Sustained remission of Cronkhite-Canada syndrome after corticosteroid and mesalazine treatment: A case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare disease of unknown etiology. The optimal treatment for CCS remains unknown. Treatment with corticosteroids is considered the mainstay treatment because of its high efficacy, but the therapeutic strategy for steroid-resistant CCS is not yet established. CASE SUMMARY: This is the case of an 81-year-old woman who was diagnosed with CCS. Given her severe diarrhea, nausea, vomiting, and hypoproteinemia, hormone therapy (40 mg/d) was administered, and the symptoms improved within 1 wk. After 3 mo, the patient had no obvious symptoms. The polyps were significantly reduced on review gastroscopy and colonoscopy, thus hormone reduction gradually began. The hormone level was maintained at 10 mg/d after 6 mo. Despite the age of the patient and the side effects of hormones, the patient had no obvious discomfort. However, hormone drugs were discontinued, and mesalazine was administered orally at 3 g/d. The patient's symptoms continued to improve after a follow-up of 5 years. CONCLUSION: Corticosteroids and mesalazine are potential treatment options for CCS.

Cronkhite-Canada syndrome with esophagus involvement and six-year follow-up: A case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, noninherited disease characterized by gastrointestinal polyposis with diarrhea and ectodermal abnormalities. CCS polyps are distributed through the whole digestive tract, and they are common in the stomach and colon but very uncommon in the esophagus. CASE SUMMARY: Here, we present a case of a 63-year-old man with skin hyperpigmentation accompanied by diarrhea, alopecia, and loss of his fingernails. Laboratory data indicated anemia, hypoalbuminemia, hypocalcemia, hypokalemia, and positive fecal occult blood. Endoscopy showed numerous polyps scattered throughout the digestive tract, including the esophagus. He was treated with nutritional support and glucocorticoids with remission of his symptoms. CONCLUSION: Comprehensive treatment led by hormonal therapy can result in partial or full remission of clinical symptoms. Treatment should be individualized for each patient according to their therapy response. Surveillance endoscopy is necessary for assessing mucosal disease activity and detecting malignant transformation.

Pathology of Gastrointestinal Polyposis Disorders.

Gastrointestinal polyposis disorders are a group of syndromes defined by clinicopathologic features that include the predominant histologic type of colorectal polyp and specific inherited gene mutations. Adenomatous polyposis syndromes comprise the prototypical familial adenomatous polyposis syndrome and other recently identified genetic conditions inherited in a dominant or recessive manner. Serrated polyposis syndrome is defined by arbitrary clinical criteria. The diagnosis of hamartomatous polyposis syndromes can be suggested from the histologic characteristics of colorectal polyps and the association with various extraintestinal manifestations. Proper identification of affected individuals is important due to an increased risk of gastrointestinal and extragastrointestinal cancers.

Cronkhite-Canada Syndrome Masquerading as Inflammatory Bowel Disease.

Cronkhite-Canada syndrome (CCS) is a rare nonhereditary gastrointestinal polyposis syndrome. We illustrate a case with clinical presentation of dysgeusia, chronic diarrhea and weight loss, and endoscopic features of diffuse gastric mucosa nodularity with circumferential nodular pancolitis and a solitary colonic polyp initially mimicking inflammatory bowel disease. After multidisciplinary discussion, the diagnosis of CCS was made. The patient received steroids with resultant clinical, endoscopic, and histological improvement. We discuss the treatment and risk of neoplasia in CCS.

Cronkhite-Canada Syndrome: A Rare Case of Chronic Diarrhea With Ectodermal Changes.

