Cronkhite-Canada syndrome: An elusive gastrointestinal disorder with multisystem involvement-pathogenesis, diagnosis, and therapeutic strategies

Abstract

Cronkhite-Canada syndrome (CCS) is a rare, non-hereditary gastrointestinal (GI) disorder characterized by diffuse polyposis in the GI tract, ectodermal abnormalities, and nutritional deficiencies. It is a multisystem disorder with a multifactorial origin, particularly autoimmune, with only about 500 cases reported from around the world. This narrative review aims to consolidate current knowledge on CCS, focusing on its epidemiology, clinical features, pathogenesis, diagnostic techniques, and treatment strategies. Clinically, patients with CCS present with chronic diarrhea, abdominal pain, protein-losing enteropathy, alopecia, onychodystrophy, and hyperpigmentation. These symptoms often overlap with other prevalent GI conditions like ulcerative colitis, leading to misdiagnosis of CCS in earlier stages of the disease. Diagnosis of CCS requires a combination of laboratory analyses facilitated with endoscopic visualization of characteristic polyps, histopathological evaluation, and exclusion of other polyposis syndromes. Treatment remains non-standardized, with corticosteroids being the mainstay of management. Other therapeutic regimens include immunosuppressants, biologic agents, non-steroidal anti-inflammatory drugs, and proton pump inhibitors, which are often used as adjunctive therapy with steroids and paired with nutritional supplementation. On the other hand, malignant polyps need to be surgically resected. The prognosis of CCS is improving owing to improved treatment strategies and better patient outcomes. Further research is crucial to enhance our understanding of the pathologic mechanisms of CCS, ultimately aiming to improve early detection and reduce long-term morbidity and mortality.

Key Words: Cronkhite-Canada syndrome; Gastrointestinal polyposis; Pathogenesis; Diagnosis; Therapies

Core Tip: Cronkhite-Canada syndrome is a rare, non-hereditary gastrointestinal (GI) polyposis disorder with multisystem involvement and significant diagnostic challenges due to its overlap with more common GI diseases. This review provides a comprehensive synthesis of current evidence, highlighting emerging insights into its multifactorial pathogenesis, including immune dysregulation, microbiome alterations, and potential infectious triggers. It also emphasizes the evolving role of immunosuppressive and biologic therapies alongside nutritional support. By integrating clinical features, diagnostic strategies, and therapeutic approaches, this article proposes a structured framework to improve early recognition, guide management, and reduce long-term complications, including malignancy.

INTRODUCTION

Cronkhite-Canada syndrome (CCS) is a rare, sporadic disorder of the gastrointestinal tract with an incidence rate of 1/1000000[1]. The condition typically presents in late adulthood, with a mean age of onset around 63.5 years. The syndrome is characterized by polyposis, ectodermal lesions, and protein-losing enteropathy, which leads to hypoalbuminemia[2]. In addition to gastrointestinal symptoms like diarrhea, nausea, vomiting, and abdominal pain, patients frequently present with systemic manifestations including weight loss, atrophic glossitis, and malnutrition.

Cronkhite and Canada[3] first described the syndrome in 1955, reporting two cases in the New England Journal of Medicine. The first involved a 42-year-old woman presenting with a two-month history of diarrhea, vomiting, and anemia (hemoglobin 9.8 g/dL). She exhibited diffuse alopecia, particularly in the facial and axillary regions, and notable hyperpigmentation affecting the flexures, dorsum of the hands, and face. Imaging studies revealed multiple colonic polypoid masses. Despite supportive care, her condition deteriorated, with progressive weight loss, edema, and digital gangrene. She died within eight months of initial presentation[3]. The second case involved a 71-year-old female with a 10-month history of loose, watery, foul-smelling stools as well as severe hair loss, which resulted in baldness within 3 days. She exhibited onychodystrophy, generalized weakness, pedal edema, and peripheral neuropathy characterized by numbness and paresthesias. Imaging revealed multiple rib fractures due to bone demineralization, while a barium enema demonstrated diffuse colonic polyposis. Despite medical management, her anemia worsened, and she succumbed to the illness seven months later[3].

