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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.

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome., Methods: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed., Findings: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths., Interpretation: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study., Funding: Albireo Pharma, an Ipsen company., Competing Interests: Declaration of interests NO has received research support to their institution from Albireo Pharma (an Ipsen company) and Mirum, and consulting fees from Albireo Pharma (an Ipsen company). UB has received grants or contracts and consulting fees from Mirum, Albireo Pharma (an Ipsen company), and Alexion. PB has received an unrestricted research grant from Albireo Pharma (an Ipsen company) and payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum; and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. MC has received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. RF has received payments or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum, and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company). GI has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company), Mirum, and Kedrion Pharma. PR has received research support to their institution from Albireo Pharma (an Ipsen company); grants or contracts from AbbVie, Arrowhead, Gilead, Merck, Mirum, Takeda, and Travere; consulting fees from Albireo Pharma (an Ipsen company), Ambys, Audentes, BioMarin, Dicerna, Encoded, Gilead, MedinCell, Mirum, RNAV8, Takeda, and Travere; and payment or honoraria for speakers bureaus from Mirum. MR has received consulting fees from Albireo Pharma (an Ipsen company), Grifols, Mirum, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum and Takeda; and support for attending meetings or travel, or both, from Mirum and Albireo Pharma (an Ipsen company). ESt has received unrestricted grants from Albireo Pharma (an Ipsen company) and Mirum; consulting fees from Albireo Pharma (an Ipsen company) and Mirum; and payment or honoraria to their institution for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum. WvdW has received consulting fees from Mirum. HJV has received grants or contracts to their institution from Albireo Pharma (an Ipsen company), Mirum, and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition; and consulting fees paid to their institution from Albireo Pharma (an Ipsen company) and Mirum. AW has received research support from Albireo Pharma (an Ipsen company), and has participated on a data safety monitoring or advisory board for Mirum. QY was previously employed at Albireo Pharma (an Ipsen company). CC, JPM, and SM were previously employed at Albireo Pharma (an Ipsen company) and received salary and stock options. JPM also held patents with and received support for attending meetings or travel, or both, from Albireo Pharma (an Ipsen company). QN and JR are current employees of Ipsen and receive salary or stock options (or both). MA, PC, ÖD, WSL, AB, WWK, FL, GM, and ESo declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: 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., Methods: Case report., Results: 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., Conclusion: 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.

Background and Aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study., Approach and Results: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings., Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Objective: Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS., Methods: We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation., Results: Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin., Conclusion: Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Alagille syndrome (AGS) is a genetic disorder due to mutations in the JAGGED 1 or NOTCH 2 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., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Gallbladder and biliary diseases (GBDs) are one of the most common digestive diseases. The connections between GBDs and several organs other than the liver have gradually surfaced accompanied by the changes in people's diet structure and the continuous improvement of medical diagnosis technology. Among them, cholecardia syndrome that takes the heart as the important target of GBDs complications has been paid close attention. However, there are still no systematic report about its corresponding clinical manifestations and pathogenesis. This review summarized recent reported types of cholecardia syndrome and found that arrhythmia, myocardial injury, acute coronary syndrome and heart failure are common in the general population. Besides, the clinical diagnosis rate of intrahepatic cholestasis of pregnancy (ICP) and Alagille syndrome associated with gene mutation is also increasing. Accordingly, the underlying pathogenesis including abnormal secretion of bile acid, gene mutation, translocation and deletion (JAG1, NOTCH2, ABCG5/8 and CYP7A1), nerve reflex and autonomic neuropathy were further revealed. Finally, the potential treatment measures and clinical medication represented by ursodeoxycholic acid were summarized to provide assistance for clinical diagnosis and treatment., Competing Interests: Declaration of Competing Interest All authors have no financial or scientific conflicts of interest with regard to the research described in this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

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. 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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

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 JAG1 or NOTCH2 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 JAG1 and NOTCH2 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 JAG1 gene-eight frameshift variants (c.1619&#95;1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168&#95;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 NOTCH2 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.

Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1 Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1 Ndr/Ndr mice, using retina as a model. Jag1 Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1 Ndr/Ndr mice represent a new model for vascular compromise in ALGS., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

BACKGROUND Alagille syndrome (ALGS) is a multisystem hereditary illness with a dominant pattern and partial penetrance. Multiple organ abnormalities can be caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene. Notch receptor 2 (NOTCH2) gene mutations are also uncommon. ALGS is also characterized by deformed or narrowed bile ducts and is notoriously difficult to diagnose due to the wide range of symptoms and absence of unambiguous genotype-phenotype connections. Little is known about ALGS patients who have NOTCH2 mutations. We present a patient who developed progressive liver failure due to a unique pathogenic heterozygous variation of the NOTCH2 gene, c.1076c>T p. (Ser359Phe) chr1: 120512166, resulting in type 2 ALGS. CASE REPORT A Saudi Arabian newborn with bilateral hazy eyes, ectropion, dry ichthyic skin, normal male genitalia, and bilateral undescended testes was born at 31 weeks. Previous miscarriages, pregnancy-induced maternal cholestasis, fatty liver, or neonatal jaundice were not reported in the family history. He had developed worsening cholestatic jaundice by the third week of hospitalization. The extensive work-up for metabolic, infectious, and other relevant etiologies was negative. Following gram-negative sepsis, he died of multiorgan failure. A NOTCH2 gene mutation explained the phenotypic difference in our situation. Another intriguing observation was the presence of ichthysis and craniosynostosis in ALGS with a NOTCH2 mutation. CONCLUSIONS Cholestasis in newborns can be difficult to diagnose. Next-generation sequencing detects 112 copy number variants in the cholestasis gene panel blood test. More research is needed to understand why NOTCH2 mutations are relatively rare in ALGS.

Objectives: This study aims to report liver transplantation (LT) outcomes and cardiac disease manifestations in children with Alagille Syndrome (ALGS) in a contemporary cohort., Methods: This project used a novel linkage between the Scientific Registry of Transplant Recipients and Pediatric Health Information System databases. All children ≤21 years undergoing a first LT were identified (2002-2018). The presence of ALGS was identified using Scientific Registry of Transplant Recipients diagnosis coding. Subjects with ALGS were age-matched 1:2 to LT recipients with biliary atresia (BA). The Kaplan-Meier method and log-rank test were used to compare patient and graft survival between groups., Results: A total of 156 LT recipients with ALGS were identified and matched to a control group of 312 LT recipients with BA. Children with ALGS were more likely to have an associated diagnosis of congenital heart disease (80.7% vs 16.4%; P = 0.001) compared with children with BA with 40 (25.6%) children with AGS requiring cardiac intervention (catheter or surgical) either before or after LT. Those patients with ALGS had a higher creatinine, laboratory MELD, and PELD scores before LT. No difference was observed regarding patient or graft survival between children with ALGS and children with BA ( P = 0.08 and P = 0.27, respectively)., Conclusions: Despite increased rate of congenital heart defects and cardiac interventions, higher creatinine, and higher laboratory MELD/PELD scores at time of transplant, this study demonstrates that there is no difference in either patient or graft survival between patients with ALGS and BA., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Objective: We report a novel frameshift variant of JAG1 in the prenatal setting, associated with Alagille syndrome1 with incomplete penetrance in a Chinese family., Case Report: A pregnant woman was referred to our center due to fetal cardiovascular abnormality. Whole exome sequencing was employed for this family. A novel heterozygous maternal-origin frameshift variant c.1794&#95;1797del in JAG1 was identified in the fetus. The mother and the fetus had the identical variant, but they demonstrated different clinical manifestations. The fetus was diagnosed with Alagille syndrome 1., Conclusion: A novel frameshift variant in JAG1 was detected in a fetus diagnosed with Alagille syndrome 1, and it showed incomplete penetrance in the family., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background Despite favorable outcomes of surgical pulmonary artery (PA) reconstruction, isolated proximal stenting of the central PAs is common clinical practice for patients with peripheral PA stenosis in association with Williams and Alagille syndromes. Given the technical challenges of PA reconstruction and the morbidities associated with transcatheter interventions, the hemodynamic consequences of all treatment strategies must be rigorously assessed. Our study aims to model, assess, and predict hemodynamic outcomes of transcatheter interventions in these patients. Methods and Results Isolated proximal and "extensive" interventions (stenting and/or balloon angioplasty of proximal and lobar vessels) were performed in silico on 6 patient-specific PA models. Autoregulatory adaptation of the cardiac output and downstream arterial resistance was modeled in response to intervention-induced hemodynamic perturbations. Postintervention computational fluid dynamics predictions were validated in 2 stented patients and quantitatively assessed in 4 surgical patients. Our computational methods accurately predicted postinterventional PA pressures, the primary indicators of success for treatment of peripheral PA stenosis. Proximal and extensive treatment achieved median reductions of 14% and 40% in main PA systolic pressure, 27% and 56% in pulmonary vascular resistance, and 10% and 45% in right ventricular stroke work, respectively. Conclusions In patients with Williams and Alagille syndromes, extensive transcatheter intervention is required to sufficiently reduce PA pressures and right ventricular stroke work. Transcatheter therapy was shown to be ineffective for long-segment stenosis and pales hemodynamically in comparison with published outcomes of surgical reconstruction. Regardless of the chosen strategy, a virtual treatment planning platform could identify lesions most critical for optimizing right ventricular afterload.

Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment., Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease., Results: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ., Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions., Competing Interests: Conflicts of Interest: D.H.L. reports grant/research support from Abbvie, Gilead, and CF Foundation; he also serves on advisory panels for Merck and Gilead. B.M.K. is a consultant for Mirum, Albireo and Audentes; she has unrestricted educational grants from Mirum and Albireo. V.L.N. is a consultant for Albireo. P.R. reports grants from Gilead, Merck, BMS, AbbVie, Travere Therapeutics, Albireo, and Mirum, Arrowhead; and serving as a consultant for Gilead, Mirum, Albireo, Audentes, and Vertex. R.J.S. reports consulting for Albireo, Mirum/Shire, and Retrophin (all <$10,000 per year). K.M.L. reports consulting for Albireo, Mirum and Retrophin (now known as Travere Therapeutics). The remaining authors report no conflicts of interest. The study sponsors did not have a role in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

In this article, we describe a case of a 33-year-old female with Alagille syndrome complicated by bilateral branch pulmonary artery stenosis resulting in moderate pulmonary hypertension, end-stage liver disease complicated by portal hypertension, and chronic renal disease who presented for combined liver-kidney transplant. Alagille syndrome is an autosomal dominant disease affecting the liver, heart, and kidneys. Multidisciplinary preoperative evaluation was performed with a team consisting of a congenital heart disease cardiologist, a cardiac anesthesiologist, a nephrologist, and a transplant surgeon. We describe Alagille syndrome and our intraoperative management. To our knowledge, this is the first description of a combined liver-kidney transplant in an adult patient with Alagille syndrome.

Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of the main renal artery trunks or to fibromuscular dysplasia. These two causes of renal artery stenosis have been extensively discussed in recent reviews and consensus. The aim of the current article is to provide comprehensive and up-to-date information on the remaining causes. While these causes are rare or extremely rare, etiologic and differential diagnosis matters both for prognosis and management. Therefore, the clinician cannot ignore them. For didactic reasons, we have grouped these different entities into stenotic lesions (neurofibromatosis type 1 and other rare syndromes, dissection, arteritis, and segmental arterial mediolysis) often associated with aortic coarctation and other arterial abnormalities, and nonstenotic lesions, where hypertension is secondary to compression of adjacent arteries and changes in arterial pulsatility (aneurysm) or to the formation of a shunt, leading to kidney ischemia (arteriovenous fistula). Finally, thrombotic disorders of the renal artery may also be responsible for renovascular hypertension. Although thrombotic/embolic lesions do not represent primary vessel wall disease, they are characterized by frequent macrovascular involvement. In this review, we illustrate the most characteristic aspects of these different entities responsible for renovascular hypertension and discuss their prevalence, pathophysiology, clinical presentation, management, and prognosis.

