Early-Onset and Rapidly Progressive Hereditary Pancreatitis Associated with PRSS1 Mutations in a Romanian Pediatric Cohort

Abstract

Objectives

CPRSS1-associated hereditary pancreatitis in children is characterized by early onset and rapid progression to chronic disease; however, data from Eastern European populations remain limited. This study aimed to evaluate disease severity, recurrence burden and progression to chronic pancreatitis in a Romanian pediatric cohort with PRSS1-associated hereditary pancreatitis.

Materials and methods

We conducted a retrospective observational study that included pediatric patients with pathogenic or likely pathogenic PRSS1 mutations. Clinical variables analyzed comprised age at onset, number of acute pancreatitis episodes, disease severity, complications and progression to chronic pancreatitis. Descriptive statistics were used.

Results

Five pediatric patients were included. All subjects developed recurrent acute pancreatitis. Patients with severe disease exhibited a higher recurrence burden compared to those with mild disease. Progression to chronic pancreatitis occurred in 80% of cases. Structural pancreatic changes and local complications were frequently observed.

Conclusions

PRSS1-associated hereditary pancreatitis in children is characterized by early onset, high recurrence burden and frequent progression to chronic disease. Disease severity appears to be associated with recurrence burden, suggesting a more aggressive clinical phenotype in affected patients.

INTRODUCTION

Acute pancreatitis (AP) in children has been increasingly recognized over the past two decades, with a rising reported incidence and improved diagnostic awareness (1). While biliary, metabolic and idiopathic causes remain common, genetic factors play a substantial role in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP), particularly in early-onset cases (2, 3). In contrast to adult populations – where alcohol and metabolic factors predominate – hereditary determinants represent a major etiological category in children with recurrent or unexplained disease (4).

Hereditary pancreatitis is most frequently associated with pathogenic variants in the PRSS1 gene, which encodes cationic trypsinogen (5). These variants promote dysregulated intrapancreatic trypsin activation or impaired degradation, leading to recurrent inflammatory episodes and progressive pancreatic injury (6). Classical mutations such as p.Arg122His and p.Asn11Ile are typically inherited in an autosomal dominant pattern with variable penetrance (5, 7, 8). Repeated inflammatory episodes may result in cumulative pancreatic damage, including ductal abnormalities, fibrosis and progressive exocrine or endocrine dysfunction (3).

Clinically, PRSS1-associated disease typically presents in childhood with recurrent acute pancreatitis and carries a substantial risk of progression to chronic pancreatitis over time (3, 5, 7). Long-term data have also indicated an increased lifetime risk of pancreatic malignancy in mutation carriers, highlighting the importance of early etiological identification and longitudinal monitoring (9).

Despite increasing recognition of hereditary pancreatitis in pediatric populations, comprehensive genotype–phenotype correlations remain limited, particularly in Eastern European cohorts. Available data emphasize the heterogeneity of clinical expression and the need for region-specific characterization (10, 11), while emerging evidence from Romanian pediatric cohorts has highlighted the role of genetic variants in influencing disease severity, recurrence patterns and progression (11). In this context, further evaluation of clinically characterized pediatric cohorts with genetically confirmed PRSS1 mutations may provide relevant insights into disease expression and progression patterns in this population.

The aim of the present study was to evaluate the clinical severity, recurrence burden and progression to chronic pancreatitis in pediatric patients with PRSS1 mutations managed in a single tertiary center in Romania. We hypothesized that PRSS1-associated disease is characterized by an aggressive clinical course, with increased recurrence burden and a high rate of progression to chronic pancreatitis.

MATERIALS AND METHODS

Study design and ethical approval

This retrospective observational study included pediatric patients diagnosed with PRSS1-associated hereditary pancreatitis at “Grigore Alexandrescu” Children’s Emergency Clinical Hospital, Bucharest, Romania, between January 2022 and June 2025.

The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional Ethics Committee (protocol code 5304, approved 24 February 2022).