Jarnum and Jensen later formally coined the term “Cronkhite-Canada syndrome” in 1966[4]. Despite its recognition, CCS remains poorly understood, with most literature limited to individual case reports. Hence, it poses significant diagnostic and therapeutic challenges, as no standardized treatment exists, and mortality remains high, exceeding 55% at five years. The primary contributors to mortality are severe anemia and malabsorption-related complications, highlighting the urgent need for improved disease management.

This review aims to explore the current literature on CCS and provide an overview of its pathophysiology, diagnostic challenges, and management strategies. By analyzing multiple case studies, we intend to find disease patterns and compare CCS to other polyposis syndromes with similar clinical presentations, guiding clinical practice and aiding further research.

SEARCH STRATEGY

The object of the study was to provide a comprehensive overview. Therefore, a narrative review study design was employed. A literature search was conducted using PubMed and Scopus, targeting studies published from inception to 30 April, 2025. The search string included the following keywords: ‘Cronkhite-Canada syndrome’, ‘epidemiology’, ‘pathogenesis’, ‘diagnosis’, and ‘treatment’, combined with Boolean operators (AND, OR) to enhance coverage. All types of peer-reviewed studies, including original studies, randomized controlled trials, case reports, and review articles, that provided insights into the pathophysiology, epidemiology, clinical characteristics, diagnostic methods, and treatment strategies were included. Their titles and abstracts were reviewed to assess their relevance to the topic. The reference lists of included studies were further screened to identify any relevant studies. Studies in languages other than English and animal studies were excluded. Figure 1 summarizes the study selection process for the review.

Figure 1  Flowchart of the study selection process.

Data extraction

A total of 365 studies were identified after screening. High yield studies with the greatest relevance to study objectives were prioritized for discussion. Key data regarding epidemiology, pathophysiology, diagnosis, and treatment of CCS were extracted and narratively synthesized in this review.

Epidemiology

Although CCS was initially considered a medical rarity, reported cases have gradually increased since its first description in the 1950s. To date, just over 500 cases have been documented worldwide[5]. The average age at diagnosis is 63.5 years, although cases in younger individuals, including pediatric presentations, have been documented[6]. The syndrome shows a slight male predominance (male-to-female ratio of 3:2) and is notably clustered in Japan, which accounts for approximately 75% of reported cases, including a single cohort study with 180 patients[1].

Although definitive risk factors remain unknown, growing evidence suggests an autoimmune and inflammatory etiology. CCS has been associated with rheumatoid arthritis, systemic lupus erythematosus (SLE), and membranous glomerulonephritis. The clinical efficacy of corticosteroids in many cases further supports an immunological basis[7]. Familial cases are exceptionally rare, with only a single reported instance of a father and son developing CCS, suggesting a low likelihood of a genetic link to the disease[8]. Psychological and physical stress have also been proposed as potential disease triggers. Importantly, CCS is a multisystem disorder with manifestations that extend well beyond the gastrointestinal tract.

The ectodermal manifestations include sudden-onset alopecia, hyperpigmentation (affecting the face, hands, mucosa, and neck), and onychodystrophy (nail thinning, splitting, and eventual loss)[9,10]. Additional systemic manifestations include cardiac complications (thrombosis, heart failure, and coagulation abnormalities)[11], neurological deficits (anosmia, peripheral neuropathy, vestibular disturbances)[12-15], and psychiatric conditions (depression, anxiety, and cognitive impairments)[16].

Malabsorption is the major cause of morbidity and mortality in CCS, resulting in a cascade of metabolic and nutritional complications. Deficiencies in key electrolytes and micronutrients can precipitate anemia, paresthesias, seizures, and tetany. In some cases, these imbalances have been implicated in the development of acute pancreatitis[17].