Alagille syndrome (AS) is a rare multisystem disease of the liver, heart, eyes, face, skeleton, kidneys, and vascular system. The occurrence of pseudotumor cerebri syndrome (PTCS) in patients with AS has been reported only exceptionally. Owning to its rarity and a mostly atypical presentation, the diagnosis and natural history of affected patients remain uncertain. We report an atypical case of PTCS in a 4-year-old boy with a known history of AS who presented with bilateral papilledema (PE) on a routine ophthalmological examination. Visual findings deteriorated after treatment with acetazolamide. Continuous intracranial pressure (ICP) monitoring was then utilized to investigate ICP dynamics. Successful treatment with resolution of PE was achieved after ventriculoperitoneal shunting but relapsed due to growth-related dislocation of the ventricular catheter. This report brings new insights into the ICP dynamics and the resulting treatment in this possibly underdiagnosed subgroup of PTCS patients. It also demonstrates that ventriculoperitoneal shunting can provide long-term improvement of symptoms for more than 10 years., (© 2021. The Author(s).)

Inherited liver diseases may present in infancy as cholestatic jaundice progressing to severe hepatic dysfunction. Congenital cytomegalovirus (cCMV) infection may initially involve the liver, yet in otherwise healthy hosts rarely leads to long-term hepatic disease. We report a series of three patients, diagnosed with hereditary liver diseases: progressive familial intrahepatic cholestasis (PFIC) type IV, alpha 1 anti-trypsin deficiency (A1ATD) and Alagille syndrome (ALGS), who were also diagnosed with cCMV infection. All patients were treated with valgancilovir for symptomatic cCMV infection (6-12 months), followed by suppressive dosing in the 2 patients with PFIC and A1ATD. Following 15-24 months of follow-up - the patients with PFIC and A1ATD developed severe liver failure, and the third had ongoing cholestatic disease with stable synthetic function. We propose a significant contribution of cCMV infection to the course of the inherited primary disease, possibly leading to further compromise of the liver. We recommend screening patients with inherited liver disease for cCMV, and considering anti-viral treatment with valganciclovir to delay hepatic disease progression., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Alagille syndrome (ALGS) is a multisystem autosomal dominant developmental disorder caused predominantly by pathogenic variants in JAGGED1 (JAG1), and also by pathogenic variants in NOTCH2 in a much smaller number of individuals. Clinical presentation is highly variable and includes liver, heart, eye, skeleton, and facial abnormalities, with a subset of individuals also presenting with kidney, vascular, and central nervous system phenotypes. Hepatocellular carcinoma (HCC) is a rare complication of ALGS, though little is known about its incidence or etiology among affected individuals. Previous reports have identified HCC occurrence in both pediatric and adult cases of ALGS. We present a case report of HCC in a 58-year-old woman with a pathogenic JAG1 variant and no overt hepatic features of ALGS. Through a comprehensive literature review, we compile all reported pediatric and adult cases, and further highlight one previously reported case of HCC onset in an adult ALGS patient without any hepatic disease features, similar to our own described patient. Our case report and literature review suggest that ALGS-causing variants could confer risk for developing HCC regardless of phenotypic severity and highlight a need for a cancer screening protocol that would enable early detection and treatment in this at-risk population., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Alagille syndrome is an inherited multisystemic disorder. We herein report an atypical case of a Japanese adult patient with Alagille syndrome. He had been diagnosed with Alagille syndrome as an infant based on a liver biopsy. At 27 years of age, he needed to start hemodialysis therapy, but an arteriovenous fistula was not created because his peripheral blood vessels were too narrow. He also had a recurrent brain infarction due to cerebral vascular stenosis. Alagille syndrome is generally recognized as a pediatric hepatic disease, but general physicians should be aware of its potential existence with renal involvement and vascular abnormalities.

