Search Results (10)

Background/Objectives: Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) vary both in European countries and in other geographical regions. The aim of our retrospective study was to present the genetic variants identified in a group of 48 CF patients from the Moldova region (Romania), as well as to establish genotype–phenotype correlations. Methods: Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or those in whom no mutation was detected, CFTR gene sequencing (NGS) was performed. Results: The compound heterozygous genotype was identified in 26 (54.16%) of the patients (with one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by G542X (6.25%, 6/96). Several new variants were also identified that had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). Phenotypic manifestations in patients with CFTR class I, II, III and VII variants (homozygous and compound heterozygous) were more severe compared to those in patients with CFTR class IV, V and VI mutations, with the data obtained being consistent with those in the literature. Respiratory tract involvement was present in 77.08% of the patients, being more frequent in patients with the compound heterozygous genotype compared to the homozygous F508del genotype. Most patients had exocrine pancreatic insufficiency (EPI) (85.41%). Gastrointestinal manifestations included hepatocytolysis (66.66%) and biliary cirrhosis (0.41%). Meconium ileus was detected in 18.75% of patients, all with a compound heterozygous genotype. Conclusions: We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis. Full article

The early management of neonates with meconium ileus (MI) and cystic fibrosis (CF) is highly variable across countries and is not standardized. We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The protocol was registered in PROSPERO (CRD42024522838). Studies from three providers of academic search engines were checked for inclusion criteria, using the following search terms: meconium ileus AND cystic fibrosis OR mucoviscidosis. Regarding the patient population studied, the inclusion criteria were defined using our predefined PICOT framework: studies on neonates with simple or complicated meconium which were confirmed to have cystic fibrosis and were conservatively managed or surgically treated. Results: A total of 566 publications from the last 10 years were verified by the authors of this review to find the most recent and relevant data, and only 8 met the inclusion criteria. Prenatally diagnosed meconium pseudocysts, bowel dilation, and ascites on ultrasound are predictors of neonatal surgery and risk factor for negative 12-month clinical outcomes in MI-CF newborns. For simple MI, conservative treatment with hypertonic solutions enemas can be effective in more than 25% of cases. If repeated enemas fail to disimpact the bowels, the Bishop–Koop stoma is a safe option. No comprehensive research has been conducted so far to determine the ideal surgical protocol for complicated MI. We only found three studies that reported the types of stomas performed and another study comparing the outcomes of patients depending on the surgical management; the conclusions are contradictory especially since the number of cases analyzed in each study was small. Between 18% and 38% of patients with complicated MI will require reoperation for various complications and the mortality rate varies between 0% and 8%. Conclusion: This study reveals a lack of strong data to support management decisions, unequivocally shows that the care of infants with MI is not standardized, and suggests a great need for international collaborative studies. Full article

Necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP) and meconium-related ileus (MI) requiring surgical intervention are associated with a high risk of severe short- and long-term complications in very-low-birth-weight (VLBW) infants including poor growth, cholestasis and neurodevelopmental impairment. This retrospective study aimed to identify risk factors for such complications in a cohort of 55 VLBW preterm infants requiring surgery with enterostomy creation due to NEC, SIP or MI. Long-term follow-up was available for 43 (78%) infants. Multiple regression analyses revealed that the duration of inflammation and longitudinal growth determined the risk of cholestasis and neurodevelopmental outcome at 2 years corrected age independent of the aetiology of the intestinal complication. Direct bilirubin increased by 4.9 μmol/L (95%CI 0.26–9.5), 1.4 μmol/L (95%CI 0.6–2.2) and 0.8 μmol/L (95%CI 0.22–1.13) with every day of elevated (Interleukin-6) IL-6, (C-reactive protein) CrP and parenteral nutrition. The mental development index at 2 years corrected age decreased by 3.8 (95%CI −7.3–−0.36), 0.4 (95%CI 0.07–0.80) and 0.3 (95%CI 0.08–0.57) with every day of elevated IL-6 and every 1 point decrease in weight percentile at discharge and 2 years. These data stress the importance of optimal timing for the initial surgery in order to prevent prolonged inflammation and an early reversal of the enterostomy in case of poor growth or insufficient enteral nutrition. Full article

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above (“high”) and below (“low”) the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with “high” CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with “low” CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce “high” IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce “low” IRT CFFNs. Full article