Pathogenesis and etiology

Due to the rarity of the disease, it has been challenging to understand its etiology. However, current evidence supports a multifactorial origin involving immune dysregulation, microbial dysbiosis, environmental triggers, and possibly somatic or germline genetic alterations[7,18,19]. Although CCS is generally regarded as a sporadic, acquired condition with no consistent familial pattern, a genome-wide study has identified a mutation in the PRKDC gene as a potential genetic cause[20]. Further investigation is required to clarify the role of such mutations and their implications for disease susceptibility.

Multiple studies strongly point towards an autoimmune origin. CCS has been frequently reported in association with other autoimmune disorders, such as hypothyroidism, rheumatoid arthritis, scleroderma, membranous nephropathy, and SLE[10,17,21-23]. Notably, studies have reported elevated antinuclear antibody (ANA), anti-Saccharomyces cerevisiae antibody, and IgG4 levels in patients with CCS[11,19,23-26]. Additionally, a potential link between Helicobacter pylori(H. pylori) infection and CCS has also been observed. A nationwide survey conducted by Watanabe et al[2] in Japan found that 54% of CCS patients had H. pylori infection, with symptom improvement following eradication therapy[2,27,28]. However, whether the bacterium serves as a primary etiological agent or acts to amplify underlying immune dysfunction remains to be determined.

Furthermore, the gut microbiota, which supports gut immunity, homeostasis, and pathogen defense, is believed to be linked to CCS. Dysbiosis may disrupt immune regulation, potentially contributing to disease development[29,30]. Studies have shown that CCS patients possess distinct microbial profiles compared to healthy controls, suggesting a potential link between intestinal flora imbalance and disease activity[31].

Histopathological findings include edema of the lamina propria with significant mononuclear and eosinophilic infiltration in both polyps and surrounding non-polyp mucosa[32,33]. CCS may also cause dysregulation of intestinal stem cells, and mast cell dysfunction may contribute to the etiology of the disease[34].

Drug hypersensitivity reactions have also been proposed as potential etiological factors[24]. In a case reported by Wu et al[35], a patient exhibited increased levels of serum IgE after being administered an oral traditional Chinese medication. Similarly, oral thyroxine therapy has been linked to CCS, however, evidence remains limited[36]. More recently, Poplaski et al[37] observed increased serotonin-producing enteroendocrine cells in intestinal organoids derived from CCS patients, suggesting a possible link between serotonin dysregulation and abnormal epithelial proliferation. However, the precise role of serotonergic signaling in CCS pathogenesis remains unconfirmed. Potential etiological factors that may cause CCS have been summarized in Figure 2.

Figure 2  Potential etiological factors that may cause Cronkhite-Canada syndrome.

Clinical presentation and differential diagnosis

CCS is characterized by gastrointestinal disturbances and ectodermal manifestations. It is marked by the presence of multiple, diffuse gastrointestinal polyps, most commonly found in the stomach and small intestine, while the esophagus is uniquely spared[1,17,38]. Common symptoms include chronic diarrhea, abdominal pain, anorexia, xerostomia, and altered taste (hypogeusia)[35,39]. Protein-losing enteropathy is also frequently observed in patients[40]. Patients with electrolyte abnormalities may also experience paraesthesias, tetany, and seizures[17].

In addition to gastrointestinal symptoms, CCS is associated with distinct ectodermal abnormalities, such as cutaneous hyperpigmentation, nail dystrophy, alopecia, and loss of eyelashes and eyebrows[39-42]. Microscopic examination of biopsied skin in CCS patients often reveals excessive melanin deposition, either alone or alongside increased melanocyte proliferation. The hyperpigmentation typically presents as diffuse, light-to-dark brown macular lesions, commonly appearing on the face, neck, palms, extremities, and soles[25,38,42]. Nail dystrophy is characterized by thin, triangular nails with splitting and detachment of the nails from their beds[9,42]. These ectodermal abnormalities are commonly believed to be a cause of malnutrition[38,40].

