Cronkhite-Canada Syndrome: A Diagnostic Challenge and Management With Vedolizumab

Introduction

Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal (GI) non-malignant polyposis, commonly presenting with refractory diarrhea, abdominal pain, and anorexia [1,2]. Ectodermal changes were also commonly reported, including alopecia, onychodystrophy, dysgeusia/glossitis, or skin hyperpigmentation, which can be associated with malnutrition in this population [1,3]. CCS is most commonly reported in the middle-age and elderly populations (50 to 70 years old), and it is slightly more prevalent in men [4–6]. Although CCS can develop in different ethnic groups, more cases have been reported in the Asian population [4]. A nationwide survey based on the mid-year population of Japan in 2017, reported the prevalence of CCS per 1 000 000 population was 3.7 [7]. There is no single confirmatory test for CCS; rather, the diagnosis is based on a combination of clinical, laboratory, endoscopic, radiologic, and histopathologic findings [8]. Due to its rarity, early recognition requires awareness and a high level of suspicion in patients with concurrent presentation of chronic GI symptoms along with ectodermal manifestations.

Here, we present a case of CCS that was initially thought to be Crohn’s disease, managed with vedolizumab for lower gastrointestinal symptoms, and ultimately required total parenteral nutrition (TPN) due to severe malnutrition. To the best of our knowledge, this is the first reported case of CCS managed with vedolizumab.

Case Report

A 65-year-old man with a past medical history of hypertension, hyperlipidemia, and gastroesophageal reflux disease presented with 2 months of progressive postprandial abdominal pain, 11 kg unintentional weight loss, nausea, bloating, and approximately 10 episodes of non-bloody diarrhea per day. He was prescribed Bentyl by his primary care physician for generalized abdominal pain, which was temporarily helpful. He also reported a persistent “greasy” and “foul” taste in his mouth. He noted nail changes to all fingers and toes, described as nails “lifting from the nailbeds”. He did not smoke or drink alcohol. He did not have any recorded allergies or history of autoimmune disorder. There was no family history of colorectal cancer or inflammatory bowel disease (IBD).

He was initially seen by his primary care physician and was found to have a positive Cologuard test. C. difficile testing was negative, and fecal calprotectin was markedly elevated at 2160 ug/g. Complete blood count (CBC) and C-reactive protein (CRP) were within normal limits (Table 1). A computed tomography (CT) scan of the abdomen revealed an unremarkable stomach, but mild wall thickening of the colon at the splenic flexure and descending colon.

A colonoscopy was performed in August 2023, which showed cobblestoned, edematous, and nodular mucosa in the terminal ileum and ileocecal valve, as well as diffusely erythematous and adenomatous-appearing mucosa from the cecum to proximal rectum (Figure 1A, 1B).

Histopathology from random biopsies demonstrated primarily mild active chronic inflammation from the cecum to transverse colon, with active chronic inflammation and hyperplastic epithelial changes from the descending colon to the rectosigmoid colon, and rectal sparing. There was also a focal increase in lamina propria eosinophils (Figure 2A, 2B). Magnetic resonance (MR) enterography showed no active small-bowel inflammation or complications of Crohn’s disease, but did reveal possible submucosal gastric edema. Based on the endoscopic findings showing rectal sparing, pathology suggestive of IBD, and clinical symptoms, an initial diagnosis of colonic Crohn’s disease was made. The patient was started on a 2-month treatment with prednisone 40 mg with weekly taper and began induction and maintenance therapy with vedolizumab every 8 weeks. He was referred to a dietitian and started taking nutritional supplements.

Two months after initiating vedolizumab and prednisone, the patient showed improvement in abdominal pain and dysgeusia, and he had gained around 9 kg body weight. Given the initial improvement on prednisone and vedolizumab, IBD remained the leading diagnosis. However, at an 8-month follow-up, he reported loose bowel movements, 6–8 times daily, and postprandial abdominal pain. His body weight continued to decrease, and he was found to be iron deficient. Due to ongoing symptoms, his vedolizumab dosing was increased to every 4 weeks, with the plan to endoscopically reassess disease activity in 6 months.

