Advances in therapy for the Cronkhite-Canada syndrome have increased survival: And that’s the way it is

By Warren R. Heymann, MD, FAAD
Aug. 28, 2024
Vol. 6, No. 35

Part of the folklore at the Albert Einstein College of Medicine when I rotated as a fourth-year medical student in dermatology was that a prior resident made the correct diagnosis of Cronkhite-Canada syndrome (CCS). The constellation of findings was seared in my cerebral cortex so I could make the diagnosis one day. In life, I have never seen it, but I was thrilled to instantly diagnose CCS after reading Case 39-2023 of the New England Journal of Medicine, entitled “A 43-year-old woman with chronic diarrhea, hair loss, and nail and skin changes.” (1) It has been 45 years since I thought about CCS. It is high time for a refresher course.

Cronkhite (an internist) and Canada (a radiologist), reported their findings in 1955 (when I was 3 weeks old!). “Two cases are reported below in which the presenting complaints were disturbances in gastrointestinal function, pigmentation of the skin, alopecia and atrophy of the fingernails and toenails. In each case the underlying pathologic process seemed to be generalized gastrointestinal polyposis in which virtually the entire gastrointestinal mucosa was replaced by polypoid lesions.” (2) The paper is brilliant. In our era of multi-authored manuscripts, I was awed by their scholarship and wanted to learn more about them. Both Leonard W. Cronkhite, Jr and Wilma Jeanne Canada were extraordinarily talented and fascinating people. If you have a moment, please read about their lives:

• Leonard W. Cronkhite, Jr (PDF)

• Wilma Jeanne Canada

Approximately 500 cases of CCS have been reported worldwide, with about 75% from Japan. The male-to-female ratio of cases is up to 2:1. (3) The disease typically manifests in the sixth decade of life. CCS most commonly presents with gastrointestinal symptoms (diarrhea, weight loss, nausea, vomiting, hypogeusia, and anorexia). Diffuse polyposis may appear throughout the GI tract (sparing the esophagus) that histologically are inflammatory or “retention” polyps. (4) The polyps have also been called “hamartomatous.” (5) Complications include protein-losing enteropathy, GI bleeding, intussusception, and prolapse. (4) The malignant potential of the polyps is controversial, although the overall risk of colorectal cancer has been suggested to be as high as 25%. (5)

The cutaneous manifestations of the disease possibly result from malabsorption and malnutrition and include nail dystrophy, alopecia, and diffuse hyperpigmentation. (4) Nail dystrophy has been described in 98% of patients and can include thinning, splitting, yellowing, onycholysis, and onychomadesis. (4,6) Alopecia is variable, ranging from patches to alopecia totalis, involving both the scalp and body hair. (4) The likelihood is that some cases of alopecia are due to telogen effluvium and others alopecia areata. (7) Hyperpigmentation ranges from light to dark macular lesions predominantly involving the face, palms, soles, and neck. Histologically, hyperpigmented lesions reveal an increase in melanin pigmentation. (4) The second index case, a 75-year-old woman case also had vitiligo on her upper extremities. (2) The cutaneous features may correlate with disease activity and may improve with therapy and disease control. (1)

Other complications of CCS include hypothyroidism, nephrotic syndrome, sepsis, myelodysplastic syndrome, aplastic anemia, acute encephalopathy syndrome, and deep vein thrombosis. (6,8) The hypercoagulable state in CCS is due to a loss of intrinsic anticoagulants, such as protein C and protein S, meaning that consideration should be given for prophylactic anticoagulants. (1)

The pathogenesis of CCS is obscure but is considered an autoimmune disorder. It is not inherited, although there is a report of CCS in a man and his son. (9) Perhaps there is inherited susceptibility, as genome-wide association studies have revealed mutations in the PRKDC and APC genes. (6) IgG4 mononuclear staining in CCS polyps suggests autoimmunity. (5) CCS has also been associated with other autoimmune disorders such as lupus, rheumatoid arthritis, scleroderma, and previously mentioned, vitiligo, alopecia areata, and hypothyroidism. Other factors may include concomitant infection with Helicobacter pylori infection, mental stress, and alterations in the intestinal microbiome. (3,7,10)

Therapy of CCS includes: 1) nutritional support (including parenteral feeding if necessary); 2) treatment of H. pylori infection if present; 3) treatment of gastroesophageal reflux disease (histamine type 2 receptor antagonists, proton-pump inhibitors); 4) immunosuppression with an initial trial of glucocorticoids (with or without mesalamine) followed by other immunosuppressive agents (azathioprine, cyclosporine, tumor necrosis-alpha inhibitors such as infliximab) if necessary. (1)

Although CCS is known as a relentless, progressive disease with a poor prognosis and a reported 5-year mortality rate of 55%, there is reason for optimism. Pham et al reviewed 17 CCS cases at the Mayo Clinic over 20 years. Fifteen patients achieved complete clinical remission, and eleven patients achieved complete endoscopic remission after pharmacotherapy initiation. Seven patients required gastrointestinal surgeries during their disease course. The 5-year overall survival was 93.3%. The authors concluded that “The prognosis and overall survival of patients with CCS have markedly improved with advancement in disease understanding and therapies. Pharmacotherapy, including corticosteroids and immunomodulators, is effective in inducing and maintaining remission, and gastrointestinal surgery is commonly needed as an adjunct for managing CCS disease complications.” (11)

Even if I never encounter a case of CCS, it is reassuring that the prognosis is far better than when I first heard of it. For these rare cases, recognition and medical intervention are key. To quote another Cronkite (Walter), “And that’s the way it is.”

