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Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1−/− mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1−/− mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1−/− mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS. Synopsis: Despite severe cholestatic liver disease due to bile duct paucity, intrahepatic fibrosis in Alagille syndrome (ALGS) differs from other cholestatic liver diseases. The way cell populations are affected by ALGS and interact to influence disease progression was investigated in an ALGS mouse model. Intrahepatic ALGS-like pericellular fibrosis is recapitulated by Jag1Ndr/Ndr mice. Single-cell transcriptomics and flow cytometry identified dysregulation of maturing hepatocytes and T cells during fibrosis onset and propagation. Jag1Ndr/Ndr and ALGS hepatocytes express a hepatoblast-like signature, suggesting disrupted hepatocyte maturation and compromised activation. Regulatory T cells are enriched in Jag1Ndr/Ndr mice and can limit periportal fibrosis, as demonstrated by Jag1Ndr/Ndr cell transplantations into immunodeficient mice followed by surgically induced cholestasis Despite severe cholestatic liver disease due to bile duct paucity, intrahepatic fibrosis in Alagille syndrome (ALGS) differs from other cholestatic liver diseases. The way cell populations are affected by ALGS and interact to influence disease progression was investigated in an ALGS mouse model. [ABSTRACT FROM AUTHOR]

Purpose: To explore patterns of disease expression in Alagille syndrome (ALGS). Methods: Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry. Results: The proband (P1) had a heterozygous pathogenic variant in JAG1; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina. Conclusion: Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes. [ABSTRACT FROM AUTHOR]

Abstract Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1 Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1 Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1 Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1 −/− mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1 Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1 +/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1 −/− mice with Jag1 Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1 −/− mice with Jag1 +/+ lymphocytes. Finally, the Jag1 Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients’ liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

Alagille syndrome is an autosomal dominant and multisystemic disease that generally manifests itself with intrahepatic bile ducts paucity, chronic cholestasis, xanthomas and with other less frequent clinical manifestations such as congenital heart disease, skeletal abnomalies, ophthalmic, vascular, renal and growth failure. Symptoms can be subclinical or very severe. Is caused by various genetic mutations and the majority of patients have a detectable mutation in JAG1 (90%), the remainder have mutations in NOTCH2. The diagnosis is molecular and the incidence is approximately 1 in 30,000 – 50.000. Patient management can be very complex and treatment depends on the district affected and on the symptoms. In more serious cases, with terminal liver disease, liver transplantation is used. We describe a case with main bile duct hypoplasia, intrahepatic bile ducts paucity, cholestasis and gallbladder dimorphism associated with renal malrotation and butterfly vertebrae.

Abstract Background Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis. Methods We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022. Results The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period. Conclusions Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Introduction: Alagille syndrome (ALGS) is a rare, genetic, multisystem disorder commonly associated with cholestatic liver disease; patients with ALGS may experience elevated serum bile acids and severe pruritus with associated impaired sleep. The ileal bile acid transporter (IBAT) is located on the luminal surface of enterocytes in the terminal ileum; this transport protein mediates resorption of conjugated bile acids for recirculation back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids. Areas covered: Here, the role of odevixibat as a novel, nonsurgical approach to interrupting the enterohepatic circulation from the intestine by inhibition of IBAT is reviewed, specifically in reference to currently available data on pharmacologic IBAT inhibition. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of cholestatic liver diseases in children including ALGS. Expert opinion: Odevixibat or IBAT inhibitor should be considered as a first-line treatment for ALGS to improve pruritis, quality of life and liver-related outcomes including absence of liver transplant, surgical biliary diversion, hepatic decompensation, and death. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the JAG1 gene are a primary cause of the multi-system disorder Alagille syndrome. Although variant detection rates are high for this disease, there is uncertainty associated with the classification of missense variants that leads to reduced diagnostic yield. Consequently, up to 85% of reported JAG1 missense variants have uncertain or conflicting classifications. We generated a library of 2,832 JAG1 nucleotide variants within exons 1–7, a region with a high number of reported missense variants, and designed a high-throughput assay to measure JAG1 membrane expression, a requirement for normal function. After calibration using a set of 175 known or predicted pathogenic and benign variants included within the variant library, 486 variants were characterized as functionally abnormal (n = 277 abnormal and n = 209 likely abnormal), of which 439 (90.3%) were missense. We identified divergent membrane expression occurring at specific residues, indicating that loss of the wild-type residue itself does not drive pathogenicity, a finding supported by structural modeling data and with broad implications for clinical variant classification both for Alagille syndrome and globally across other disease genes. Of 144 uncertain variants reported in patients undergoing clinical or research testing, 27 had functionally abnormal membrane expression, and inclusion of our data resulted in the reclassification of 26 to likely pathogenic. Functional evidence augments the classification of genomic variants, reducing uncertainty and improving diagnostics. Inclusion of this repository of functional evidence during JAG1 variant reclassification will significantly affect resolution of variant pathogenicity, making a critical impact on the molecular diagnosis of Alagille syndrome. [Display omitted] JAG1 haploinsufficiency is the most common cause of the multi-system disorder, Alagille syndrome. We analyzed cellular localization of 2,832 missense and synonymous variants. We show that 486 tested variants are not appropriately expressed on the membrane and that integration of this data during clinical variant classification reduces uncertainty. [ABSTRACT FROM AUTHOR]

