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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 -
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 -
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 -
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 -
Journal of Pediatric Surgery Dec 2021Intra hospital transfer of sick newborns is known to cause adverse events with potential morbidity. Interventions at the bedside in a sick neonate can reduce the need...
BACKGROUND/PURPOSE
Intra hospital transfer of sick newborns is known to cause adverse events with potential morbidity. Interventions at the bedside in a sick neonate can reduce the need for transport and in turn, potential hazards of transfer. Our single institute experience of performing bedside laparotomies in unstable newborns is reported here.
MATERIALS AND METHODS
Seven-year data was collected from electronic medical records. This was a retrospective comparative study with level III evidence. Twenty-eight neonates operated at bedside for intraabdominal sepsis due to Necrotising Enterocolitis (NEC), Spontaneous Intestinal Perforation (SIP), complicated meconium ileus and perforation secondary to atresias were included Group A. Group B had 60 neonates operated for similar indications in the conventional operation theatres.
RESULTS
The average corrected gestational age at surgery, associated co-morbidities, average volume of blood loss and duration of surgery were compared between the groups. Group A had lower weight at surgery (1098 vs 1872 gs), greater percentage of neonates on inotropic support (78% vs 20%) with requirement of High Frequency Ventilation (HFO) (50% vs none). A quarter of neonates (7 of 28) in Group A had NEC Totalis as against only one case in group B. There was 25% survival in group A and 76.67% in group B. The lower survival in group A can be attributed to lower weight at surgery, higher inotrope requirement and need for unconventional modes of ventilation.
CONCLUSION
Bedside laparotomy is a feasible option in unstable neonates deemed unsuitable for transport.
Topics: Enterocolitis, Necrotizing; Humans; Infant, Newborn; Intestinal Perforation; Laparotomy; Meconium Ileus; Retrospective Studies
PubMed: 33334555
DOI: 10.1016/j.jpedsurg.2020.11.029 -
Pediatric Pulmonology Nov 2020To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the...
OBJECTIVES
To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the rates of misdiagnosis and missed diagnoses in China.
METHODS
The EMBASE, Cochrane Library, PubMed and SinoMed databases were searched for studies involving Chinese CF patients from January 1975 to August 2019.
RESULTS
In total, 113 Chinese patients, including 53 males and 60 females, were reported. Nineteen patients had a family history of CF. The median age at diagnosis was 8.7 years. Among Chinese CF patients, 70.8% had bronchiectasis, 9.7% had a hemoptysis history, 33.6% had clubbed fingers, 17.7% had allergic bronchopulmonary aspergillosis, and 29.2% had chronic diarrhea; the incidence of malnutrition was 52.2%. Five patients had jaundice, 26 patients had hepatomegaly, and 9 patients had meconium ileus in the neonatal period, and the incidence of liver cirrhosis was 5.3%. The predominant organism in airways was Pseudomonas aeruginosa, followed by Staphylococcus aureus. Seventy-nine patients underwent the sweat test, and all of them were positive, with an average chloride ion level of 122.2 mmol/L. Eighty-eight Chinese CF patients underwent genetic testing, and 74 CF transmembrane conductance regulator (CFTR) gene mutations were reported. The most common gene mutation was c.2909G→A. One Phe508del gene mutation was observed.
CONCLUSION
The common clinical manifestations and CFTR gene mutations in Chinese CF patients are different from those in Caucasian patients. The age at CF diagnosis in China is relatively old, suggesting that the CF incidence in China may be seriously underestimated.
Topics: Asian People; Bacterial Infections; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans
PubMed: 32716133
DOI: 10.1002/ppul.24980 -
Zhonghua Jie He He Hu Xi Za Zhi =... Apr 2023Cystic fibrosis (CF) is one of the most common autosomal recessive genetic diseases in Caucasians, but CF patients in China are rare, and it was listed as the first...
