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Frontiers in Pediatrics 2024Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often...
INTRODUCTION
Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.
METHODS
We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.
RESULTS AND DISCUSSION
In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.
PubMed: 38665380
DOI: 10.3389/fped.2024.1387171 -
American Journal of Human Genetics Oct 2022Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related...
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Genome-Wide Association Study; Humans; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Obstruction
PubMed: 36206743
DOI: 10.1016/j.ajhg.2022.09.004 -
European Journal of Pediatrics Sep 2023Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to...
UNLABELLED
Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to improving outcomes. Enteric nervous system (ENS) immaturity has been proposed as a key factor in NEC pathophysiology. Gastrointestinal dysmotility is associated with ENS immaturity and may serve as a predictive factor for the development of NEC. In this case-control study, preterm infants (gestational age (GA) < 30 weeks) were included in two level-IV neonatal intensive care units. Infants with NEC in the first month of life were 1:3 matched to controls based on GA (± 3 days). Odds ratios for NEC development were analyzed by logistic regression for time to first passage of meconium (TFPM), duration of meconial stool, and mean daily defecation frequency over the 72 h preceding clinical NEC onset (DF < T0). A total of 39 NEC cases and 117 matched controls (median GA 27 + 4 weeks) were included. Median TFPM was comparable in cases and controls (36 h [IQR 13-65] vs. 30 h [IQR 9-66], p = 0.83). In 21% of both cases and controls, TFPM was ≥ 72 h (p = 0.87). Duration of meconial stool and DF < T0 were comparable in the NEC and control group (median 4 and 3, resp. in both groups). Odds of NEC were not significantly associated with TFPM, duration of meconial stools, and DF < T0 (adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.03], 1.16 [0.86-1.55] and 0.97 [0.72-1.31], resp.).
CONCLUSION
In this cohort, no association was found between TFPM, duration of meconium stool, and DF < T0 and the development of NEC.
WHAT IS KNOWN
• Necrotizing enterocolitis (NEC) is a life-threatening acute intestinal inflammatory disease of the young preterm infant. Early clinical risk factors for NEC have been investigated in order to facilitate early diagnosis and treatment. • Signs of disrupted gastrointestinal mobility, such as gastric retention and paralytic ileus, have been established to support the diagnosis of NEC. Nevertheless, defecation patterns have insufficiently been studied in relation to the disease.
WHAT IS NEW
• Defecation patterns in the three days preceding NEC did not differ from gestational age-matched controls of corresponding postnatal age. Additionally, the first passage of meconium and the duration of meconium passage were comparable between cases and controls. Currently, defecation patterns are not useful as early warning signs for NEC. It remains to be elucidated whether these parameters are different based on the location of intestinal necrosis.
PubMed: 37349579
DOI: 10.1007/s00431-023-05035-8 -
HGG Advances Jan 2023Phasing of heterozygous alleles is critical for interpretation of -effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using...
Phasing of heterozygous alleles is critical for interpretation of -effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are pancreas eQTLs (p = 9.5 × 10 and p = 1.4 × 10, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.
Topics: Infant, Newborn; Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Meconium Ileus; Meconium; Intestinal Obstruction; Trypsin; Trypsinogen
PubMed: 36386424
DOI: 10.1016/j.xhgg.2022.100156 -
Genes Mar 2021The 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...
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 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.
Topics: Black People; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; False Negative Reactions; Female; Humans; Infant; Infant, Newborn; Male; Mutation; Neonatal Screening; Paris; Phenotype; Reagent Kits, Diagnostic; Retrospective Studies; Sensitivity and Specificity
PubMed: 33807078
DOI: 10.3390/genes12030458 -
AJP Reports Jan 2022Today, more infants weighing less than or equal to 300 g are born, and they survive because of the improvements in neonatal care and treatment. However, their detailed...
Today, more infants weighing less than or equal to 300 g are born, and they survive because of the improvements in neonatal care and treatment. However, their detailed clinical course and neonatal intensive care unit management remain unknown due to their low survival rate and dearth of reports. A male infant was born at 24 weeks and 5 days of gestation and weighed 258 g. The infant received 72 days of invasive and 92 days of noninvasive respiratory support, including high-frequency oscillatory ventilation with volume guarantee and noninvasive neurally adjusted ventilatory assist. Meconium-related ileus was safely treated using diatrizoate. Although the infant was diagnosed with severe bronchopulmonary dysplasia and retinopathy of prematurity requiring laser photocoagulation, he had no other severe complications. He was discharged 201 days postdelivery (3 months of corrected age) with a weight of 3.396 kg. Although managing infants weighing less than or equal to 300 g is difficult, our experience shows that it is possible by combining traditional and modern management methods. The management of such infants requires an understanding of the expected difficulties and adaptation of existing methods to their management. The management techniques described here should help improve their survival and long-term prognosis.