Purpose: Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported prevalence of 30–40% and can increase the risk of stroke by 16%. Few reports document the frequency and evolution of cerebrovascular abnormalities (CVAs) in children with ALGS. We aimed to define the spectrum, frequency, and evolution of CVAs in a series of children with ALGS using magnetic resonance angiography (MRA). Methods: We conducted a single-center, retrospective study in a large tertiary pediatric hospital. CVAs were grouped into 4 categories: 1) Stenosis or narrowing; 2) Aneurysms and ectasias; 3) Tortuosity; and 4) Vascular anomalies and anatomical variants. Results: Thirty-two children met the inclusion criteria. The median age at initial diagnosis was 6 (3.8–10.3) years. Thirteen (40%) had follow-up MRI at a mean of 55 (31.5–66) months. Eighteen (56%) had CVAs; the most frequent fell into group 1 (n = 12, 37.5%). CVAs were stable over time, except for one patient with Moyamoya arteriopathy (MMA). One patient developed a transient ischemic attack secondary to an embolic event. Three (9.3%) had microhemorrhages at the initial diagnosis secondary to Tetralogy of Fallot. Another patient had recurrent subdural hematomas of unknown cause. Conclusion: CVAs were stable except in the presence of MMA. Vascular strokes, which are reported in older patients with ALGS, were not a common feature in children under 16 years of age, either at presentation or over the 31.5–66 month follow-up period. [ABSTRACT FROM AUTHOR]

Background. Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 (JAG1) and Notch Receptor 2 (NOTCH2). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs. Methods. Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed. Results. We identified eleven rare NOTCH2 variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain. Conclusions. Our results increased the knowledge about NOTCH2 variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS. [ABSTRACT FROM AUTHOR]

Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS. Case report. This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid. The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE. This case report highlights the presence of focal choroidal excavation and unilateral macular atrophy in a patient with Alagille syndrome. The genetic analysis identified a pathogenic variant in the JAG1 gene. [ABSTRACT FROM AUTHOR]

Summary: Haploinsufficiency of JAG1 is the primary cause of Alagille syndrome (ALGS), a rare, multisystem disorder. The identification of JAG1 intronic variants outside of the canonical splice region as well as missense variants, both of which lead to uncertain associations with disease, confuses diagnostics. Strategies to determine whether these variants affect splicing include the study of patient RNA or minigene constructs, which are not always available or can be laborious to design, as well as the utilization of computational splice prediction tools. These tools, including SpliceAI and Pangolin, use algorithms to calculate the probability that a variant results in a splice alteration, expressed as a Δ score, with higher Δ scores (>0.2 on a 0–1 scale) positively correlated with aberrant splicing. We studied the consequence of 10 putative splice variants in ALGS patient samples through RNA analysis and compared this to SpliceAI and Pangolin predictions. We identified eight variants with aberrant splicing, seven of which had not been previously validated. Combining these data with non-canonical and missense splice variants reported in the literature, we identified a predictive threshold for SpliceAI and Pangolin with high sensitivity (Δ score >0.6). Moreover, we showed reduced specificity for variants with low Δ scores (

Background and aimsDetailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.Approach and resultsA targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p

A female infant, born at 37 week 5 days to a mother via induced vaginal delivery for preeclampsia, was prenatally diagnosed with a right aortic arch with vascular ring. On the third day of life, the infant exhibited a bronze-gray coloration, and a direct bilirubin of 1.7 mg/dL was detected. The abdominal ultrasound did not visualize the gallbladder. Clinically, the infant displayed features consistent with Alagille syndrome, including unusual facial appearance, butterfly vertebrae, cardiovascular defects, and cholestasis. The geneticist noted that the mother of the patient also exhibited similar features. Both the infant and the mother were diagnosed with Alagille syndrome, both having the same heterozygous JAG1 gene (NM_000214.2) variant (c.1890_1893del, p.Ile630Metfs*112). We believe that the vascular ring observed in our patient is the first reported instance of a vascular ring associated with Alagille syndrome.

