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Pediatric Pulmonology Feb 2024Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple organ systems, including the liver, leading to CF-related liver disease (CFLD). It was noted...
BACKGROUND
Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple organ systems, including the liver, leading to CF-related liver disease (CFLD). It was noted that CFLD in Egyptian children with CF is more common than in non-Egyptian people with CF (pwCF). This study aimed to determine the incidence of CFLD and the potential risk factors for developing CFLD in Egyptian children. The correlation between CFLD and the various genotypes prevalent in Egyptian CF children will be discussed. In addition, comparison of CFLD in Egyptian and non-Egyptian CF patients will be presented.
METHODS
This cross-sectional study included 50 pwCF from Ain Sham University's Pediatric Pulmonology Clinic in Children's Hospital, Cairo, Egypt. The sweat chloride test and genetic studies were done at the time of diagnosis. Additionally, all subjects underwent detailed history taking, laboratory investigations, clinical assessment, and pelvic abdominal ultrasound for evaluation of hepatic involvement.
RESULTS
One-third of the Egyptian children with CF were found to have liver disease. The following independent risk factors for developing CFLD were identified as: male sex, severe genetic mutation (class I and II), long duration of CF disease, early onset of the CF, pancreatic insufficiency, as well as history of meconium ileus. In addition, diabetes mellitus and severe lung disease were proven to significantly increase the risk of developing CFLD.
CONCLUSION
CFLD is common in Egyptian pwCF. CFLD's risk factors are similar to other reported research from other countries in the region.
Topics: Child; Humans; Male; Cystic Fibrosis; Egypt; Cross-Sectional Studies; Liver Diseases; Risk Factors; Liver Cirrhosis
PubMed: 38038166
DOI: 10.1002/ppul.26775 -
The Journal of Biological Chemistry Jan 2024Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory...
Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory bowel disease that continues into adulthood. Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans.
Topics: Animals; Child; Humans; Mice; Diarrhea; Enterotoxins; Guanylate Cyclase; Ligands; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Gastrointestinal Diseases
PubMed: 38029963
DOI: 10.1016/j.jbc.2023.105505 -
RSC Medicinal Chemistry Nov 2023A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus,...
A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine). SLC26A6 (putative anion transporter 1, PAT1) is a Cl/HCO exchanger at the luminal membrane of small intestinal epithelial cells which facilitates Cl and fluid absorption. We recently identified first-in-class PAT1 inhibitors by high-throughput screening. Isoxazolopyrimidine PAT1-A01 was a hit compound, which had low potency (IC 5.2 μM) for SLC26A6 inhibition precluding further preclinical development. Here we performed structure-activity relationship studies to optimize isoxazolopyrimidine SLC26A6 inhibitors and tested a potent inhibitor in mouse models of intestinal fluid absorption. Structure-activity studies of 377 isoxazolopyrimidine analogs identified PAT1-A0030 (ethyl 4-(benzyl(methyl)amino)-3-methylisoxazolo[5,4-]pyrimidine-6-carboxylate) as the most potent SLC26A6 inhibitor with a 1.0 μM IC. Selectivity studies showed that PAT1-A030 has no activity on relevant ion transporters/channels (SLC26A3, SLC26A4, SLC26A9, CFTR, TMEM16A). In a closed-loop model of intestinal fluid absorption, intraluminal PAT1-A0030 treatment inhibited fluid absorption in the ileum of wild-type and CF mice () with >90% prevention of a decrease in loop fluid volume and loop weight/length ratio at 30 minutes. These results suggest that SLC26A6 is the key transporter mediating Cl and fluid absorption in the ileum and SLC26A6 inhibitors are novel drug candidates for treatment of CF-associated small intestinal disorders.
PubMed: 37974969
DOI: 10.1039/d3md00302g -
Archives of Disease in Childhood Mar 2024The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children's...
BACKGROUND
The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children's Hospital at Royal Stoke and Birmingham Children's Hospital). CF newborn bloodspot screening (NBS) in this region started in November 2006 prior to the UK national roll-out in 2007. It uses an immunoreactive trypsinogen (IRT)/DNA/IRT protocol. We report the outcomes from 15 years of CF screening.
METHODS
The West Midlands CF NBS outcomes from 1 November 2006 to 31 October 2021 were reviewed. Clinical data were also obtained for babies referred to the CF centres as 'CF suspected'.
RESULTS
1 075 161 babies were screened, with 402 referred as 'CF suspected' and 205 identified as CF carriers. Of the 'CF suspected' babies, 268 were diagnosed with CF, 33 with CF screen positive, inconclusive diagnosis (CFSPID) and 17 as a CF carrier. Any CF-related diagnosis was excluded in 67. Outcome data were not available for 17, of whom 14 had died. Eighteen children with a negative CF NBS have subsequently been diagnosed with CF, 10 had meconium ileus and 8 were true 'affected not detected', presenting with respiratory symptoms or failure to thrive. This gives the West Midlands a CF birth prevalence of 1 in 4012 live births and the NBS protocol a sensitivity of 97.1% and a positive predictive value of 66.7%.
CONCLUSIONS
This large regional data set has excellent case ascertainment and demonstrates successful performance of the CF NBS protocol, with low numbers identified as CFSPID or CF carriers.
Topics: Infant; Infant, Newborn; Humans; Child; Cystic Fibrosis; Neonatal Screening; Genetic Testing; Cystic Fibrosis Transmembrane Conductance Regulator; Trypsinogen; United Kingdom
PubMed: 37973197
DOI: 10.1136/archdischild-2023-325955 -
World Journal of Gastroenterology Sep 2023Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious... (Review)
Review
Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.
