The Clinical Characteristics And Potential Pathogenesis Of Cronkhite-Canada Syndrome

Background:Cronkhite-Canada syndrome(CCS)is a rare disease characterized by diffuse gastrointestinal(GI)polyposis and ectodermal changes.The pathogenesis of CCS remains unknown,and autoimmune dysfunction and mucosal barrier abnormalities may be involved.While no consensus on the treatment and monitoring strategies has been reached,glucocorticoids are the current mainstream treatment options.This study aims to:1)summarize the baseline characteristics based on the CCS cohort of our center;2)follow up their survival status,clinical and endoscopic outcomes;3)explore the expression profile of CCS colonic lesions through RNA sequencing(RNASeq).Methods:The clinical characteristics,laboratory examinations,endoscopic and histopathological results of CCS patients were collected and analyzed.The treatment responses and survival outcomes were collected through telephone or face-to-face interview to update survival data and to explore prognostic factors.The serum mucosal barrier indexes were detected via lactic acid/bacterial endotoxin/diamine oxidase kit.Five pairs of colonic lesion tissues of active CCS patients and age-and gender-matched healthy control colonic tissues were collected for RNASeq.Differential expression analysis and functional enrichment was performed with threshold of p.adjust<0.05,|log2FoldChange|>2.Quantitative polymerase chain reaction(qPCR)was performed to verify the expression levels of certain genes in the interleukin 17(IL-17)pathway.Results:44 CCS patients were enrolled,including 32 males(72.7%),with a median onset age of 58.0(53.0-64.0)years.The incidences of onychodystrophy,diarrhea,hyperpigmentation,alopecia,hypogeusia/dysgeusia and anorexia were 100%,93.2%,86.4%,81.8%,68.2%and 50%,respectively.22.7%of the patients had autoimmune diseases,and 4.5%reported GI malignancies.The positive rate of antinuclear antibody was 26.7%.The most severely involved parts of the upper GI tract are the gastric antrum and the lower part of the stomach.Rectum was spared in nearly half of the patients.The serum albumin level of patients with diffuse stomach involvement was significantly lower than that of patients with gastric fundus and cardia unaffected[(29.1 ± 7.2)g/L vs(36.8 ± 5.0)g/L,P=0.04)].The maximum diameter of colon polyps was positively correlated with the length of disease course(rho=0.48,P=0.0078).Hamartoma was the most frequently detected histopathological type,and the percentages of pathological types vary in different GI segments.Adenomas were detected in 47.5%of patients during the disease course,most of which were located in the colon and rectum.38 CCS patients were followed for 45.5(25.3-78.8)months,during which time 8 deaths were observed.The 5-year overall survival(OS)was 84.3%(95%CI:72.4%-98.2%),and the 3-year relapse-free survival(RFS)was 62.8%(95%CI:47.5%-83.0%).Univariate Cox regression analysis revealed that treatment response(HR:11,95%CI:1.956-61.91,P=0.007)and disease course(HR:1.015,95%CI:1.002-1.028,P=0.028)were associated OS,and gastric polyp diameter(HR:2.638,95%CI:1.171-5.940,P=0.019)was associated with RFS.At last follow-up,25(65.8%)and 16(42.1%)patients reported remission of GI and ectodermal symptoms,respectively.The proportion of patients who achieved complete remission under colonoscopy was significantly higher than that of gastroscopy(60%vs 40%,P=0.03).The serum D-lactic acid of CCS patients was significantly higher than that of the control group.No significant difference in D-Iactic acid concentration,diamine oxidase and bacterial endotoxin activity was found between CCS patients in active and remission states.RNASeq revealed 711 differentially expressed genes(491 up-regulated genes and 220 down-regulated genes)in CCS patients.Enrichment analysis indicated several biological processes and pathways related to immune response,chemotaxis,migration,cytokines,and signal transduction.The expression levels of LCN2,IL1B,CXCL1,and CXCL3 were significantly higher in CCS patients than the control group,while no significant difference was found in IL17A,RORC,S100A8,FOSL1,and MMP3.Conclusions:Some CCS patients are complicated with autoimmune diseases.Most CCS patients respond well to glucocorticoids with an improved prognosis than previously reported.The permeability of intestinal mucosal barrier might be impaired in CCS patients.The expression levels of some autoimmune and inflammation-related pathways changed in colonic lesion tissues of CCS patients.