*Karolina Wejnarska1, Agnieszka Magdalena Rygiel2, Katarzyna Wertheim-Tysarowska2, Elwira Kołodziejczyk1, Agnieszka Sobczyńska-Tomaszewska2, 3, Maciej Dądalski1, Grzegorz Oracz1
Analysis of clinical course of chronic pancreatitis in children with IVS8-5T variant in comparison with patients with CFTR mutation-related pancreatitis
Analiza przebiegu przewlekłego zapalenia trzustki u dzieci z wariantem IVS8-5T w porównaniu z pacjentami z przewlekłym zapaleniem trzustki związanym z mutacjami w genie CFTR
1Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw
Head of the Department: prof. Józef Ryżko, MD, PhD
2Department of Medical Genetics, Institute of Mother and Child, Warsaw
Head of Department: prof. Jerzy Bal, MD, PhD
3Medgen Medical Centre, Warsaw
Streszczenie
Wstęp. Przewlekłe zapalenie trzustki (PZT) jest chorobą o zróżnicowanej etiologii, rzadko występującą u dzieci. Udowodniono, że mutacje w genach SPINK1, CFTR, PRSS1, CTRC i CPA1 mają związek z etiologią PZT i są to najczęstsze czynniki etiologiczne u dzieci. Jednym z najczęściej opisywanych wariantów genetycznych jest polimorfizm w intronie 8 (IVS8-5T) w genie CFTR. Istnieją dane potwierdzające związek polimorfizmu IVS8-5T z etiologią PZT, lecz zagadnienie pozostaje nierozstrzygnięte. Informacje o roli wariantu w PZT u dzieci są bardzo ograniczone.
Cel pracy. Celem pracy była analiza przebiegu klinicznego PZT u dzieci z wariantem 5T w porównaniu z PZT związanym z mutacją w genie CFTR.
Materiał i metody. Do badania włączono 277 dzieci w PZT hospitalizowanych w Klinice Gastroenterologii, Hepatologii, Zaburzeń Odżywiania i Pediatrii w latach 1988-2015. Wariant 5T jako jedyną zmianę genetyczną związaną z PZT wykryto u 15 dzieci (grupa 1), mutację w genie CFTR u 10 dzieci (grupa 2). Przeanalizowano historie choroby pacjentów oraz porównano dane kliniczne.
Wyniki. Nie odnaleziono istotnych statystycznie różnic w zakresie wieku rozpoznania choroby (1,58-17,27 vs. 3,48-16,81 roku; NS), liczby zaostrzeń PZT (1,0-6,0 vs. 1,0-9,0; NS), stanu odżywienia (średnia wskaźnika Cole’a 93,7 vs. 100,9%; NS), liczby zwapnień uwidocznionych w badaniach obrazowych (4 vs. 3; NS), częstości stentowania przewodu trzustkowego (4 vs. 4; NS), operacji (6 vs. 1; NS) czy niewydolności wewnątrz- (2 vs. 0; NS) i zewnątrzwydzielniczej (1 vs. 1; NS).
Wnioski. Przebieg kliniczny PZT u dzieci z wariantem 5T oraz u dzieci z mutacją w genie CFTR jest porównywalny.
Summary
Introduction. Chronic pancreatitis (CP) in children is a rare entity with varied etiological factors. Gene mutations are proven to be related with pancreatitis and account for the most common cause of CP in children. One of the most frequently described genetic variant is the 5T polymorphism in intron 8 (IVS8-5T) of CFTR gene. Its contribution to development pancreatitis remains unclear and is still investigated. Data about 5T variant in etiology of children CP are very limited.
Aim. The aim of the study was to analyze the clinical course of CP in children with the 5T variant in comparison with CP children with CFTR mutations.
Material and methods. The 277 children with CP hospitalized in the Department of Gastroenterology of The Children’s Memorial Health Institute between 1988 and 2015 were enrolled into the study. As the only potential genetic factor causing CP, the 5T variant was found in 15 children (group 1) and CFTR mutation in 10 children (group 2). Medical charts of patients were reviewed, clinical data was compared between groups.
Results. We found no statistically significant differences in the age of diagnosis (1.58-17.27 vs. 3.48-16.81 years; NS), number of pancreatitis episodes (1.0-6.0 vs. 1.0-9.0; NS), nutrition status (Cole’s ratio mean 93.7 vs. 100.9%; NS), number of calcifications on imaging (4 vs. 3; NS), frequency of pancreatic duct stenting (4 vs. 4; NS), surgical interventions (6 vs. 1; NS) or endocrine (2 vs. 0; NS) and exocrine insufficiency (1 vs. 1; NS).
Conclusions. The clinical course of CP in children with the 5T variant and children with CFTR mutation is comparable.
Introduction
Chronic pancreatitis (CP) is a rare entity in children, but with increasing prevalence all over the world. Causes of CP in pediatric patients differ significantly from those described in adults, and the most frequent are gene mutations, anatomical defects, biliary tract diseases or lipid disorders. The most important genes which mutations are associated with pancreatitis include: PRSS1 (cationic trypsinogen/serine protease 1) (1), SPINK1 (serine protease inhibitor, Kazal type 1) (2), CFTR (cystic fibrosis transmembrane conductance regulator) (3), CTRC (chymotrypsin C) (4) and CPA1 (carboxypeptidase A1) (5). Mutation in the PRSS1 gene is a confirmed cause of chronic pancreatitis (6-8) in contrast to other genes, which mutations only increase the risk of the disease (7, 9). Despite the dynamic development of imaging techniques and genetic testing, a great number of pancreatitis still remains idiopathic.
