary in other patients.

Controlling the macronutrient and micronutrient balance, periodically performing endoscopic examination of the gastrointestinal tract, and testing for occult blood presence in the stool are recommended.

It is essential to explain that patients must be reliable with follow-up care and regular examination of the gastrointestinal tract. Large polyps (>1 cm in diameter) require biopsy and pathologic examination.

Cronkhite Canada syndrome prognosis

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. The mortality rate exceeds 50% regardless of therapy. The longest-surviving patients were alive 15 and 17.5 years after successful surgical treatment.

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 ³⁵.

The first two described patients with Cronkhite-Canada syndrome died of starvation 7 and 8 months after the onset of symptoms.

Cases of spontaneous remission after nutritional support have been reported.

The prognosis in children is believed to be generally less optimistic than in adults.

Causes of death are attributable to severe cachexia, anemia, congestive heart failure, embolism, shock, bronchopneumonia, and postoperative complications. One third of patients die from intractable nutritional deficiency.

Appropriate corticosteroid therapy alongside nutritional support can alter the natural history of Cronkhite-Canada syndrome. Lasting polyp regression is associated with a markedly improved prognosis and decreased risk of cancer ³⁶.

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