Long-lasting remission in a case of Cronkhite-Canada syndrome

Abstract

Cronkhite-Canada syndrome is a rare disease characterised by diffuse gastrointestinal polyposis, diarrhoea, weight loss, skin hyperpigmentation, onychodystrophy and alopecia. More than 500 cases have been described in the medical literature so far. The disease is probably caused by immune-mediated inflammatory mechanisms, and the diagnosis is based on clinical history, physical examination, endoscopic findings and histology. Differentiating this condition from other clinical entities presenting with similar signs and symptoms may be challenging. We present here the case of a 70-year-old Sardinian man where apparently the syndrome was induced by a mental strain triggered by a work-related accident. Continuous treatment with low-dose of antidepressant, anti-inflammatory and immunosuppressive medications in addition to nutritional support was remarkably effective and resulted in sustained (longer than 8 years) disappearance of clinical manifestations as well as the persistence of physical and psychological well-being. This case argues against the poor prognosis previously ascribed to patients with this syndrome.

Background

Cronkhite-Canada Syndrome (CCS) is a rare non-familial disease characterised by gastrointestinal polyposis, diarrhoea, skin hyperpigmentation, onychodystrophy, taste disturbance and alopecia which was described for the first time by Cronkhite and Canada in 1955.¹ Since then, it has been reported sporadically, especially in Asian countries, and no more than 500 cases can be found in the medical literature.^2–6 The aetiology and pathophysiology of CCS are still unknown, although immune-mediated inflammatory mechanisms have been implicated based on the prompt response to immunosuppressive and anti-inflammatory drugs.⁷ However, some authors suggested that mental strain and psychiatric disorders may trigger CCS.⁸ The syndrome is characterised by a high morbidity and 5 years mortality of around 55%. In Italy, the syndrome is very rare and only three adult cases have been described in the literature.^9–11 Among more than 21 000 endoscopic procedures performed in our hospital, only one case of CCS was observed, confirming its extreme rarity also in Sardinia. Treatment with a low dose of antidepressant, anti-inflammatory and immunosuppressive medications in addition to nutritional support was remarkably effective resulting in a sustained disappearance of clinical manifestations and a general well-being, after 8 years of follow-up.

Case presentation

In 2009, a 70-years-old Caucasian male from Sardinia, Italy, was referred to the Gastroenterology Unit of our hospital (University of Sassari, Italy) for a clinical history of mild bloody diarrhoea (up to four bowel movements per day, characterised by urgency after meals), flatulence, abdominal pain, dyspeptic symptoms and progressive weight loss (7 kg in the last year). In addition, the patient complained ageusia and ‘a bad mood’ with insomnia. A marked onychodystrophia was present at physical examination in both hands and feet in addition to palmar and plantar spotty pigmentation (figures 1 and 2). Alopecia was not observed and the remaining visit was unremarkable. The patient, a former bricklayer, reported that all signs and symptoms appeared in conjunction with a depressive syndrome that followed a work-related accident in 2003. Despite several neurological, psychiatric and gastroenterological consultations, a definite diagnosis of CCS was never made. The patient denied any family history of gastrointestinal polyposis syndromes and his family history was significant only for epilepsy (two sons out of four).

Figure 1.

Skin lesions detected in the clinical case. Bilateral palmoplantar melanosis (hyperpigmentation).

Figure 2.

Onychodystrophy of toe nails.

Investigations

Major findings in the laboratory tests were: mild vitamin B12, folate and protein depletion without evidence of overt protein-losing enteropathy. Additional serum markers were found to be normal except for positivity for immunoglobulin G antibodies against Helicobacter pylori. The infection was successfully eradicated in the past. There was no clinical and/or laboratory evidence of autoimmunity. Upper gastrointestinal endoscopy showed redundant folds and a bulky, polypoid mass (large around 20 cm in the main diameter) originating in the duodenal bulb and gastric antrum with several additional minor polyps. Histological examination (figure 3) revealed a hyperplastic, inflammatory tissue (described by the pathologist as hamartomatous pseudopolyps) with an eosinophilic infiltrate in the lamina propria. Pancolonoscopy showed a hyperaemic mucosa with multiple erythematous pseudopolyps, especially clustered near to the ileocecal valve. The morphological aspect of colonic specimens was similar to the one observed in the gastric mucosa. The diagnostic workup was completed with an enteric-CT scan, which ruled out the involvement of the entire small bowel. On the basis of a combination of clinical characteristics, biochemical testing, serology markers and histopathological features a final diagnosis of CCS was established.

Figure 3.

Morphology of a pseudopolyp at the histological examination showing hyperplastic, inflammatory tissue with eosinophilic infiltrate in the lamina propria.

