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31 January 2023

CFTR-Related Metabolic Syndrome: Genetic Variants Increasing Pancreatitis Risk in the Pediatric Puerto Rican Population

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Department of Pediatrics and Basic Science, Ponce Health Sciences University, Ponce, PR 00716, USA
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Author to whom correspondence should be addressed.
Children2023, 10(2), 280;https://doi.org/10.3390/children10020280
This article belongs to the Special Issue Cystic Fibrosis in Children
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Abstract

CFTR-related metabolic syndrome (CRMS) is a novel diagnosis due to widespread use of and advances in the newborn screening (NBS) process for cystic fibrosis (CF) in the United States of America, allowing for the diagnosis of asymptomatic children with CF. Before 2015, a large Puerto Rican pediatric population was not screened for CF in the NBS test. Studies have shown that patients presenting with idiopathic recurrent or chronic pancreatitis have an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We present a retrospective chart review of 12 pediatric cases (n = 12) that were presented to an outpatient community clinic with clinical manifestations associated with CF. The pancreatic insufficiency prevalence (PIP) score was calculated on CFTR mutations. The mutations considered for the calculation of the PIP score were: F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519_1521del), and L1335P (c.4004T > C). V201M mutation was classified as mild in both PIP scores, and a correlation with pancreatitis was noted. Clinical manifestations vary in cases with the V201M variant (c.601G > A). One case was diagnosed with CFTR-related disorder (CRD) and recurrent pancreatitis. It is important to consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico due to the implications and increased risk of pancreatitis and other CF-related complications.

1. Introduction

Advances in genetics, the implementation of newborn screening (NBS), and the availability of sweat tests allow for early diagnosis of children with cystic fibrosis (CF) and CFTR-related metabolic syndrome (CRMS) in the United States of America. When a CF screening test does not meet the established criteria as per CF guidelines [1], other entities, such as CRMS and CFTR-related disorder (CRD), should be a diagnostic consideration as part of the differential diagnosis in a patient with clinical symptoms. It is suggested that the term CRMS be used to refer to newborns with hypertrypsinogenemia on the NBS who have sweat chloride readings <60 mmol/L and up to two CFTR variants, at least one of which is not characterized as a CF-disease-causing variant, and who do not match the criteria set out by the CF Foundation for the diagnosis of CF [2]. CRD is a nonclassical CF induced by disease-causing variants of different severity, resulting in either single or multiorgan involvement, depending on each organ's susceptibility to malfunctioning of the cystic fibrosis transmembrane conductance regulator (CFTR) protein [3]. In Puerto Rico, it is estimated that the incidence of CF is one in every 17,000 births. Since 2015, it has been mandatory by law to include an immunoreactive trypsinogen (IRT) test to screen for CF as part of the NBS at all hospitals around the island. However, a large portion of the Puerto Rican pediatric population was not tested for CF in the NBS in Puerto Rico before 2015. As a result, there is a hypothetical likelihood of having undiagnosed CF in the adolescent and adult Puerto Rican population. In addition, until 2021, there was just one laboratory on the island that could perform the analysis of sweat samples, currently the gold standard for CF diagnostic confirmation.
Patients presenting with recurrent-acute or chronic pancreatitis have an increased frequency of mutations in the CFTR gene [4]. A small percentage of this group can fulfill the criteria for CF diagnosis, and the remaining individuals who do not fulfill the criteria could be diagnosed with CRD in the presence of CFTR variants [5]. The pancreatic insufficiency prevalence (PIP) score is a practical approach to understanding how patients who carry CFTR variants with mild phenotypic effects have a greater risk of developing pancreatitis than those associated with moderate-to-severe phenotypes. This CFTR genotype–phenotype correlation found in pancreatitis is unique compared to other organ manifestations related to the complex monogenic nature of the CF disease [6]. As a result of the related long-term implications, clinical suspicion of CRMS or CRD should be explored in pediatric patients who suddenly develop idiopathic recurrent or chronic pancreatitis. The purpose of this research is to provide a description of the disease-causing variations of the CFTR gene that are now elevating the risk of pancreatitis in the Puerto Rican pediatric population.