Cronkhite-Canada syndrome (CCS) is a rare cause of chronic diarrhea and malabsorption where patients develop multiple polyps throughout the gastrointestinal (GI) tract, accompanied by ectodermal changes. Due to its rarity, early detection and diagnosis are challenging for physicians, inevitably leading to high mortality. CCS patients have a higher prevalence of GI cancer compared to the general population. Therefore, a follow-up endoscopy is necessary. We report a new case of CCS in an 85-year-old male who presented with chronic watery diarrhea, weight loss, and skin changes including alopecia, nail dystrophy, and hyperpigmentation. Laboratory results showed anemia and hypoalbuminemia. He underwent an endoscopy that found diffuse edematous polyposis in the stomach, duodenum, terminal ileum, and large intestine. The biopsy result confirmed the diagnosis of CCS. The patient received supportive treatment with total parenteral nutrition with improvement in his symptoms. He was placed on corticosteroid taper and azathioprine upon discharge. At the one-year follow-up, he was found in endoscopic remission.

Cronkhite-Canada syndrome: First case report from Egypt and North Africa.

BACKGROUND: Gastrointestinal (GI) polyposis is a rare condition in GI diseases. To date about 500 cases of Cronkhite-Canada syndrome (CCS) have been reported worldwide. CASE SUMMARY: We report a 60-year-old female patient who presented with dyspepsia, abdominal pain, and weight loss of 1-year duration. Her physical examination showed alopecia and onychodystrophy. Upper endoscopy revealed diffuse markedly thickened gastric mucosa involving the whole stomach with thickened gastric rugae and numerous polypoidal lesions. Histopathological examination showed marked hyperplasia of the foveolar glands with inflammatory cell infiltration. Endoscopic ultrasound showed a significantly hypertrophic mucosa and muscularis mucosa, while the submucosa and the muscularis propria were spared, favouring its benign nature. Colonoscopy showed multiple sessile polyps scattered at different parts of the colon. Histopathological examination revealed tubular adenomatous polyps with low-grade dysplasia. Differential diagnoses included CCS, Menterier disease (MD), other polyposis syndromes, lymphoma, amyloidosis, and gastric malignancies. The presence of alopecia, nail dystrophy, GI polyposis, markedly thickened gastric mucosa and folds, abdominal pain, weight loss, and marked foveolar gland hyperplasia; all was in favour of CCS. Lymphoma was excluded due to sparing of the muscularis propria. The presence of colonic polyps and antral and duodenal infiltration, and the absence of hypoproteinaemia decreased the possibility for MD. CONCLUSION: The patient was diagnosed as having CCS.

Clinical and Pathological Diagnosis of Hereditary Gastrointestinal Polyposis in Jack Russell Terriers.

Hereditary GI polyposis in JRTs is a novel hereditary disease characterized by the development of solitary and multiple polypoid tumors, predominantly in the stomach and/or colorectum. Our recent study indicated that JRTs with GI neoplastic polyps harbor an identical germline variant in the APC gene, c.[462_463delinsTT], in a heterozygous state. Unlike sporadic cases, dogs afflicted with hereditary GI polyposis can be expected to have a prolonged survival time, as hereditary tumors are noninvasive. Since the discovery of this disease, the number of newly diagnosed cases in Japan has increased, allowing us to update the clinical and pathological features and provide a large number of diagnostic images. The present clinical case series study employing various diagnostic imaging techniques revealed that some of the cases harbored tumors in the small intestine in addition to the stomach and colorectum. Moreover, although rare, hereditary GI cancers can progress to the advanced stage and develop systemic metastasis, similar to sporadic GI tumors. These findings indicate that there is a wider range of variation in disease severity than was initially recognized. Our results can contribute to the accurate diagnosis of hereditary GI polyposis in clinical practice, pathological examinations, and future research.

Cronkhite-Canada syndrome: A case report and review of the literature.

