Cronkhite-Canada Syndrome Complicated with Three Malignant Tumors: A Case Report and Whole Exome Sequencing Analysis
Cronkhite-Canada syndrome (CCS) is a rare, non-hereditary condition characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although the polyps associated with CCS are generally considered non-neoplastic, a significant proportion of patients—ranging from 15% to 25%—are diagnosed with colorectal or gastric cancer at the time of CCS diagnosis. Additionally, up to 40% of patients exhibit adenomas or adenomatous changes. While extra-gastrointestinal neoplasms have been sporadically reported in CCS patients, their association with the syndrome remains unclear. The underlying mechanisms of CCS are poorly understood, with only one prior study utilizing whole exome sequencing (WES) to identify a potential pathogenic variant in the protein kinase DNA-activated catalytic subunit (PRKDC) gene. This case report presents a unique instance of CCS complicated by three malignant tumors and employs WES to explore potential germline mutations that may contribute to the pathogenesis of the syndrome and concurrent malignancies.
Case Presentation
The patient, a 46-year-old Chinese male, was initially admitted to the hospital with symptoms including diarrhea, alopecia, nail separation, and skin hyperpigmentation, which had persisted for four months. A diagnosis of CCS was established, and concurrent colonic adenocarcinoma was identified during the diagnostic workup. Follow-up endoscopy revealed multiple polyps lining both the stomach and colon. The patient’s medical history included a diagnosis of seminoma at the age of 30 and small cell lung cancer at the age of 58. Additionally, he had a family history of gastric cancer, with both his father and sister affected by the disease.
The coexistence of CCS and a complex cancer history in this patient presented a rare and intriguing clinical scenario. To investigate potential genetic predispositions, WES was performed to identify germline mutations that might explain the susceptibility to CCS and the concurrent malignancies.
Whole Exome Sequencing Analysis
DNA samples from the patient were sequenced using the Illumina HiSeq 2500 platform with a pair-end method and a sequencing depth of 50x. The analysis focused on rare missense mutations with a frequency of less than 0.05, as determined by the 1000 Genomes Project (East Asian population) and the Exome Aggregation Consortium (ExAC) databases. Functional annotations of the identified genes were performed using GeneCodis3.
A total of 814 variants in 625 genes were identified. Among these, 37 genes contained two rare missense mutations, and 24 genes contained more than three missense mutations. Functional annotation analysis revealed nine genes associated with known diseases. Further literature review highlighted MUC3A and MUC5B as potential candidates involved in the pathogenesis of both inflammatory diseases and cancers. Bioinformatics analysis predicted that mutations in MUC3A could lead to changes in its O-glycosylation and phosphorylation sites, while mutations in MUC5B were not predicted to alter protein structure or function.
Immunohistochemical Findings
Immunohistochemical staining of the patient’s gastric hyperplastic polyps demonstrated reduced expression of MUC3A compared to normal gastric mucosa. In contrast, the expression levels of MUC1 and MUC2 remained unchanged in the polyps. This finding suggests that MUC3A may play a role in the pathogenesis of CCS and the development of hyperplastic polyps in this patient.
Discussion
This case report highlights a rare instance of CCS complicated by three distinct malignancies: colonic adenocarcinoma, seminoma, and small cell lung cancer. The patient’s family history of gastric cancer further underscores the potential genetic underpinnings of his condition. The WES analysis identified germline mutations in MUC3A and MUC5B, with MUC3A showing reduced expression in hyperplastic polyps. These findings suggest that MUC3A may contribute to the pathogenesis of CCS and the associated malignancies in this patient.
The role of MUC3A in gastrointestinal diseases and cancer has been previously explored. MUC3A is a member of the mucin family, which plays a critical role in maintaining the integrity of the mucosal barrier. Alterations in mucin expression and function have been implicated in various inflammatory and neoplastic conditions. The reduced expression of MUC3A observed in this patient’s hyperplastic polyps may indicate a loss of mucosal barrier function, potentially facilitating the development of polyps and subsequent malignant transformation.
While the mutations in MUC5B were not predicted to alter protein function, the gene’s involvement in inflammatory and neoplastic processes warrants further investigation. The identification of multiple rare missense mutations in genes associated with known diseases suggests a complex genetic landscape that may contribute to the pathogenesis of CCS and concurrent malignancies.
Conclusion
This case report provides valuable insights into the genetic and molecular mechanisms underlying CCS and its association with multiple malignancies. The identification of germline mutations in MUC3A and the reduced expression of MUC3A in hyperplastic polyps suggest a potential role for this gene in the pathogenesis of CCS and the development of associated cancers. Further studies involving larger cohorts of CCS patients are needed to elucidate the molecular landscape of this rare syndrome and to explore the potential for targeted therapeutic interventions.
The findings from this case underscore the importance of genetic analysis in understanding the pathogenesis of rare diseases and their associated complications. By identifying specific genetic mutations and their functional consequences, researchers can gain a deeper understanding of disease mechanisms and develop more effective strategies for diagnosis and treatment.
doi.org/10.1097/CM9.0000000000000508
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