Cronkhite-Canada Syndrome

Are You Confident of the Diagnosis?

A constellation of dermatologic signs including alopecia, skin hyperpigmentation and nail dystrophy associated with gastrointestinal (GI) symptoms like diarrhea, abdominal pain, intestinal malabsorption and weight loss suggest the diagnosis of Cronkhite-Canada syndrome (CCS). CCS is a rare, acquired syndrome involving both the skin and GI tract. It is a condition of unknown etiology, characterized by non-familial GI polyposis associated with ectodermal changes.

Characteristic findings on physical examination

Physical examination reveals ectodermal changes starting several weeks after the GI symptoms, likely due to profound malnutrition. Features of skin hyperpigmentation are present in over 85% of patients. The pigmentary abnormalities are lentigous, light to dark-brownish macules, commonly involving the upper and lower extremities, face, palms and soles (Figure 1). They range from a few millimetres to 10 cm in diameter and may coalescence and may be accompanied by patchy vitiligo. The mucous membranes are normally spared.

Figure 1.

Vitiligo and lentigo-like macules on the digits. The nails show onychomadesis at a distance of about 3mm from the lunula.

The typical nail changes of CCS are characterized by the presence of a thin and soft triangular area in the proximal half of the nail that is bordered by a thick and ridged nail plate. The nail color may vary from white to yellow to brown-black. Onycholysis, prominent Beau’s lines and onychomadesis have also been reported. Partial or total regeneration of the nails may occur spontaneously, in spite of active disease, or during remission. Recurrent onychomadesis can be seen following recurrent relapses (Figure 2).

Figure 2.

A short nail plate separates two bands of onychomadesis. It indicates recurrence of matrix damage.

Alopecia is initially patchy, but it usually rapidly progresses and leads to complete hair loss. Other signs are often secondary to long-standing protein, vitamin and mineral depletion. Findings include glossitis, sensation of burning in the mouth and throat associated with marked taste disturbance, xerostomia, hypogeusia and edema that can range from mild peripheral to anasarca.

Expected results of diagnostic studies

Laboratory findings include hypoproteinemia, particularly hypoalbuminemia, anemia, electrolyte imbalance, and deficiencies of vitamins (vitamin B12) and minerals (zinc and magnesium). It is unclear whether the nutritional deficiency associated with CCS is an etiologic factor or a consequence of the syndrome. Of upmost importance, the electrolyte imbalance may be severe and may lead to seizures or tetany.

Endoscopic characteristics of CCS are impressive. Gastroscopy and coloscopy reveal marked widespread polyposis of stomach, duodenum and colon. Histologic examination of multiple biopsies reveals chronic active inflammation without epithelial dysplasia. The inflammatory sessile polyps are composed of intact surface epithelium, focally dilated irregular foveolar glands within an edematous inflamed lamina propria. The mucosa often contains engorged vascular channels and prominent eosinophilic infiltration.

The workup is based on history and physicial examination followed by imaging and endoscopy, while histologic examination is used to confirm the diagnosis of GI polyposis. Endoscopic morphologic findings are not specific. Endoscopic appearance of CCS varies according to current literature. Gastric mucosa has been described as being thickened with hypertrophic gastric folds mimicking Menetrier’s disease, to atrophic with polypoid lesions. In one study, colonic polyps have been characterized as sessile and “strawberry like”.

Diagnosis confirmation

Differential diagnosis includes juvenile polyposis syndrome (JPS), which is the most common GI hamartomatous polyposis syndrome, and Cowden syndrome, which is characterized by multiple hamartomas and neoplasms of ectodermal, endodermal and mesodermal origin affecting akin, oral mucosa, GI tract, bones, and genitourinary tract. Its mucocutaneous features include trichilemmomas, oral mucosal papillomatosis, acral keratosis and palmoplantar keratosis.

Other polyposis syndromes to be considered in differential diagnosis are inflammatory polyposis, lymphomatous polyposis and Peutz-Jeghers polyposis (PJS). PJS consisting of GI hamartoma and mucocutaneous hyperpigmentation. The pigmented maculae may be present at birth but usually develop in early childhood. Round, oval or irregular patches of brown pigmentation of 1 to 5mm in diameter are most commonly found around the mouth, nose, lower lip, buccal mucosa, hands and feet. Rarely the nails may be pigmented, diffusely or in longitudinal bands. The presence of distinct ectodermal findings is necessary to confirm the diagnosis of CCS.

What is the Cause of the Disease?

The etiology of CCS is currently unknown. There is no strong evidence to suggest a familial predisposition. The estimated incidence of CCS is one per million, based on the largest study performed to date. The mean age of onset is estimated to be in the fifth to sixth decade, with a slight male predominance (3:2 ratio).

Although it has a worlwide distribution, most cases of CCS are reported from Japan, Europe, and the United States. Since 1955, when the syndrome was first documented, about 400 cases have been reported worldwide. Interestingly, cases have been associated with elevated antinuclear antibody (ANA) and IgG4 levels. There is also an association between CCS and hypothyroidism and various autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis and scleroderma). Mental stress and physical fatigue may also contribute to the etiology.

Systemic Implications and Complications

The usual clinical presentation consists of diarrhea with abdominal pain, protein-losing enteropathy and associated weight loss, weakness, paresthesias and xerostomia. Malabsorption is proportional to the degree of small bowel mucosal injury. Patients report 5 to 7 loose bowel movements per day. Diarrhea may be bloody and the bloody loss may be so significant as to require tranfusions. The disease tends to wax and wane, but the course may be rapidly progressive.