Topics: Animals; Cattle; Female; Infant; Pregnancy; Humans; Milk Hypersensitivity; Constipation; Biopsy; Diarrhea; Hirschsprung Disease
PubMed: 37731998
DOI: 10.3748/wjg.v29.i33.4920 -
Balkan Journal of Medical Genetics :... Jul 2023Pre-implantation genetic diagnosis (PGD) is not often performed when donor gametes are used, due to its high cost. This is with the presumption that the donors are...
Pre-implantation genetic diagnosis (PGD) is not often performed when donor gametes are used, due to its high cost. This is with the presumption that the donors are healthy. We report on five cases of babies with confirmed cystic fibrosis (CF), being the result from in vitro fertilization (IVF) with donor (4 cases) or own gametes (one case). There has been no family history for CF in any of the families affected. The clinical presentation in the children ranged from meconium ileus to recurrent respiratory infections and severe nasal polyposis. The age of diagnosis also varied from birth until 9 years. Since one of the presented cases was discovered in a very renowned private IVF clinic, the clinic changed their own protocol, and currently they test every donor for CF carriership. The percentage of CF carriers in the donor population is roughly the same as the one predicted in the general population of Bulgaria - 1/33. Although PGD is costly, the costs for proper care for a CF patient are currently much higher. The more economical option would to screen every donor for CF carriership. IVF requires a lot of physical and psychological stamina. The couples that go through this procedure also require a great deal of hope. It is essential to be more preconscious for possible congenital diseases. We advocate every IVF center to test the donors for CF carriership or to provide PGD for their clients.
PubMed: 37576787
DOI: 10.2478/bjmg-2023-0001 -
ERJ Open Research May 2023To examine the trajectory of forced expiratory volume in 1 s (FEV) using data from the European Cystic Fibrosis Society patient registry (ECFPR) collected from 2008 to...
AIM
To examine the trajectory of forced expiratory volume in 1 s (FEV) using data from the European Cystic Fibrosis Society patient registry (ECFPR) collected from 2008 to 2016, the era before highly effective modulator therapy (HEMT). We evaluated risk factors for FEV decline.
METHODS
The study population included patients with a confirmed diagnosis of cystic fibrosis recorded in the ECFPR (2008-2016). The evolution of FEV % predicted (%FEV) with age, and the yearly change in %FEV were evaluated. Risk factors considered were cystic fibrosis transmembrane conductance regulator () mutation class, gender, age at diagnosis, neonatal screening, meconium ileus, sweat chloride concentration at diagnosis and country's income level.
RESULTS
We used 199 604 FEV recordings from 38 734 patients. The fastest decline was seen during puberty and in patients diagnosed before the age of 10 years. Males had a higher %FEV, but a higher yearly %FEV loss between the ages of 15 and 25 years. We showed stabilisation and even improvement in %FEV over age in adults with a class III mutation, but a steady decline in patients homozygous for F508del or with both mutations of classes I/II. A faster decline in %FEV was found in patients from low-income countries compared to a similar %FEV evolution in patients from middle- and high-income countries.
CONCLUSIONS
These longitudinal FEV data reflect the reality of cystic fibrosis across Europe in the era pre-HEMT, and can serve as baseline for comparison with the post-HEMT era. The similar evolution in middle- and high-income countries underlines opportunities for low-income countries.
PubMed: 37483280
DOI: 10.1183/23120541.00449-2022 -
Radiographics : a Review Publication of... Aug 2023Radiologic evaluation of neonatal bowel obstruction is challenging owing to the overlapping clinical features and imaging appearances of the most common differential...
Radiologic evaluation of neonatal bowel obstruction is challenging owing to the overlapping clinical features and imaging appearances of the most common differential diagnoses. The key to providing an appropriate differential diagnosis comes from a combination of the patient's gestational age, clinical features, and imaging findings. While assessment of radiographs can confirm bowel obstruction and indicate whether it is likely proximal or distal, additional findings at upper or lower gastrointestinal contrast study together with use of US are important in providing an appropriate differential diagnosis. The authors provide an in-depth assessment of the appearances of the most common differential diagnoses of proximal and distal neonatal bowel obstruction at abdominal radiography and upper and lower gastrointestinal contrast studies. These are divided into imaging patterns and their associated differential diagnoses on the basis of abdominal radiographic findings. These findings include esophageal atresia variants including the "single bubble," "double bubble," and "triple bubble" and distal bowel obstruction involving the small and large bowel. Entities discussed include esophageal atresia, hypertrophic pyloric stenosis, pyloric atresia, duodenal atresia, duodenal web, malrotation with midgut volvulus, jejunal atresia, ileal atresia, meconium ileus, segmental volvulus, internal hernia, colonic atresia, Hirschsprung disease, and functional immaturity of the large bowel. The authors include the advantages of abdominal US in this algorithm, particularly for hypertrophic pyloric stenosis, duodenal web, malrotation with midgut volvulus, and segmental volvulus. RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.
Topics: Infant, Newborn; Humans; Intestinal Volvulus; Esophageal Atresia; Pyloric Stenosis, Hypertrophic; Intestinal Obstruction; Duodenal Obstruction; Digestive System Abnormalities; Radiography, Abdominal; Duodenal Diseases
PubMed: 37471246
DOI: 10.1148/rg.230035 -
Journal of Cystic Fibrosis : Official... Nov 2023Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR)... (Review)
Review
Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.
Topics: Infant, Newborn; Child; Infant; Female; Pregnancy; Humans; Child, Preschool; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis; Meconium Ileus; Mutation; Phenotype; Ileus; Meconium
PubMed: 37423798
DOI: 10.1016/j.jcf.2023.02.002