2. Materials and Methods

We present a retrospective chart review of 12 pediatric cases (n = 12) referred to an outpatient community clinic specialized in the evaluation of rare pediatric pulmonary disorders in Puerto Rico. Each pediatric patient was previously or recently diagnosed, as per CF Foundation guidelines [1], with having either CF, CRMS, or CRD, or classified as a CF carrier. Failure to thrive (FTT) was defined by a body mass index (BMI) below the 3rd percentile for age. The diagnosis classification process included a review of sweat chloride assays, as well as genetic testing for CFTR variants. Genetic testing results were analyzed regarding the base change, protein/intron position, zygosity, and variant classification. An electronic chart review of the enzymatic measurements of lipase, amylase, and pancreatic stool elastase levels was assessed when available. Based on the reference values, patients were classified as either exocrine pancreatic insufficient (EPI) (<200 mcg/g stool elastase) or exocrine pancreatic sufficient (EPS) (>200 mcg/g stool elastase). The pancreatic insufficiency prevalence (PIP) score was calculated and compared to those in the CFTR2 database for the same mutations. CFTR mutations found were explored in the Clinical and Functional Translation of CFTR (CFTR2) database from patients from the United States and around the world [7]. An analysis of the CFTR variant name, exocrine pancreatic insufficiency (EPI) patients, exocrine pancreatic sufficiency (EPS) patients, and the total number of patients with each variant in the database was completed. The CFTR variants in the cohort with a PIP score of ≤0.25 were classified as mild. The PIP score was also calculated for CFTR2 patients and compared with those found in our retrospective cohort of pediatric patients from Puerto Rico. The Institutional Review Board of the Ponce Health Sciences University in Ponce, Puerto Rico approved data collection and analysis for the protection of human subjects.

3. Results

From a total of 12 pediatric patients (n = 12), seven were males (58%) and five were females (42%) with a median age of 7.55 years and Puerto Rican ethnicity. The most frequently reported findings were FTT, recurrent pancreatitis, and abnormal IRT. The complete data list for CFTR base change, protein/intron position, zygosity, and mutation classification is presented in Table A1. In some cases, data on sweat tests, lipase levels, amylase levels, and pancreatic stool elastase were unavailable. A total of six EPS cases were reported, three EPI, and in three, data were unavailable (Table 1).
Table 1. Laboratory measurements of pancreatic function of 12 Puerto Rican pediatric patients with CFTR variants.
The mutations F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519 1521del), and L1335P (c.4004T > C), which were present in two or more cases, were considered for the calculation of the PIP score. F508del obtained a PIP score of 0.25 in our cohort and 0.88 in the CFTR2 database, V201M PIP scores of 0.00 and 0.23, I507del PIP scores of 1.00 and 0.89, and finally, L1335P PIP scores of 0.50 and 0.37. V201M mutation was classified as mild in both PIP scores of 0.00 and 0.23. The CFTR2 database had a total of 53,480 EPI patients for F508del, 3 EPI patients for V201M, 529 EPI patients for I507del, and 11 EPI patients for L1335P. Our cohort had one EPI patient for F508del, zero EPI patients for V201M, two EPI patients for I507del, and finally, one EPI patient for L1335P, which are presented in Table 2 and Table 3.
Table 2. Pancreatic insufficiency prevalence (PIP) score calculated on CFTR variants present two or more times in our Puerto Rican pediatric cohort.
Table 3. Pancreatic insufficiency prevalence (PIP) score calculated on CFTR mutations present two or more times in our Puerto Rican pediatric cohort using the CFTR2 database to compare.