Cronkhite -Canada Syndrome (CCS) is a rare non-hereditary disease characterized by multiple polyps in the alimentary tract and ectoderm changes, and there is no clearly diagnostic criteria and treatment methods. A 55-year-old Chinese woman was admitted to our hospital with diarrhea. She was diagnosed with Cronkhite-Canada Syndrome (CCS). The clinical symptoms of the patient included diarrhea, nausea, retching, anorexia, weight loss, and we found that she had alopecia, onychatrophy, rampant caries and skin pigmentation from the physical examination. Gastrointestinal endoscopy revealed multiple polyps in the gastric antrum, stomach body, ileocecal part and colon, and from the microscopically the polype hyperplsique was observed. The patient was treated by eradicating Helicobacter pylori and regulating the intestinal flora disbalance and his diarrhea improved within a short period of time. We suggested that she should take glucocorticoids orally, but the patient refused. Follow-up at 1 year showed that the symptoms of the patient had recurred sometimes, and she had taken Chinese herbal medicine orally a few times. At present, the symptoms of diarrhea are relieved, the weight of the patient has increased, and the hair and nails of the patient have grown again. From this case, we learned CCS can be likely ignored and not be diagnosed promptly because the low morbidity of CCS.

PTEN and LKB1 are differentially required in Gli1-expressing mesenchymal cells to suppress gastrointestinal polyposis.

PTEN and LKB1 are intimately associated with gastrointestinal tumorigenesis. Mutations of PTEN or LKB1 lead to Cowden syndrome and Peutz-Jeghers syndrome characterized by development of gastrointestinal polyps. However, the cells of origin of these polyps and underlying mechanism remain unclear. Here, we reveal that PTEN or LKB1 deficiency in Gli1+ gut mesenchymal cells, but not intestinal epithelium, drives polyp formation histologically resembling polyposis in human patients. Mechanistically, although PTEN and LKB1 converge to regulate mTOR/AKT signaling in various tumor contexts, we find that mTOR is essential for PTEN-deletion-induced polyp formation but is largely dispensable for polyposis induced by mesenchymal LKB1 deficiency. Altogether, our studies identify Gli1-expressing mesenchymal cells as a common cell of origin for polyposis associated with PTEN and LKB1 and reveal their engagement of different downstream pathways in gut mesenchyme to suppress gastrointestinal tumorigenesis.

Molecular epidemiological study of germline APC variant associated with hereditary gastrointestinal polyposis in dogs: current frequency in Jack Russell Terriers in Japan and breed distribution.

BACKGROUND: Cases of gastrointestinal (GI) neoplastic polyps in Jack Russell Terriers (JRTs) have increased in Japan since the late 2000s. We recently demonstrated that JRTs with GI polyps heterozygously harbor an identical germline variant in the adenomatous polyposis coli (APC) gene, c.[462_463delinsTT]; therefore, this is an autosomal dominant hereditary disease. We conducted a molecular epidemiological study to explore the current frequency of the APC variant in JRTs in Japan and the breed distribution of this disease. RESULTS: Peripheral blood samples from 792 JRTs were collected at 93 veterinary hospitals in Japan in 2020. Using an established polymerase chain reaction-restriction fragment length polymorphism assay, the germline APC variant was detected in 15 JRTs, with an overall frequency of 1.89%. The frequency was not significantly different for sex, age, and coat type criteria. Notably, the variant carriers had a current or previous history of GI neoplastic polyps, providing further evidence of the association of the germline APC variant with GI polyposis. Pedigree analysis of carrier dogs revealed that the germline APC variant was no longer confined to a few specific families but was widely spread among JRTs in Japan. Furthermore, some ancestors of the carriers were from Australia or New Zealand, suggesting the possible presence of carriers in countries other than Japan. Next, we retrospectively investigated the germline APC variant status of dogs with GI epithelial tumors using genomic DNA samples extracted from archived pathological specimens (28 purebred dogs of 14 breeds and four mixed-breed dog), as well as those stored in a canine genome bank (38 dogs of 18 breeds and a mixed-breed dogs). In total, 66 purebred dogs of 25 breeds, including another four JRTs, and five mixed-breed dogs were examined. While three variant carriers were found in JRTs, the germline APC variant was not detected in any of the other breeds. CONCLUSION: The current frequency of the germline APC variant was approximately 2% in JRTs in Japan and the frequency remained roughly flat during the last 15 years. In addition, hereditary GI polyposis associated with the variant was virtually specific to JRTs.

