Pediatric Cronkhite-Canada Syndrome Clinical Presentation

Updated: Oct 20, 2017
  • Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: Carmen Cuffari, MD  more...
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Presentation

History

At the time of presentation and throughout the course of Cronkhite-Canada syndrome the symptoms are manifestations of the degree of dermatologic and GI mucosal disease. The duration from onset of symptoms to diagnosis is less than 3 months in about 50% of patients. The most common symptoms at presentation noted in Japan were diarrhea (70%), dysgeusia, disordered sense of taste (65%), alopecia (49%), onychodystrophy, changes in nail morphology (64%), and hyperpigmentation (49%). [2]

Several recognized patterns of disease evolution include either diarrhea or dysgeusia as the initial symptom. Diarrhea usually occurs, followed by a variable sequence of the triad that includes nail dystrophy, alopecia, and hyperpigmentation (see Staging).

The etiology of dysgeusia is uncertain. It has been noted in other clinical settings with zinc deficiency, possibly secondary to diarrhea or mucosal changes. In some individuals, xerostomia (dry mouth with or without unusual oropharyngeal sensation) precedes diarrhea or ectodermal changes. Another pattern in which ectodermal changes precede diarrhea is less common but well described.

Diarrhea is multifactorial and is observed in 80% of patients. Patients can typically have 5-7 loose, watery bowel movements each day, with stool volumes as much as 4-6 L. Hematochezia and steatorrhea both occur. Abdominal pain, anorexia, emesis, weakness, and weight loss often greater than 10 kg accompany the diarrhea. Weakness can be related to caloric deprivation, muscle wasting, dehydration, and fecal electrolyte losses, including calcium, magnesium, potassium, and zinc.

A few patients may have neurologic symptoms, including numbness and tingling in the extremities, dysphagia, anosmia, vestibular disturbances, and seizures. Convulsions are often secondary to electrolyte imbalance. Whether recent reports of CCS in patients with psychiatric illness has any significance besides coincidence is unclear. [10, 11, 12]

Other manifestations include cataracts, thrombosis and coagulation disorders, cardiac failure, recurrent acute pancreatitis, and psychiatric disorders. [12]

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Physical

Physical examination reveals characteristic ectodermal changes starting several weeks or months after the initial GI symptoms in almost all patients. Most patients have 2 or more of the cutaneous triad that consists of alopecia, nail changes, and hyperpigmentation.

Alopecia

The alopecia is initially patchy; however, it rapidly progresses and leads to complete hair loss.

Hair loss typically involves the scalp, eyebrows, face, axillae, pubic areas, and extremities; however, loss of only scalp hair has also been described.

Regrowth is noted after treatment, during spontaneous remissions, and despite ongoing active disease.

Onychodystrophy (nail changes)

Nail changes involve thinning, splitting, and color changes in all fingernails and toenails.

Onycholysis (partial separation of the nail from its bed) leads to a unique pattern of an inverted triangle of normal nail bordered by a dystrophic nail.

Onychomadesis (the loss of all finger and toenails) occurs over several weeks.

Partial or total regeneration of nails occurs spontaneously in spite of active disease or remission.

Hyperpigmentation

Hyperpigmented light-to-dark brownish macules and plaques are diffusely distributed. Although they are most commonly found on the palms, soles, hands, and arms, they are also found on the legs, face, neck, trunk, and elsewhere.

They may coalesce and range from a few millimeters to 10 cm in diameter.

Patchy vitiligo is relatively common.

Similar to the other ectodermal changes, pigmentation can persist or resolve after medical therapy, surgical treatment, or no therapy.

Other signs

Other signs are often secondary to long-standing protein, vitamin, and mineral depletion.

Findings include Chvostek and Trousseau signs, glossitis, edema that can range from mild peripheral findings to anasarca, vestibular disturbances, and evidence of osteoporosis and osteopenia, including rib fractures. [13]

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Causes

Although the efficacy of corticosteroids provides the strongest evidence to suggest an inflammatory cause for CCS, additional reports could support this theory. Patients with CCS have been described with coexisting autoimmune conditions such as type 1 diabetes mellitushypothyroidism, membranous glomerulopathy, and myelodysplastic syndrome. [14]  High titers of antinuclear antibody were found in 28% of the Japanese patients, and individuals refractory to steroids have responded to calcineurin inhibitors, azathioprine, and anti-TNF agents. [2]

Two recent groups provided documentation of immunoglobulin G4 (IgG4)–producing plasma cells infiltrating CCS polyps. Both described this finding in half of the CCS polyps removed from 7 [15]  and 14 [16]  patients studied. One group found only 12% positive immunostaining in juvenile polyposis syndrome polyps and no staining in control tissue. [16]  This histochemical finding is the criteria for IgG4–related autoimmune disease (IRAD), which includes autoimmune pancreatitissclerosing cholangitis, and retroperitoneal fibrosis. The authors of the first report speculated that CCS is an intestinal manifestation of IRAD. [15]

The author of a large series described mental stress, such as mental suffering or family problems, and physical fatigue as the most frequent precipitating factors for Japanese patients. [6]  Onset of symptoms following a fracture was reported in one case. [17]

Unlike many other GI polyposis syndromes, familial patterns of inheritance have not been identified. In particular, mutations in PTEN, which are responsible for Cowden disease, have not been found in patients with Cronkhite-Canada syndrome.

The unique involvement of two epithelial tissues in CCS suggests that potentially reversible derangements in epithelial cell-to-cell signaling or maturation may play a pivotal role in initiating the syndrome. Although no experimental evidence has validated this hypothesis, the observation that sulindac administration led to regression of CCS polyps may be interpreted as consistent with this mechanism. [18] Nonsteroidal anti-inflammatory drugs (NSAIDs) are felt to inhibit cellular proliferation through various methods, including influencing cell-cycle regulatory proteins.

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Physical Examination

Characteristic changes in the ectoderm (hair loss, nail dystrophy, hyperpigmentation) are usually the initial findings that suggest CCS.

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Complications

Besides intractable diarrhea leading to malnutrition, various vitamin deficiencies, weight loss, and hypoalbuminemia, and the ectodermal changes, the most significant issue is GI cancer arising in one of the many polyps. Rarely, GI bleeding occurs. 

A case report described a large gastric adenocarcinoma that was limited to the mucosa, which resembled the hyperplasia seen in CCS polyps. These investigators determined that the phenotypic expression of the mucins was MUC2(-) and MUC5AC(+) typical of a gastric type well differentiated adenocarcinoma. Their literature search confirmed that previous reports on 32 gastric carcinomas in CCS patients were also most limited to within the submucosa despite their huge size. [19]

A handful of histopathologic studies have provided evidence that suggests that carcinogenesis in CCS patients does not universally follow the adenoma to adenocarcinoma. [3]

Carcinomas of the colorectum (most often distal) and stomach have been documented in 15-25% of patients with Cronkhite-Canada Syndrome at diagnosis and may be multiple. [12]

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