Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.

Hepatocellular adenomas (HCAs) are rare benign liver tumours. Predisposing factors and complication rates appear to differ among children and adults. In the present study, we aimed to systematically characterise paediatric HCAs and determine their course, complications, and management. Medical history, clinical symptoms, imaging, histopathology, and genetics of children with HCAs were collected through a systematic and comprehensive review of the published literature. A total of 316 children with HCAs were included in the present study. HCAs were diagnosed primarily in girls (59.3%) and at a mean age of 11.5 (range 0-17.7) years. The majority (83.6%) of HCAs occurred in children with predisposing diseases, of which glycogen storage disease was the most common, followed by portosystemic shunts and MODY3 (maturity-onset diabetes of the young type 3). Each of these diseases leads to a well-defined HCA molecular pattern. A significant number of HCAs either bled (24.7%) or transformed (14.8%) over time. HCA transformation was significantly more frequent in children with portosystemic shunts and in β-catenin-mutated HCAs, while haemorrhages were more frequent in children exposed to hormones and those with larger lesions. Management was primarily guided by any predisposing conditions and the number of lesions. Therefore, vascular shunts were closed when possible, while complicated lesions were resected. Liver transplantation has made it possible to treat adenomatosis, as well as any underlying diseases. Progress in understanding genetic and/or malformative contributions, which appear to be significant in paediatric HCAs, have provided insights into tumour pathogenesis and will further guide patient surveillance and management.

Background/Objectives: Liver retransplantation (reLT) is the only option for pediatric patients experiencing graft loss. Despite recent advancements in surgical techniques and perioperative management, it remains a high-risk procedure. Our aim is to describe our experience in pediatric reLT, focusing on the technical aspects and surgical challenges. Methods: We systematically analyzed surgical reports from pediatric reLT performed at our center between 2006 and 2023 to identify recurrent intraoperative findings and specific surgical techniques. We focused on challenges encountered during different phases of reLT, including hepatectomy, vascular, and biliary reconstruction. Additionally, we compared patient and graft survival rates among different groups. Results: During the study period, 23 children underwent 25 reLT procedures at our center. Major surgical challenges included complex hepatectomy and vascular reconstructions, necessitating tailored approaches. Our analysis shows that patient and graft survival were significantly lower for reLT compared to primary transplantation (p = 0.002). Early reLT had a significantly lower graft survival compared to late reLT (p = 0.002), although patient survival was comparable (p = 0.278). Patient and graft survival rates were comparable between the first and second reLT (p = 0.300, p = 0.597). Patient survival tended to be higher after living-donor liver transplantation (LDLT) compared to deceased-donor liver transplantation (DDLT), although the difference was not statistically significant (p = 0.511). Conclusions: Pediatric reLT involves significant technical challenges and lower survival rates. Advances in perioperative management are crucial for improving outcomes. Further research is needed to optimize surgical strategies and evaluate the long-term benefits of LDLT in pediatric reLT.

Background: While pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. Objective: We investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. Design: We analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. Results: Mutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with HNF1B and NPHP3 mutations. Conclusion: We describe a previously unrecognized pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft. What is already known on this topic: Ciliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. Pancreatic cysts have been sporadically reported in syndromic ciliopathies. The pancreas is not currently recognized as a major target organ of ciliary dysfunction. A clear link between ciliary gene mutations and pancreatic anomalies is still unknown. Animal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. What this study adds: Identifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). Demonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. Reveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. Shows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. Defines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. How this study might affect research, practice or policy: Establishes the pancreas as a novel and clinically relevant target of ciliopathies. Expands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. Suggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. Highlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. Opens new research avenues into the role of primary cilia in pancreatic homeostasis and disease.