Hypoguesia may precede other manifestations and in some cases, be the initial presenting symptom. Gastrointestinal complaints and later ectodermal changes typically follow. Hypogeusia has been linked to micronutrient deficiencies, particularly zinc and copper, and few patients have shown improvement with zinc supplementation[4,43-45]. However, the response of ectodermal features to nutritional therapy is variable[46]. Chuamanochan et al[47] proposed that these ectodermal changes may be caused by inflammation rather than malabsorption alone. This deduction was based on their finding of hypergranulosis in the nail matrix, which indicates an inflammatory process. Common clinical features of CCS have been summarized in Figure 3.

Figure 3  Common clinical features of Cronkhite-Canada syndrome.

In its early stages, CCS may be mistaken for more common gastrointestinal disorders, such as inflammatory bowel disease, given overlapping symptoms like abdominal cramping, diarrhea, and blood- or mucus-streaked stools. Endoscopic findings may further mimic colitis, delaying accurate diagnosis[48]. As the disease progresses, characteristic features, such as dysgeusia, alopecia, and diffuse polyposis, become more apparent. Misdiagnoses have included ulcerative colitis, intestinal tuberculosis, and eosinophilic gastroenteritis[35,48,49]. Interestingly, some studies have reported cases where CCS was misdiagnosed as a coronavirus disease 2019 (COVID-19) or COVID-19 vaccination-related condition[50,51]. This diagnostic confusion may have arisen because both alopecia and dysgeusia are also commonly reported in COVID-19, leading clinicians to overlook CCS as a potential differential in patients presenting with these overlapping features[50].

The clinical and endoscopic features of CCS can resemble those of other gastrointestinal polyposis syndromes, including Peutz-Jeghers syndrome (PJS), Familial Adenomatous Polyposis (FAP), Juvenile Polyposis syndrome, Ménétrier’s disease, cap polyposis, and Cowden’s disease[40,52]. Unlike CCS, FAP has a familial predisposition and is inherited in an autosomal dominant pattern[53]. FAP primarily affects the rectum and colon, whereas CCS most commonly involves the stomach and small intestine[53,54]. Additionally, FAP typically manifests in adolescents, while CCS is more common in middle-aged and elderly individuals[2,54]. On the other hand, PJS is an autosomal dominant polyposis syndrome that frequently affects the small intestine but may also involve the colon, stomach, and rectum[55]. Similarly to CCS, it is associated with hyperpigmentation, which occurs in more than two-thirds of PJS patients[56]. However, nail dystrophy and alopecia are uncommon in PJS. Given these overlapping features, the diagnosis of CCS requires careful consideration of the patient’s clinical presentation, endoscopic findings, and pathological features. These differences have been summarized in Table 1[57-77].

Table 1 Differences between Cronkhite-Canada syndrome and other syndromes causing gastrointestinal polyps.

	Cronkhite-Canada syndrome	Peutz-Jeghers syndrome	Juvenile Polyposis syndrome	Familial adenomatous polyposis
Etiology	Idiopathic	Genetic (STK11 mutation)[57]	Genetic (SMAD4 or BMPR1A mutation)[58]	Genetic (APC gene)[59]
Inheritance	Sporadic (non-familial)	Autosomal dominant[60]	Autosomal dominant[61]	Autosomal dominant[62]
Age	Middle-age	Adolescents[63]	Teenage (16-18 years)[61]	About 16 years[64]
Polyp type	Inflammatory and hamartomatous	Hamartomatous[65]	Hamartomatous polyps[61]	Adenomatous polyps[66]
Polyp distribution	Diffuse throughout the stomach and small intestine. The esophagus is commonly spared	Predominantly the small intestine; also the colon and the stomach[65]	Mainly the colon and rectum[67]	Initially, mostly in the distal colon (rectosigmoid), but later spread throughout the colon[68]
GI symptoms	Chronic diarrhea, abdominal pain, anorexia, protein-losing enteropathy	Intestinal obstruction, bleeding, stomach pain, intussusception[69]	Rectal bleeding, anemia[70]	Abdominal pain, change in bowel habits, constipation, diarrhea, abdominal pain, or palpable abdominal masses[71]
Ectodermal manifestations	Alopecia, nail dystrophy, hyperpigmentation, xerostomia, hypogeusia	Mucocutaneous pigmentation (lips, buccal mucosa)[69]	None	Anemia, osteomas, dental abnormalities, Congenital Hypertrophy of the Retinal Pigment Epithelium, desmoid tumors, or extracolonic cancers (thyroid, liver, bile ducts, central nervous system)[72]
Histo-pathology	Edematous lamina propria, cystic gland dilation, inflammatory infiltrate	Arborizing smooth muscle core in polyps[73]	Cystically dilated glands with inflammatory stroma[74]	Ranges from tubular, tubulo-villous, and villous[68]
Malignancy risk	Moderate (adenomatous transformation possible)	High (GI and pancreatic cancers)[75]	Moderate (colorectal cancer risk)[76]	Low (GI, pancreatic, mucinous adenomas, brain tumors, hepatoblastoma)[77]