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. [ABSTRACT FROM AUTHOR]

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder caused by variants in one of the JAG1 or the NOTCH2 genes. It presents with a wide spectrum of clinical manifestations that most commonly include hepatic, cardiac, skeletal, ophthalmologic and renal abnormalities, along with characteristic facial features. The prognosis and mortality risk vary according to the different organ involvement and its severity, and the management requires a multidisciplinary approach, depending on the findings of each affected individual. We report the case of a 2-year-old boy who presented with neonatal cholestasis, distinctive facial features and pulmonary artery stenosis, who progressively developed severe hypercholesterolemia, hypertriglyceridemia and intractable pruritus, with a significant decrease in the quality of life. [ABSTRACT FROM AUTHOR]

Background: Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF). Coarctation of aorta (CoA), renal and intracranial arteries are commonly involved vessels in Alagille syndrome. We present two cases with rare cardiovascular manifestations of Alagille syndrome. Case description: Case 1: A 25-year-old female with a history of Alagille syndrome presented to the cardiologist office for progressive exertional dyspnoea, orthopnoea, and palpitations. She was tachycardiac on examination and had an apical diastolic rumble. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 60% and parachute mitral valve (PMV) with severe mitral stenosis. A transoesophageal echocardiogram (TOE) showed insertion of chordae into the anterolateral papillary muscle, severe mitral stenosis with a valve area of 0.7 cm. She was referred to a congenital heart disease specialist and underwent robotic mitral valve replacement with improvement in her symptoms. Case 2: A 27-year-old female with known Alagille syndrome and resistant hypertension presented to the cardiologist office due to progressive exertional dyspnoea for a year. She was hypertensive and had a new 2/6 systolic ejection murmur along the left upper sternal border. TTE revealed an LVEF of 60% and pulmonary artery pressure of 19 mmHg. A CoA was suspected distal to the left subclavian artery due to a peak gradient of 38 mmHg. Cardiac magnetic resonance (CMR) imaging ruled out CoA, and diffuse narrowing of the descending thoracic aorta measuring 13–14 mm in diameter was noted. The patient was referred to a congenital heart disease specialist for further management. Conclusion: PMV presenting as mitral stenosis and mid-aortic syndrome are not commonly described anomalies in association with Alagille syndrome. TTE, TOE and CMR played a key role in diagnosis and management of these patients.

INTRODUCTION: The aim of this report is to describe a case of gastrointestinal bleeding that started at 1 month of age in a patient with Alagille Syndrome. CASE REPORT: Patient started recurrent gastrointestinal bleeding, leading to hypovolemic shock in the second month of life. During the investigation, cholestasis and incoagulable INR were evidenced. The facial stigmata, associated with the posterior embryotoxon in the ophthalmologic examination and transthoracic echocardiogram with stenosis of the pulmonary branches and patent foramen ovale, suggested the hypothesis of Alagille Syndrome, later confirmed by compatible liver biopsy and genetic testing with a mutation in the JAGGED1 gene. After administration of vitamin K, the patient evolved with normalization of the coagulogram, without new episodes of gastrointestinal bleeding. At follow-up, replacement of fat-soluble vitamins and treatment with ursodeoxycholic acid were initiated. DISCUSSION: Reports in the literature describe bleeding episodes in patients with Alagille Syndrome, however, the main site of bleeding is the central nervous system. There is no description of bleeding in the gastrointestinal tract as the initial and neonatal manifestation of the syndrome. The case reported is an uncommon form of presentation and shows the importance of diagnostic suspicion in cases of neonatal cholestasis with gastrointestinal bleeding, allowing for adequate treatment and improved prognosis.