Aims and Background: Ophthalmic abnormalities are amongst the 5 major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudopapilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report 9 pediatric cases of ALGS with bilateral papilledema, 5 of which were diagnosed with ICHT., Methods: The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation (LT) for other indications were also analyzed., Results: Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all 9 patients were normal. These 9 patients were categorized into 4 groups: a nontransplant group (n = 1), a group with pretransplant papilledema persistent after LT (n = 2), a group with papilledema occurring after LT with spontaneous resolution (n = 1), and a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in 2 of the 5 cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT., Conclusions: True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

Alagille syndrome (AGS) is a multisystem disorder classically involving liver and heart failure, characteristic vertebral and facial features and ocular abnormalities. AGS is caused by heterozygous mutations in JAG1 or NOTCH2, with variable phenotype penetrance. We report two cases of AGS in children with tooth defects characterised by green discolouration and hypomineralisation. The role of hyperbilirubinaemia (HB) in this atypical colour, a classical feature of AGS, has been well described. However, it does not totally explain the dental phenotype. As JAG1 and NOTCH2 mutations can affect bone development and considering common physiological pathways between bone and tooth mineralisation, both mutations could participate in this unusual dental phenotype. The role of HB and genetics in the development of the dental phenotype of AGS is discussed in two prototypical cases. Future research should focus on the underlying genetic component of tooth abnormalities., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the incidence, severity, and outcomes of pulmonary hemorrhage in children with Alagille syndrome (AGS) undergoing cardiac catheterization, and to find variables associated with hemorrhage in this population., Background: Children with AGS have a high incidence of bleeding complications during invasive procedures. It has been our impression that catheterization-associated pulmonary hemorrhage is more common in children with AGS, but there are no published data on this topic., Methods: This was a retrospective single institution study of children with AGS undergoing catheterization from 2010 to 2018. Pulmonary hemorrhage was defined as angiographic or fluoroscopic evidence of extravasated blood in the lung parenchyma, or blood suctioned from the endotracheal tube with documentation of pulmonary hemorrhage by the anesthesiologist or intensivist. Univariate comparisons were made between catheterizations that did and did not have pulmonary hemorrhage., Results: Thirty children with AGS underwent 87 catheterizations, 32 (37%) with interventions on the branch pulmonary arteries (PA). There were 26 (30%) procedures with hemorrhage, the majority (65%) of which were self-limited or required less than 24 hr of mechanical ventilation. Moderate and severe hemorrhage occurred only in children with tetralogy of Fallot (TOF; 5 of 14, 36%). A higher right ventricle to aorta systolic pressure ratio (1.0 [0.85-1.1] vs. 0.88 [0.59-1.0], p = .029) and interventions on the branch PAs (14 of 26, 54% vs. 18 of 61, 30%, p = .032) were associated with hemorrhage., Conclusions: Pulmonary hemorrhage was common in children with AGS undergoing both intervention and diagnostic cardiac catheterization, and was associated with TOF, higher RV to aorta pressure ratio, and interventions on the branch PAs., (© 2019 Wiley Periodicals, Inc.)

Alagille syndrome (ALGS) is an autosomal-dominant multisystem disorder caused by mutations in Jagged 1 (JAG1) or NOTCH2. The penetrance is low but highly variable. It is almost exclusively diagnosed in children with cholestasis and, more rarely, in their adult relatives. Here, we report the case of a patient diagnosed with ALGS in adulthood. The patient was a 28-year-old male who presented with characteristic facial features, an eye abnormality, chronic cholestasis with bile duct paucity on liver biopsy, atrial defects and stenosis of the left internal carotid artery. A novel frameshift mutation, c.2087&#95;2088insAAAAATGG (p. W697Kfs*49), in JAG1 was identified. To our knowledge, this is the first case of ALGS diagnosed in adulthood in China. ALGS should be considered as a differential diagnosis for intrahepatic cholestasis in adult patients with a wide variety of clinical manifestations, including cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features.