4. Discussion

CF is a clinical diagnosis due to the broad spectrum and severity of symptoms and organs affected amongst individuals [8,9,10,11]. CF can also be defined genetically by the presence of biallelic CF-disease causing variants in the CFTR gene. Physiologically, it is a disorder of chloride and bicarbonate transport through epithelial membranes resulting from the absence or inappropriate functioning of the CFTR protein [9]. CRMS or CRD should be a diagnostic consideration in the appropriate clinical setting when a clinical entity associated with CFTR dysfunction does not meet the criteria of CF guidelines [1,11]. Gastrointestinal manifestations in CRMS and CRD are important to be addressed by clinicians due to the potential implications for children's nutrition, growth, and overall development.
Recurrent-acute or chronic pancreatitis illustrates an accurate phenotype of CFTR dysfunction [12]. CF-disease-causing variants, such as F508del being the most frequent and severe, generally have less than 2% CFTR protein function, leading to EPI in homozygote patients. However, CF cases with mild genotypes that have more than 5% of normal CFTR function are considered EPS [11]. A published systematic study of 277 EPS with CF participants with or without pancreatitis demonstrated that the risk of developing pancreatitis was linked to the severity of the CFTR genotype [13]. After PIP score calculation, patients with mild mutations had a greater risk of developing pancreatitis than those with moderate or severe CFTR genotypes [14]. In the literature, the V201M missense variant of CFTR and other missense mutations of CFTR have not yet been identified for their role in gene expression and function [15]. In our study, the V201M mutation was considered mild; similarly, the CFTR2 database classifies the V201M mutation as mild. In contrast, F508del was classified as mild in our cohort, going against the CFTR2 database. This discrepancy could be attributed to the small sample size of our retrospective study, which limited our observations. Another reason for the discrepancy found in our cohort could be non-CFTR factors that affect and modify, both genetically and environmentally, the phenotype and clinical progression of the pancreatic function of this Puerto Rican cohort with F508del versus those found in the CFTR2 database [16,17].
In our study cohort, the I507del and L1335P variations were classed as moderate, as they are in the CFTR2 database. Cases 7 and 9 in our study cohort presented with the V201M variant (c.601G > A) but clinical manifestations, physical findings, and diagnoses varied between the two cases. Case 7 was diagnosed with CRMS, and clinical manifestations and physical findings were remarkable for the history of recurrent pancreatitis. Currently, case 7 is EPS, and the diagnosis of pancreatitis increases her risk of developing EPI in the future [18]. The exact pathogenesis of the development of EPI is still unknown and under investigation, but the leading cause is thought to be obstructive tubulopathy due to CFTR channel dysfunction in the pancreatic duct [19]. Case 9 was diagnosed as a CF carrier and asymptomatic. It is important for asymptomatic CF carriers with specific mutations to be monitored long-term as studies show that CF carriers exhibit slight CFTR dysfunction and are at risk of CRD and, therefore, chronic pancreatitis in heterozygous carriers [20]. Case 5 was remarkable for recurrent pancreatitis, the EPS status was maintained, and the F508del was considered mild under the PIP score in our cohort compared to the CFTR2 database. This observation is consistent with the complex nature of CF, particularly in children, in whom all CF manifestations may or may not be present at the beginning. Over time, we can expect that the damage to the pancreatic acinar tissue will cause EPI in most cases [21]. As recommended by CF Foundation guidelines, in pediatric cases, close monitoring and serial clinical evaluations will help us understand and detect EPI and recurrent pancreatitis in populations with less common CFTR genetic mutations, such as in Puerto Rico [22]. To address the increased risk of pancreatitis and CF among Puerto Rican children, a collaborative and multidisciplinary strategy involving a pediatrician, gastroenterologist, pulmonologist, geneticist, and dietician with experience in CF, CRD, and CRMS will be required. Table 4 provides a suggested guide for the multidisciplinary approach and clinical investigations necessary to evaluate patients with CF, CRD, and CRMS in Puerto Rico.
Table 4. Pediatric multidisciplinary approach and clinical investigations for CF, CRD, and CRMS in Puerto Rico.