Cystic fibrosis (CF) is one of the most common autosomal recessive genetic diseases in Caucasians, but CF patients in China are rare, and it was listed as the first batch of rare diseases in China in 2018. In recent years, CF has been gradually recognized in China, and the number of CF patients reported in China in the past 10 years is more than 2.5 times the total number in the previous 30 years, and the total number of CF patients is estimated to be more than 20 000. The research progress of CF gene modification has led to the innovation of CF treatment. However, the sweat test as an important test for the diagnosis of CF has not been widely implemented in China. At present, the diagnosis and treatment of CF in China still lacks standardized recommendations. In view of these updates, the Chinese Experts Cystic Fibrosis Consensus Committee has formed "the Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis" based on extensive opinion gathering, literatures review, multiple meetings and discussions. This consensus collects 38 core issues related to CF, including pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and patient management. Finally, 32 recommendations were formulated. The consensus used the modified GRADE methodology to grade the evidence evaluation and recommendations. This is the current state of CF consensus in China, and we hope to improve the diagnosis and treatment of CF in China in the future.CF should be suspected if there is: (1) a family history of CF; (2) delayed meconium expulsion or meconium ileus; (3) pancreatic exocrine insufficiency, mainly characterized by long-standing steatorrhea and malnutrition; (4) recurrent lower respiratory tract infections of infantile onset, especially infections of respiratory aetiology; (5) chronic sinusitis, especially when combined with juvenile presentation of nasal polyps; (6) chest CT abnormalities such as the presence of air trapping, bronchiectasis (upper lobe predominant); (7) pseudo-Bartter syndrome; (8) absence of vas deferens in males; (9) clubbing in young bronchiectasis patients(1C).1.1 Presence of one or more of the characteristic clinical manifestations or family history consistent with CF, and meeting at least one of the following definite diagnostic criteria in 1.2 or 1.3.1.2 Sweat chloride testing:(1) Concentrations of more than 60 mmol/L are diagnostic; (2) concentrations between 30-59 mmol/L are intermediate, and genetic variation must be considered to confirm the diagnosis; (3) concentrations less than 30 mmol/L are considered normal.1.3 Genetic testing:(1) Detection of two disease-causing (cystic fibrosis transmembrane conductance regulator) mutations on biallelic alleles; (2) The variants are of undetermined significance, but tests such as sweat chloride concentration, intestinal current measurement, or nasal mucosal potential difference suggest abnormal CFTR function, then CF is diagnostic(1C).Sweat chloride testing and gene analysis are recommended in all patients suspected of CF(1D).Sweat chloride testing is the gold standard for the clinical diagnosis of CF(1C).Biallelic pathogenic variants of are a definitive diagnosis of CF(1D).Chest CT is a sensitive test for early stages of lung disease in patients with CF and is appropriate in younger patients and to assess disease progression. The imaging findings of abdominal visceral involvement in CF lack specificity(2C).Fecal elastase may be used as the first indicator to assess pancreatic exocrine function in patients with CF (2C).CF related liver disease was diagnosed when CF was confirmed and 2 of the following 4 criteria were met: (1) hepatomegaly and/or splenomegaly confirmed by ultrasound; (2) ALT, AST, and GGT on three consecutive occasions above the upper limit of normal on three consecutive occasions for more than 12 months and excluding other causes; (3) had evidence of liver involvement, portal hypertension, or bile duct dilatation by ultrasound; (4) liver biopsy confirmation (focal biliary cirrhosis or multilobular cirrhosis) may be indicated if the diagnosis is suspected(2D).Pulmonary exacerbations are indicated when any 4 of the following 12 signs or symptoms are met: increased sputum; new onset haemoptysis or increased haemoptysis; exacerbation of cough; increased dyspnea; malaise, fatigue, or somnolence; body temperature above 38 ℃; anorexia or weight loss; sinus pain or tenderness; increased sinus secretions; new chest signs; FEV≥10% decline from previous; imaging changes suggestive of pulmonary infection(2D).Diagnostic criteria for CF related diabetes are the same as those for diabetes in the population(1D).Anthropometric parameters reflecting nutritional status should be assessed regularly. And the goal of nutritional assessment is to evaluate and monitor whether pediatric patients are achieving normal standards of growth and development or whether adult patients are maintaining adequate nutritional status(1C).Pathohistological biopsy is not recommended as a first-line diagnostic method in patients with a suspected diagnosis of CF(1D).At least 6 months of azithromycin treatment is recommended for CF patients with chronic PA infection(2A).Long term treatment with hypertonic saline is recommended for patients with CF(1A).Long term use of DNase is recommended in patients with CF aged 6 years and older(1A).Inhaled mannitol therapy is recommended for more than 6 months in patients with CF aged 18 years and older when other inhaled treatments are unavailable or intolerable(2A).When sputum cultures from patients with CF are positive for , it needs to determine the characteristics of the infection first. The purpose for acute infection is to eradicate . Chronic colonization does not need to be eradicated, and the main purpose is to reduce the bacterial load and improve symptoms(1A).Inhaled antibiotic therapy is recommended for CF patients with infection(1A).In patients with CF without asthma or ABPA, routine inhaled or systemic glucocorticoids are not recommended (2A).Bronchodilators can be used in the short