Point to Remember: Early recognition and treatment of the Cronkhite-Canada syndrome may significantly improve the prognosis of this potentially lethal disease.

Our expert’s viewpoint

Seth Sweetser, MD
Associate Professor of Medicine
Division of Gastroenterology and Hepatology
Mayo Clinic College of Medicine, Rochester, Minnesota

Cronkhite-Canada syndrome (CCS) is a rare non-hereditary condition of unknown etiology characterized by diffuse inflammatory gastrointestinal polyposis together with protein-losing enterocolopathy and ectodermal abnormalities. The classic dermatologic triad of CCS consists of skin hyperpigmentation, alopecia, and onychodystrophy. The combination of inflammatory gastrointestinal polyposis and the dermatologic triad is specific for the diagnosis of CCS and should reflexively make one consider this diagnosis. However, non-familiarity of clinicians with this rare entity frequently results in delayed diagnosis and poor outcome. Although rarely encountered in clinical practice, knowledge of the nearly pathognomonic combination of inflammatory gastrointestinal polyposis and dermatologic triad, may lead to earlier diagnosis, initiation of treatment, and a better prognosis for CCS patients. This reminds us that our perception of the world is influenced by our knowledge as summarized by the quote of English novelist DH Lawrence: “The eyes can’t see what the mind does not know.”

1. Lai JCT, Wu WKC, Chan WSA, Lau LHS, Leung HHW. Case 39-2023: A 43-Year-Old Woman with Chronic Diarrhea, Hair Loss, and Nail and Skin Changes. N Engl J Med. 2023 Dec 21;389(25):2377-2385. doi: 10.1056/NEJMcpc2301032. PMID: 38118028.

2. Cronkhite LW Jr, Canada WJ. Generalized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med. 1955 Jun 16;252(24):1011-5. doi: 10.1056/NEJM195506162522401. PMID: 14383952.

3. Hu H, Wu Y, Zhang Y, Zhang L, Zhang J, Zhang R. Comprehensive treatment of Cronkhite-Canada syndrome: A case report and literature review. Medicine (Baltimore). 2023 Feb 10;102(6):e32714. doi: 10.1097/MD.0000000000032714. PMID: 36820546; PMCID: PMC9907941.

4. Shah KR, Boland CR, Patel M, Thrash B, Menter A. Cutaneous manifestations of gastrointestinal disease: part I. J Am Acad Dermatol. 2013 Feb;68(2):189.e1-21; quiz 210. doi: 10.1016/j.jaad.2012.10.037. PMID: 23317980.

5. Sweetser S, Boardman LA. Cronkhite-Canada syndrome: an acquired condition of gastrointestinal polyposis and dermatologic abnormalities. Gastroenterol Hepatol (N Y). 2012 Mar;8(3):201-3. PMID: 22675285; PMCID: PMC3365526.

6. Lv YQ, Wang ML, Tang TY, Li YQ. Comprehensive treatment and a rare presentation of Cronkhite-Canada syndrome: Two case reports and review of literature. World J Gastrointest Surg. 2023 Nov 27;15(11):2646-2656. doi: 10.4240/wjgs.v15.i11.2646. PMID: 38111781; PMCID: PMC10725548.

7. Ong S, Rodriguez-Garcia C, Grabczynska S, Carton J, Osborn M, Walters J, Kubba F, Stefanato CM. Alopecia areata incognita in Cronkhite-Canada syndrome. Br J Dermatol. 2017 Aug;177(2):531-534. doi: 10.1111/bjd.15293. Epub 2017 May 24. PMID: 28029683.

8. Feng XK, Chen XF, Wang BB, Zeng ZG, Liu C, Sha WH, Ma J. Deep vein thrombosis in a patient with Cronkhite-Canada syndrome: a complex case report. Thromb J. 2023 Mar 15;21(1):29. doi: 10.1186/s12959-023-00473-8. PMID: 36922808; PMCID: PMC10018956.

9. Patil V, Patil LS, Jakareddy R, Verma A, Gupta AB. Cronkhite-Canada syndrome: a report of two familial cases. Indian J Gastroenterol. 2013 Mar;32(2):119-22. doi: 10.1007/s12664-012-0296-8. Epub 2013 Feb 14. PMID: 23408256.

10. Honjo H, Masuta Y, Otsuka Y, Masaki S, Minaga K, Kudo M, Watanabe T. Analyses of cytokine gene expression and fecal microbiota in a patient with Cronkhite-Canada syndrome successfully treated with prednisolone. DEN Open. 2023 May 8;4(1):e222. doi: 10.1002/deo2.222. PMID: 37168272; PMCID: PMC10165462.

11. Pham JT, Kisiel JB, Sweetser S. Cronkhite-Canada syndrome: treatment responses and improved overall survival. Int J Colorectal Dis. 2023 Feb 13;38(1):39. doi: 10.1007/s00384-023-04332-w. PMID: 36781513.

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