Medical Management of Cronkhite-Canada Syndrome.

ABSTRACT: We report the case of a patient with Cronkhite-Canada syndrome (CCS) successfully treated with combination medical therapy. This rare, noninherited gastrointestinal polyposis syndrome is associated with characteristic ectodermal abnormalities. The etiology and pathogenesis of CCS are not known. No medical therapy has been shown to be consistently effective, and the disease is usually fatal. The patient described herein was successfully treated with a novel combination regimen consisting of [H.sub.1]- and [H.sub.2]-receptor antagonists, cromolyn sodium, prednisone, and suppressive antibiotics. This regimen has resulted in sustained improvement in symptoms, and follow-up endoscopy has shown regression of the diffuse polyposis. Our patient's response to such therapy may provide insight into the optimal treatment for CCS.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited gastrointestinal polyposis syndrome first described in 1955. (1) The cardinal manifestations of the syndrome are gastrointestinal polyposis, diffuse skin hyperpigmentation, alopecia, and onychodystrophy. (2) The polyps are nonadenomatous juvenile or hamartomatous polyps that occur throughout the gastrointestinal tract except for characteristic sparing of the esophagus. (3) Presenting symptoms in CCS include diarrhea, weight loss, abdominal pain, hematochezia, and hypogeusia. (3) Laboratory evaluation usually reveals evidence of gastrointestinal malabsorption, including anemia, electrolyte disturbances, and hypoproteinemia. (3) The diagnosis is based on these features in the setting of characteristic clinical and endoscopic findings. The pathogenesis of CCS is unknown. The syndrome has never been described in relatives of an affected patient. Most patients are over the acre of 50 at the time of diagnosis, with a mean age of 59 at onset, and there is a slight male predominance. Most patients are of European or Asian descent. (3)

A number of therapeutic agents have been used to treat CCS, but no single medication has been shown to be consistently effective. Corticosteroids, (3-6) anabolic steroids, (3, 7) various antibiotics, (3, 8) dietary supplementation, (3) ranitidine, (9) and symptomatic treatment for diarrhea and abdominal pain (3) have all been used. Patients will rarely achieve remission while being treated with these agents and more commonly have only temporary symptomatic improvement. The optimal therapy for this condition, therefore, is not known.

Cronkhite-Canada syndrome tends to follow a progressive course, with a high rate of mortality despite treatment. Immune dysfunction with an increased susceptibility to infection has also been reported. (10) Fatal complications of the disease include gastrointestinal bleeding, infection, and congestive heart failure. (3) Adenomatous changes in the polyps and carcinomas occurring in the stomach and colon have been reported in association with CCS. (11-15) but whether CCS is truly a precursor of malignancy is controversial.

CASE REPORT

A 68-year-old white man presented with a 7-month history of anorexia, hypogeusia, and watery diarrhea, with an estimated weight loss of 40 lb during this period. Physical examination showed diffuse hyperpigmentation, alopecia, and onychodystrophy of the nails of the hands and feet. Laboratory evaluation revealed normochromic, normocytic anemia and decreased serum levels of ionized calcium (4.4 mg/dL; normal, 4.7 to 5.4 mg/dL), albumin (3.0 g/dL; normal, 3.5 to 5.0 g/dL), copper (0.73 [mu]g/mL; normal, 0.75 to 1.45 [mu]g/mL), ionized magnesium (0.51 mmol/L; normal, 0.53 to 0.67 mmol/L), zinc (0.61 [mu]g/mL; normal, 0.66 to 1.1 [mu]g/mL), iron (222 [mu]g/dL; normal, 50 to 150 [mu]g/dL), carotene (31 [mu]g/dL; normal, 48 to 200 [mu]g/dL), and retinol (256 [mu]g/L, normal 360 to 1,200 [mu]g/L). Radiologic studies including computed tomography (CT) of the abdomen were unremarkable. Upper and lower endoscopy revealed innumerable diminutive polyps in the stomach, duodenum, terminal ileum, and right colon. On histop athology, the lesions were consistent with hamartomatous polyps with myxoid expansion of the lamina propria, numerous degranulated eosinophils, and occasional mast cells. These characteristic endoscopic and pathologic findings as well as the classic ectodermal changes led to the diagnosis of CCS.

The patient was first treated with nutritional hyperalimentation with multivitamin and zinc supplementation. He initially responded with improvement in symptoms; however, within 6 months after beginning this therapy, he again began to lose weight. His course was also complicated by recurrent gram-negative bacterial sepsis and idiopathic thrombocytopenic purpura requiring splenectomy. At this point, oral combination therapy was started with prednisone (40 mg daily), cromolyn sodium (200 mg four times a day), ranitidine (150 mg twice a day), and loratadine (10 mg daily). This regimen was based on the possible role of mast cell dysfunction in the pathogenesis of this syndrome. Long-term suppressive antibiotic therapy was also given in the form of a fluoroquinolone (ciprofloxacin). Over the next 12 months, the patient's condition improved significantly, with marked regression of the intestinal polyposis, resolution of the diarrhea and hypoalbuminemia, weight gain, regrowth of body hair, and normalization of the nail and skin findings. Prednisone was then tapered and discontinued while treatment with the other medications (ranitidine, loratadine, and cromolyn) was continued.

