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Cronkhite-Canada Syndrome

Polyposis Skin Pigmentation Alopecia and Fingernail Changes

Cronkhite-Canada syndrome (CCS) is a rare disorder characterized by generalized gastrointestinal polyps, alopecia, nail changes and hyperpigmentation.


Presentation

In many cases, the symptoms appear in the following order:

The ectodermal changes occur after a few weeks or a few months. The first and major complaint from patients is that of periodic or constant pain in the upper or lower abdomen. The intensity varies greatly from mild and localized to generalized and severe [8]. The pain comes with recurrent watery diarrhea or chronic diarrhea and in some cases, melena.

The watery bowel movements may be reported 7 times or more each day. In some cases, stool volume as high as 4-6 L/d are reported. Following the diarrhea is progressive weight loss.

Anorexia have been reported in some patients and loss of smell and change in taste sensations have equally been reported
Other gastrointestinal symptoms are nausea and vomiting and this is more readily seen in female patients.

Typically, the patients experience hair loss and swallowing difficulties have been reported as well. The hair loss happens in tandem across the extremities, pubic areas, axillae, face, eyebrows and scalp. However, some patients have presented loss of hair in only the scalp area. Alopecia takes place very fast with reports of total hair loss with a few days common [9].

Other ectodermal changes that happen in many cases include hyperpigmentation of the skin, vitiligo, discoloured and ragged fingernails (nail dystrophy) which often results in onycholysis. Some neurologoc symptoms have been reported as well and these include sensory neuropathy, syncope, seizures, vestibular disturbances (ie, gaze-evoked nystagmus, dysequilibrium) and sensory neuropathy.

All of the symptoms reported above do not appear in all cases and in two reported cases there was a blistering episode before the Cronkhite-Canada syndrome fully set in.

