Genetically influenced pediatric chronic pancreatitis: Radiologic perspectives

Abstract

BACKGROUND

Genetic factors are widely recognized as major contributors to the etiology of chronic pancreatitis in the pediatric population. Variants in CFTR, PRSS1, PRSS2, SPINK1, CTRC, and CASR may be associated with specific radiologic findings involving the pancreatic parenchyma or ductal architecture and may influence clinical phenotype and disease course through effects on pancreatic enzyme secretion, ductal function, and inflammatory responses.

AIM

To compare clinical and radiologic findings among pediatric patients with chronic pancreatitis according to genetic subtype.

METHODS

Data from 18 pediatric patients with genetically defined chronic pancreatitis were retrospectively reviewed. Patients with genetic variants were categorized into three exploratory groups: CFTR, CTRC/PRSS1, and SPINK1. Collected data included demographic and clinical characteristics, identified variants, cross-sectional imaging findings [magnetic resonance imaging (MRI) and/or computed tomography (CT)], and laboratory results. All radiologic images were evaluated by a pediatric radiologist using predefined descriptive criteria. Given the small sample size and retrospective design, all analyses were considered exploratory.

RESULTS

Pancreatic atrophy was detected more frequently on MRI and CT in the CFTR (88.9%) and CTRC/PRSS1 (80.0%) groups. Median amylase levels were highest in the CTRC/PRSS1 group [median: 1655 (790-3000)]. The SPINK1 group showed nominally higher serum calcium levels (P = 0.021); however, this comparison was based on a small subgroup, and multiple subgroup comparisons were performed.

CONCLUSION

These exploratory findings suggest that radiologic and biochemical features may vary according to genetic background in pediatric chronic pancreatitis. Larger prospective studies with standardized imaging assessment are needed to validate these observations.

Key Words: Pancreatic inflammation; Genetic variants; Children; Genotype-phenotype correlation; Radiologic findings

Core Tip: Although genetic factors constitute a major component of the etiology of pediatric chronic pancreatitis, radiologic phenotypic differences among genetic subtypes remain poorly characterized. In this study, genetically associated pediatric chronic pancreatitis cases were categorized into CFTR, CTRC/PRSS1, and SPINK1 subgroups, and their clinical, biochemical, and cross-sectional imaging findings were compared. These findings suggest that genetic background may contribute to radiologic and biochemical differences in pediatric chronic pancreatitis.

INTRODUCTION

Chronic pancreatitis (CP) is characterized by recurrent inflammation of pancreatic tissue and progressive fibrosis[1]. Although CP was once considered rare in childhood, it is now recognized increasingly among pediatric patients, even the very-young population[2]. The etiologies of CP in children differ from those in adults, with genetic and anatomical factors representing the primary underlying causes[3].

Although CP is more common in adults, known risk factors for its development include gallstone disease, smoking, excessive alcohol consumption, hyperlipidemia, hypercalcemia, medication-related adverse effects, pancreatic injury, and pancreatic malformations[4]. Genetic testing plays an important role in identifying underlying hereditary factors in children who present with recurrent pancreatitis, have a family history of similar disease in first- or second-degree relatives, or lack an identifiable etiological cause[5,6].

Patients with hereditary pancreatitis syndromes typically present with pancreatitis and exocrine pancreatic insufficiency[7]. Over time, they may also develop diabetes mellitus and obstructive jaundice secondary to associated biliary strictures[8,9]. Gene products encoded by CFTR, PRSS1, PRSS2, SPINK1, CTRC, and CASR play key roles in pancreatic function. Pathogenic variants in these genes may predispose individuals to hereditary pancreatitis by promoting inappropriate activation of pancreatic enzymes[1].

Children with CP are frequently hospitalized because of recurrent attacks, and emergency department visits are significantly increased. These recurrent attacks contribute to increased school absenteeism and substantial limitations in daily activities. Childhood CP affects not only patients but also their families and the healthcare system, resulting in a high disease burden and increased societal healthcare costs[10]. Ultrasonography (US), endoscopic US, magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and computed tomography (CT) are commonly used imaging modalities for evaluating pancreatic pathology, including cystic lesions, pancreatic insufficiency, CP, and iron deposition[7].

Clinical and radiological profiles of pediatric CP stratified by gene and variant remain poorly characterized in the literature. Therefore, this study aimed to compare clinical findings and imaging features among children with different genetic variants to improve the understanding of genotype-phenotype relationships.