Abstract Background Alagille syndrome is a rare autosomal-dominant disorder, representing 10 to 15% of the causes of neonatal cholestasis with no gender predominance. The diagnosis is based on the association of liver, heart, eye, skeleton abnormalities, and characteristic facial appearance. Case presentation An 18-year-old male patient, with a family history of benign recurrent intrahepatic cholestasis in a brother, was diagnosed at birth with bile duct paucity. He consulted in adulthood for cholestatic jaundice and pruritus. Physical exam found cutaneous jaundice, particular face, skeletal abnormality of fingers, posterior embryotoxon, and splenomegaly. An echocardiogram found cardiovascular abnormalities. The diagnosis of Alagille syndrome was made in front of five major criteria. A liver biopsy revealed a cirrhosis liver. Upper gastrointestinal endoscopy revealed grade II esophageal varices of portal hypertension. Laboratory tests revealed bicytopenia related to hypersplenism, hypoferritinemia, cytolysis with cholestasis, high bilirubin levels, low prothrombin time, hypoalbuminemia, decreased factor V activity, and hypocholesterolemia. The patient had vitamin K supplementation and was put on ursodeoxycholic acid, propranolol for the liver disease, a high protein hypercaloric diet for malnutrition, vitamin D supplementation and bisphosphonate for the osteoporosis, therapeutic abstention with monitoring for the asymptomatic cardiac disease. After a year of treatment, the patient had an overall health status improvement. Abdominal ultrasound found liver nodules. A biliary MRI showed a multinodular liver. The complement by CT hepatic angiography did not show any nodules while the MRI angiography revealed multiple dysplastic nodules. A liver biopsy was performed and found regenerative nodules. Conclusion The treatment of Alagille syndrome is based on managing the cholestasis and its complications, especially pruritus because it can have a significant impact on quality of life. Due to the complexity of presentation and multi-organ involvement, management of cases with Alagille syndrome should be done by a multidisciplinary team. Liver disease is responsible for morbidity while cardiac disease is a mortality risk factor in this population.

Objective: In this paper, we share our single-center experience of successful multidisciplinary management of patients with Alagille syndrome. In addition, we aim to highlight the need for an Alagille program for effectively managing these patients, in general, and particularly peripheral pulmonary artery stenosis associated with this syndrome. Study Design: This is a retrospective review of six children with Alagille syndrome and advanced liver involvement who underwent pulmonary artery reconstruction between 2021 and 2022. Cardiac diagnosis, co-existing liver disease burdens, management approach, and short-term outcomes were analyzed. Results: All the patients underwent one-stage extensive bilateral branch pulmonary rehabilitation. Concomitant procedures included repair of tetralogy of Fallot in one patient and repair of supravalvar pulmonary artery stenosis in two. One patient had balloon pulmonary branch angioplasty before surgery. In all patients, there was a decrease in right ventricular systolic pressure post-operatively. Three patients underwent liver transplantation for pre-existing liver dysfunction. At a median 3-year follow-up, all the patients were alive with their right ventricular systolic pressure less than half of their systemic systolic pressure. One patient underwent balloon angioplasty due to new and recurrent left pulmonary artery stenosis 13 months after surgery. Conclusion: Pulmonary arteries can be successfully rehabilitated surgically in the presence of complex branch disease. Patients with advanced liver disease can undergo successful complex pulmonary artery reconstruction, which can facilitate their future liver transplantation course. A multidisciplinary team approach is a key for successful management of Alagille patients.

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in either the JAG1 gene (ALGS type 1) or the NOTCH2 gene (ALGS type 2). The disease has been difficult to diagnose and treat due to its muti-system clinical presentation, variable expressivity, and prenatal onset for some of the features. The generation of this iPSC line (TRNDi032-A) carrying a heterozygous mutation, p.Cys682Leufs*7 (c.2044dup), in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.

Background: Alagille syndrome is a rare autosomal-dominant disorder, representing 10 to 15% of the causes of neonatal cholestasis with no gender predominance. The diagnosis is based on the association of liver, heart, eye, skeleton abnormalities, and characteristic facial appearance. Case presentation: An 18-year-old male patient, with a family history of benign recurrent intrahepatic cholestasis in a brother, was diagnosed at birth with bile duct paucity. He consulted in adulthood for cholestatic jaundice and pruritus. Physical exam found cutaneous jaundice, particular face, skeletal abnormality of fingers, posterior embryotoxon, and splenomegaly. An echocardiogram found cardiovascular abnormalities. The diagnosis of Alagille syndrome was made in front of five major criteria. A liver biopsy revealed a cirrhosis liver. Upper gastrointestinal endoscopy revealed grade II esophageal varices of portal hypertension. Laboratory tests revealed bicytopenia related to hypersplenism, hypoferritinemia, cytolysis with cholestasis, high bilirubin levels, low prothrombin time, hypoalbuminemia, decreased factor V activity, and hypocholesterolemia. The patient had vitamin K supplementation and was put on ursodeoxycholic acid, propranolol for the liver disease, a high protein hypercaloric diet for malnutrition, vitamin D supplementation and bisphosphonate for the osteoporosis, therapeutic abstention with monitoring for the asymptomatic cardiac disease. After a year of treatment, the patient had an overall health status improvement. Abdominal ultrasound found liver nodules. A biliary MRI showed a multinodular liver. The complement by CT hepatic angiography did not show any nodules while the MRI angiography revealed multiple dysplastic nodules. A liver biopsy was performed and found regenerative nodules. Conclusion: The treatment of Alagille syndrome is based on managing the cholestasis and its complications, especially pruritus because it can have a significant impact on quality of life. Due to the complexity of presentation and multi-organ involvement, management of cases with Alagille syndrome should be done by a multidisciplinary team. Liver disease is responsible for morbidity while cardiac disease is a mortality risk factor in this population. [ABSTRACT FROM AUTHOR]