A Rare Case of Juvenile Polyposis Syndrome Mimicking Ménétrier's Disease.

There is a wide differential diagnosis within polyposis syndromes. Our case represents an interesting and diagnostically challenging diagnosis involving a 41-year-old male who presented with an incidental gastric mass on imaging and a colonic mass seen on colonoscopy. Following multiple endoscopic evaluations, histological analysis, and genetic testing, the patient was ultimately diagnosed with juvenile polyposis syndrome (JPS)/hereditary hemorrhagic telangiectasia (HHT) despite the initial suspicion for Ménétrier's disease. His disease course was complicated by an acute upper extremity thrombus and diagnosis of colorectal carcinoma. This case highlights the importance of a thorough evaluation when polyposis syndromes are suspected. Prompt and accurate diagnosis can aid in the treatment, surveillance, and prevention of colorectal carcinoma.

Cronkhite­Canada syndrome / Cronkhite-Canada-szindróma.

Összefoglaló. A Cronkhite-Canada-szindróma egy extrém ritka, nem öröklodo, gyomor-bél rendszeri polyposissal, fehérjeveszto enteropathiával és ectodermalis elváltozásokkal járó megbetegedés. A világon eddig összesen körülbelül 500 esetet jegyeztek fel. Az etiológia pontosan nem tisztázott, hátterében elsosorban autoimmun folyamatot feltételeznek. A diagnózis a páciens kórtörténetén, a fizikális vizsgálaton, az endoszkópos képen és a szövettani leleten alapul. A jelen közleményben egy 71 éves férfi beteg esetét mutatjuk be. A klinikai kép és az elvégzett vizsgálatok alapján a tünetek hátterében Cronkhite-Canada-szindrómát igazoltunk, majd a szakirodalomban leggyakrabban alkalmazott kombinált protonpumpagátló, kortikoszteroid és meszalazin adását vezettük be, illetve táplálásterápiát alkalmaztunk. Tudomásunk szerint Cronkhite-Canada-szindrómás beteg esete Magyarországon elsoként kerül ismertetésre. Orv Hetil. 2021; 162(11): 432-438. Summary. Cronkhite-Canada syndrome is an extremely rare, noninherited disease, characterized by gastrointestinal polyposis, protein-losing enteropathy and ectodermal abnormalities. Approximately 500 cases have been reported worldwide. The aetiology is unknown, most probably autoimmune mechanisms may be involved. The diagnosis is based on patient history, physical examination, endoscopic findings and histology. Here we report the case of a 71-year-old male, diagnosed with Cronkhite-Canada syndrome. The treatment consisted of proton-pump inhibitor, corticosteroids, mesalazin and nutritional therapy. To the best of our knowledge, this is the first report of Cronkhite-Canada syndrome in Hungary. Orv Hetil. 2021; 162(11): 432-438.

Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review.

Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps. Despite both displayed striking clinical (and, in the first case, familial) manifestations of Cowden Syndrome (PTEN Hamartoma Tumor Syndrome-PHTS), they had not been recognized before. Diagnosis of PHTS was confirmed by the detection of causative PTEN variants. Pathological examination of the polyps showed multiple histology types: hyperplastic, juvenile, serrated and lymphoid. Hyperplastic polyps analyzed from both patients failed to show BRAF V600E and KRAS codon 12/13 mutations, which provides evidence against their potential to evolve to colorectal cancer through the serrated pathway. We then reviewed the literature on gastrointestinal polyps detected in patients with Cowden Syndrome, in order to provide a comprehensive scenario of presentations: among a total of 568 patients reported in the literature, 91.7 % presented with colon polyps, with 63.0 % having two or more different histological types of polyps; besides, 58.5 % had extra-colonic polyps (located either in stomach and/or in small intestine). Finding multiple polyps with mixed and/or unusual histology should alert gastroenterologists and pathologists about the possible diagnosis of Cowden Syndrome and prompt the search for other manifestations of this condition in the patient.