MATERIALS AND METHODS

Ethics statement

This study was approved by the Erciyes University Ethics Committee (No. 2024/261). Given the retrospective design and use of anonymized medical record data, the requirement for written informed consent was waived by the ethics committee. All procedures were conducted in accordance with institutional ethical standards and the principles of the Declaration of Helsinki.

Study design

This retrospective cross-sectional study included children diagnosed with genetically associated CP who were followed up at the Erciyes University Department of Pediatric Gastroenterology between 2019 and 2023. Clinical data were extracted from medical records.

Participants and data collection

The study population consisted of 18 patients aged 8-17 years with genetically mediated CP. Clinical features, laboratory parameters, and genetic findings were retrospectively obtained from medical records during acute presentations. Patients were stratified according to the affected gene into three groups: CFTR, CTRC/PRSS1, and SPINK1.

Because of the limited sample size, patients with CTRC and PRSS1 variants were combined into a single subgroup to facilitate statistical comparisons, based on their shared biochemical roles in the pancreatic trypsin activation pathway. This classification does not imply clinical, functional, or pathogenic equivalence. Variant-level American College of Medical Genetics and Genomics (ACMG) classification[11] was available for 12 of 18 patients. The remaining 6 patients did not have accessible variant interpretation data; therefore, pathogenicity could not be assessed in these cases, which may have affected genotype-phenotype interpretation. Pancreatic elastase levels were not available for any patient. No patients had a family history of pancreatitis. Cases 1 and 12 were receiving pancreatic enzyme replacement therapy because of poor weight gain and steatorrhea.

Radiological evaluation

All MRI/MRCP and CT examinations were retrospectively reviewed by a pediatric radiologist with expertise in pancreatic imaging who was blinded to the patients’ genetic analysis results. To ensure consistency in radiologic assessment, all imaging studies were reviewed by the same radiologist. Interobserver reliability could not be assessed because all images were evaluated by a single reviewer.

Radiologic evaluation was based on predefined imaging criteria. Assessed imaging features included pancreatic atrophy, main pancreatic duct dilatation, common bile duct dilatation, pancreatic calcifications, findings of acute pancreatitis, and acute necrotic collections.

Pancreatic atrophy was defined as diffuse reduction in pancreatic parenchymal volume and thickness relative to the expected appearance for age. Main pancreatic duct dilatation was defined as enlargement of the duct beyond the expected age-adjusted caliber. Imaging findings of acute pancreatitis included pancreatic enlargement, parenchymal edema, peripancreatic inflammatory changes, fluid collections, or abnormal contrast enhancement.

Statistical analysis

Data were analyzed using IBM SPSS Statistics, version 22 (IBM Corporation, Armonk, NY, United States). Descriptive statistics were reported as minimum, maximum, and median values for continuous variables and as n (%) for categorical variables. For continuous variables that were not normally distributed, the Kruskal-Wallis H test was used to compare more than two groups. Categorical variables were compared using Fisher’s exact test or the Fisher-Freeman-Halton exact test, as appropriate. Statistical significance was defined as P < 0.05. Because this study was exploratory and hypothesis-generating, no formal correction for multiple comparisons was applied; therefore, P values were interpreted as nominal and evaluated in the context of potential type I error. The small subgroup sizes were also recognized as increasing the risk of type II error for nonsignificant comparisons.

RESULTS

Clinical characteristics according to genetic subgroups

Eighteen patients aged 8-17 years (median: 13 years) were evaluated after stratification according to the affected gene. Cross-sectional imaging findings obtained from MRI and/or CT were analyzed according to genetic subgroup. Imaging findings, including pancreatic atrophy, main pancreatic duct dilatation, common bile duct dilatation, acute pancreatitis, and pancreatic calcifications, are summarized in Table 1.

Table 1 Genotype-associated cross-sectional imaging findings in patients.