The Robert Debre Pediatric Cystic Fibrosis (CF) centre, located in the North East of Paris, a multicultural area, is in charge of a cohort of around a hundred and sixty children diagnosed with CF. Between 2000 and 2019, the proportion of children of African descent in this centre increased from 2% to 10%. We report the clinical features of 17 children of African descent diagnosed with CF: 4 (23%) were diagnosed after a meconium ileus, 14 (83%) had exocrine pancreatic insufficiency, and 7 (41%) had early Pseudomonas aeruginosa infection before the age of two. Even though the majority of patients were diagnosed through NBS, the twenty-nine-mutation testing kit proved less effective in non-Caucasian populations, with a false negative rate of 25% in this series. CF is definitely not solely a Caucasian disease and the literature reveals similar phenotypes in Caucasian and African people provided that they present the same CFTR mutations. Clinicians have to keep in mind that the diagnosis of CF in patients of African descent must be evoked in the case of symptoms and a sweat test must be performed, despite a negative result for NBS. Full article

The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1—patients carrying c.3844T>C and severe class I or II variant in trans; group 2—3849+10kbC>T/F508del patients; group 3—F508del/F508del patients; and group 4—patients with W1282R and “mild” variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype. Full article

Screening metrics are essential to both quality assessment and improvement, but are highly dependent on the way positive tests and cases are counted. In cystic fibrosis (CF) screening, key factors include how mild cases of late-presenting CF and CF screen positive, inconclusive diagnosis (CFSPID) are counted, whether those at prior increased risk of CF are excluded from the screened population, and which aspects of the screening pathway are considered. This paper draws on the New Zealand experience of almost forty years of newborn screening for CF. We demonstrate how different definitions impact the calculation of screening sensitivity. We suggest that, to enable meaningful comparison, CF screening reports should clarify what steps in the screening pathway are included in the assessment, as well as the algorithm used and screening target. Full article

Vitamin A is a fundamental micronutrient that regulates various cellular patterns. Vitamin A deficiency (VAT) is a worldwide problem and the primary cause of nocturnal blindness especially in low income countries. Cystic fibrosis (CF) is a known risk factor of VAD because of liposoluble vitamin malabsorption due to pancreatic insufficiency. We describe a case of a 9-year-old girl who experienced recurrent episodes of nocturnal blindness due to profound VAD. This little girl is paradigmatic for the explanation of the key role of the gut–liver axis in vitamin A metabolism. She presents with meconium ileus at birth, requiring intestinal resection that led to a transient intestinal failure with parenteral nutrition need. In addition, she suffered from cholestatic liver disease due to CF and intestinal failure-associated liver disease. The interaction of pancreatic function, intestinal absorption and liver storage is fundamental for the correct metabolism of vitamin A. Full article

Genistein is a naturally occurring isoflavone found in soy. Genistein has been shown to increase the open probability of the most common cystic fibrosis (CF) disease-associated mutation, ∆F508-CFTR. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis patients. This study tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), homozygous ∆F508 mice were maintained on one of three diet regimens for a period of up to 65 days: normal diet, normal diet plus colyte, or genistein diet. Survival rates for males were as follows: standard diet (38%, n = 21), standard diet plus colyte (83%, n = 42) and genistein diet (60%, n = 15). Survival rates for females were as follows: standard diet (47%, n = 19), standard diet plus colyte (71%, n = 38), and genistein diet (87%, n = 15). Average weight of male mice fed genistein diet increased by ~2.5 g more (p = 0.006) compared to those with colyte treatment. Genistein diet did not change final body weight of females. Expression of intestinal SGLT-1 increased 2-fold (p = 0.0005) with genistein diet in females (no change in males, p = 0.722). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micrometer of crypt depth in female (p = 0.0483), yet was without effect in males (p = 0.7267). The results from this study demonstrate that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice (precluding the requirement for laxatives), and genistein only improves weight gain in males. Full article

Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years) with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests every 6 months and annual liver ultrasonography. The cumulative prevalence of liver disease was 11.2% (7/62 cases). All patients had ΔF508 mutation and pancreatic insufficiency, none had meconium ileus. The liver involvement became clinically evident at a mean age of 8 years (3-15 years), revealed by hepatomegaly or hepatosplenomegaly (3 cases) and/ or abnormalities of liver function tests (3 cases) changes of liver ultrasound (7 cases) with evidence of portal hypertension (2 cases). Four patients were submitted to liver biopsy; biliary fibrosis was documented in one case, focal biliary cirrhosis in 2 cases and multilobular cirrhosis in another case. Within a median 11.6 years follow-up period (all patients under UDCA therapy after liver disease diagnosis), progression of liver disease was observed in 2 patients; one patient developed refractory variceal bleeding and progressive hepatic failure, requiring liver transplant. The results of the present study agree with those of previous pediatric studies, further documenting clinical expression of liver disease in CF patients, which is usually detected in the first decade of life and emphasize the contribution of ultrasound to early diagnosis of liver involvement. Moreover, although advanced liver disease is a relatively rare event, early isolated liver transplantation may have to be considered at this age group. Full article