PubMed: 35154903
DOI: 10.1055/a-1678-3755 -
BMC Pediatrics May 2022This case report describes a child born with both cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1ATD). Both are autosomal recessive inherited diseases,... (Review)
Review
BACKGROUND
This case report describes a child born with both cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1ATD). Both are autosomal recessive inherited diseases, mainly affecting the lungs and the liver. The combination of both diseases together is rare and may lead to a fulminant disease with limited life span. To the best of our knowledge, no case has been reported of a patient born with both diseases.
CASE PRESENTATION
After an uneventful pregnancy, a male baby was born with meconium ileus. The suspected diagnosis of CF was confirmed based on the sweat test and genetic analysis. The child developed persisting cholestasis, too severe to be likely caused by CF alone and indicating an associated problem. The diagnosis of A1ATD was established based on clinical suspicion (persisting cholestasis), decreased serum alpha-1 antitrypsin and genetic analysis. Supportive therapy was started, however the boy evolved to rapidly progressive liver disease leading to liver failure which necessitated an infant liver transplantation.
CONCLUSIONS
This case illustrates the complexity of care in case of two severe inherited diseases as well as post solid organ transplant care.
Topics: Child; Cholestasis; Cystic Fibrosis; Humans; Infant; Liver Transplantation; Male; alpha 1-Antitrypsin Deficiency
PubMed: 35505316
DOI: 10.1186/s12887-022-03290-6 -
Jornal de Pediatria 2020To evaluate the demographics, genotype, and clinical presentation of pediatric patients presenting with distal intestinal obstruction syndrome (DIOS), and factors...
OBJECTIVE
To evaluate the demographics, genotype, and clinical presentation of pediatric patients presenting with distal intestinal obstruction syndrome (DIOS), and factors associated with DIOS recurrence.
METHODS
Case series of ten patients (median age 13.2 years), followed-up in a reference center, retrospectively assessed. Data analyzed included age, gender, cystic fibrosis genotype, meconium ileus at birth, hydration status, pulmonary exacerbation, Pseudomonas aeruginosa colonization, pancreatic insufficiency (PI), body mass index (BMI) at the episodes, clinical manifestations of DIOS, imaging studies performed, acute management of DIOS, maintenance therapy, and recurrence on follow-up.
RESULTS
All patients had two positive sweat chloride tests, and nine of ten also had genotype study. The most common genotype identified was homozygosis for the delta F508 mutation. In seven cases, a previous history of meconium ileus was reported. All patients had pancreatic insufficiency. Diagnosis of DIOS was based on clinical and imaging findings. Of the total number of episodes, 85% were successfully managed with oral osmotic laxatives and/or rectal therapy (glycerin enema or saline irrigation). Recurrence was observed in five of ten patients.
CONCLUSION
In this first report of pediatric DIOS in South America, the presence of two risk factors for DIOS occurrence was universal: pancreatic insufficiency and severe genotype. Medical history of meconium ileus at birth was present in most patients, as well as in the subgroup with DIOS recurrence. The diagnosis relied mainly on the clinical presentation and on abdominal imaging. The practices in the management of episodes varied, likely reflecting changes in the management of this syndrome throughout time.
Topics: Adolescent; Child; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Humans; Intestinal Obstruction; Retrospective Studies; South America
PubMed: 31654616
DOI: 10.1016/j.jped.2019.08.009 -
International Journal of Pediatrics &... Mar 2022Meconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is...
INTRODUCTION
Meconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.
OBJECTIVES
To find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.
METHODOLOGY
Retrospective review of the medical documentations of all MI patients during the period of 1989-2018.
RESULTS
A total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.
CONCLUSION
CF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.
PubMed: 35573065
DOI: 10.1016/j.ijpam.2021.03.008 -
Clinical complications in children with false-negative results in cystic fibrosis newborn screening.Jornal de Pediatria 2022To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS).
OBJECTIVE
To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS).
MATERIALS AND METHODS
All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRT to IRT/DNA/EGA.
RESULTS
The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening.
CONCLUSION
In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.
Topics: Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Humans; Infant, Newborn; Neonatal Screening
PubMed: 34953776
DOI: 10.1016/j.jped.2021.11.007