Case	Age/sex	Gene	Variant	Protein change	ACMG class	MRI and/or CT findings
1	11/M	SPINK1	c.194+2T>C	Splice-site	P	Pancreatic atrophy with signs of acute pancreatitis; multifocal calcifications
2	11/F	SPINK1	c.101A>G	p.Asn34Ser	LP	Normal
3	12/F	SPINK1	c.101A>G	p.Asn34Ser	LP	Pancreatic atrophy (mild)
4	13/M	SPINK1	NA	NA	NA	Pancreatic atrophy; MPD dilatation
5	15/M	PRSS1	NA	NA	NA	Pancreatic atrophy; MPD and CBD dilatation
6	17/M	PRSS1	NA	NA	NA	Acute necrotic collection; pancreatic atrophy; MPD dilatation
7	10/F	CTRC	c.649G>A	p.Gly217Ser	LP	Pancreatic atrophy; MPD dilatation
8	17/M	CTRC	c.650A>G	p.Glu217Gly	VUS	Pancreatic atrophy; acute pancreatitis; MPD dilatation
9	16/M	CTRC	NA	NA	NA	Pancreatic atrophy; CBD dilatation; acute pancreatitis
10	10/M	CFTR	c.3154T>G	p.Phe1052Val	LP	Pancreatic atrophy
11	8/M	CFTR	c.1624G>T	p.Gly542Cys	LP	Pancreatic atrophy
12	16/M	CFTR	c.3154T>G	p.Phe1052Val	LP	Pancreatic atrophy; MPD dilatation; multifocal calcifications
13	14/M	CFTR	c.1210-12T[5]	Poly-T tract	VUS	Pancreatic atrophy; acute pancreatitis
14	13/F	CFTR	c.4202A>G	p.Glu1401Gly	VUS	Pancreatic atrophy; MPD dilatation
15	9/F	CFTR	c.1521-1523delCTT/c.1210-12T[5]	p.Phe508del/-	P + VUS	Pancreatic atrophy; acute pancreatitis
16	13/M	CFTR	NA	NA	NA	Pancreatic atrophy
17	17/M	CFTR	NA	NA	NA	Acute necrotic collection; pancreatic atrophy; MPD dilatation
18	10/M	CFTR	c.1624G>T	p.Gly542Cys	LP	Pancreatic atrophy

M: Male; F: Female; NA: Not available; P: Pathogenic; LP: Likely pathogenic; VUS: Variant of uncertain significance; ACMG: American College of Medical Genetics and Genomics classification; MRI: Magnetic resonance imaging; CT: Computed tomography; CBD: Common bile duct; MPD: Main pancreatic duct.

Comparisons of clinical and radiological features revealed no statistically significant differences among the groups in terms of sex distribution or the presence of concomitant diseases (P > 0.05) (Table 2). However, males represented a higher proportion of the CFTR group (66.7%), whereas females comprised a larger proportion of the CTRC/PRSS1 group (60.0%). Among concomitant diseases, celiac disease (n = 1), cystic fibrosis (n = 1), and CFTR-related disorder (n = 1) were observed only in the CFTR group (Table 2).

Table 2 Clinical and radiological characteristics of patients according to gene groups.

Variables		CFTR		CTRC/PRSS1		SPINK1		P value
		n	%	n	%	n	%
Sex	M	6	66.7	2	40.0	2	50.0	0.610
	F	3	33.3	3	60.0	2	50.0
Variant	LP	3	27.3	1	9.1	2	18.2	0.428
	P	1	9.1	0	0.0	1	9.1
	VUS	3	27.3	1	9.1	0	0.0
Imaging findings: MRI/CT
Pancreatic atrophy	Yes	8	88.9	4	80.0	2	50.0	0.311
	No	1	11.1	1	20.0	2	50.0
Acute pancreatitis	Yes	1	11.1	1	20.0	0	0.0	0.667
	No	8	88.9	4	80.0	4	100.0
Dilatation of the CBD	Yes	0	0.0	1	20.0	0	0.0	0.273
	No	9	100.0	4	80.0	4	100.0
Dilatation of the MPD	Yes	4	44.4	3	60.0	1	25.0	0.587
	No	5	55.6	2	40.0	3	75.0
Acute necrotic collections	Yes	1	11.1	0	0.0	0	0.0	0.611
	No	8	88.9	5	100.0	4	100.0
Multifocal pancreatic calcifications	Yes	1	11.1	0	0.0	1	25.0	0.638
	No	8	88.9	5	100.0	3	75.0

P values were calculated using Fisher’s exact test for two-category comparisons and the Fisher-Freeman-Halton exact test for multi-category comparisons. M: Male; F: Female; P: Pathogenic; LP: Likely pathogenic; VUS: Variant of uncertain significance; MRI: Magnetic resonance imaging; CT: Computed tomography; CBD: Common bile duct; MPD: Main pancreatic duct.