Patient selection

Eligible patients fulfilled the following inclusion criteria: age <18 years at the first episode of pancreatitis; genetically confirmed pathogenic or likely pathogenic variant in the PRSS1 gene; and diagnosis of acute pancreatitis (AP), acute recurrent pancreatitis (ARP), or chronic pancreatitis (CP) defined according to INSPPIRE criteria (12). According to these criteria, AP was defined by the presence of at least two of the following: abdominal pain consistent with pancreatitis; serum amylase and/or lipase levels elevated to at least three times the upper limit of normal; and imaging findings characteristic of pancreatic inflammation. Acute recurrent pancreatitis was defined as two or more distinct episodes of AP with complete clinical resolution between episodes. Chronic pancreatitis was defined by the presence of irreversible structural pancreatic changes documented by imaging studies, regardless of associated exocrine or endocrine dysfunction.

Patients were excluded if pancreatitis was attributable to gallstone disease, hypertriglyceridemia, hypercalcemia, drug-induced pancreatic injury, abdominal trauma, structural pancreaticobiliary anomalies explaining the clinical presentation, or systemic infections identified as the primary etiology.

Additionally, genetic variants classified as variants of uncertain significance (VUS) were not considered sufficient for study inclusion.

Genetic testing

Genetic testing was performed using a next-generation sequencing–based pancreatitis gene panel (Blueprint Genetics Pancreatitis Panel Plus Analysis, version 4, October 19, 2019), including PRSS1 and other pancreatitis-associated genes (APOA5, APOC2, CFTR, CPA1, CTRC, GPIHBP1, SPINK1 and UBR1) (13-15).

Genomic DNA was extracted from peripheral blood collected in EDTA tubes. Sequencing, copy number variant analysis and variant interpretation were conducted in an accredited genetic laboratory. Variants were classified according to ACMG/AMP criteria as pathogenic, likely pathogenic, or of uncertain significance. Only patients carrying pathogenic or likely pathogenic PRSS1 variants were included in the analysis.

Data collection and variables

Clinical data were extracted from electronic medical records and included sex, age at first episode of pancreatitis, number of documented acute pancreatitis episodes and disease severity.

Imaging findings, includin abdominal ultrasound, computed tomography (CT) and magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI/MRCP) were recorded. Additional variables included surgical complications or interventions, family history of pancreatitis, progression to chronic pancreatitis and duration of follow-up.

For analytical purposes, the relationship between disease severity and recurrence burden was explored descriptively.

Severity classification

Disease severity was categorized as mild, moderately severe, or severe according to the NASPGHAN Pancreas Committee criteria (16). Mild AP was defined by the absence of organ failure and local or systemic complications. Moderately severe AP was characterized by transient organ failure (<48 hours) and/or local or systemic complications without persistent organ dysfunction. Severe AP was defined by persistent organ failure exceeding 48 hours regardless of associated local complications, including pancreatic necrosis.

Follow-up and outcome assessment

Patients were followed from the first documented episode of pancreatitis until the last recorded clinical evaluation within the study period. Progression to CP was defined as the development of imaging-confirmed irreversible structural pancreatic changes during follow-up.

Definition of chronic pancreatitis

Chronic pancreatitis was defined based on imaging-confirmed irreversible structural pancreatic abnormalities and/or documented pancreatic exocrine insufficiency.

Structural criteria included persistent ductal irregularities or dilatation of the main pancreatic duct (Wirsung), pancreatic atrophy, calcifications, or parenchymal fibrosis identified by ultrasound, CT, or MRI/MRCP (12, 17).

Exocrine pancreatic insufficiency was defined by decreased fecal elastase levels below the laboratory reference threshold (12).

Statistical analysis

Given the limited sample size (n = 5), statistical analysis was restricted to descriptive methods. Continuous variables were reported as median values with corresponding ranges, while categorical variables were expressed as absolute numbers and percentages.

No inferential statistical analyses were performed; however, descriptive comparisons were used to explore patterns between disease severity and recurrence burden.