Weight Loss
  • The disease is characterized by diffuse gastrointestinal polyposis, dystrophic changes of the fingernails, alopecia, cutaneous hyperpigmentation, diarrhea, weight loss, and abdominal pain. An autoimmune etiology is suspected.[ncbi.nlm.nih.gov]
  • A high index of suspicion for CCS should exist in patients who present with weight loss, diarrhoea and polyposis. If diagnosed early, the disease can be treated with the goal of clinical remission.[ncbi.nlm.nih.gov]
  • We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg.[ncbi.nlm.nih.gov]
  • The patient presented with weight loss, alopecia, nail dystrophy, taste disturbance and classic radiologic and endoscopic features of CCS.[ncbi.nlm.nih.gov]
  • On questioning, a history of diarrhoea, taste disturbance and weight loss was found. The onset of these changes coincided with the administration of thyroxine prescribed for a benign multinodular goitre.[ncbi.nlm.nih.gov]
Anemia
  • A 54-year-old woman, diagnosed as MDS the prior year after evaluation of anemia, visited our hospital with the chief complaint of epigastric discomfort.[ncbi.nlm.nih.gov]
  • The blood test showed mild anemia and hypoalbuminemia. The esophagogastroduodenoscopy and colonoscopy revealed diffuse and reddened sessile to semi-pedunculated polyps, resulting in the diagnosis of CCS.[ncbi.nlm.nih.gov]
  • Anemia, positive stool occult blood, serum electrolyte disturbances, and low serum proteins are the main clinical features of patients with Cronkhite-Canada syndrome.[ncbi.nlm.nih.gov]
  • Laboratory investigations showed mild anemia, hypoproteinemia and hypoalbuminemia. Colonoscopy identified the numerous, hyperemic and sessile polyps with mucous exudation of various sizes throughout the colorectum.[ncbi.nlm.nih.gov]
  • Because of iron deficiency anemia and occult gastrointestinal bleeding, she underwent a colonoscopic examination. Colonoscopy revealed multiple broad-based polyps.[ncbi.nlm.nih.gov]
Asymptomatic
  • The concept that Cronkhite-Canada Syndrome is a late-onset disease should probably be reconsidered as it may remain asymptomatic, and thus not diagnosed, for a long a time.[ncbi.nlm.nih.gov]
  • The concept that Cronkhite–Canada Syndrome is a late-onset disease should probably be reconsidered as it may remain asymptomatic, and thus not diagnosed, for a long a time.[doi.org]
  • […] describe two familial cases-one a 50-year-old male patient with chronic diarrhea and epigastric pain since 1.5 years with hyperpigmentation of the hand and foot, alopecia, anorexia, hypogeusia, and weight loss; other case was his 22-year-old son who was asymptomatic[ncbi.nlm.nih.gov]
  • He improved within 10 weeks and is currently asymptomatic. A high index of suspicion for CCS should exist in patients who present with weight loss, diarrhoea and polyposis.[ncbi.nlm.nih.gov]
  • This is the first report to describe an asymptomatic case of CCS probably detected in the early phase of the disease, by magnifying IEE which enabled detection and treatment for associated colonic adenomas.[ncbi.nlm.nih.gov]
Mucosal Edema
  • Colonoscopy also revealed mucosal edema and diffuse polyposis.[ncbi.nlm.nih.gov]
  • Histologically, there were hyperplastic polyps in five cases, tubular adenoma in three, and juvenile polyp in one with chronic inflammation and mucosal edema.[ncbi.nlm.nih.gov]
  • On histologic review, the main findings in the gastric mucosa were a prominent mucosal edema, a mixed inflammatory infiltrate rich in eosinophils, and architectural changes with gland dilatation and withering.[ncbi.nlm.nih.gov]
  • Upper and lower endoscopy were performed, which revealed numerous sessile polyps with mucosal edema and hyperemia involving the stomach, duodenum, and colon, except the esophagus ( Fig. 2 ).[synapse.koreamed.org]
  • Pathological diagnosis Histological assessment showed hyperplastic polyps in five cases, tubular adenoma in three, and juvenile polyp in one with chronic inflammation and mucosal edema.[wjgnet.com]
Diarrhea
  • However, after 4 months, his fingernails were again found atrophic along with mild abdominal discomfort without diarrhea. Colonoscopy revealed a recurrence of the polyps in March 2011.[ncbi.nlm.nih.gov]
  • After 1 week of steroid therapy, the patient's watery diarrhea improved.[ncbi.nlm.nih.gov]
  • The disease is characterized by diffuse gastrointestinal polyposis, dystrophic changes of the fingernails, alopecia, cutaneous hyperpigmentation, diarrhea, weight loss, and abdominal pain. An autoimmune etiology is suspected.[ncbi.nlm.nih.gov]
  • In addition to watery diarrhea, alopecia, and a complete loss of toenails and fingernails, the patient had been suffering from dysgeusia and rapid weight loss of more than 10.0 kg within a few months.[ncbi.nlm.nih.gov]
