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BMJ Case Reports Feb 2024Alagille syndrome (AGS) is a genetic disorder due to mutations in the or genes leading to multisystemic manifestations. Though these patients are at risk of developing...
Alagille syndrome (AGS) is a genetic disorder due to mutations in the or genes leading to multisystemic manifestations. Though these patients are at risk of developing various liver tumours, no cases of hepatoblastoma among young children with cirrhosis in AGS have been reported. We report a male toddler, with cirrhosis due to AGS who developed a hepatoblastoma. He underwent a liver transplant for decompensated chronic liver disease with marked pruritus, very high alpha-fetoprotein levels and malignant liver lesions on positron emission tomography CT. His explant histology revealed a paucity of bile ducts and liver lesions turned out to be hepatoblastoma for which he received postoperative chemotherapy. The genetic testing sent before transplantation confirmed the clinical diagnosis of AGS. Hepatoblastoma should be suspected in any child with AGS presenting with a right upper quadrant mass even in the setting of chronic liver disease.
Topics: Humans; Male; Infant; Child, Preschool; Alagille Syndrome; Hepatoblastoma; Tomography, X-Ray Computed; Liver Neoplasms; Liver Cirrhosis
PubMed: 38417945
DOI: 10.1136/bcr-2022-253080 -
Current Pediatric Reviews Feb 2024Cholestatic liver disease is an important cause of morbidity and mortality and a leading indication for liver transplantation in children. These include diseases, such...
BACKGROUND
Cholestatic liver disease is an important cause of morbidity and mortality and a leading indication for liver transplantation in children. These include diseases, such as biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, sclerosing cholangitis, bile acid synthesis defects, and many others.
CASE PRESENTATION
NGS was used as a diagnostic tool to identify the genetic cause in the patient with cholestatic syndrome and to figure out and describe what mutation will be found. In the present observation, the cholestasis syndrome with low GGT activity and intense pruritus was the leading symptom of the patient. The examination also revealed other characteristic features of osteo- oto-hepato-enteric syndrome. The patient had facial features that mimicked Alagille syndrome, which complicated the diagnostic search. Moreover, the genetic test revealed two new pathogenic variants in the UNC45A gene.
CONCLUSION
This clinical observation demonstrates the importance of a multidisciplinary approach in the diagnosis of rare genetic diseases and using WES, which can accelerate the diagnosis compared with outdated gene panels.
PubMed: 38375845
DOI: 10.2174/0115733963264010231213103328 -
Scientific Reports Jan 2024Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic...
Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic expression of ALGS can lead to challenges in accurately diagnosing affected infants, potentially resulting in misdiagnoses or underdiagnoses. This study highlights novel JAG1 gene mutations in two cases of ALGS. The first case with a novel p.Pro325Leufs*87 variant was diagnosed at 2 months of age and exhibited a favorable prognosis and an unexpected manifestation of congenital hypothyroidism. Before the age of 2, the second patient was incorrectly diagnosed with liver structural abnormalities, necessitating extensive treatment. In addition, he exhibited delays in language acquisition that may have been a result of SNAP25 haploinsufficiency. The identification of ALGS remains challenging, highlighting the importance of early detection and genetic testing for effective patient management. The variant p.Pro325Leufs*87 is distinct from reported variants linked to congenital hypothyroidism in ALGS patients, thereby further confirming the clinical and genetic complexity of ALGS. This emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.
Topics: Humans; Infant; Male; Alagille Syndrome; China; Congenital Hypothyroidism; Genetic Testing; Jagged-1 Protein
PubMed: 38245625
DOI: 10.1038/s41598-024-52357-0 -
Experimental and Clinical... Feb 2024Alagille syndrome is an autosomal-dominantinherited disease characterized by intrahepatic bile duct involvement, congenital heart disease, eye anomalies, skeletal and...
Alagille syndrome is an autosomal-dominantinherited disease characterized by intrahepatic bile duct involvement, congenital heart disease, eye anomalies, skeletal and central nervous system involvement, kidney anomalies, and facial appearance. Liver transplant is the only treatment option for patients with end-stage liver disease and Alagille syndrome. Bilateral peripheral pulmonary artery stenosis is a contraindication for liver transplant due to high mortality, and the decision for liver transplant in patients with bilateral peripheral pulmonary artery stenosis is extremely challenging for anesthesiologists andtransplant surgeons.Wepresent a 2-year-oldfemale patient with successful anesthetic management of a pediatric living donor liver transplant with mild bilateral pulmonary artery stenosis, mild aortic stenosis, and mitral regurgitation due to Alagille syndrome. Anesthesiologists should know the underlying pathophysiological condition and perform a comprehensive preoperative evaluation to determine the correct anesthesia plan in patients with Alagille syndrome who will undergo liver transplants to treat multiple system disorders. Successful perioperative management of Alagille syndrome requires effective communication and collaboration between specialists through a multidisciplinary team approach.
Topics: Humans; Child; Child, Preschool; Alagille Syndrome; Stenosis, Pulmonary Artery; Liver Transplantation; Living Donors; Pulmonary Artery; Anesthesia
PubMed: 38511987
DOI: 10.6002/ect.2023.0308 -
Retinal Cases & Brief Reports Mar 2024To report a case of atypical Alagille syndrome with progressive chorioretinal atrophy.