Differential diagnosis

In the present case, CCS was hypothesised relatively early because of the simultaneous appearance of syndrome features, making an extensive differential diagnosis superfluous.

Treatment

The treatment focused on symptomatic management and nutritional support consisting of vitamin supplementation, trazodone 50 mg per day increased gradually up to 300 mg plus etizolam 1 mg daily at bedtime, metronidazole 500 mg twice daily for 10 days, low dose corticosteroid therapy (prednisone 5 mg daily), proton pump inhibitors (pantoprazole 20 mg daily) and mesalamine (2.4 g daily). In addition, it was recommended to consume a protein-rich diet.

Outcome and follow-up

In the further 6 months, the patient’s clinical conditions improved dramatically. He gained 5 kg, the finger nails recovered progressively and the palmar and plantar pigmentation partially resolved. Follow-up upper endoscopies at 6 and 12 months demonstrated a marked reduction in the gastroduodenal polyp mass. After 1 year, the patient completely regained the sense of taste, palmar and plantar pigmentation disappeared and the finger and toe nails rescued entirely. Moreover, abdominal pain and diarrhoea became very rare and, most importantly, the mood improved. At that point, the patient, in a pretty good health, refused any kind of invasive follow-up with the exception of lab tests. Medications from October 2010 up to October 2017 consisted of etizolam 1 mg plus prednisone 5 mg, pantoprazole 20 mg plus mesalamine 2.4 g daily, doxazosin 4 mg daily for blood hypertension, rifaximin 1200 mg daily for 7 days and folic acid, B12 and D vitamins supplementation every 2–3 months. In addition, over all this time, a protein-rich diet was encouraged. The treatment with trazodone was discontinued after 1 year.

Discussion

CCS is an uncommon, non-inherited gastrointestinal polyposis syndrome associated with a variety of signs including cutaneous hyperpigmentation, onychodystrophy, diffuse alopecia and symptoms such as diarrhoea, gastrointestinal bleeding, weight loss and hypogeusia.¹ It is a debilitating and life-threatening disease with a mortality rate of 55% at 5 years.⁷ Differential diagnosis may be extensive. A mixed morphology of polyps has been described in CCS, generally ranging from hyperplastic, tubular adenomas, juvenile polyps, inflammatory and hamartomatous polyps. The optimal therapy for CCS is not known but several treatment options have been described. Nutritional support, antibiotics, corticosteroids, histamine-receptor antagonists and surgical treatment have been reported as effective. Unfortunately, because of the rarity of the disease, controlled therapeutic trials are missing. More importantly, a specific treatment, proven to be effective in all cases, is still unavailable. Contrary to earlier observations, our case, according to a number of recent reports, suggested that a favourable prognosis may be achieved by removing the trigger and setting up a treatment protocol with corticosteroid associated with nutritional supplementation.

Since the majority of CCS cases were observed in Japan and China, where the diet is more plant based than meat based, and therefore less likely able to create a proinflammatory environment, it is reasonable to speculate that an important role in this syndrome is played by nutritional factors. According to this observation, it is possible that the depressive status perceived by the patient, the associated hyporexia and diarrhoea may have determined a vitamin unbalance. Moreover, it has been suggested that CCS could be triggered by a variety of psychiatric conditions,⁶ and more specifically in one report, the syndrome was associated with schizophrenia.⁸ Patient mood in our case improved alongside with symptoms resolution, although a minimum treatment with psychotropic agents was kept and, we can say with hindsight, this was determinant for a complete rescue of taste and appetite. In addition, the mood improvement and the use of steroids may have attenuated autoimmunity and inflammation. This may explain the polyps reduction observed in the second and third follow-up endoscopy.⁷

We are not able to confirm a complete disappearance of polyps from the stomach and duodenum (because of the patient’s choice to refuse any invasive test in the follow-up). However, despite a treatment combination of drugs at a minimal dosage and nutritional supplementation during all 8 years of follow-up, our patient is in good health and the need of surgery avoided.

Patient’s perspective.

• I am very grateful to the medical team for the management of my disease. In particular, the team helped me greatly from a psychological point of view. I felt to be treated appropriately and in a familial environment.

• My depression, consequence of my work accident, caused me to face with a vicious circle and I felt frustrated because I could no longer give support to my family relatives (my wife and my two sick children). Therefore, with the improvement of the symptoms, my mood also improved and vice versa.

• At present, despite my age of 78, I feel myself in complete well-being.

Learning points.

• Cronkhite-Canada syndrome is a rare disease believed to entail a poor prognosis.

• The syndrome may be triggered by mood disorders that in turn may interfere with appetite, nutritional status and immune system.

• Clinical outcome of Cronkhite-Canada syndrome may be favourable by removing the trigger, adjusting for nutritional unbalance and keeping the immunosuppressive therapy at minimum.