Background: paucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1β mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1β defect., Case Presentation: A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control., Conclusions: Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.

Severe pulmonary hypertension is a contraindication for liver transplantation owing to high mortality. However, decision-making regarding the treatment approach for patients with bilateral peripheral pulmonary artery stenosis, typically complicated by elevated main pulmonary artery and right ventricle pressures, can be challenging. Here, we report successful living donor liver transplantation after bilateral pulmonary artery stent implantation in a patient with Alagille syndrome, severe bilateral peripheral pulmonary artery stenosis, and extremely high main pulmonary artery and right ventricle pressures.

A 2-year-old boy with Alagille syndrome who had esotropia underwent bilateral medial rectus recession. One month postoperatively, esotropia reoccurred and was aggravated thereafter. Right lateral rectus resection was unsuccessful because the insertion site could not be identified. Careful preoperative imaging may be necessary in patients with Alagille syndrome to detect any abnormal extraocular muscle insertion. [J Pediatr Ophthalmol. 2018;55:e36-e38.]., (Copyright 2018, SLACK Incorporated.)

Objective: Williams and Alagille syndromes are genetic disorders associated with pathologic arterial narrowing. We hypothesized that fetal idiopathic ductus arteriosus (DA) constriction may represent a prenatal manifestation of the arteriopathy associated with these syndromes., Methods: Multi-institutional case series review of the pre- and postnatal medical records, echocardiograms, and genetic test results of fetuses presenting with idiopathic DA constriction., Results: We identified four cases of idiopathic fetal DA constriction at 21-36 weeks of gestation. All had right ventricular hypertension, dilation, hypertrophy, and dysfunction and either DA constriction or absence. All demonstrated progressive peripheral pulmonary artery stenosis after birth. Three met clinical diagnostic criteria for Alagille syndrome; two tested had confirmatory JAG1 mutations. One also developed supravalvar aortic stenosis after birth and was positive for 7q11.23 deletion (Williams syndrome)., Conclusion: This is the first case series to suggest that idiopathic fetal DA constriction may be a prenatal manifestation of genetic arteriopathy.

Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system. Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality. Current therapies are supportive, but the future is promising for the development of targeted interventions to augment Notch pathway signaling in involved tissues., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alagille syndrome is associated with decreased bile ducts, cardiac abnormalities, vertebral body fusion defects, and a typical facies. While regenerative nodules and hepatocellular carcinoma have been described in these patients, hepatic adenoma has not. Herein, we present a patient with Alagille syndrome caused by a mutation in NOTCH2 with a hepatic adenoma. The clinical, imaging, and histologic features are discussed.

