Pediatric Cronkhite-Canada Syndrome Clinical Presentation

• At the time of presentation and throughout the course of Cronkhite-Canada syndrome (CCS), the symptoms are manifestations of the degree of GI mucosal disease. The duration from onset of symptoms to diagnosis is less than 3 months in about 50% of patients.
• Several recognized patterns of disease evolution include either diarrhea or hypogeusia (taste disturbances) 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 hypogeusia is uncertain; it may result from disturbances of zinc absorption, possibly secondary to diarrhea or mucosal changes. In some individuals, xerostomia (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 90% of patients. Patients 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 have neurologic symptoms. These include numbness and tingling in the extremities, dysphagia, and seizures. Convulsions are often secondary to electrolyte imbalance. Whether recent reports of Cronkhite-Canada syndrome in patients with psychiatric illness has any significance besides coincidence is unclear.

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 hands and arms, they are also found on the legs, face, palms, soles, 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, and vestibular disturbances.

• At this time, speculation on the etiology is limited to anecdotal associations. The author of the largest series described mental stress, such as mental suffering or family problems, and physical fatigue as the most frequent precipitating factors for Japanese patients.^[3] 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 2 epithelial tissues in Cronkhite-Canada syndrome 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 Cronkhite-Canada syndrome polyps may be interpreted as consistent with this mechanism.^[5] Nonsteroidal anti-inflammatory drugs (NSAIDs) are felt to inhibit cellular proliferation through various methods, including influencing cell-cycle regulatory proteins.
• Although the efficacy of corticosteroids provides the strongest evidence to suggest an inflammatory cause for Cronkhite-Canada syndrome, additional reports could support this theory. Patients with Cronkhite-Canada syndrome have been described with coexisting autoimmune conditions such as type 1 diabetes mellitus, hypothyroidism, membranous glomerulopathy, and high titers of antinuclear antibody.
• A recent provocative report described the infiltration of immunoglobulin G4 (IgG4)–producing plasma cells in half of the Cronkhite-Canada syndrome polyps studied in 7 affected individuals.^[6] This histochemical finding is the criteria for IgG4–related autoimmune disease (IRAD), which includes autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis. The authors of this report speculate that Cronkhite-Canada syndrome is an intestinal manifestation of IRAD.
• As detailed above, many signs and symptoms are secondary to the changes in the GI mucosa and the consequential malabsorption of nutrients.