AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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 CCS. The stress acts on the gastrointestinal mucosa, inducing a local inflammatory reaction.

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 CCS. Senesse et al described CCS in association with arsenic poisoning. Murata et al suggested the possible role of an autoimmune response in the pathogenesis of CCS because of the presence of antinuclear antibodies in a serum of a patient with CCS who had a history of chronic pityriasis lichenoides. The effectiveness of corticosteroid therapy in many cases of CCS seems to support the involvement of the immune system in the pathogenesis of CCS.

Gastrointestinal lesions in CCS 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 CCS.

Infantile CCS (similar to typical CCS) includes juvenile gastrointestinal polyps, alopecia, nail changes, and macrocephaly. Infantile CCS 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 CCS may be a sporadic condition.

Frequency

International

CCS 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

CCS is considered a relentlessly progressive disease with a variable course and poor prognosis depending mainly on control of protein and electrolyte balance. As reported in cases of CCS, coexistent malignant changes in the polyps, gastrointestinal bleeding, and the possibility of intussusception or prolapse of gastric polyp-bearing mucosa increase the mortality.

• The first 2 described patients with CCS 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. CCS has a worldwide distribution; however, most reported cases come from Japan.

Sex

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

Age

The typical onset of CCS is during middle or old age. The average age is 55 years; the range is 31-86 years. Vernio et al have suggested that the disease may remain asymptomatic, thus not being diagnosed for a long time.

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.
• 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).
• In some reported cases, not all of the symptoms described above were present.
• In 2 cases, CCS 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 CCS 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, swollen tongue with loss of papillae
  • Fingernails and toenails - Discoloration; proximal nail plate separation and shedding; soft and spongy look of proximal nails; ragged distal fingernails; often irregular regenerated distal plate
  • 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 CCS (adenocarcinoma arising from the mucosal hyperplasia). CCS associated with colorectal cancer frequently (40%) includes polyps containing serrated adenoma lesions.
• Other
• • Edema ranging from mild and peripheral edema to massive anasarca
  • Wasting of muscle
  • Streaks of tan pigment in the retina
  • Cataract
  • Xanthelasmas, cheilosis papillary atrophy of the tongue
  • Positive Chvostek and Trousseau signs
  • Acute psychotic symptoms, possibly caused by electrolyte loss (Peitl, 2006)
• 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 CCS.

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 (Kim, 2006).
  • 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 CCS.
• • The 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.
  • 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 CCS, is unknown. An increase of arachnoid cysts was demonstrated.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Peutz-Jeghers syndrome
Bandler syndrome (mucocutaneous pigmentation with intestinal hemangiomatosis)
Ménétrier disease
Familial polyposis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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
• H pylori infection test

Imaging Studies

• Endoscopic (also wireless capsule endoscopy; Cao, 2006) procedures (ie, gastroscopy, colonoscopy, sigmoidoscopy) reveal polyp lesions of the sessile or semipedunculated type throughout the stomach, duodenum, ileum, and colon, sparing the esophagus.
• • Ikeda et al found pedunculated polyps in patients with CCS. Their size varied from a few millimeters to 2 cm in diameter.
  • Endoscopic findings in the stomach also include reddish and edematous granular lesions with mucoid exudate and giant folds.
  • Abdominal computed tomographic scan may reveal thickened gastric folds.
• Regarding radiography, a barium enema and small intestine double-contrast radiology examination show polypoid lesions.
• 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

• Presence of antinuclear antibodies and 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 Salmonella, Shigella, Yersinia, and Campylobacter species and for parasites.

Procedures

• Endoscopic procedures (gastroscopic, duodenoscopic, and colonoscopic examinations)
• X-ray procedures (eg, barium enema examination, small intestine double-contrast radiology after Sellink)
• Fluoroscopic examination of the gastrointestinal tract
• Abdominal computed tomographic scan
• Endoscopic biopsy of the polypoid lesion
• Histologic examination of polypoid lesions and, if necessary, the scalp lesion

Histologic Findings

Hyperpigmentation is related to an increase in melanin within the basal layer without the melanocyte proliferation.

Scalp biopsy shows a marked noninflammatory loss of follicular units, miniaturization of the hair shafts, markedly dilated follicles, and a heavy deposition of glycosaminoglycans in the reticular dermis.

Histologically, polyps in patients with CCS are pseudopolypoid-inflammatory changes with cystic dilatation. Ikeda et al 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.

According to Burke and Sobin, CCS polyps are characterized by their broad sessile base, expanded edematous lamina propria, and cystic glands. The only reliable distinction between CCS and colonic juvenile polyposis is the pedunculated growth of the latter with the exception of the gastric polyps. Gastric polyps in CCS 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 CCS polyps are quite similar to juvenile or hyperplastic polyps.

The most constant features of CCS 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Because of the unknown etiology, treatment 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. The indication for corticosteroids is gastrointestinal inflammation; however, its origin is not clear. Nutritional supplementation comprises oral and/or intravenous fluids, electrolytes, vitamins, minerals, amino acids, albumins, and lipids. Transfusions because of severe anemia or acute blood loss sometimes are required. In one reported case with elevated gastric acid secretion, the patient responded very well to ranitidine therapy. Other medications used are sulfasalazine and metronidazole.
• After H pylori eradication, gastric polypectomy can be of value (Kim, 2006).

Surgical Care

• At present, surgery is available only for complications of CCS, 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.

Consultations

• Gastroenterologist consultation always is required to establish number, localization, and size of polypoid lesions.
• Consultation with a surgeon can help determine if surgical intervention is necessary.
• Acute brain syndrome requires psychiatrist consultation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In described cases of CCS, drugs used include corticosteroids, mesalamine (also know as mesalazine or 5-aminosalicylic acid), and antibiotics (ie, tetracycline, metronidazole). H1- and H2-receptor blockers have been used. Therapy with antiplasmin agents has also been reported. These agents interfere with fibrinolysis in the gastrointestinal tract, thereby reducing the loss of proteins.