It is essential to continue monitoring and consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico with complaints such as failure to thrive, abdominal pain, and pancreatitis. A considerable portion of the Puerto Rican pediatric population was not screened for CF prior to 2015 since IRT levels were not yet included in the NBS. At the same time, access to sweat tests on the island was limited, with only one laboratory previously available. As a result, adolescents may be at risk of complications of CFTR dysfunction, such as pancreatitis, in Puerto Rico. Our team has recently established a second laboratory for sweat test collection and analysis, which has been operating since 2021. This facility adheres to the guidelines established by the CF Foundation, makes use of cutting-edge equipment, and is fully accredited by the Clinical Laboratory Improvement Amendments (CLIA). Table 5 summarizes the challenges of studying and treating CF and CF-related pancreatitis in the Puerto Rican population.
Table 5. Challenges to studying and treating CF and CF-related pancreatitis in Puerto Rico.
All these efforts will help us to increase awareness about the disease, which may help to identify and recruit more patients for research in Puerto Rico. In the pediatric population, the risk of malignancy is low. However, as the age of survival continues to rise, there is an increased risk of malignancy in the gastrointestinal and biliary tracts for patients with CFTR variants associated with an increased risk of pancreatitis [23]. Insight into the molecular mechanisms relating to CFTR variants and functions is much needed to understand and develop targeted drug treatments for underrepresented populations in research. Currently, there is no specific therapy for CF-related pancreatitis, but new and highly effective CFTR modulator therapies aiming to modulate and potentiate the CFTR function may have implications for specific mutations affecting the gastrointestinal component of patients with CF-related pancreatitis and EPI [24,25].
Similarly, challenges with CF identification are lower in North American and European countries compared to Latin American nations due to a lack of official patient registries, universal access to newborn screening, up-to-date diagnostic technologies, and interdisciplinary and specialized clinical centers [26]. Table 6 summarizes the published studies evaluating CFTR variants in Latin America. Specific screening panels customized to their population's genetic profile were researched in Ecuador, demonstrating the need to study Puerto Rico's genetic profile to understand our unique CFTR variability [27]. However, doing so in Latin America has been difficult in recent decades due to the resources required for molecular testing and the poor detection rates of known CFTR variants [28,29]. Prior epidemiologic studies aimed at identifying CF patients and genetic variations in different parts of the nation were necessary for understanding CF in Latin America [28,30]. The Health State Department manages the Puerto Rican CF incidence, and no epidemiological research has been conducted on the CF Puerto Rican population. Only one study documented the frequency of CFTR variants in Puerto Rico and the Dominic Republic, showing an increased variability of the CFTR variants, with a high potential to be missed by the newborn screening [22]. In the same study, the most frequent CFTR variant for Puerto Rico was F508del, congruent with our observations. A cross-sectional investigation in Uruguay found that the incidence of CF was significantly lower than the state authorities claimed [31]. Additional studies are needed to determine the incidence of CF in Puerto Rico as the NBS was not mandated by legislation in Puerto Rican hospitals before 2015 and probably missed uncommon CFTR genetic variants in our population, especially in adults.
Table 6. Summary of published studies evaluating CFTR variants in Latin America.
As a result of the heterogeneity of CF, a registry of CFTR variants is required, as demonstrated by a study in Colombia [32], to tailor specific screening tests for common variants such as F508del and other rarer and understudied CFTR variants to the mixture of European, Amerindian, and African ancestry in many Latin American countries such as Puerto Rico. According to research, Mexico has one of the most diversified CFTR spectra in the world [33]. This trend of genetic variability in Latin American countries was demonstrated in other studies, where the F508del was present but at lower rates than in European countries [34]. The presence of rare mutations with the calculation of the PIP score may have health implications in these countries, as demonstrated in our Puerto Rican cohort with pancreatitis. A better understanding of the ancestry of CFTR variants in Latin America may help to clarify the complexity and segregation of rare CFTR variants in our communities.

