eMedicine Specialties > Dermatology > Internal Medicine

Cronkhite-Canada Syndrome

Author: Agnieszka B Serwin, MD, Consulting Staff, Department of Dermatology and Venereology, Medical Academy of Bialystok, Poland
Coauthor(s): Hanna Mysliwiec, MD, Staff Physician, Department of Dermatology and Venereology, Medical Academy of Bialystok, Poland
Contributor Information and Disclosures

Updated: Feb 24, 2009

Introduction

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 2 female patients with generalized gastrointestinal polyps, cutaneous pigmentation, alopecia, and onychodystrophy.¹

Pathophysiology

The etiology of the disease is unknown. 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 2 weeks after starting oral thyroxine, and the cutaneous signs improved following cessation of the treatment.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.³ Senesse et al described Cronkhite-Canada syndrome in association with arsenic poisoning.⁴ 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.⁵ 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.

Gastrointestinal lesions in Cronkhite-Canada syndrome are hamartomatous polyps (or polyps of polyposis syndromes according to a newly proposed classification; World Health Organization tumorlike lesions), histologically revealing pseudopolypoid-inflammatory changes. 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, paternal consanguinity was not present in either described case. This raises the question of whether infantile Cronkhite-Canada syndrome may be a sporadic condition.⁶

Frequency

International

Cronkhite-Canada syndrome has a worldwide distribution,⁷ and 75% of reports come from Japan. Cronkhite-Canada syndrome is a rare disorder. At the end of 2002, only 467 cases have been reported in the world literature, 354 of which were reported by Japanese groups.

Mortality/Morbidity

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. 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.⁸

• The first 2 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.

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 seems to affect both sexes almost equally. The male-to-female ratio is approximately 1.5-1.3:1.

Age

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.⁹

• Most patients are older than 50 years at the time of presentation.
• The reported cases of infantile Cronkhite-Canada syndrome are scant (<10).

Clinical

History

In most cases, symptoms appear in the sequence of gastrointestinal symptoms, weight loss, weakness, edema, and then ectodermal changes after a few weeks or a few months.

• 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 were reported.
  • Progressive weight loss follows the diarrhea.
• Change in taste sensation and loss of smell, with or without hypogeusia, also were reported as early symptoms.
• Most patients lose more than 20 kg during the course of the disease.
• Progressive anorexia has been reported in several patients.
• Other gastrointestinal symptoms are nausea and vomiting, apparently more frequent in female patients.
• A case of a patient with Cronkhite-Canada syndrome and severe recurrent acute pancreatitis owing to a polyp on the ampulla of Vater has been described.¹⁰
• Swallowing difficulties are reported.
• Patients typically experience hair loss.
  • In most patients, hair loss takes place simultaneously from the scalp, eyebrows, face, axillae, pubic areas, and extremities.
  • In some cases, loss of scalp hair only was described.
  • Alopecia usually occurs rapidly; total hair loss within a few days was reported.
  • Hair loss was specially denied in 1 reported patient.
• Other ectodermal changes include skin hyperpigmentation, vitiligo, and nail dystrophy (discoloration, ragged fingernails) leading to onycholysis.
• Neurologic symptoms may include sensory neuropathy, seizures, syncope, and/or vestibular disturbances (ie, gaze-evoked nystagmus, dysequilibrium).¹¹
• In some reported cases, not all of the symptoms described above were present.
• In 2 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 2 months after hemicolectomy of the descending colon for a carcinoma and 3 neighboring polyps, followed by 4 weeks of chemotherapy.

Physical

Physical examination typically reveals the following ectodermal and gastrointestinal changes:

• Ectodermal lesions
  • Skin - spotty (lentigolike macules ranging from a few millimeters to 10 cm in diameter) and diffuse hyperpigmentation notably localized on the dorsal surface of the hands, palms, arms, neck, face, scalp, anterior chest region, and body folds; ill-defined brown patches on the perioral and buccal areas; reported cases without hyperpigmentation; patchy vitiligo
  • Buccal mucosa - Brownish pigmentation and swollen tongue with loss of papillae
  • Fingernails and toenails¹² - Discoloration; proximal nail plate separation and shedding; soft and spongy look of proximal nails; ragged distal fingernails; often irregular regenerated distal plate; onychoschizia (splitting of nails into layers); onychomadesis (nail shedding staring at the base and extending forward)
  • Hair loss on the scalp and other body areas
• Gastrointestinal symptoms
  • Multiple sessile or semipedunculated polyps ranging from 0.5-2 cm in diameter located principally in the colon but also in the stomach ("carpetlike" polyposis) and small intestine
  • Rough granular changes of stomach mucosa with edematous giant rugae
  • Almost 40 cases of colorectal cancer have been reported in association with Cronkhite-Canada syndrome (adenocarcinoma arising from the mucosal hyperplasia). Cronkhite-Canada syndrome associated with colorectal cancer frequently (40%) includes polyps containing serrated adenoma lesions.¹³
• Other
  • Edema ranging from mild and peripheral edema to massive anasarca
  • Wasting of muscle
  • Streaks of tan pigment in the retina
  • Cataract¹⁴
  • Xanthelasmas, cheilosis papillary atrophy of the tongue
  • Positive Chvostek and Trousseau signs
  • Acute psychotic symptoms, possibly caused by electrolyte loss, and, possibly schizophrenia^15,16
• Children
  • A symmetric desquamating rash on the lower back, buttocks, genital area, lips, and perioral region, similar to skin lesions in acrodermatitis enteropathica (zinc deficiency), also is present.
  • Macrocephaly is a typical sign of infantile Cronkhite-Canada syndrome.

Causes

The pathogenesis of the disease 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. (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 manifestation preceded onset of diarrhea in some 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
  • 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.
• Cataract progression probably 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.

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• Cronkhite-Canada Syndrome (Pediatrics: General Medicine)
• Dermatologic Manifestations of Gastrointestinal Disease (Dermatology)
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