Although CCS is considered a benign condition, the occurrence of cancer in the stomach and colorectum in CCS patients is about 13%. Addtionally, there is a possibility of the serrated adenocarcinoma sequence in colorectal cancer. The coincidental occurrence of carcinomas such as superficial esophageal cancer or lung cancer has been reported. The long-term prognosis of CCS is quite poor according to early studies, the overall mortality rate as high as 55%, due to the many complications, such as fatal GI bleeding, intussusception, electrolyte abnormalities, protein-losing enteropathy, infections and severe acute pancreatitis.

Treatment Options

Dermatologists are involved in the diagnosis of CCS, but there are no therapies available to treat nails, hair and skin changes associated with the syndrome. An improvement of dermatologic signs can be observed after adequate nutritional support and gastroenterologic symptoms management.

Optimal Therapeutic Approach for this Disease

Current literature favors a combination therapy, which can induce remission, based on symptomatic management of the patient, enteric nutritional support, multivitamin supplementation and corticosteroid administration.

The standard regimen for CCS is daily oral administration of 30mg prednisolone. Other therapies such as antihistamine receptor antagonist agents (eg, ranitidina 150mg twice a day or loratadine 10mg daily) and cromolyn sodium (200mg 4 times a day) have also been used as supplemental therapy in cases in which degranulation eosinophils and mast cells are seen on biopsy.

Patient Management

Dermatologists are involved in the diagnosis of this disease, in association with gastroenterologists. We reccomend a clinical 4- to 6-month dermatologic follow-up, since nail abnormalities may be the sign of an uncontrolled disease. The team that successfully cares for a patient with CCS includes a nutritional support group, a surgeon and a gastroenterologist able to perform diagnostic and therapeutic endoscopy.

Unusual Clinical Scenarios to Consider in Patient Management

Although CCS is considered a benign condition, the occurrence of gastric and colorectal cancers has been described. Complications are not frequent, even though CCS has been associated with fatal GI bleeding, intussusception, protein-losing enteropathy, electrolyte abnormalities and severe acute pancreatitis. A report describes a case complicated by multiple rib fractures, likely secondary to persistent hypocalcemia and malnutrition. Moreover, prolonged corticosteroid therapy carries with it the greatest risk of osteoporotic fracture.

What is the Evidence?

Cronkhite, LW, Canada, WJ. “Generalized gastrointestinal polyposis: an unusual syndrome of polyposis, pigmentation, alopecia and onychoatrophia”. N Engl J Med. vol. 252. 1955. pp. 1011-5. (In this paper Chronkhite and Canada first recognize and describe a syndrome characteried by polyposis, GI disturbances, skin pigmentation and nails atrophy.)

Nakajama, M, Muta, H, Somada, S, Maeda, T, Mutoh, T, Shimizu, K. “Cronkhite-Canada syndrome associated with schizophrenia”. Intern Med. vol. 46. 2006. pp. 175-80. (This is the first report of CCS in a patient with schizophrenia.)

Kaneko, Y, Kato, H, Tachimori, Y, Watanabe, H, Ushio, K, Yamaguchi, H. “Triple carcinomas in Cronkhite-Canada syndrome”. Jap J Clin Oncol. vol. 21. 1991. pp. 194-202. (The case described herein is the first case of CCS associated with esophageal, gastric and lung cancer.)

Ho, V, Banney, L, Falhammer, H. “Hyperpigmentation, nail dystrophy and alopecia with generalised intestinal polyposis: Cronkhite-Canada syndrome”. Australasian J Dermatol. vol. 49. 2008. pp. 223-5. (A case of CCS in a Malaysian woman presenting with a constellation of typical skin signs and a history of diarrhea and weight loss after the administration of thyroxine prescribed for a benign multinodular goitre.)

Kao, KT, Patel, JK, Pampati, V. “Cronkhite-Canada syndrome: a case report and review of literature”. Gastroenterol Res Pract. 2009. (The workup is based on history and physical examination followed by imaging and endoscopy with biopsy to confirm GI polyposis. The goal of treatment focuses on symptomatic management of the patient and nutritional support.)

Bosi, Y, Xinxin, J, Renmin, Z, Xiaohua, Z, Jiong, L, Haijing, W. “Cronkhite-Canada syndrome associated with rib fractures: a case report”. BMC Gastroenterol. vol. 10. 2010. pp. 121(This is the first report of a CCS patient with multiple rib fractures. The report aims to underline an increased risk of osteoporotic fracture in CCS patients who accept prolonged corticosteroid therapy.)

Piraccini, BM, Rech, G, Sisti, A, Bellavista, S. “Twenty nail onychomadesis: an unusual finding in Cronkhite-Canada syndrome”. J Am Acad Dermatol. vol. 63. 2010. pp. 172-4. (A case of CCS presented with a peculiar nail manifestation consisting on onychomadesis of the 20 nails related to the systemic illness)

Ward, E, Wolfsen, HC, Christine, NG. “Medical management of Cronkhite-Canada syndrome”. Southern Med J. vol. 95. 2002. pp. 272-4. (A case of CCS successfully treated with a combination regimen consisting of H1- and H2 -receptor antagonists, cromolyn sodium, prednisone and suppressive antibiotics.)

Yuan, B, Jin, X, Zhu, R, Zhang, X, Liu, J, Wan, H. “Cronkhite-Canada syndrome associated with rib fractures: a case report”. BMC Gastroenterol. vol. 10. 2010. pp. 121(This is the first report of a CCS patient with multiple rib fractures. Prolonged corticosteroid therapy will result in an increased risk of osteoporotic fracture.)