Six months later, he continued to have 6–8 bowel movements per day and postprandial abdominal pain. He reported severe dysgeusia. Around this time, he was diagnosed with atrophic glossitis. A repeat CT scan showed a large gastric mass extending into the duodenum, with multiple enlarged perigastric lymph nodes. The worsening symptoms prompted repeat endoscopic evaluation. EGD and endoscopic ultrasound showed multiple mucosal nodular masses in the stomach and duodenum, with the largest measuring 48 mm in thickness, with some cystic components. A single 30×30 mm polypoid mass in the duodenal bulb covered half the circumference (Figure 3). Colonoscopy showed nodular mucosa in the terminal ileum, ascending and transverse colon, and inflammatory polyps (5–10 mm) in the left colon, with normal intervening mucosa (Figure 4A, 4B). On histology, the biopsies showed diffuse changes throughout the gastrointestinal tract, including epithelial hyperplasia and mucosal edema and inflammation (Figure 5A, 5B). In the stomach, these changes resulted in hyperplastic-appearing polyps (Figure 6). Rectal biopsy revealed a tubular adenoma. There were no findings of malignancy.

The case was reviewed at a multidisciplinary conference with input from gastroenterology, pathology, radiology, and colorectal surgery. The clinical picture, prominent polyposis, and pathology were deemed more consistent with CCS rather than Crohn’s disease. Vedolizumab was continued due to partial symptomatic relief, and the patient was referred to surgical oncology to consider gastrectomy given his significant gastric polyposis. Surgery was deferred due to the absence of malignancy or gastric outlet obstruction and high perioperative morbidity and mortality in the context of his severe malnutrition.

By 18 months after the initial presentation, he continued to have dysgeusia and had lost a total of 45 kg body weight. He developed anasarca and had a serum albumin of 2.3 (g/dL). He was referred to the hospital from the GI clinic for admission and management of severe protein-calorie malnutrition. Percutaneous gastrostomy or jejunostomy tube placement was not feasible due to the obstructing duodenal polyp and diffuse gastric mucosal involvement from CCS. Surgical placement of a gastrostomy or jejunostomy tube was discussed; however, it required significant improvement with his nutritional status before considering surgical interventions. Therefore, he was initiated on TPN. He was discharged with the hope that his nutritional status would improve, making him a candidate for surgical placement of a surgical feeding tube.

Discussion

CCS is a rare, non-inherited gastrointestinal disorder characterized by polyposis, protein-losing enteropathy, and ectodermal symptoms [3]. The etiology and pathogenesis of CCS remain poorly understood due to the rareness of the disease, although autoimmune and chronic inflammatory processes and impairments in innate immunity and glycosylation have been proposed as the underlying cause of the disease [9]. No animal models have been reported in the literature. Some of these proposed etiologies have been supported by evidence of infiltration of CCS polyps with IgG4 plasma cells, upregulation of innate immune response pathways in the polyps, concomitant autoimmune disorders, and response to immunosuppressive therapies [10,11]. A study using patient tissue stem cell-derived intestinal organoids showed increased 5HT-producing enteroendocrine cells in intestinal epithelium, which, they hypothesized, provoked the inflammation and induced cellular proliferation in the intestinal epithelium of the patients, leading to formation of the non-adenomatous cystic polyps [12].

Diagnosis of CCS is made clinically based on symptoms (eg, diarrhea, abdominal pain, nausea, dysgeusia), ectodermal changes (eg, hyperpigmentation, alopecia, nail dystrophy), endoscopic evaluation (eg, diffuse polyposis stomach, small bowel, and colon, but sparing the esophagus), typical histologic findings (eg, lamina propria edema, mononuclear infiltrate, cystic gland dilation) often described as hamartomatous, hyperplastic, or inflammatory polyps [8,13]. Additionally, other hamartomatous polyposis syndromes should be excluded, including juvenile polyposis syndrome (differentiated histologically and by genetic testing for germline BMPR1A and SMAD4 mutations, but insufficient for diagnosis), Peutz-Jeghers (pigmented mucocutaneous macules, typically with STK11 germline mutation), and PTEN mutation syndromes, including Cowden syndrome (eg, PTEN mutation, trichilemmomas, oral papillomas) [14–16].

Given that no single genetic marker has been identified as a cause of CCS, future research should focus on comprehensive genomic approaches using next-generation sequencing or single-nucleotide polymorphism in international registries or multicenter collaborations. This would also pave the way for developing transgenic or genetically engineered animal models.