GI: Gastrointestinal.

Diagnosis

Laboratory analyses: Laboratory investigations in CCS play a critical role in supporting diagnosis, excluding alternative etiologies, and assessing systemic involvement. Fecal occult blood testing may be positive due to bleeding from intestinal polyps. While some studies, such as Wen et al[24] have reported parasitic elements in stool samples (e.g., maw worm eggs), their relevance to CCS pathophysiology remains uncertain. Laboratory abnormalities commonly reflect malabsorptive sequelae and include hypoalbuminemia, hypoproteinemia, and various micronutrient deficiencies[78]. A complete blood count may reveal anemia due to chronic gastrointestinal bleeding, while eosinophil count and IgE levels may be elevated, suggesting an inflammatory or allergic component[22]. Additional tests such as ANA, anti-Saccharomyces cerevisiae antibodies, H. pylori serology, and autoantibody tests can be performed as well[59,66]. Other useful tests include C-reactive protein, erythrocyte sedimentation rate, renal function tests, thyroid function tests, and liver function tests to assess multisystem involvement[35,79,80].

Endoscopic approach: Endoscopic evaluation is central to the diagnosis of CCS, allowing direct visualization of the diffuse polyposis that characterizes the disease. Polyps may be pedunculated or sessile with either smooth or rough surfaces. On gastroscopy, the gastric mucosa often appears thickened, with hypertrophic mucosal folds resembling a “carpet”. These polyps appear strawberry-like, edematous, and granular. The small intestine appears denuded with loss of villi. The mucosa of the duodenum is swollen with scant villi and nodulations. Villi are greatly reduced on the top of mucosal folds of the jejunum. However, the rest of the jejunum appears to have normal villi. Colonic polyps are mostly sessile and strawberry-like[40,81-83].

A retrospective analysis was conducted by Wang et al[38] to understand the endoscopic features of CCS. Findings from upper gastrointestinal endoscopy from 75 cases reported the occurrence of gastric polyps in all 75 cases, whereas duodenal polyps were detected in 42 cases (56%). Esophageal polyps were found in none of the cases. Colonoscopy was performed in 74 cases, and 22 of those cases (29.73%) also had terminal ileal polyps. The vast majority of polyps in both the gastric and intestinal tracts were bright red. Capsule endoscopy and enteroscopy were performed in a limited number of patients, but provided enhanced mucosal visualization, revealing elongated villi with a “waterweed-like” morphology and widespread polyp distribution throughout the small intestine[38].

Histopathology: Histologically, CCS polyps are typically benign and classified as juvenile or hamartomatous. Specimens from the stomach, small intestine, and colon typically present with massive submucosal edema, primarily in the lamina propria, focal hyperplastic features with foveolar epithelium hyperplasia, mild infiltration of inflammatory cells, including eosinophils, and cystic dilatation of the mucosal glands. Additional histological variants, such as adenomatous, hyperplastic, inflammatory, and serrated adenomas have been documented. Some serrated adenomas exhibit a saw-toothed crypt growth pattern, raising concerns about dysplastic potential[40,84,85].