5. Conclusions

Our study cohort of 12 Puerto Rican pediatric patients demonstrated the presence of CFTR variants causing recurrent pancreatitis and EPI in Puerto Rico. We described the association between V201M CFTR mutation and CRMS diagnosis with a greater risk of developing chronic pancreatitis in Puerto Ricans. High clinical suspicion of Puerto Rican pediatric and adult patients presenting with recurrent pancreatitis is needed between healthcare providers to consider CRMS or CRD in the differential diagnosis. CF screening is even more critical considering that, before 2015, NBS tests were not mandatory for CF in Puerto Rico, and a large portion of the pediatric population was not screened for an elevation of IRT nor the most common mutations of the CFTR gene. For this reason, many patients may continue to go undiagnosed with chronic pancreatitis in adulthood. Early diagnosis allows for a better prognosis and quality of life for CF, CRMS, and CRD patients, along with CF carriers. Additional basic, clinical, and translational research in underrepresented minority groups, such as patients living in Latin America, is needed to develop specific treatments for CF-related pancreatitis. A better understanding of the CF genotype–phenotype relationship is necessary for Hispanic populations such as Puerto Ricans, especially in children. Teamwork among pediatric pulmonologists and general pediatricians in Puerto Rico is vital to raise awareness about CF and to enable us to fully understand the CFTR spectrum of disease.

Author Contributions

Conceptualization, W.D.J.-R. and J.M.M.-M.; review outline, W.D.J.-R. and J.M.M.-M.; literature review, W.D.J.-R. and J.M.M.-M.; writing—original draft preparation, W.D.J.-R. and J.M.M.-M.; writing—review and editing, W.D.J.-R. and J.M.M.-M.; visualization/s, W.D.J.-R. and J.M.M.-M.; supervision, W.D.J.-R.; funding acquisition, W.D.J.-R. and J.M.M.-M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Mission:Cure.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Ponce Health Sciences University (protocol code 221226338 and 15 December 2022).

Data Availability Statement

All data analyzed in this study are included in this published article.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. Clinical manifestations and CFTR variants of 12 Puerto Rican patients.
Table A1. Clinical manifestations and CFTR variants of 12 Puerto Rican patients.
Case #DiagnosisClinical ManifestationsBase ChangeProtein/Intron
Position		ZygosityClassification
1CF carrier12-year-old female with recurrent pulmonary infections and abdominal painc.1230-34TG(12)T(5)Intron 9HeterozygousPathogenic
2CF carrier3-year-old male with FTT and asthmac.4004T > C

c.1210-34TG(11)T(5)		p.Leu1335Pro
Intron 9		Heterozygous

Heterozygous		Pathogenic
Pathogenic
(low penetrance)
3CF17-year-old male with FTT, osteoporosis, bronchiectasis, and clubbingc.1519_1521delp.Ile507delHeterozygousPathogenic
c.1521_1523delp.Phe508delHeterozygousPathogenic
4CRMS30-month-old male with FTT and recurrent pneumoniac.1521_1523delp.Phe508delHeterozygousPathogenic
5CF12-year-old with FTT and chronic pancreatitisc.1521_1523delp.Phe508delHeterozygousPathogenic
6CF19-months-old with FTT and chronic pancreatitisc.1521_1523delp.Phe508delHeterozygousPathogenic
c.601G > Ap.Val201MetHeterozygousPathogenic
7CRMS9-years-old female with FTT and recurrent pancreatitisc.601G > Ap.Val201MetHeterozygousPathogenic
8CF carrier33-months-old male with chronic coughc.1210-34TG(11)T(5)Intron 9HeterozygousPathogenic
(low penetrance)
9CF carrier15-months-old female with abnormal IRTc.1000C > Tp.Arg334TrpHeterozygousPathogenic
10CF carrier20-year-old male asymptomaticc.601G > Ap.Val201MetHeterozygousPathogenic
11CRMS9-year-old male with FTT and chronic bronchitisc.4004T > Cp.Leu1335ProHeterozygousPathogenic
c.1210-34TG(11)T(5)Intron 9HeterozygousPathogenic
(low penetrance)
12CF7-month-old male with FTT, steatorrhea, anemia, and pneumothoraxc.1519_1521delp.Ile507delHeterozygousPathogenic
c.3196C > Tp.Arg1066CysHeterozygousPathogenic
CF: cystic fibrosis, CRMS: CFTR-related metabolic syndrome, FTT: failure to thrive, IRT: immunoreactive trypsinogen.

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