term to improve symptoms in patients with CF in the presence of airway obstruction, but the long-term benefit is insufficient (2B).Patients with CF can take acetylcysteine orally or aerosolized(2A).Intensive implementation of non-antimicrobial therapy is recommended during pulmonary exacerbations in patients with CF. Antimicrobials with activity against PA were selected for empirical treatment, and the treatment was adjusted according to the results of bacterial culture and drug susceptibility testing. A 21-day long course of anti-infective therapy is not recommended(1B).Medical therapy is recommended for CF patients with ABPA who meet any of the following criteria: patients with elevated immunoglobulin E levels and concomitant worsening of pulmonary function and/or pulmonary symptoms, or imaging suggesting new infiltrative foci in the chest(1D).Glucocorticoids are recommended for ABPA exacerbations in CF patients without contraindications(2D).Itraconazole should be added if the patient presents with poor response to corticosteroids, recurrence of ABPA, corticosteroid dependence, or corticosteroid toxicity(2D).Patients with CF may be evaluated for lung transplantation when they meet the following criteria after optimal medical therapy: (1) FEV<30% predicted; (2) FEV<40% predicted (<50% predicted in children) with the following: 6-minute walk distance<400 meters; PaCO>50 mmHg(1 mmHg=0.133 kPa); hypoxia at rest or after activity; pulmonary artery pressure measured by cardiotocography>50 mmHg or right heart dysfunction; continued deterioration despite aggressive supplementation of nutritional support; two exacerbations requiring intravenous antibiotic therapy per year; massive hemoptysis (>240 ml) requiring pulmonary artery embolization; presented with pneumothorax; (3) FEV<50% predicted and rapid decline in lung function or rapid worsening of symptoms; (4) Presented with an acute exacerbation requiring positive pressure mechanical ventilation(2C).Pancreatic enzyme replacement therapy is recommended in patients with CF pancreatic disease(1A).Ursodeoxycholic acid is not recommended in asymptomatic patients with CF hepatobiliary disease(2B).Acid suppression is recommended for CF patients with gastrointestinal symptoms such as acid regurgitation (2B).Insulin therapy is recommended in CF related diabetes(1B).Energy intake in patients with CF is recommended to be 110%-200% of the energy requirement of a healthy person under equivalent physiological conditions. And maintaining adequate protein, appropriate intake of fats, electrolytes, and fat-soluble vitamins are recommanded(1A).Airway clearance therapy and appropriate exercise are recommended for patients with CF(1A).Patients with CF should have regular follow-up. Adult patients are recommended to be followed every 3-6 months, and children should be followed more frequently(2A).Inpatients and outpatients are recommended to be separated according to microbiota carriage status(1D).Good hand hygiene is recommended for the patients with CF and their contacts(1D).It is recommended that CF patients wear masks in healthcare settings. This may reduce the release of potentially infectious aerosols during coughing (1D).Annual influenza vaccination is recommended for patients with CF>6 months of age and for all family members of patients with CF and all healthcare workers caring for these patients(2D).Palivizumab may be considered for the prevention of respiratory syncytial virus infection in patients with CF under two years of age(2A).
Topics: Adult; Child; Child, Preschool; Humans; Male; Adrenal Cortex Hormones; Anti-Bacterial Agents; Bronchiectasis; Bronchodilator Agents; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Deoxyribonucleases; Hemoptysis; Mannitol
PubMed: 36990700
DOI: 10.3760/cma.j.cn112147-20221214-00971 -
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 -
Archives of Disease in Childhood. Fetal... Mar 2023Newborn screening (NBS) for cystic fibrosis (CF) was introduced in Switzerland in 2011 based on an immunoreactive trypsinogen (IRT)-DNA-IRT protocol. CF diagnosis was...
OBJECTIVE
Newborn screening (NBS) for cystic fibrosis (CF) was introduced in Switzerland in 2011 based on an immunoreactive trypsinogen (IRT)-DNA-IRT protocol. CF diagnosis was confirmed by sweat test and/or genetics but remained inconclusive for some newborns (cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID)). We aimed to (1) Describe IRT levels in healthy newborns in the first year of life and by gestational age (GA), and (2) Compare IRT at two time points between healthy newborns and newborns with CF and CRMS/CFSPID.
DESIGN
Retrospective study.
SETTING
National NBS database.
PATIENTS
All children with an IRT measurement by heel prick test from 2011 to 2019.
INTERVENTIONS
None.
MAIN OUTCOME MEASURES
IRT values were extracted from the National NBS Laboratory, and clinical characteristics of positively screened children from the CF-NBS database. Second IRT assessment in positively screened children was usually performed after 18-24 days. We calculated internal IRT Z-Scores and multiples of the median to compare our results across different laboratory tools.
RESULTS
Among 815 899 children; 232 were diagnosed with CF, of whom 36 had meconium ileus (MI); 27 had CRMS/CFSPID. Among all samples analysed, mean IRT Z-Scores were higher for newborns with GA <33 weeks and ≥43 weeks (all Z-Scores >0.11) compared with term babies (all Z-Scores ≤0.06). Repeated IRT Z-Scores after a median (IQR) of 19 (17-22) days remained high for infants with CF with or without MI but decreased for infants with CRMS/CFSPID.
CONCLUSIONS
Measurement of a second IRT value can help distinguish between children with CRMS/CFSPID and CF, early in life.
Topics: Child; Humans; Infant; Infant, Newborn; Cystic Fibrosis; Trypsinogen; Cystic Fibrosis Transmembrane Conductance Regulator; Retrospective Studies; Neonatal Screening; Metabolic Syndrome
PubMed: 36351789
DOI: 10.1136/archdischild-2021-323549 -
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