A retrospective analysis by Wang et al[38] found that hamartomatous polyps were the most common subtype in the upper gastrointestinal tract, followed by hyperplastic polyps (31.58%). In the colorectal region, the most dominant polyps were hamartomatous (35.48%), followed by mixed-type polyps (27.42%), adenomatous polyps (19.35%), and hyperplastic polyps (16.13%)[38]. Malignant transformations were as high as 7.02% and 17.74% of cases with upper gastrointestinal and colorectal polyps, respectively[38]. Moreover, Egawa et al[86] reported the occurrence of colorectal and gastric carcinoma in 9% and 5% of patients with CCS, respectively. Yashiro et al[84] further identified serrated adenoma lesions in 40% of cases among 31 instances of colorectal cancer, hinting at the possibility of a serrated adenoma-carcinoma sequence contributing to the malignancy[84]. Figure 4 summarizes the diagnostic approaches discussed.

Figure 4 Flowchart demonstrating the diagnostic approach used for Cronkhite-Canada syndrome. Patients, who present with nail and connective tissue changes without any digestive disturbances, should be advised to perform laboratory tests. In case of normal results, follow up and symptomatic treatment is advised. However, patients with abnormal laboratory test results and those who had digestive symptoms along with nail and connective tissue changes at the time of presentation should undergo endoscopy. If multiple polyps with pathological features are found during endoscopy, diagnosis of Cronkhite-Canada Syndrome (CCS) is established. If polyps are absent and there are no mucosal changes, follow up and symptomatic treatment is recommended. For patients who demonstrate mucosal changes, biopsy should be performed. If non-specific signs of inflammation are detected, such patients are advised regular follow-ups and symptomatic treatment. However, if eosinophilic infiltration is identified in biopsy specimen, diagnosis of CCS should be considered. CCS: Cronkhite-Canada syndrome; FOBT: Fecal occult blood test; CBC: Complete blood count; LFT: Liver function test; CRP: C-reactive protein; TFT: Thyroid function test.

Treatment strategies

Due to the low prevalence of CCS, treatment strategies have evolved through case reports and small studies, and no standardized protocol currently exists. The mainstay of treatment comprises oral corticosteroids in combination with nutritional supplements[35,87]. Corticosteroid therapy has a varied regimen depending on the patient. According to the reported cases, the starting dose of prednisolone can begin from as low as 20 mg/day and increase up to 60 mg/day[35]. The ideal dose, however, appears to be 30-49 mg/day in most cases, whereas those exceeding 60 mg/day were accompanied by adverse side effects such as thrombosis and sepsis[2].

It has commonly been observed that most patients improve with steroid therapy, both clinically and endoscopically. Therefore, corticosteroids are considered the most common first line therapy. However, current evidence has mostly been derived from case reports and not from randomized clinical trials. Therefore, due to scarcity of data, no treatment can be deemed superior to others. Since CCS is still a rare phenomenon, knowledge beyond the scope of these case reports remains limited, with most of the therapeutic approaches being experimental in nature. Treatment decisions are hence usually tailored according to the patient’s needs by the physician. According to the largest scale study available, the Japanese study with 210 patients, steroids had the most effective response rate with nutritional support being concurrent[2]. However, this may be subject to geographical bias since much of this data derives from Japan. Moreover, different case reports perceive effectiveness and good disease outcome in a number of ways, such as symptom improvement, albumin normalization, or even weight gain. Thus, this makes data difficult to compare.

Biologic agents, particularly tumor necrosis factor-alpha (TNF-α) inhibitors, have shown therapeutic potential in CCS, likely due to the elevated TNF-α expression observed in intestinal mucosa[2]. Multiple case reports have demonstrated marked clinical improvement with anti-TNF drugs like infliximab[81,88]. For patients unresponsive to corticosteroids, combination immunosuppressive therapy with agents such as azathioprine or cyclosporine has been successful. Boland et al[20] reported a case where infliximab and azathioprine led to complete symptom resolution, while Ohmiya et al[89] documented successful remission with azathioprine and cyclosporine. These findings underscore the need for individualized treatment plans based on disease severity and response. However, it is difficult to establish a strong link between biologic agents and successful remission in CCS patients. This is because symptoms in CCS overlap with other diseases, like inflammatory bowel disease. Apart from diagnostic ambiguity, there is also the likelihood that only successful cases tend to be reported. This also makes the success rate of any drug difficult to establish.