PURPOSE
To report a case of atypical Alagille syndrome with progressive chorioretinal atrophy.
METHODS
Case Report.
RESULTS
A 42-year-old Japanese man presented with atypical Alagille syndrome. At the first visit, funduscopy revealed anterior circumferential chorioretinal atrophy in the peripheral retina and peripapillary region with posterior pole sparing in both eyes. Fundus autofluorescence showed hypoautofluorescence in the peripheral and peripapillary regions, but normal findings in the macular region. After follow-up for 3 years, hypopigmented area with well visualized large choroidal vessels extended to mid-peripheral region. On Fundus autofluorescence images, hypoautofluorescence newly appeared in macular region in both eyes. Perivascular hypoautofluorescence and granular hyperautofluorescence scattering within the posterior pole were also observed. BCVA deteriorated and concentric visual field contraction worsened progressively.
CONCLUSION
Alagille syndrome is known to have many ophthalmic manifestations, most of which are stable with minimal threat to vision. In the present case, chorioretinal atrophy progressed during 3-year follow-up, suggesting that progression of chorioretinal atrophy with vision loss may occur over time in Alagille syndrome.
Topics: Male; Humans; Adult; Alagille Syndrome; Follow-Up Studies; Retina; Retinal Degeneration; Atrophy; Fluorescein Angiography; Retrospective Studies; Choroid Diseases
PubMed: 36730824
DOI: 10.1097/ICB.0000000000001368 -
Stem Cell Research Jun 2024Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in JAG1 or less frequently, mutations in NOTCH2. The disease has been...
Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in JAG1 or less frequently, mutations in NOTCH2. The disease has been difficult to diagnose and treat due to variable expression. The generation of this iPSC line (TRNDi036-A) carrying a heterozygous mutation (p.Cys693*) in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Induced Pluripotent Stem Cells; Heterozygote; Mutation; Cell Line; Male; Female
PubMed: 38703666
DOI: 10.1016/j.scr.2024.103429 -
International Journal of Molecular... Apr 2024The hepatic deletion of Rbpjκ () in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and...
The hepatic deletion of Rbpjκ () in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the mouse by hepatic deletion of in compound mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of and genes involved in bile acid homeostasis was significantly reduced in compared to mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
Topics: Animals; Kelch-Like ECH-Associated Protein 1; Mice; Hypercholesterolemia; Liver; Hepatomegaly; Immunoglobulin J Recombination Signal Sequence-Binding Protein; NF-E2-Related Factor 2; Lipid Metabolism; Gene Deletion; Signal Transduction; Cholesterol; Mice, Knockout; Male; Bile Acids and Salts
PubMed: 38731931
DOI: 10.3390/ijms25094712 -
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 -
Andes Pediatrica : Revista Chilena de... Apr 2024Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal...
UNLABELLED
Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal abnormalities, and distinct facial features. Most cases are due to variants in the JAG1 gene, with only a small percentage involving a complete gene deletion.
OBJECTIVE
to contribute to the phenotype delineation and interpretation of a microdeletion not previously described in the literature on chromosome 20.
CLINICAL CASE
A 4-month-old female patient was diagnosed with a heart murmur. An echocardiogram revealed pulmonary artery stenosis, which, combined with a prominent forehead observed on physical examination, determined her referral to clinical genetics. Because ALGS was suspected, complementary studies were performed, revealing butterfly vertebras and a genetic panel identified a pathogenic heterozygous deletion, encompassing the entire coding sequence of the JAG1 gene. To rule out a more extensive deletion, a chromosome microarray was performed, confirming a pathogenic microdeletion on chromosome 20 of 378 kb (arr[GRCh37] 20p12.2(10414643_10792802)x1).
CONCLUSIONS
A targeted sequencing panel followed by confirmation with a chromosome microarray allowed the identification and delineation of a pathogenic microdeletion not previously reported in the literature, including the complete JAG1 gene in a Chilean patient whose phenotype is consistent with ALGS.
Topics: Humans; Alagille Syndrome; Jagged-1 Protein; Female; Gene Deletion; Infant; Phenotype
PubMed: 38801368
DOI: 10.32641/andespediatr.v95i2.4820 -
Stem Cell Research Oct 2023Alagille syndrome (ALGS) is a multisystem disease with high variability in clinical features. ALGS is predominantly caused by pathogenic variants in the Notch ligand...
Alagille syndrome (ALGS) is a multisystem disease with high variability in clinical features. ALGS is predominantly caused by pathogenic variants in the Notch ligand JAG1. An iPSC line, NCHi011-A, was generated from a ALGS patient with complex cardiac phenotypes consisting of pulmonic valve and branch pulmonary artery stenosis. NCHi011-A is heterozygous for a single base duplication causing a frameshift in the JAG1 gene. This iPSC line demonstrates normal cellular morphology, expression of pluripotency markers, trilineage differentiation potential, and identity to the source patient. NCHi011-A provides a resource for modeling ALGS and investigating the role of Notch signaling in the disease.
Topics: Female; Humans; Young Adult; Adult; Alagille Syndrome; Induced Pluripotent Stem Cells; Jagged-1 Protein; Heart; Cell Differentiation
PubMed: 37774637
DOI: 10.1016/j.scr.2023.103213