Distinct polyp recurrence timing and STK11 mutation status underlie clinical heterogeneity in pediatric Peutz-Jeghers...

Clinically, recurrent polyp growth is a characteristic feature of pediatric Peutz-Jeghers syndrome (PJS) patients. However, the clinical characteristics of pediatric PJS patients grouped by postoperative recurrence time remain undefined. Furthermore, differences in clinical features between serine/threonine kinase 11 (STK11)-positive and -negative patients, and the influence of STK11 mutation types on polyp recurrence time need to be elucidated. Our study aimed to characterize pediatric PJS based on postoperative polyp recurrence time and STK11 mutation status.

We collected clinical data from 74 pediatric PJS patients diagnosed at Hunan Children's Hospital over the past decade. STK11 genomic profiling was performed using Sanger sequencing combined with multiplex ligation-dependent probe amplification (MLPA) or whole exome sequencing (WES). Variables associated with gastrointestinal polyp recurrence were identified through least absolute shrinkage and selection operator (LASSO) regression, followed by multivariate logistic regression analysis of significant variables.

All 74 pediatric PJS patients who experienced polyp recurrence post-polypectomy were stratified by recurrence time (>3, 1-3, and ≤1 year). Notably, 49.2% (31/63) of STK11-positive (STK11^pos) patients recurred within ≤1 year after polypectomy, while 81.8% (9/11) of STK11-negative (STK11^neg) patients with recurrence >3 years after polypectomy. LASSO and multivariate logistic regression identified multiple jejunal polyps (odds ratio [OR]: 4.18, 95% confidence interval [CI]: 1.09-15.98) and giant small bowel polyps (OR: 4.06, 95% CI: 1.15-14.34) as independent risk factors for recurrence ≤1 year after polypectomy. Compared to STK11^neg patients, STK11^pos patients, especially when combined with a positive PJS family history exhibited significantly earlier symptom onset, higher gastrointestinal giant polyp burden, and higher polyp burden in the jejunum/colon versus ileum. Analysis of 63 STK11^pos patients revealed diverse mutation types/sites and identified 15 novel pathogenic variants. STK11^pos patients with de novo mutations exhibited a significantly higher incidence of hematochezia, along with a greater overall burden of giant polyps in the colon. No significant association was found between major mutation subtypes (frameshift, missense, deletion, and nonsense) and recurrence time, though missense mutations showed a trend toward earlier recurrence.

This study reveals distinct clinical profiles across polyp recurrence intervals and between STK11-positive and -negative patients, while delineating the STK11 mutation landscape in pediatric PJS. These findings provide the genomic resource for pediatric PJS, offering critical insights into disease mechanisms and clinical management.