Purpose of Review: Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. Recent Findings: Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Summary: Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge. [ABSTRACT FROM AUTHOR]

Objective: Alagille syndrome (ALGS), known as arteriohepatic dysplasia, is an autosomal dominant multisystem disorder primarily linked to JAG1 gene variants. It features distinctive anomalies in the liver, heart, eyes, spine, and facial morphology. Material and Method: Patients diagnosed with ALGS and referred to Istanbul Faculty of Medicine, Department of Medical Genetics between January 2016 and December 2022 were included in the study. The clinical, radiological, cytogenetic, and molecular findings of the patients as well as their families were re-assessed retrospectively. Karyotype, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and JAG1 gene sequencing utilizing next-generation and Sanger sequencing methodologies were conducted. Result: The presence of both large deletion and small variants associated with Alagille syndrome was detected in all cases. In karyotype and aCGH analysis of a single case, a 20p deletion was identified. Subsequent next-generation sequencing (NGS) of the JAG1 gene revealed the following findings: a heterozygous pathogenic variant c.2122_2125del/p.(Gln708Valfs*34), a heterozygous likely pathogenic variant c.1754_1755del/p.(Asn585Argfs*4), a heterozygous pathogenic variant c.2026del/p.(Cys676Alafs*67), a heterozygous pathogenic variant c.753C>A/p.(Cys251*), and a heterozygous likely pathogenic variant c.2458+2_2458+4delTAAinsGAC/p. (?). In one case, FISH analysis revealed a 20p deletion inherited from the mother. Analysis of available family members further indicated that three variants were inherited within the family. One of the two novel truncating variants, the c.1754_1755del variant was identified as de novo, while the other c.2458+2_2458+4delTAAinsGAC variant was determined to be familial. Conclusion: In summary, the research effectively identified various JAG1 gene alterations and underlined the significance of incorporating molecular cytogenetic analysis in conjunction with sequence analysis of the JAG1 gene for accurate genetic diagnosis and counseling. Furthermore, study highlights the valuable outcome of screening parents, siblings, and children to clarify the genetic etiopathogenesis, as there is a remarkable intra- and inter-familial phenotypic variability in patients with ALGS. [ABSTRACT FROM AUTHOR]

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Alagille syndrome (AS) commonly presents with cholestasis, much like other liver diseases, making the diagnosis challenging. We report a case of a patient with AS mimicking biliary atresia (BA) with a poor outcome. The infant, a product of a non-consanguineous marriage, presented with jaundice, clay stools, peripheral pulmonary stenosis, atrial septal defect, and butterfly vertebrae. Cholescintigraphy showed an absence of radiotracer excretion. Surgical exploration revealed the presence of a hypoplastic hepatic duct but a normal gallbladder, cystic, and common bile ducts. Intraoperative cholangiogram favored BA, and a Kasai procedure was performed. The liver biopsy demonstrated focal areas of ductular proliferation and periportal ballooning degeneration without bile duct paucity. The patient exhibited worsening cardiac and liver conditions, growth failure, and developmental delay. She died suddenly at home at the age of 34 months. The cholangiographic and histological abnormalities found in our patient were suggestive of BA. At the same time, she displayed four out of five diagnostic criteria for AS. Based on our experience with this case, we suggest expeditious genetic testing should be considered for any case of neonatal cholestasis with diagnostic uncertainty. This may help avoid unwarranted surgical interventions, potentially associated with worse outcomes. [ABSTRACT FROM AUTHOR]

Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes. While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023. The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management. [ABSTRACT FROM AUTHOR]

A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the neonatal period because of initial misdiagnosis of biliary atresia. Laboratory investigations showed hyperbilirubinemia (total bilirubin 1.76 mg/dL [