Background
Cronkhite-Canada syndrome (CCS) is a rare, sporadically occurring, 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 two female patients with generalized gastrointestinal polyps, cutaneous pigmentation, alopecia, and onychodystrophy. [1]
Pathophysiology
The etiology of Cronkhite-Canada syndrome (CCS) is unknown. No evidence exists to suggest a familial predisposition. The possibilities of asymptomatic offspring or afflicted patients have not been excluded. Reports suggest immune dysregulation as the basis of Cronkhite-Canada syndrome. [2, 3, 4, 5] Many patients with Cronkhite-Canada syndrome have positive antinuclear antibodies as well as a variety of autoimmune diseases such as systemic lupus erythematous, rheumatoid arthritis, scleroderma, polymyalgia rheumatica, or hypothyroidism. [6, 7] 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. [8, 9] The autoimmune etiology is further supported by the excellent clinical response to systemic steroids and azathioprine. [2]
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 (Cowden disease), is not detected in persons with Cronkhite-Canada syndrome. [10] Boland et al 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). [11]
Senesse et al described Cronkhite-Canada syndrome in association with arsenic poisoning. [12]
Gastrointestinal lesions in Cronkhite-Canada syndrome are hamartomatous polyps generally involving the entire gastrointestinal tract except for the esophagus. [4, 5, 13] Histologically they reveal pseudopolypoid-inflammatory changes. One report describes an esophageal squamous cell papilloma. [14]
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. [15, 16]
Etiology
The pathogenesis of Cronkhite-Canada syndrome (CCS) is unknown.
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 etiology 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. [17] 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. [18] Moreover, based on the latest scalp biopsy histological findings, the hypothesis of an autoimmune causality for Cronkhite-Canada syndrome hair loss have been proposed. [19] 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. [20]
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.
Epidemiology
Frequency
Cronkhite-Canada syndrome (CCS) has a worldwide distribution; over 500 cases have been reported. [21] The majority of these cases have been documented in Japan, including a large series of 180 patients. [22] Cronkhite-Canada syndrome is a rare disorder. [22, 23, 24, 25] Based on the large Japanese series, the estimated incidence of Cronkhite-Canada syndrome is about 1 case per million population. [22]
Race
No data are available on racial predisposition. Cronkhite-Canada syndrome has a worldwide distribution; however, most reported cases come from Japan.
Sex
Cronkhite-Canada syndrome does show a slight male predominance, with a male-to-female ratio of 3:2. [13]
Age
The typical onset of Cronkhite-Canada syndrome is during middle or old age. The average age is 59 years; the range is 31-86 years. Some reports suggest that the disease may remain asymptomatic, thus not being diagnosed for a long time. [26, 27]
Most patients are older than 50 years at the time of presentation.
The reported cases of infantile Cronkhite-Canada syndrome are scant (< 10). [15]
Prognosis
Cronkhite-Canada syndrome (CCS) 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. [28]
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. [29]