At about this time, more than 2 years after the initial diagnosis, follow-up studies detected an abnormality in the pancreatic bed in association with a rising serum gastrin level (940 pg/mL; normal, 0 to 200 pg/mL) and elevated chromogranin A level (94.0 ng/mL; normal, 2.3 to 14.3 ng/mL). A CT scan of the abdomen revealed an area of abnormal signal attenuation in the head of the pancreas, but this finding was not seen on magnetic resonance cholangiopancreatography. Clinically, the patient began to have recurrent symptoms of diarrhea and weight loss. Ultimately, an octreotide scan and endoscopic ultrasound studies were done but failed to detect significant pancreaticoduodenal abnormalities. The corticosteroids were then restarted (prednisone 20 mg/day), and the patient's symptoms have promptly abated with reversal of weight loss and resolution of laboratory abnormalities, indicating disease remission.

DISCUSSION

Cronkhite-Canada syndrome usually follows a progressive course with a high rate of mortality due to complications such as anemia, gastrointestinal bleeding, congestive heart failure, and septicemia. (3) The optimal therapy for this disease is not known, in part because the disease is so rare. However, our patient has had a sustained symptomatic response to the novel combination therapy of a corticosteroid, [H.sub.2]- and [H.sub.2]-receptor blockers, and cromolyn sodium. Corticosteroids, ranitidine, and antibiotics have been used individually for the treatment of CCS, but the use of this combination of medications has not previously been reported in the medical literature. This regimen was based on the presence of mast cells seen on histopathologic analysis of intestinal biopsies and the possible role of mast cell dysfunction in the pathogenesis of CCS. Stabilization of the mast cells by cromolyn sodium and the antihistamine effects of loratadine and ranitidine may account for this regimen's effectiveness if indeed mast cell dysfunction is involved in the development of the syndrome. However, without the concomitant use of corticosteroids, these medications have been unable to maintain clinical remission. Our patient's response to this combination therapy may provide insight into the optimal treatment for this progressive and usually fatal disease.

From the Division of Gastroenterology and Hepatology, and the Department of Dermatology, Mayo Clinic, Jacksonville, Fla.

Reprint requests to Herbert C. Wolfsen, MD, Mayo Clinic, Division of Gastroenterology and Hepatology, 4500 San Pablo Rd, Jacksonville, FL 32224.

References

(1.) Cronkhite LW, Canada WJ: Generalized gastrointestinal polyposis: an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 1955; 252:1011-1015

(2.) Finan MC, Ray MK Gastrointestinal polyposis syndromes. Dermalol Clin 1989; 7:419-434

(3.) Daniel ES, Ludwig SL, Lewin KJ, et al: The Cronkhite-Canada syndrome. an analysis of clinical and pathologic features and therapy in 55 patients. Medicine (Baltimore) 1982; 61:293-309

(4.) Ogawa A, Takewa M, Izeki Y, et al: A case of Cronkhite-Canada syndrome with aphasia treated with prednisolone. Jpn J Gastroenterol 1975; 72:606

(5.) Takahata J, Okubo K, Komeda T, et al: Generalized gastrointestinal polyposis associated with ectodermal changes and protein-losing enteropathy with a dramatic response to prednisolone. Digestion 1972; 5:153-161

(6.) Sakita T, Fukutomi H: A case of gastrointestinal polyposis with pigmentation, onychodystrophy and alopecia. Stomach Intestine 1966; 1:49

(7.) Miyoshi M. Fujii H, Iwasa N, et al: Two autopsy cases of diffuse gastrointestinal polyposis with ectodermal changes. Cronkhite-Canada syndrome. Am J Castroenterol 1975; 64:357-364

(8.) Cunliffe WJ, Anderson J: Case of Cronkhite-Canada syndrome with associated jejunal diverticulosis. BMJ 1967; 4:601-602

(9.) Allbritton J. Simmons-O'Brien E, Hutcheons D, et al: Cronkhite-Canada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option. Culis 1998; 61:229-232

(10.) Lin HJ, Tsai YT, Lee SD, et al: The Cronkhite-Canada syndrome with focus on immunity and infection, report of a case. J. Clin Gastroenterol 1987; 9:568-570

(11.) Watanabe T, Kudo M, Shirane H, et al: Cronkhite-Canada syndrome associated with triple gastric cancers: a case report. Gastrointest Endosc 1999; 50:688-691

(12.) Malhotra R, Sheffield A: Cronkhite-Canada syndrome associated with colon carcinoma and adenomatous changes in C-C polyps. Am J Gastroenterol 1988; 83:772-776

(13.) Rappaport LB, Sperling HV, Stavrides A: Colon cancer in the Cronkhite-Canada syndrome. J Clin Gastroenterol 1986; 8:199-201

(14.) Nakatsubo N, Wakasa R, Kiyosaki K, et al: Cronkhite-Canada syndrome associated with carcinoma of the sigmoid colon: report of a case. Surg Today 1997; 27:345-348

(15.) Katayama Y, Kimura M, Konn M: Cronkhite-Canada syndrome associated with a rectal cancer and adenomatous changes in colonic polyps. Am J Surg Pathol 1985; 9:65-71

RELATED ARTICLE: KEY POINTS

* The Cronkhite-Canada syndrome is a rare, noninherited nonadenomatous gastrointestinal polyposis syndrome.

* The etiology and pathogenesis of this syndrome are unknown.

* Characteristic dermatologic abnormalities include hyperpigmentation, alopecia, and onychodystrophy.

* No medical therapy has been demonstrated to be consistently effective to date.

* This report describes sustained clinical and endoscopic responses in a patient with Cronkhite-Canada syndrome who was treated with a novel medical regimen.