Apart from steroids and immunomodulators, nutritional supplementation has been shown to play a role in treatment as well. Given the risk of protein-losing enteropathy, it is crucial to maintain adequate nutrition[40,90]. Long term CCS patients are prone to developing hypoproteinemia, serum electrolyte imbalances, and anemia due to chronic diarrhea and malnutrition[91]. Hence, nutritional supplementation is vital. High-protein diets, micronutrient supplementation, including zinc and vitamins, and proton pump inhibitors have been shown to improve clinical status[44,90]. Nutrient supplementation is essential not only to combat malnutrition and protein losses in chronic CCS patients, but zinc therapy has also been effective in alleviating symptoms of hypoguesia in some patients[44,91]. H. pylori infection has been implicated in some CCS cases, with symptom resolution reported following eradication therapy. Okamoto et al[27] reported a case where a patient with H. pylori-associated CCS experienced resolution of polyposis and normalization of albumin levels following triple therapy with clarithromycin, amoxicillin, and lansoprazole. Non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac and the disease-modifying antirheumatic drug drug salazosulfapyridine, have shown efficacy in reducing CCS-associated polyps in some cases[87,92]. Hizawa et al[92] documented remarkable regression of colorectal adenomas and CCS polyps following sulindac therapy. Additionally, combination therapy with corticosteroids and mesalazine has led to symptom resolution, with some patients successfully transitioned to mesalazine monotherapy during remission[93]. However, the evidence supporting the use of triple regime therapy and NSAIDS for symptom resolution in CCS is largely anecdotal, where the patient had concurrent infection with H. pylori or overlapping symptoms. In some instances, like the case reported by Ueyama et al[87] the patient did not show any characteristic features of CCS, but the diagnosis was established by pathology.

Surgery is used as a last resort for refractory cases poorly responsive to pharmacotherapeutic interventions or when endoscopy reveals polyposis. Laparoscopic subtotal colectomy has been successfully used to treat severe protein-losing enteropathy induced by CCS[94]. Additionally, surgical resection may be necessary for polyps with malignant potential or when endoscopic surveillance reveals neoplastic transformation[28,35]. In such cases, resection of polyps often leads to improvement of symptoms and overall health of the patient. Therefore, early resection of suspicious lesions is advised, followed by routine endoscopic monitoring to reduce the risk of recurrence or malignancy[2].

While all of these are experimental approaches, no definite treatment has yet been established for CCS. The most consistently reported drug in most literature is corticosteroids. Therefore, it is the closest equivalent to a first line medication that can be established. This is mainly due to the lack of data, most of which is only present in the form of case reports, which have hindered research into better therapeutic strategies. This has, however, underscored the need for advanced therapeutic interventions that can be made possible with more data and further research on the disease. Figure 5 summarizes the treatment strategies discussed.

Figure 5 Treatment strategies used for Cronkhite-Canada syndrome. NSAIDs: Non-steroidal anti-inflammatory drugs; H. pylori: Helicobacter pylori.

Prognosis and long-term outcomes

Historically, CCS was considered to have a poor prognosis, given its progressive nature and lack of a standardized treatment strategy. However, recent advancements in immunosuppressive therapy, nutritional support, and surveillance strategies have markedly improved outcomes. While early studies estimated a 5-year mortality rate as high as 55%[40,85], more recent data from a 2020 cohort suggest a 5-year overall survival rate of 87.4%[95].