RESULTS

Demographic characteristics

Five pediatric patients with pathogenic or likely pathogenic variants in PRSS1 were identified during the study period. The cohort included three males (60%) and two females (40%). The median age at the first documented episode of pancreatitis was six years (range: 3–16 years). All patients (5/5, 100%) developed recurrent acute pancreatitis during follow-up, indicating a uniform recurrence pattern in this genetically defined cohort.

Genetic profile

All patients carried heterozygous pathogenic or likely pathogenic variants in PRSS1. The identified variants included c.311T>C, p.(Leu104Pro) in two patients (40%), c.365G>A, p.(Arg122His) in one patient (20%) and p.(Ala16Val) (A16V) in one patient (20%). In one patient (20%), a pathogenic PRSS1 mutation was documented at the gene level, although complete HGVS-level annotation was not available in archived laboratory records. All variants were consistent with an autosomal dominant inheritance pattern. A positive paternal history of pancreatitis was documented in three patients (60%), supporting vertical transmission. An additional patient (20%) reported a maternal history of biliary disease. Overall, a positive family history of pancreatic or biliary pathology was present in four patients (80%), while the remaining one (20%) had no documented familial history.

Disease severity and recurrence burden

Acute pancreatitis severity was classified as severe in three out of five patients (60%) and mild in two out of five patients (40%), with no cases of moderately severe disease.

The overall recurrence burden was high, with a median of six acute pancreatitis episodes per patient (range: 3–15) and a mean of 7.4 ± 4.62 episodes.

When stratified by disease severity, patients with severe acute pancreatitis (n = 3) exhibited a higher recurrence burden compared to those with mild disease (n = 2). Specifically, the severe group had a median of eight episodes (mean 9.33; range 5–15), whereas the mild group had a median of 4.5 episodes (mean 4.5; range 3–6). This pattern suggests a trend toward increased recurrence burden in patients with more severe disease (Figure 1). Given the limited sample size, no inferential statistical testing was performed.

Scatter plot illustrating the relationship between disease severity and the number of AP episodes. Each point represents an individual patient. Horizontal lines indicate the median number of episodes within each severity group. Patients with severe disease demonstrated a higher recurrence burden compared to those with mild presentation.

Surgical complications

Pancreatitis-related surgical complications were documented in three out of five patients (60%). Pancreatic necrosis occurred in two patients (40%), while one patient (20%) developed a pancreatic pseudocyst. No additional major surgical complications were recorded.

Progression to chronic pancreatitis

During follow-up, four out of five patients (80%) progressed to chronic pancreatitis, indicating a high rate of structural disease evolution in this cohort. Among these, two patients (40%) developed both pancreatic exocrine insufficiency and imaging-confirmed ductal abnormalities, while two patients (40%) presented imaging-confirmed chronic pancreatitis without documented exocrine insufficiency. One patient (20%) did not meet structural or functional criteria for chronic pancreatitis at the last recorded evaluation.

Characteristic Wirsung duct abnormalities were identified in two patients (40%), both of whom requiring endoscopic ductal stenting.

FIGURE 1.

Severity and recurrence burden in PRSS1-associated hereditary pancreatitis

DISCUSSION

This study evaluates the clinical phenotype and disease progression of pediatric patients carrying pathogenic or likely pathogenic variants in the PRSS1 gene within a single tertiary center. Despite the limited sample size, our findings indicate an aggressive clinical course characterized by early onset, high recurrence burden and frequent progression to CP, consistent with the established profile of PRSS1-associated hereditary pancreatitis. These findings are consistent with previously reported data from Romanian pediatric cohorts, which also demonstrated the impact of genetic mutations on disease severity, recurrence burden and progression to chronic pancreatitis (11).

Early onset and demographic characteristics

In our PRSS1-positive pediatric cohort (n = 5), the median age at first pancreatitis episode was six years (range 3–16), supporting the established pattern of early childhood onset in PRSS1-associated hereditary pancreatitis. This finding is consistent with data from GeneReviews, which report a median age at diagnosis of seven years (IQR 3–16) in large multifamily cohorts, highlighting the predominantly pediatric presentation of this condition (9).