PCR-based genotyping assays to detect germline APC variant associated with hereditary gastrointestinal polyposis in Jack Russell terriers.

BACKGROUND: The prevalence of gastrointestinal (GI) neoplastic polyps in Jack Russell terriers (JRTs) has increased in Japan since the late 2000s. Recently, we demonstrated that JRTs with GI polyps harbor identical germline variant in the APC gene (c.[462_463delinsTT]) in the heterozygous state. Thus, this disease is an autosomal dominant hereditary disorder. Although the affected JRTs have distinct features, such as the development of multiple GI polyps and an early age of disease onset, genetic testing is indispensable for a definitive diagnosis. Here, polymerase chain reaction (PCR)-based assays capable of detecting germline APC variant were designed and validated using synthetic wild-type and mutant DNAs and genomic DNAs from carrier and non-carrier dogs. RESULT: First, the PCR-restriction fragment length polymorphism (PCR-RFLP) assay was developed by taking advantage of the germline APC variant creating a new restriction site for MseI. In the PCR-RFLP assay, the 156-bp region containing the variant site was amplified by PCR and subsequently digested with MseI, yielding diagnostic 51 and 58 bp fragments from the mutant allele and allowing determination of the APC genotypes. It was possible to determine the genotypes using genomic DNA extracted from the peripheral blood, buccal swab, or formalin-fixed paraffin-embedded tissue. Next, a TaqMan duplex real-time PCR assay was developed, where a 78-bp region flanking the variant was amplified in the presence of wild-type allele- and mutant allele-specific fluorescent probes. Using blood-derived DNA, altogether 40 cycles of PCR amplification determined the APC genotypes of all examined samples by measuring the fluorescence intensities. Importantly, false-positive and false-negative errors were never detected in both assays. CONCLUSION: In this study, we developed highly reliable genetic tests for hereditary GI polyposis in JRTs, providing accurate assessment of the presence of the causative germline APC variant. The genotyping assays could contribute to the diagnosis and prevention of hereditary GI polyposis in dogs.

[Endoscopic features and clinical correlation analysis of 24 patients with Cronkhite-Canada syndrome].

Objective: To clarify the endoscopic changes prior to corticosteroid therapy in Cronkhite-Canada syndrome (CCS) patients and to explore the correlation between endoscopic features and clinical characteristics. Methods: A total of 24 CCS patients who were hospitalized in Peking Union Medical College Hospital from January 1999 to June 2019 and underwent gastroscopy and colonoscopy before corticosteroid therapy were retrospectively enrolled. The endoscopic images were re-interpreted. The demographic characteristics, clinical manifestations, laboratory tests and histopathological data were collected and analyzed. Results: Of all 24 patients, 15 (62.5%) were male and 9(37.5%) were female, with an average age of (59±10) years and disease course of 6 (1~36) months. Based on the endoscopic findings, the percentages of stomach, colon, duodenum, rectum and terminal ileum involvement were 100%, 100%, 95.7%, 66.7% and 50.0% respectively. Gastric involvement was more severe in the lower part of the body and the antrum of the stomach, while the cardia and the fundus were spared in 5 (20.8%) cases. Colonic involvement was more severe in the right colon. No patient showed remarkable esophageal involvement. The typical appearance under endoscopy were diffuse mucosal hyperemia and edema with polyps or nodular changes. The lesions may have mulberry-like or imbricate changes in severe cases. Lymphatic dilation in the duodenum was found in 47.8% patients. Most of the polyps were pedunculated or sub-pedunculated, with occasionally seen sessile polyps in the colon. The pit patterns of the 12 resected colon polyps in 11 patients could be classified as Kudo type Ⅲ(S), Ⅲ(L), Ⅳ and Ⅴ(I), among which 2 tubular adenomas had the Kudo type Ⅲ(L). Other resected polyps were hyperplastic polyps or CCS polyps. The disease duration prior to diagnosis was positively correlated with the maximum diameter of colon polyps (r=0.625, P=0.006). Serum albumin levels in patients with whole stomach involvement were significantly lower than those in patients with cardia spared [(29±8) g/L vs (37±5) g/L, P=0.034]. Conclusions: The typical initial endoscopic finding of CCS is multiple polyps or nodular changes on the background of diffuse hyperemia and edema lining the gastric, duodenal and colonic mucosa. Lymphatic dilatation in the duodenum could also be found. Some endoscopic features are correlated to clinical characteristics.

Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described, rare gastric polyposis syndrome. It is characterized by extensive involvement of the fundus and body of the stomach with fundic gland polyps sparing the antrum and lesser curvature, an autosomal dominant inheritance pattern with incomplete penetrance, and a significant predisposition for the development of gastric adenocarcinoma. Due to the recent discovery of APC promotor IB mutations (c.-191T>C, c.-192A>G, and c.-195A>C), which reduce binding of the transcription factor Yin Yang 1 (YY1) and transcriptional activity of the promotor, as its underlying genetic perturbation, GAPPS has been added to the growing molecular class of APC-associated disorders. Recent reports on family members afflicted by gastric polyposis due to GAPPS have described the development of metastatic cancer or the presence of invasive gastric adenocarcinoma in total gastrectomy specimens after variable periods of endoscopic surveillance emphasizing the need for an improved understanding of the to-date poorly characterized natural history of the syndrome. There are, however, currently no guidelines on screening, timing of prophylactic gastrectomy, or endoscopic surveillance for GAPPS available. In this review, we summarize the clinical, pathological, and genetic aspects of GAPPS as well as management approaches to this rare cancer predisposition syndrome, highlighting the need for early recognition, a multidisciplinary approach, and the creation of prospective family registries and consensus guidelines in the near future.

Recombinant Thrombomodulin Used to Successfully Treat Cronkhite-Canada Syndrome with Disseminated Intravascular Coagulation due to Sepsis in a Compromised Patient.

Cronkhite-Canada syndrome (CCS) is a rare non-inherited disease characterized by gastrointestinal polyposis, chronic diarrhea, ectodermal dysplasia, skin hyperpigmentation, hair loss and nail atrophy. Although the efficacy of corticosteroid and immunomodulatory agents has been demonstrated, no standard therapy regimen has been established, and the prognosis of CCS is still poor due to various complications. We here in report a CCS patient complicated with severe sepsis and disseminated intravascular coagulation who was successfully treated by combined modality therapies, including recombinant human soluble thrombomodulin.

Cronkhite-Canada syndrome polyps infiltrated with IgG4-positive plasma cells.

Cronkhite-Canada syndrome (CCS) is a rare but serious protein-losing enteropathy, but little is known about the mechanism. Further more, misdiagnosis is common due to non-familiarity of its clinical manifestation. A 40-year-old male patient was admitted to our hospital because of diarrhea and hypogeusia associated with weight loss for 4 mo. On physical examination, skin pigmentation, dystrophic nail changes and alopecia were noted. He had no alike family history. Laboratory results revealed low levels of serum albumin (30.1 g/L, range: 35.0-55.0 g/L), serum potassium (2.61 mmol/L, range: 3.5-5.5 mmol/L) and blood glucose (2.6 mmol/L, range: 3.9-6.1 mmol/L). The erythrocyte sedimentation rate was elevated to 17 mm/h (range: 0-15 mm/h). X-ray of chest and mandible was normal. The endoscopic examination showed multiple sessile polyps in the stomach, small bowel and colorectum. Histopathologic examination of biopsies obtained from those polyps showed hyperplastic change, cystic dilatation and distortion of glands with inflammatory infiltration, eosinophilic predominance and stromal edema. Immune staining for IgG4 plasma cells was positive in polyps of stomach and colon. The patient was diagnosed of CCS and treated with steroid, he had a good response to steroid. Both histologic findings and treatment response to steroid suggested an autoimmune mechanism underling CCS.