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Gastroenterology Nursing : the Official...Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located...
Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located on the short arm of chromosome 20. This case is reported as per the CA se RE ports (CARE) guidelines (2013). A 14-year-old boy who is a known case of chronic cholestatic liver disease of neonatal onset, was diagnosed with Alagille syndrome as evident from a NOTCH 2 mutation in genetic analysis and paucity of intrahepatic bile ducts on biopsy. He presented with portal hypertension, growth failure, and persistent hyperbilirubinemia. This case highlights the gamut of multisystem dysfunctions faced by this child. He is currently on conservative management and worked up for liver transplantation. The condition is often rare and challenging due to the multisystem pathogenesis. Thus, the nursing care is also multifaceted. This case study identified relevant North American Nursing Diagnosis Association (NANDA) Classification, Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) concepts to describe care of children with Alagille syndrome based on actual patient data.
Topics: Male; Child; Infant, Newborn; Humans; Adolescent; Alagille Syndrome; Standardized Nursing Terminology; Nursing Diagnosis; Patient Care
PubMed: 37581873
DOI: 10.1097/SGA.0000000000000755 -
Hepatology Communications Sep 2023We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of...
BACKGROUND
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.
METHODS
We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.
RESULTS
DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.
CONCLUSIONS
YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
Topics: Animals; Male; Mice; Adaptor Proteins, Signal Transducing; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cholestasis; Endoderm; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Trans-Activators; Transcription Factors; YAP-Signaling Proteins; Female
PubMed: 37556373
DOI: 10.1097/HC9.0000000000000220 -
Stem Cell Research Sep 2023Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with...
Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with pathogenic variants in JAG1, encoding the Jagged1 ligand that binds to Notch receptors. The iPSC line NCHi012-A was derived from an ALGS patient with cholestatic liver disease and mild pulmonary stenosis, who is heterozygous for a 2 bp deletion in the JAG1 coding sequence. We report here an initial characterization of NCHi012-A to evaluate its morphology, pluripotency, differentiation potential, genotype, karyotype and identity to the source patient.
Topics: Humans; Alagille Syndrome; Induced Pluripotent Stem Cells; Receptors, Notch; Heart; Jagged-1 Protein
PubMed: 37549562
DOI: 10.1016/j.scr.2023.103177 -
International Journal of Molecular... Jul 2023Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton,...
Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the or gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the and genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the gene-eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.
Topics: Humans; Alagille Syndrome; Cholestasis; Mutation; Mutation, Missense; Phenotype; Jagged-1 Protein
PubMed: 37511516
DOI: 10.3390/ijms241411758 -
Pediatric Nephrology (Berlin, Germany) Oct 2023
Topics: Child; Humans; Liver Diseases; Renal Insufficiency, Chronic
PubMed: 37405491
DOI: 10.1007/s00467-023-05949-3 -
Archives de Pediatrie : Organe Officiel... Aug 2023Multiple causes of congenital neonatal cholestasis have been identified, and are classified as extrahepatic or intrahepatic. Biliary atresia (BA), Alagille syndrome...
Multiple causes of congenital neonatal cholestasis have been identified, and are classified as extrahepatic or intrahepatic. Biliary atresia (BA), Alagille syndrome (AGS), and progressive familial intrahepatic cholestasis (PFIC) are the most common of these. Many factors associated with cholestatic diseases are known to degrade the oral health of these children. What are the oral manifestations associated with these diseases in the pediatric population? The aim of this article was to evaluate the impact of congenital cholestasis on oral health in pediatric patients. A systematic review of case reports and case series was carried out in PubMed, the Cochrane Library, and the Web of Science to identify relevant articles in French and English published up to April 2022. The review included 19 studies, 16 case reports, and three case series. Only studies dealing with BA and AGS were found. These studies showed an impact on jaw morphology, dental structure, and periodontal health. The facial dysmorphism observed in AGS was specific. Exposure to high levels of bilirubin during the period of dental calcification led to particular coloration. Regarding periodontal status, gingival inflammation was common in these patients, probably resulting from the use of certain treatment-associated drugs and poor oral hygiene. Cohort studies are needed to confirm the classification of these children as being at high individual risk of caries. Many major oral manifestations are found in children with AGS and BA, confirming the need to include a dentist in the care team of patients with congenital cholestatic disease as early as possible. It appears necessary to carry out individual prospective studies of each phenotype in order to confirm and better describe the oral impact of these cholestatic diseases and provide adequate medical care.
Topics: Child; Humans; Infant, Newborn; Biliary Atresia; Prospective Studies; Cholestasis; Cholestasis, Intrahepatic; Alagille Syndrome
PubMed: 37394364
DOI: 10.1016/j.arcped.2023.06.003 -
Lancet (London, England) Aug 2023
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Peptides
PubMed: 37369233
DOI: 10.1016/S0140-6736(23)01201-1 -
Hepatology (Baltimore, Md.) Dec 2023Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated...
BACKGROUND AND AIMS
Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.
APPROACH AND RESULTS
We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival.
CONCLUSIONS
Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.
Topics: Humans; Alagille Syndrome; Progression-Free Survival; Retrospective Studies; Bilirubin; Pruritus; Bile Acids and Salts
PubMed: 37278241
DOI: 10.1097/HEP.0000000000000502 -
Stem Cell Research Aug 2023Pathogenic variants in Jagged-1 (JAG1), which encodes the ligand of the Notch receptor, had been demonstrated to cause Alagille syndrome. However, there is no evidence...
Pathogenic variants in Jagged-1 (JAG1), which encodes the ligand of the Notch receptor, had been demonstrated to cause Alagille syndrome. However, there is no evidence to support any genotype-phenotype correlations. Here, we generated a gene-edited human embryonic stem cell (hESC) line (H9) carrying the c.1615C > T mutation in JAG1 that was identified in a patient with Alagille syndrome (ALGS). This modified cell line was accomplished by using cytosine base editor (CBE), and may serve as a valuable model for JAG1 mutaion related disease, and facilitate to gain more insight into the biological function of JAG1.
Topics: Humans; Alagille Syndrome; Human Embryonic Stem Cells; Jagged-1 Protein; Phenotype; Mutation; Cell Line
PubMed: 37245339
DOI: 10.1016/j.scr.2023.103120