Comparable results were reported by Oracz et al in a Polish pediatric cohort of 41 children, where symptom onset occurred in childhood and was earlier in cases with paternal inheritance (5.9 vs. 9.1 years). In our series, 60% of patients had a paternal history of pancreatitis, supporting vertical transmission as a contributor to early manifestation (18).

Although a slight male predominance was observed in our cohort (60%), multicenter data from the INSPPIRE study demonstrated a relatively balanced sex distribution across ARP and CP phenotypes, suggesting that sex is unlikely to significantly influence disease expression (3). Therefore, the distribution observed in our cohort most likely reflects sample size rather than a true biological difference.

Genetic profile and variant spectrum

All patients in our cohort carried pathogenic or likely pathogenic variants in PRSS1, including three defined missense variants, including p.(Leu104Pro), p.(Arg122His) and p.(Ala16Val), while in one case complete HGVS annotation was unavailable. The p.(Arg122His) variant represents a well-established high-penetrance gain-of-function mutation that enhances intrapancreatic trypsin activity and underlies the classical autosomal dominant form of hereditary pancreatitis (19).

In addition to classical gain-of-function mechanisms, increasing evidence supports mechanistic heterogeneity among PRSS1 variants. Certain mutations induce protein misfolding and endoplasmic reticulum stress, contributing to pancreatic injury through alternative pathways. Functional studies have shown that p.(Leu104Pro) is associated with impaired secretion, intracellular retention and ER stress (20). The relatively high frequency of this variant in our cohort (40%) is therefore notable, as misfolding variants are less frequently reported and may be underrecognized in pediatric populations (21).

The p.(Ala16Val) variant has been described as a potential modifier allele with variable penetrance. Its contribution to disease expression appears context-dependent and may involve interaction with additional genetic or environmental factors (9).

Overall, the variant distribution in our cohort reflects the heterogeneity of pathogenic mechanisms in hereditary pancreatitis. The predominance of p.(Leu104Pro) may reflect regional or referral-related factors and highlights the need for larger studies to better define genotype–phenotype correlations.

Familial aggregation and vertical transmission

In our cohort, 60% of patients had a paternal history of pancreatitis, with an overall positive family history in 80% of cases. This distribution is consistent with the autosomal dominant inheritance and variable penetrance characteristic of PRSS1-associated disease.

Familial aggregation has been consistently reported since the initial description of PRSS1-related pancreatitis (19) and remains well documented in pediatric studies. Oracz et al reported a positive family history in approximately 70% of affected children, while data from the INSPPIRE consortium further emphasize the importance of hereditary predisposition in early-onset disease (3, 18).

These findings reinforce the importance of detailed family history assessment and support current recommendations for early genetic evaluation in children with recurrent pancreatitis.

Disease severity and acute episode burden

In our cohort, 60% of patients experienced severe acute pancreatitis episodes and the overall recurrence burden was high, with a median of six episodes (range 3–15). When stratified by severity, patients with severe disease exhibited nearly twice the median number of episodes compared to those with mild disease, suggesting a relationship between disease severity and recurrence burden. Similar observations have been reported in Romanian cohort analyses, where PRSS1 variants were associated with earlier onset and a more severe clinical course (11).

This observation is consistent with existing literature indicating that PRSS1-associated pancreatitis is characterized by a more aggressive clinical course and increased recurrence rates (21, 22). Data from the INSPPIRE consortium demonstrated that genetic etiologies, particularly PRSS1 mutations, are associated with higher rates of recurrent disease and progression to CP (3).

Additional studies have shown that hereditary risk factors are associated with increased disease burden and more rapid progression from initial acute pancreatitis to recurrent or chronic forms (3, 23, 24). Recurrent inflammatory episodes are recognized drivers of long-term pancreatic remodeling, fibrogenesis and functional impairment (5, 25).