Radiological findings according to genetic subgroups

On radiological evaluation, pancreatic atrophy was observed at high rates in the CFTR (88.9%) and CTRC/PRSS1 (80.0%) groups, whereas a lower rate was observed (50.0%) in the SPINK1 group. Findings of acute pancreatitis were reported in the CFTR (11.1%) and CTRC/PRSS1 (20.0%) groups, while no radiologic features of acute pancreatitis were detected in the SPINK1 group. Common bile duct dilatation was observed only in the CTRC/PRSS1 group (20.0%). Main pancreatic duct dilatation was less common (25.0%) in the SPINK1 group than in the CFTR (44.4%) and CTRC/PRSS1 groups (60.0%). Acute necrotic collections were observed only in the CFTR group (11.1%) (Table 2).

Biochemical findings according to genetic subgroups

Comparisons of clinical and biochemical parameters among genetic subgroups revealed no statistically significant differences in age, total number of pancreatitis attacks, disease duration, amylase, lipase, total and conjugated bilirubin, alkaline phosphatase (ALP), serum phosphorus, parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], triglycerides, total cholesterol, or immunoglobulin G4 (IgG4) levels (P > 0.05 for all comparisons).

However, median amylase levels were numerically highest in the CTRC/PRSS1 group [median (minimum-maximum): 1655.00 (790-3000)] compared with the other groups, although this difference did not reach statistical significance (P = 0.071). Similarly, lipase levels were highest in the CTRC/PRSS1 group and lowest in the SPINK1 group. These numerical differences were interpreted as descriptive trends only.

ALP levels were numerically higher in the CFTR group and lower in the CTRC/PRSS1 group, approaching nominal statistical significance (P = 0.051). No statistically significant differences were observed among the groups in total or conjugated bilirubin levels.

Serum calcium levels showed a nominally significant difference across genetic subgroups (P = 0.021), with higher levels observed in the SPINK1 group [median (minimum-maximum): 9.35 (9.1-9.4)] compared with the CFTR and CTRC/PRSS1 groups. However, this finding should be interpreted cautiously given the small subgroup size and absence of correction for multiple comparisons. No statistically significant differences were observed in phosphorus, PTH, nor 25(OH)D levels among the groups (Table 3).

Table 3 Clinical, laboratory, and biochemical characteristics of patients according to gene groups.

Variables	CFTR	CTRC/PRSS1	SPINK1	H value	P value
	Median (min-max)	Median (min-max)	Median (min-max)
Age (years)	13.00 (8-17)	16.00 (10-17)	11.50 (11-13)	3.270	0.195
Pancreatitis attacks (n)	4.00 (2-8)	3.00 (3-4)	4.00 (2-6)	1.749	0.417
Disease duration (years)	3.00 (1-7)	2.00 (1-3)	2.50 (1-3.5)	1.278	0.528
Serum amylase (U/L)	502.00 (133-2165)	1655.00 (790-3000)	1075.00 (480-1468)	5.303	0.071
Serum lipase (U/L)	1223.00 (133-2652)	1210.00 (703-1900)	700.00 (450-1614)	0.775	0.679
Total bilirubin (mg/dL)	0.40 (0.28-1.30)	0.70 (0.30-0.70)	0.70 (0.39-0.70)	1.412	0.494
Conjugated bilirubin (mg/dL)	0.12 (0.06-0.41)	0.30 (0.20-0.40)	0.30 (0.15-0.30)	4.198	0.123
ALP (U/L)	133.00 (116-433)	88.00 (65-206)	116.00 (84-130)	5.934	0.051
Serum calcium (mg/dL)	8.80 (8.6-9.2)	8.90 (8.5-9.3)	9.35 (9.1-9.4)	7.730	0.021a
Serum phosphorus (mg/dL)	3.90 (3.1-4.7)	4.00 (3.8-4.3)	4.00 (3.6-4.0)	0.356	0.837
PTH (pg/mL)	54.40 (38.4-74.0)	62.00 (62.0-62.0)	55.65 (49.3-66.2)	0.167	0.920
25(OH)D (ng/mL)	28.00 (14-35)	26.00 (22-41)	22.00 (22-22)	1.741	0.419
Serum triglycerides (mg/dL)	100.00 (90-104)	98.00 (85-110)	100.00 (85-110)	0.021	0.990
Total cholesterol (mg/dL)	162.50 (150-198)	172.50 (130-205)	180.00 (140-180)	0.040	0.980
IgG4 (mg/dL)	76.30 (34.6-115.8)	110.00 (63.0-110.0)	51.10 (44.2-58.0)	2.431	0.297

^aP < 0.05.