Drug Category: Corticosteroids

Inhibits inflammation within gastrointestinal mucosa.

Drug Category: Antibiotics

Used for the concomitant bacterial overgrowth within gastrointestinal mucosa.

Drug Category: Histamine H2 blockers

An increased gastric acid secretion is found in some patients with CCS.

Drug Category: Anti-inflammatories

Inhibit inflammatory lesions within gastrointestinal mucosa.

Drug Category: Proton pump inhibitors

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Emergent re-admission of patients with CCS may be because of significant diarrhea, gastrointestinal bleeding, intussusception, prolapse of gastric polyp-bearing mucosa, and thromboembolic episodes due to dehydration.

Further Outpatient Care

• Some 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.

Complications

• Principal complications are related to gastrointestinal involvement (number, size, location of polyps).
• • Water, protein, and electrolyte loss
  • Gastrointestinal bleeding (due to erosions on the surface of polyps)
  • Intussusception
  • Prolapse of gastric polyp-bearing mucosa
  • Thromboembolic episodes due to dehydration
  • Cachexia
  • Heart failure
• Nagata et al suggest that CCS has a definite malignant potential, although the rate of malignant transformation is thought to be low.

Prognosis

• CCS is a relentlessly progressive syndrome with a poor prognosis; however, cases of spontaneous remission have been reported.
• The longest surviving patients were alive 15 and 17.5 years after successful surgical treatment.
• 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• CCS is a rare disorder; failure to make a correct diagnosis is quite possible.
• Failure to discuss the prognosis and serious adverse effects of treatment (eg, surgical intervention, systemic steroids) may cause problems.

Special Concerns

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

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Allbritton J, Simmons-O''Brien E, Hutcheons D, Whitmore SE. Cronkhite-Canada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option. Cutis. Apr 1998;61(4):229-32. [Medline].
• Bacher T, Schonekas H, Steurer KT, Wunsch PH. [The Cronkhite-Canada Syndrome. A rare differential diagnosis of generalized gastrointestinal polyposis]. Dtsch Med Wochenschr. May 23 1997;122(21):676-81. [Medline].
• Bruce A, Ng CS, Wolfsen HC, et al. Cutaneous clues to Cronkhite-Canada syndrome: a case report. Arch Dermatol. Feb 1999;135(2):212. [Medline].
• Burke AP, Sobin LH. The pathology of Cronkhite-Canada polyps. A comparison to juvenile polyposis. Am J Surg Pathol. Nov 1989;13(11):940-6. [Medline].
• Cronkhite LW Jr, Canada WJ. Generalized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med. Jun 16 1955;252(24):1011-5. [Medline].
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• Hutnik CM, Nichols BD. Cataracts in systemic diseases and syndromes. Curr Opin Ophthalmol. Feb 1999;10(1):22-8. [Medline].
• Ikeda K, Sannohe Y, Murayama H. A case of Cronkhite-Canada syndrome developing after hemi-colectomy. Endoscopy. Nov 1981;13(6):251-3. [Medline].
• Kim MS, Jung HK, Jung HS, et al. A case of Cronkhite-Canada syndromr showing resolution with Helicobacter pylori eradication and omeprazole. Korean J Gastroenterol. 2006;47:59-64. [Medline].
• Murata I, Yoshikawa I, Endo M, et al. Cronkhite-Canada syndrome: report of two cases. J Gastroenterol. 2000;35(9):706-11. [Medline].
• Nakayama M, Muta H, Somada S. Cronkhite-Canada syndrome associated with schizophrenia. Intern Med. 2007;46(4):175-80. [Medline].
• Naoshima-Ishibashi Y, Murofushi T. A case of Cronkhite-Canada syndrome with vestibular disturbances. Eur Arch Otorhinolaryngol. Nov 2004;261(10):558-9. [Medline].
• Negoro K, Takahashi S, Kinouchi Y, et al. Analysis of the PTEN gene mutation in polyposis syndromes and sporadic gastrointestinal tumors in Japanese patients. Dis Colon Rectum. Oct 2000;43(10 Suppl):S29-33. [Medline].
• Oberhuber G, Stolte M. Gastric polyps: an update of their pathology and biological significance. Virchows Arch. Dec 2000;437(6):581-90. [Medline].
• Peitl A, Vucic Peitl M, Pavlovic E, Ljubicic D. Acute brain syndrome as a consequence of the Cronkhite-Canada syndrome. Psychiatr Danub. 2005;17:90-93. [Medline].
• Senesse P, Justrabo E, Boschi F, et al. [Cronkhite-Canada syndrome and arsenic poisoning: fortuitous association or new etiological hypothesis?]. Gastroenterol Clin Biol. Mar 1999;23(3):399-402. [Medline].
• Takahura M, Adachi H, Tsuchihashi N. A case of Cronkhite-Canada Syndrome markedly improved with mesalazine therapy. Digest Endos. 2004;16:74-8.
• Vernia P, Mercheggiano A, Marinaro V, et al. Is Cronkhite-Canada syndrome necessarily a late-onset disease?. Eur J Gastroenterol Hepatol. 2005;17:1139-41. [Medline].
• Yashiro M, Kobayashi H, Kubo N, et al. Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions. Digestion. 2004;69(1):57-62. [Medline].
• de Silva DG, Fernando AD, Law FM, et al. Infantile Cronkhite-Canada syndrome. Indian J Pediatr. Mar-Apr 1997;64(2):261-6. [Medline].

Article Last Updated: Feb 26, 2007