Although pediatric pancreatitis is often considered less severe than adult disease in general populations (1, 12), genetically predisposed subgroups – particularly PRSS1 carriers – may exhibit a phenotype characterized by frequent and severe episodes, similar to adult recurrent disease (26). This is biologically plausible, as gain-of-function variants in PRSS1 promote premature trypsin activation and repeated parenchymal injury (27).

Given the absence of typical environmental risk factors in children, the observed disease severity and recurrence burden in this cohort are likely driven predominantly by genetic susceptibility, further supporting the link between genotype and clinical phenotype (3).

Local and surgical complications

Local complications were observed in 60% of patients, including pancreatic necrosis (40%) and pseudocyst formation (20%). Although necrotizing pancreatitis is less common in children than in adults (1), it has been reported more frequently in genetically predisposed or recurrent cases (3, 13).

Data from the INSPPIRE consortium indicate that local complications are more common in children with recurrent or chronic pancreatitis, particularly in the presence of genetic risk factors (3, 17). Additional studies have shown that hereditary forms are associated with increased rates of complications and often require multidisciplinary management (7, 24).

The high rate of necrosis observed in our cohort supports the concept of an aggressive inflammatory phenotype in PRSS1-associated disease, where repeated episodes contribute to cumulative pancreatic injury and structural remodeling (28).

Progression to chronic pancreatitis

In our cohort, 80% of patients progressed to CP during follow-up, exceeding general pediatric estimates. Among these, 40% developed both exocrine insufficiency and structural abnormalities, while 40% presented structural changes alone. These results are in line with previous findings from Romanian pediatric populations, where a substantial proportion of patients progressed to CP during follow-up (11).

This high progression rate is consistent with the natural history of PRSS1-associated hereditary pancreatitis (7, 21). GeneReviews emphasizes the frequent transition from recurrent acute pancreatitis to chronic structural disease, often beginning in childhood (21). Pediatric studies have reported faster progression to chronic pancreatitis in PRSS1 carriers, with median progression times of approximately 3–4 years (24).

Registry data further support a strong association between PRSS1 variants and CP in children (3). The ductal abnormalities observed in our cohort are consistent with previous findings linking imaging changes to disease progression and functional decline (17).

Overall, these findings support the concept of cumulative inflammatory injury in PRSS1-associated disease and highlight the importance of structured long-term surveillance (5).

Limitations of the study

This study is limited by its retrospective design, small sample size and single-center setting, which may overrepresent more severe cases due to referral bias in a tertiary care center. The limited number of patients also reflects the rarity of PRSS1-associated hereditary pancreatitis in pediatric populations, as well as the restricted availability of comprehensive genetic testing in certain healthcare settings. In Romania, access to advanced genetic diagnostics for pancreatitis remains limited, which may contribute to underdiagnosis and underreporting of hereditary cases. Therefore, the present cohort likely represents only a subset of the true disease burden. Despite these limitations, the findings are biologically consistent with known mechanisms of PRSS1-associated hereditary pancreatitis and align with previously published pediatric data.

CONCLUSIONS

PRSS1-associated hereditary pancreatitis in children is characterized by early onset, high recurrence burden and a substantial risk of progression to chronic pancreatitis. In our cohort, most patients developed structural pancreatic changes and a subset required endoscopic intervention due to clinically significant ductal abnormalities.

Importantly, our findings provide region-specific clinical data from a Romanian pediatric cohort, contributing to the limited genotype–phenotype evidence available from Eastern European populations. The observed association between disease severity and recurrence burden further supports the concept of an aggressive clinical phenotype in PRSS1-associated disease.

These results emphasize the role of early genetic evaluation in pediatric patients with recurrent pancreatitis and highlight the importance of structured, long-term follow-up to monitor disease progression and pancreatic functional impairment.

Further studies in larger pediatric cohorts are warranted to better define the natural history and prognostic factors of PRSS1-associated disease.

Patient consent

Written informed consent was obtained from the patients’ legal guardians.

Conflicts of interest

none declared.

Financial support

none declared.