  • We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg.[ncbi.nlm.nih.gov]
Abdominal Pain
  • This report describes a 60-year-old female who was diagnosed with Cronkhite-Canada syndrome with hypothyroidism after presenting with chronic diarrhea, alopecia, intermittent abdominal pain, generalized gastrointestinal polyposis, hyperpigmentation, and[ncbi.nlm.nih.gov]
  • A 66-year-old male patient presented with nausea, abdominal pain, occasional rectal bleeding, progressive dysgeusia, onicodystrophy, and alopecia.[ncbi.nlm.nih.gov]
  • The disease is characterized by diffuse gastrointestinal polyposis, dystrophic changes of the fingernails, alopecia, cutaneous hyperpigmentation, diarrhea, weight loss, and abdominal pain. An autoimmune etiology is suspected.[ncbi.nlm.nih.gov]
  • The principal symptoms of CCS are diarrhea, weight loss, abdominal pain, and other gastrointestinal complications, such as protein-losing enteropathy and malnutrition.It has been traditional to consider that CCS is associated with a poor prognosis.[ncbi.nlm.nih.gov]
  • A 52-year-old man who was diagnosed as CCS pathologically two years previously presented abdominal pain and sub fever-up.[ncbi.nlm.nih.gov]
Hematochezia
  • We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg.[ncbi.nlm.nih.gov]
  • Consistent with this, in the present case study, the patient initially experienced diarrhea and hematochezia, followed by abdominal pain, nail and toenail loss, onychatrophy and hyperpigmentation.[spandidos-publications.com]
  • CASE REPORT A 16-year old man was admitted to the Department of Internal Medicine of Dongsan Medical Center with the chief complaint of hematochezia. He had suffered on 4–5 occassions from hematochezia and dizziness for 5 months.[kjim.org]
  • […] till now, many complications of CCS have been reported in the literature, but rib fracture is not included.Case PresentationWe report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia[scienceopen.com]
  • […] onychodystrophy. (2) The polyps are nonadenomatous juvenile or hamartomatous polyps that occur throughout the gastrointestinal tract except for characteristic sparing of the esophagus. (3) Presenting symptoms in CCS include diarrhea, weight loss, abdominal pain, hematochezia[thefreelibrary.com]
Alopecia
  • The pathophysiology of alopecia in Cronkhite-Canada syndrome has not been definitively elucidated. We present evidence for alopecia areata incognita as a possible mechanism of hair loss.[ncbi.nlm.nih.gov]
  • […] son who was asymptomatic, with mild alopecia and hyperpigmentation over his face and hands.[ncbi.nlm.nih.gov]
  • Syndrome Gastrointestinal polyposis-skin pigmentation-alopecia-fingernail changes syndrome Cronkhite-Canada disease Gastrointestinal polyposis-ectodermal changes syndrome Polyposis skin pigmentation alopecia fingernail changes edit English Cronkhite-Canada[wikidata.org]
  • He also had alopecia, onychatrophia, and dysgeusia. The presence of multiple polyps and associated symptoms of alopecia, onychatrophia, pigmentation, and dysgeusia informed the diagnosis of CCS.[ncbi.nlm.nih.gov]
  • Further investigation of the histopathologic features of the associated alopecia may determine its cause.[ncbi.nlm.nih.gov]
Hyperpigmentation
  • […] son who was asymptomatic, with mild alopecia and hyperpigmentation over his face and hands.[ncbi.nlm.nih.gov]
  • Cronkhite-Canada syndrome is characterized by generalized gastrointestinal polyps associated with hyperpigmentation, hair loss, and onycholysis.[ncbi.nlm.nih.gov]
  • BACKGROUND AND AIMS: Cronkhite-Canada syndrome (CCS) is a noninherited condition, associated with high morbidity, and characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, hyperpigmentation, and diarrhea.[ncbi.nlm.nih.gov]
  • Cronkhite Canada syndrome is an acquired non-familial syndrome characterised by diffuse gastrointestinal polyposis with alopecia nail dystrophy and hyperpigmentation. There is chronic diarrhoea and protein losing enteropathy.[ncbi.nlm.nih.gov]
  • Cronkhite-Canada syndrome is an acquired inflammatory polyposis syndrome in which alopecia, onychomadesis and hyperpigmentation occur concurrently with gastrointestinal symptoms.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • The cutaneous manifestations of CCS have been attributed to malabsorption and malnutrition caused by the GI pathology.[orpha.net]
  • However, cutaneous manifestation precedes onset of diarrhea in some patients with Cronkhite-Canada syndrome.[flipper.diff.org]
  • It is characterized by gastrointestinal hamartomatous polyposis, diarrhoea, hypoproteinaemia and cutaneous manifestations including alopecia, onychodystrophy, hyperpigmentation with other symptoms such as dysguisea, hypoguisea and xerostomia due to zinc[peertechz.com]