P values were calculated using the Kruskal-Wallis test. For variables available for a single patient in a group, minimum and maximum values coincide. min: Minimum; max: Maximum; ALP: Alkaline phosphatase; 25(OH)D: 25-Hydroxyvitamin D; IgG4: Immunoglobulin G4; PTH: Parathyroid hormone.

Triglyceride and total cholesterol levels were similar across genetic subgroups, with no statistically significant differences detected. IgG4 levels were numerically higher in the CTRC/PRSS1 group [median (minimum-maximum): 110.00 (63.0-110.0)], although this difference did not reach statistical significance (P = 0.297) (Table 3).

DISCUSSION

Although clinical characteristics and genetic variants associated with childhood CP have been investigated, data systematically evaluating radiologic phenotypes across genetic subtypes remain limited. In this context, the present study addresses this gap by characterizing the clinical findings and radiologic profiles of subgroups classified according to CFTR, CTRC/PRSS1 and SPINK1 variants. In patients with CP, the reported prevalence of pancreatitis-associated pathogenic variants range from 15% to 80%[12-14]. CP is a rare disorder in childhood[15], and genetic factors have been associated with earlier disease onset[16].

In childhood CP, genetic factors represent the leading etiologic contributors, and pathogenic variants influence disease course through distinct pathogenic pathways involving the acinar and ductal cells of the exocrine pancreas. Impaired CFTR-mediated bicarbonate and water secretion results in hyperviscous ductal contents, promoting ductal stasis and protein aggregation. Over time, this functional impairment may predispose to irreversible structural changes in the pancreatic ducts and secondary parenchymal damage[17].

In contrast, uncontrolled intrapancreatic trypsin activity or impaired trypsin inactivation disrupts acinar cell integrity and promotes recurrent inflammatory injury[18]. SPINK1 plays a protective role by inhibiting premature trypsin activation, and loss-of-function variants weaken this defense mechanism, thereby contributing to pancreatitis[19]. Furthermore, oxidative stress and intracellular calcium dysregulation contribute to chronic inflammation and CP progression[20].

Although PRSS1, CTRC, and SPINK1 are all involved in the trypsin-dependent pathway, their roles in pancreatitis pathogenesis differ mechanistically. Variants in PRSS1 and CTRC directly disrupt trypsin activation and degradation, leading to an increased intrapancreatic burden of active trypsin, whereas SPINK1 variants primarily weaken the protective inhibitory mechanism against premature trypsin activation and often act as disease modifiers that increase susceptibility to pancreatitis. Therefore, CTRC and PRSS1 variants were analyzed together because of the limited sample size and their shared involvement in trypsin-dependent pathways. However, this grouping should be interpreted cautiously and does not imply clinical, functional, or pathogenic equivalence.

Previous studies have reported that CFTR variants are among the most frequently identified pathogenic variants in adults with idiopathic pancreatitis and in children with genetically driven CP[15,21]. Congenital obstructive anomalies, particularly pancreas divisum, have been reported as the second most important risk factor for CP after genetic etiology[21]. However, no concomitant congenital anatomical abnormalities were identified in the present study. The clinical significance of variants in CLDN2, SLC26A9, TRPV6, CEL, and SBDS, which have been implicated in pancreatic injury, remains incompletely understood[22].

The absence of significant differences in key clinical parameters, including age, disease duration, and number of pancreatitis attacks, among genetic subgroups in our study may suggest that genetic etiology influences disease progression rather than disease onset. However, this interpretation should be considered preliminary given the small sample size and the retrospective cross-sectional design.

Pancreatic atrophy is associated with an increased risk of long-term exocrine and endocrine insufficiency in CP[20]. However, CT and MRI findings may remain normal during the early stages of disease[23]. In addition, current knowledge regarding MRI evaluation of pancreatitis is largely derived from studies in adults, while data on imaging in children remain limited[24].