Mutations of CFTR gene cause cystic fibrosis (CF), an autosomal recessive condition caused by loss-of-function mutations of gene encoding CFTR protein, ion channel at the plasma membrane (10). From over 2006 known so far CFTR mutations (according to CFTR Mutation Database) (11). The p.Phe508del mutation accounts for approximately 56-70% of CF-causing alleles in Caucasian population (12). Cystic fibrosis disease phenotype is quite variable (from severe pulmonary disease with pancreatic insufficiency to severe pulmonary disease with pancreatic sufficiency or atypical CF), and other conditions are also associated with CFTR gene mutation (e.g. congenital bilateral absence of vas deferens or disseminated bronchiectasis). In 1998 Cohn et al. (3) proved a strong association between CFTR mutation and idiopathic pancreatitis. As mentioned above, many CFTR mutations has been described, and therefore a classification system has been established to simplify the genotype/phenotype correlation. Due to pancreatic function status Kristidis et al. classified mutations as severe (pancreatic insufficiency – PI) or mild (pancreatic sufficiency – PS) (13). Other classification divides mutations in classes – class I, II, III result in total loss of CFTR function, class IV or V mutations have some residual ion channel function (14). Except for mutations, clinicaly significant polymorphisms in CFTR gene have also been described (15). In polymorphic Tn locus in intron 8 of CFTR three different numbers of thymidine repeats can be found – T5, T7 or T9 (16).
Variant 8 consisting of a short polythymidine tract (5T instead of 7T or 9T) determines the efficiency by which the intron 8 splice acceptor is used what results in a high proportions of transcript without exon 9. The efficiency of splicing decreases together with decreasing number of T repeats (17). Furtheremore, the effect of 5T variant is modulated by another polymorphic tract in intron 8 – TG(n). This track typically consist of 11, 12 or 13 TG repeats. The IVS8-5T CFTR variant when accompanied with 12 or 13 TG repeats on the same allele give rise to less efficient splicing (17). A IVS8-5T(TG)12 or IVS8-5T(TG)13 CFTR gene found in compound heterozygosity with a CF-causing mutation, or possibly even in homozygosity, will in general result in a CFTR-related disorder, such as CBAVD or CP (14). On the contrary, IVS8-5T(TG)11 in such situation can lead to CFTR-related disorder or do not have any clinical relevance.
Polymorphic 5T variant was found to be connected with idiopathic chronic pancreatitis in several studies (18, 19). Furthermore, in a subgroup of patients it was found to be a single genetic alteration identified, but its contribution to the etiology of CP remains controversial.
Aim
Thus, the aim of the study was to analyze and compare the clinical course of CP between children with 5T variant and CFTR mutations.
Material and methods
Total of 277 children with CP hospitalized at the Department of Gastroenterology, The Children’s Memorial Health Institute, Warsaw, Poland, between 1988 and 2015 were enrolled in the study. The inclusion criteria were: age 18 years, diagnosis of CP verified by imaging methods (US scan, CT, magnetic resonance cholangiopancreatography [MRCP], and/or endoscopic retrograde cholangiopancreatography [ERCP]), and follow-up of 12 months from time of the first visit.
260 (94%) participants were screened for mutations in the high-risk genes associated with CP. Written consents from patients and their parents were obtained before the analysis. CFTR (cystic fibrosis transmembrane conductance regulator); OMIM (Online Mendelian Inheritance in Man) 602421; was screened for p.Phe508del (p.Phe508del), dele2,3(21kb) mutations and variant IVS8-5T. In some of patients direct Sanger sequencing of exons 9-11 was performed, which enabled additionally exclude rare CFTR mutations located in this regions). Molecular analysis was performed at the Department of Medical Genetics of Institute of Mother and Child, Warsaw, Poland (between 1988-2010, and 2012-15), Genomed S.A., Warsaw, Poland (2011-2012), or Medgen, Warsaw, Poland (2012).
All patients underwent imaging studies, including abdominal ultrasound, CT, MRCP and/or ERCP. Clinical data were recorded and analyzed. Family history, laboratory and genetic results, the results of imaging studies, surgical and endoscopic procedures were documented.
The clinical course of CP was investigated on the basis of following parameters: 1) age of the disease onset regarded as first documented episode of acute pancreatitis (acute pancreatitis was diagnosed on the basis of elevated activity of serum amylase more than triple excess over the upper normal range [reference value: 0-82 U/L], elevated urine amylase activity [reference value: 0-380 U/L], and/or serum lipase activity 5 times over the upper normal range [reference value 0-210 U/L]), 2) number of pancreatitis episodes, 3) nutrition status (BMI = actual weight [kg]/height [m2]; Cole’s ratio = (BMI actual/BMI for the 50th centile) x 100 [%]), 4) changes found on imaging studies (US scan and/or MRCP), 5) the frequency of pancreatic duct stenting, 6) frequency of surgical procedures, 7) endocrine sufficiency and 8) exocrine sufficiency based on pancreatic function tests (the 72-h fecal fat quantification, elastase-1 stool test, breath test with 13C-mixed substrates estimating exocrine pancreatic function).
Patients were divided into 2 subgroups depending on CFTR genetic alteration: group 1 – children with the 5T variant, group 2 – children with CFTR mutation. Patients with any other etiological factor accompanying investigated CFTR alterations were excluded.
Data were reported as mean standard deviation or as median and range for continuous variables, and as relative frequencies for categorical variables. The chi-square test was used to compare relative frequencies. Analysis of continuous variables was performed using the Mann-Whitney U test and Kruskal-Wallis test (Statistica for Windows, v5.0; StatSoft, Tulsa, OK, USA). Significance was assumed at P < 0.05.
Results
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