Workup

Electrolyte and micronutrient determination is carried out to check for hypokalemia, hypocalcemia and depressed serum levels of Vitamin B-12, magnesium, copper, iron and zinc [10].

Hematology tests are carried out to check for hematocrit, red blood cell count, hemoglobin and depressed white blood cell count.

Serum protein tests aid in checking hypoalbuminemia, hypoproteinamia and increase in alpha 1 globulin level.

Endoscopic tests procedures show polyps lesions of the sessile or semipedunculated type within the stomach, colon, Ileum and duodenum. The endoscopic procedures to be carried out include gastroscopy, colonoscopy and sigmoidoscopy.

Multiple Colonic Polyps
  • We herein present a 66-year-old-male patient with Cronkhite-Canada syndrome who had a carcinoma of the sigmoid colon along with multiple colonic polyps, which included juvenile-type polyps, adenomas, and hyperplastic polyps.[ncbi.nlm.nih.gov]
  • Multiple colonic polyps; juvenile polyps/hamartomas, tubular adenomas, traditional serrated adenomas. Seventy-five percent of all CCS cases reported in the global literature have been reported from Japan.[ncbi.nlm.nih.gov]
Polyps
  • Multiple polyps, 20 polyps or 2.0 cm in diameter, were found near the carcinoma of the resected rectum.[ncbi.nlm.nih.gov]
  • In addition, the polyp in the sigmoid colon was cancerated. The present case indicated that the physical stress was related to CCS and malignant transformation occurred in Cronkhite-Canada syndrome polyp.[ncbi.nlm.nih.gov]
  • Histology of a polyp from the stomach showed features of juvenile or retention type (hamartomatous) polyp. One colonic polyp revealed features of tubular adenoma, with moderate dysplasia.[ncbi.nlm.nih.gov]
  • Ten patients (71%) had adenomatous polyps and 2 (14%) had colorectal cancer. IgG4 immunostaining was positive ( 5 cells/HPF) in 52% of CCS polyps compared to 12% of JPS polyps (P 0.001); IgG4 staining was negative in all other control tissues.[ncbi.nlm.nih.gov]
  • Mucin-histochemical analysis of the cancer area showed the complete intestinal type, and thus may have differentiated the CCS polyps from that of the common gastric hyperplastic polyps.[ncbi.nlm.nih.gov]
Ischemic Changes
  • Biopsies revealed mucin distended glands and focal ischemic changes. A CT scan showed numerous polypoid-like lesions in the stomach. Upper endoscopy showed mucosal erythema and nodularity with polypoid-like lesions.[ncbi.nlm.nih.gov]

Treatment

Treatment remains predominantly symptomatic due to the unknown etiology. Management aims at correcting the fluid, electrolyte, and protein loss.

Prognosis

Cronkhite-Canada syndrome is considered a progressive disease with a variable course and poor prognosis.

Etiology

The cause of this condition is not known. Formerly, it was thought that the epidermal changes were secondary to profound malnutrition due to enteropathy which leads to loss of protein.

Newer findings have disputed this hypothesis however as hair and nail changes often do not show signs of improvement even with improved nutrition [4].

There are other conditions which show multiple harmartomatous polyps of the digestive system. These include Cowden disease, juvenile polyposis and Peutz-Jeghers syndrome. Related polyposis conditions include MUTYH, Birt–Hogg–Dubé syndrome, attenuated familial adenomatous polyposis and familial adenomatous polyposis [5].

Epidemiology

The CCS has a worldwide distribution but 75% of reports come from Japan. The Cronkhite Syndrome is a rare disorder because by the end of 2002, only 467 cases have been reported in literature across the world with 354 of those coming from groups in Japan.

Mortality/Morbidity

The CCS is regarded as a progressive condition which has poor prognosis and runs a variable course and is dependent mainly on the control of electrolyte balance and protein [2]. Regardless of therapy used, the mortality rate is more than 50%. Co-existing gastrointestinal bleeding, the possibility of intussusception and malignant changes in the polyps all lead to an increase in mortality rate.

The first two patients who were described to have the Cronkhite-Canada syndrome died of starvation 7-8 months after the beginning of symptoms. There have been reported cases of spontaneous remission after nutritional support. In children, the prognosis is often less optimistic than what is obtainable amongst adults [3].