The increased mortality rates in CCS are largely driven by disease complications, ranging from infection and malnutrition to more severe outcomes like gastrointestinal bleeding and malignancy. Prognosis is influenced by patient age and disease burden at presentation. Individuals over 60 years of age and those with extensive gastric polyposis are more likely to experience relapse and poorer outcomes[95]. While there are some rare complications associated with CCS, which include myelodysplastic syndrome, membranous glomerulonephritis, cecal intussusception, and recurrent acute pancreatitis, by far the most clinically significant long-term risk is malignant transformation to gastric or colonic cancer[40]. In a study, Kopáčová et al[40] report that up to 15% of CCS patients may develop gastric or colorectal cancer, suggesting that CCS may serve as a potential precancerous condition. Therefore, regular screening of the stomach, colon, and rectum is recommended for patients with CCS.

In another study Ueyama et al[87] report that many patients harbor adenomas, some of which may be neoplastic. The presence of numerous polyps makes early detection challenging, and polyp resection carries risks of bleeding and perforation. However, a good marker of prognosis is endoscopic remission of polyps, which reduces the risk of malignancy[2]. Therefore, early polyp resection followed by annual surveillance to detect mucosal dysplasia is effective in improving patient outcomes and reducing the risk of malignancy.

Given the aggressive nature of the disease, initiating treatment at an early stage can improve prognosis as well[96]. Many patients have shown a promising response to steroids and anti-TNF therapy in addition to nutritional supplementation. Patients who respond well to traditional pharmacotherapy are expected to have an overall better prognosis[97]. Given the rarity of the condition, current prognostic estimates are likely to be inaccurate and might even be expected to improve as better treatment protocols develop for CCS[91]. For instance, one reported case achieved sustained disease control for over eight years with nutritional and symptomatic management alone, underscoring the potential for durable remission in selected patients[98].

Future directions and research gaps

Since its initial description in 1955, the management of CCS has evolved considerably, with notable improvements in both survival and quality of life. Despite a reported 5-year survival rate of over 87%, the rarity of CCS continues to limit comprehensive understanding of its pathogenesis, optimal treatment strategies, and long-term outcomes[95]. To further improve therapeutic interventions, more prospective, multicenter studies are needed with patients of more diverse origins and comorbidities. Given the limited number of cases reported worldwide, the current information in the literature about pathogenesis and other complications associated with CCS is also restricted.

Quality-of-life outcomes in CCS remain poorly characterized and warrant dedicated investigation. Atypical or extraintestinal manifestations may also contribute to delayed diagnosis and deserve systematic study. This emphasizes the need for a global registry that would facilitate the collection of patient data from around the world, along with their clinical outcomes and treatment responses. Since most of the present information we have on CCS is through case reports, it is also challenging to gather sufficient data for research and treatment. A global registry would also enable researchers to access a larger pool of information and identify any patterns in data and demographic variations in the patient population. It would also enhance collaboration among healthcare professionals, researchers, and policymakers and accelerate the development of clinical trials and new treatments.

Emerging evidence suggests a multifactorial etiology for CCS involving immune dysregulation, gut microbiota alterations, and possibly somatic or germline mutations. Given the clinical response to immunosuppressive agents, future research should prioritize elucidating the immunopathogenic mechanisms underlying the disease. Investigating microbial dysbiosis and environmental triggers may also yield novel insights into disease initiation and progression.

Despite reported successes with immunosuppressive and nutritional therapies, the absence of standardized treatment protocols presents a significant barrier to consistent care. Hence, optimal treatment guidelines ought to be developed to ensure targeted therapies for patients with CCS. In parallel, routine endoscopic surveillance should be implemented to monitor for malignancy, which remains a significant long-term risk. Early diagnosis, tailored therapy, and structured follow-up represent key pillars in improving outcomes for CCS patients.

CONCLUSION

CCS is a rare, multisystem disorder that poses significant diagnostic and therapeutic challenges due to its heterogeneous presentation and poorly understood pathogenesis. While most reported cases originate from East Asia, its global recognition is increasing. The current body of evidence points toward an autoimmune etiology, but definitive mechanisms remains elusive. Given the absence of standardized diagnostic and treatment protocols, further research is necessary to improve early detection, improve therapeutic strategies, and reduce long-term morbidity and mortality.