Given the low prevalence of CCS, management is based on evidence from case reports and case series. Steroids are the most commonly noted means of treatment in the literature [8,17]. Poor response to steroids has been associated with worse overall survival, and symptom recurrence on steroid tapering frequently occurs. Due to the multifactorial etiology of the disease, adjuvant therapies, including mesalazine, histamine (H2 and H1) receptor antagonists, and cromolyn, have been used with success in some cases [8,18,19]. Good outcomes have been achieved using steroid-sparing immunomodulators such as azathioprine, which can be effective in preventing relapse [8,10].

Vedolizumab is a monoclonal antibody that targets the α4β7 integrin, preventing T cell migration into the intestinal mucosa to reduce lymphocyte-driven inflammation. Vedolizumab has been FDA-approved for IBD, but given its gut-selective action and favorable safety profile, it has also been used off-label in treating other non-IBD-related enteropathies [20]. To date, there are no case reports of using this drug for CCS. In our case, vedolizumab was initially started in the context of a Crohn’s diagnosis. After a CCS diagnosis was made, the medication was continued due to the initial clinical response with improvement in diarrhea, abdominal pain, and dysgeusia, along with an objective finding of fecal calprotectin decreasing from 2160 to 758. During the patient’s symptom exacerbation, we elected to continue therapy given the possible continued partial efficacy of vedolizumab and the low-risk nature of vedolizumab therapy.

Cyclosporine, infliximab, and tacrolimus for steroid-resistant cases have also been reported [21]. A case report showed clinical and endoscopic improvement of the disease after treatment with fecal microbiota transplantation as a complementary treatment in a steroid-refractory patient who could not undergo TNF alpha inhibitor treatment due to a prior history of tuberculosis [22].

Improvement in pain and overall quality of life is often inferred from clinical remission. Future research should use patient-reported outcome measures to construct a validated pain or quality of life scoring system and advance evidence-based care decisions for symptom management.

Malignant transformation of CCS polyps has been reported, with a risk as high as 25% [23]. Surveillance endoscopy is essential for a prompt detection and treatment of malignant polyps; however, the screening is only practical after the inflammation and polyp burden have been controlled with medical therapy. There is no clear guideline regarding the interval for surveillance endoscopy, but at least annual screening has been recommended [17,24]. In our case, multiple biopsies identified benign polyposis and no evidence of malignancy or dysplasia.

Nutritional support is essential in patients with CCS, given the protein loss, frequent abdominal pain, and dysgeusia. The goals of nutritional support should be to correct electrolyte imbalances and mineral and vitamin deficiencies, and improve protein-calorie deficits, particularly to improve mucosal healing in those with severe malnutrition [17,25]. An individualized and multidisciplinary approach should be pursued and include members of the nutrition team, gastroenterology team, and (potentially) surgical teams.

With the advances in disease knowledge and improvements in medical management, the prognosis of the disease has improved with time. An often-cited 1982 study reviewed 52 separate cases of CCS and found a 5-year mortality rate estimated at 55%. A recently published study of patients with CSS hospitalized between 1999 and 2023 in Peking Union Medical College Hospital reported the cumulative probability of overall survival was 90.2% at 3 years, 87.7% at 5 years, and 78.6% at 10 years [19]. Another recent study of 17 patients diagnosed and treated at the Mayo Clinic showed 93.3% 5-year overall survival [8]. The most common causes of death in patients with CCS include severe malnutrition, gastrointestinal bleeding, infections, and malignancies [17,26].

Conclusions

CCS is a rare yet increasingly recognized condition involving GI symptoms along with ectodermal changes. This case report shows that the diagnostic complexity and clinical severity of CCS can closely mimic IBD. Although our patient eventually developed worsening symptoms, he initially responded to vedolizumab therapy. Given the suspected autoimmune pathogenesis and predominant localization of disease to the gastrointestinal tract, vedolizumab was a reasonable first-line therapy. However, given his recent disease exacerbation, switching to another immunomodulating therapy with a different mechanism of action would have been reasonable. The progression of the disease led to severe malnutrition requiring TPN. This emphasizes that early recognition and multidisciplinary management are critical in CCS to avoid complications and improve outcomes in this debilitating condition.