Background: The polymalformative syndromes and craniofacial anomalies association is a well-known phenomenon in patients with Crouzon, Pfeiffer, Apert, or Muenke disease. Recently, other less frequent pathologies, such as Alagille syndrome, have shown an association with alterations in the development of cranial sutures, resulting in serious cosmetic defects and neurologic disorders., Case Description: We report an exceptional case of a 30-month-old girl, a nephroblastoma survivor diagnosed with Alagille syndrome, who was referred to our department with progressive anterior plagiocephaly and premature left coronal suture closure associated with a large compensating right bossing. Despite the patient's age, we offered aggressive surgical treatment performing a new forehead harvested from the skull vertex with orbital rim reconstruction., Conclusions: Alagille syndrome is a complex multisystem pathology with a poor craniosynostosis association and only 3 cases have been described in the literature., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To explore the clinical and molecular genetic features of patients with Alagille syndrome (AS). Methods: The clinical data of eleven pediatric patients, who were suspected to have AS at the Department of Pediatrics in the First Affiliated Hospital of Jinan University from August 2010 to March 2017, were collected and analyzed. Genomic DNA was extracted from peripheral blood leukocytes of the patients and their parents. For 5 patients collected before March 2006, all JAG1 exons and their flanking sequences were directly sequenced. For the remaining 6 patients, high-throughput gene capture technology, chromosomal microarray analysis (CMA) and whole-genome copy-number variant(CNV) analysis were utilized, when necessary, to explore the genetic causes. Results: All patients had cholestasis. However, the γ-glutamyl transpeptidase (GGT) levels in one patient were normal. Nine patients had posterior embryotoxon and facial malformations. Eight patients displayed heart defects. Seven patients presented with vertebral anomalies and among them, 1 patient had sacralization of the cubitus and radius. The condition of nine patients tended to be stabilized on follow-up, but 1 patient died of liver failure in late infancy and 1 got worse. Seven JAG1 variants were detected in 9 out of the 11 AS patients, with c.1977G>A (p.Trp659*) and c.1106&#95;1107delCC (p.Pro369fs) being two novel variants. Two heterozygous interstitial deletions of 3.0 Mb and 9.24 Mb in size, respectively, in chromosome 20 were discovered in the remaining 2 patients. Both deletions involved the entire JAG1 gene. De novo origin was unveiled for the detected variants in 7 patients and interstitial deletions in two. Although the mother of 2 patients carried the relevant variant, she did not demonstrate any clinical features of AS. Conclusions: With cholestasis, posterior embryotoxon, facial malformations, heart defects and vertebral anomalies being the major manifestations, AS demonstrated variable clinical expressivities and incomplete penetrance. This study identified a total of 7 JAG1 variants as well as 2 interstitial deletions involving this gene, and among them, the variants c.1977G>A (p.Trp659* ) and c.1106&#95;1107delCC (p.Pro369fs) as well as the 9.24 Mb chromosomal interstitial deletion had not been reported previously.

Planar xanthomas in children represent rare dermatologic findings associated with abnormalities in lipid metabolism. While planar xanthomas in Alagille's syndrome have been well described in the literature, there have been no cases reported of eruptive xanthomas in pediatric liver transplant patients. Herein we report a case of a 16-month-old boy status post-liver transplantation who presents with planar xanthomas secondary to cholangiopathy. A brief review of xanthomas and the related literature is also provided., (© 2018 Wiley Periodicals, Inc.)

Background: Alagille syndrome is a pediatric multisystem disease with increased prevalence of cerebrovascular disease. The spectrum of cerebrovascular disease in Alagille syndrome includes cerebral aneurysms, moyamoya arteriopathy and dolichoectasia. The prevalence of cerebrovascular disease in Alagille syndrome varies widely in the literature., Objective: To determine the prevalence of cerebrovascular disease in our institution's Alagille patient population by employing a full primary review of all available neuroimaging., Materials and Methods: An institutional review board-approved retrospective review of all Alagille syndrome patients seen at a tertiary care children's hospital from January 2000 to January 2014 was performed. All neuroimaging studies were reviewed for arterial or venous abnormalities. The prevalence of arterial and venous abnormalities was calculated and clinical outcomes were determined., Results: Fifty-two patients with Alagille syndrome ranging in age from 11 months to 27 years were studied. Nineteen (37%) had dedicated vascular neuroimaging. Six (32%) had cerebral arterial disease, 4 with dolichoectasia, 3 with aneurysm(s) and 2 with moyamoya arteriopathy. Three of the four patients with dolichoectasia had associated aneurysm(s). Venous anomalies were present in 4 (21%) patients. One patient with moyamoya arteriopathy underwent revascularization procedures. No deaths were attributable to cerebrovascular disease., Conclusion: Cerebral vasculopathy is an important feature of Alagille syndrome and includes dolichoectasia, cerebral aneurysms and moyamoya arteriopathy. The high prevalence identified in our study suggests noninvasive vascular neuroimaging screening should be performed in this patient population. In addition to cerebral arterial abnormalities, alterations of venous development may be a feature of Alagille syndrome.