Although majority of cases come from Japan, there is no data to prove any racial predisposition. Therefore the condition is treated as a worldwide condition.

Sex

Sex-wise, the male to female ratio is 1.5-1.31 approximately so the condition is believed to affect both sexes equally.

Age

The Cronkhite-Canda syndrome often sets in between middle age and old age with average age being 55 years. The age rang at which this condition is seen mostly is 31-86 years of age. The disease may stay asymptomatic and therefore it may not be diagnosed for quite a while. Many patients are aged 50 and above by the time of presentation. There have been very scanty reports regarding cases of infantile Cronkhite-Canada Syndrome .

Sex distribution
Age distribution

Pathophysiology

There is no evidence to show the existence of familial predisposition. There is equally the possibility of afflicted patients and offspring that are asymptomatic. The most important risk factors for the CCS are mental stress and physical stress [6].
This stress brings about a local inflammatory reaction since it acts on the gastrointestinal mucosa.

Two weeks after the start of taking oral thyroxine, some patients with the CCS develop ectodermal lesions. At cessation of treatment, the cutaneous signs improved.

The involvement of the immune system in the pathogenesis of the Cronkhite-Canada syndrome is supported by the effectiveness of corticosteroid therapy in many cases of the condition.

The gastrointestinal lesions in CCS are polyps of the harmatomatous type and these histologically show pseudopolypoid-inflammatory changes. Malabsorption is believed to be what leads to the cutaneous symptoms. Changes that occur in the ectorderm do not happen in tandem with other activities of the disease and so it improved in some cases despite gut dysfunction [7].

Prevention

There are no guidelines for prevention of Cronkhite-Canda syndrome.

Summary

Cronkhite-Canada syndrome (CCS) is a rare non-inherited disorder that was reported for the first time in 1955 by Leonard W. Cronkhite Jr and Wilma J. Canada [1].

The condition occurs sporadically. It was seen for the first time as a separate condition within 2 female patients who have onychodystrophy, alopecia, cutaneous pigmentation and generalized gastrointestinal polyps.

Patient Information

If diagnosed for this condition, one way to deal with it is to judiciously stick to medical regimes reporting anything unusual as soon as possible.

References

Article

  1. Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 1998; 280:1086.
  2. Anderson RD, Patel R, Hamilton JK, Boland CR. Cronkhite-Canada syndrome presenting as eosinophilic gastroenteritis. Proc (Bayl Univ Med Cent) 2006; 19:209.
  3. Sweetser S, Ahlquist DA, Osborn NK, et al. Clinicopathologic features and treatment outcomes in Cronkhite-Canada syndrome: support for autoimmunity. Dig Dis Sci 2012; 57:496.
  4. Hornick JL, Fletcher CD. Intestinal perineuriomas: clinicopathologic definition of a new anatomic subset in a series of 10 cases. Am J Surg Pathol 2005; 29:859.
  5. Junnarkar SP, Sloan JM, Johnston BT, Laird JD, Irwin ST. Cronkhite-Canada syndrome. The Ulster medical journal 2001 70 (1): 56–8. PMC 2449205
  6. Ward E, Wolfsen HC, Ng C. Medical management of Cronkhite-Canada syndrome. South. Med. J. 2002 95 (2): 272–4
  7. Ho V, Banney L, Falhammar H. Hyperpigmentation, nail dystrophy and alopecia with generalised intestinal polyposis: Cronkhite-Canada syndrome. Australas J Dermatol. Nov 2008;49(4):223-5.
  8. Daniel ES, Ludwig SL, Lewin KJ, Ruprecht RM, Rajacich GM, Schwabe AD. The Cronkhite-Canada Syndrome. An analysis of clinical and pathologic features and therapy in 55 patients. Medicine (Baltimore). Sep 1982;61(5):293-309.
  9. 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.
  10. 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.

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Last updated: 2019-07-11 20:33