Therefore, evaluating pancreatic morphological changes according to genetic etiology is particularly valuable in pediatric patients from a clinical perspective. Previous studies have shown that, in genetically mediated CP, pancreatic atrophy is more common in patients with CFTR and PRSS1 variants, whereas imaging findings tend to be milder in those with SPINK1 variants[25]. These observations are consistent with our findings. Accordingly, the increased prevalence of pancreatic atrophy observed in the CFTR and CTRC/PRSS1 groups in our study may suggest more pronounced progressive loss of pancreatic parenchymal architecture in these genetic subtypes. In contrast, the lower rates of atrophy in the SPINK1 group may indicate either slower progression of parenchymal damage or the absence of radiologically detectable changes during the early stages of disease. These findings suggest that disease severity of SPINK1-related pancreatitis cannot be inferred reliably from imaging features alone. The observation that necrotic collections were detected only in the CFTR and CTRC/PRSS1 groups may indicate increased susceptibility to complications in these genetic subtypes. However, larger cohorts are needed before genetic factors can be considered definitive determinants of these radiologic outcomes.

Calcium is known to promote trypsinogen activation by modulating intracellular signaling in pancreatic acinar cells[26]. SPINK1 encodes a pancreatic secretory protein that functions as trypsin inhibitor[27]. Pathogenic SPINK1 variants alone are generally insufficient to directly initiate trypsin activation or cause pancreatitis in the absence of an inflammatory trigger. However, in a substantial proportion of SPINK1-associated pancreatitis cases, disease development appears to involve more complex inheritance patterns, often modified by environmental triggers or additional genetic factors[28]. In this context, SPINK1 variants may facilitate disease onset by lowering the biological threshold for pancreatitis development. In our study, higher serum calcium levels were observed in patients carrying SPINK1 variants; however, this finding was nominal and should be interpreted cautiously given multiple exploratory comparisons, lack of adjustment for multiple testing, and small SPINK1 subgroup size.

Additionally, genetically mediated CP, including forms associated with CFTR variants, has been linked to an increased risk of pancreatic cancer in adulthood[29], underscoring the importance of genetic diagnosis for long-term surveillance and clinical management.

In the present study, no significant differences were observed among genetic subgroups in amylase, lipase, bilirubin, triglyceride, cholesterol, or IgG4 levels. These findings suggest that biochemical parameters may not reflect the structural severity of pediatric CP consistently across genetic subtypes.

The role of genetic diagnosis in the clinical management of pediatric CP is becoming increasingly important. The findings of our study suggest that radiologic and biochemical patterns may vary according to genetic subtype, which may help inform individualized follow-up strategies. However, the need for closer imaging surveillance in specific genetic subgroups should be considered hypothesis-generating rather than a direct clinical recommendation until validated in larger prospective studies.

The main limitations of this study include its retrospective design, single-center setting, small sample size, and incomplete genetic variant data. The very small subgroup sizes reduced statistical power and increased the risk of both type I and type II errors. Multiple exploratory comparisons were performed without formal adjustment, and variant-level ACMG pathogenicity classification was unavailable for 6 (of 18) patients, which may have affected subgroup interpretation. In addition, radiologic assessment was qualitative and performed by a single pediatric radiologist; therefore, interobserver reliability could not be evaluated.

Potentially relevant clinical outcomes, including exocrine pancreatic insufficiency, nutritional status, endocrine dysfunction, pain severity, and quality-of-life measures, were not systematically available. Furthermore, the single-center nature of the study limits the generalizability of the findings. Therefore, rather than establishing causal relationships or supporting definitive clinical recommendations, these results provide preliminary insights into how genetic background may modulate the clinical and radiologic course of pediatric CP. Nevertheless, this study contributes to the literature by providing additional data on genotype-phenotype relationships in this rare pediatric population.

CONCLUSION

Genetic profiling represents a crucial component of the etiologic evaluation of hereditary and genetically mediated pediatric CP. In this exploratory cohort, radiologic and biochemical findings appeared to vary across genetic subgroups; however, these observations should be interpreted cautiously given the small sample size and retrospective study design. This study suggests that genetic subtype may contribute to heterogeneity in the clinical and radiologic course of pediatric CP. However, larger, prospective, multicenter studies using standardized imaging criteria and longitudinal outcome measures are needed to validate these findings and determine whether genotype-based monitoring strategies are clinically useful.