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Survey of Ophthalmology 2017Although the connection is not often apparent, hepatic pathology may be associated with ophthalmic disease. We review the literature concerning the periocular,... (Review)
Review
Although the connection is not often apparent, hepatic pathology may be associated with ophthalmic disease. We review the literature concerning the periocular, periorbital, and orbital manifestations of various hepatic disorders. This includes periocular or periorbital jaundice, the impact of hepatitis B and C, eyelid changes in cirrhosis, orbital mass lesions in hepatocellular carcinoma, and cutaneous vascular malformations as they are related to liver disease. The motility disorders associated with Wilson disease, the ophthalmic manifestations of Alagille syndrome, and the effects of liver transplantation are also discussed.
Topics: Diagnostic Techniques, Ophthalmological; Humans; Liver Diseases; Orbit; Orbital Diseases
PubMed: 27863968
DOI: 10.1016/j.survophthal.2016.11.002 -
Seminars in Pediatric Surgery Aug 2020Progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AS) are conditions caused by either an autosomal recessive or an autosomal dominant genetic... (Review)
Review
Progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AS) are conditions caused by either an autosomal recessive or an autosomal dominant genetic defect, and they are both characterized by cholestasis, jaundice, and severe debilitating pruritus refractory to medical management. Before the advent of liver transplantation, most PFIC patients would die from end-stage liver disease in the first decade of life. Although liver transplantation has led to patients' survival, disease recurrence (PFIC-2) and severe extra-hepatic manifestations of the disease (PFIC-1) occurred post transplant. In the late 1980s, Whitington described the use of partial external biliary diversion in PFIC and AS patients as a successful way to improve symptoms and decrease circulating bile acid serum concentrations. Since then, other diversion techniques have been described (ileal exclusion and partial internal biliary diversion). These techniques have the benefit of avoiding a stoma, but equivalent results have not been demonstrated (recurrence of cholestasis after ileal exclusion, limited follow up after internal biliary diversion). Overall, studies have showed that biliary diversions in children with cholestasis are safe procedures with low morbidity and mortality, and that they can reduce inflammation and ongoing liver injury, therefore delaying or avoiding the need for liver transplantation in some patients.
Topics: Alagille Syndrome; Biliary Tract Surgical Procedures; Child; Cholestasis, Intrahepatic; Humans
PubMed: 32861450
DOI: 10.1016/j.sempedsurg.2020.150946 -
Clinical Genetics Jan 2019The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important... (Review)
Review
The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes.
Topics: Alagille Syndrome; CADASIL; Cardiovascular Diseases; Cell Proliferation; Ectodermal Dysplasia; Humans; Limb Deformities, Congenital; Mutation; Receptor, Notch1; Receptor, Notch2; Receptor, Notch3; Scalp Dermatoses
PubMed: 29767458
DOI: 10.1111/cge.13382 -
Gastroenterology Mar 2018Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations....
BACKGROUND & AIMS
Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms.
METHODS
Mice with a missense mutation (H268Q) in Jag1 (Jag1 mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1 mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1 livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1 to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1 via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines.
RESULTS
Jag1 mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1 mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1 liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1 cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1 compared with JAG1.
CONCLUSIONS
In mice, expression of a missense mutant of Jag1 (Jag1) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1 does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.
Topics: Alagille Syndrome; Animals; Bile Ducts, Intrahepatic; Cell Differentiation; Coculture Techniques; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; HEK293 Cells; Humans; Jagged-1 Protein; Male; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Morphogenesis; Mutation, Missense; Organoids; Phenotype; Receptor, Notch2; Signal Transduction; Transfection
PubMed: 29162437
DOI: 10.1053/j.gastro.2017.11.002 -
Advances in Experimental Medicine and... 2020The evolutionary highly conserved Notch pathway governs many cellular core processes including cell fate decisions. Although it is characterized by a simple molecular... (Review)
Review
The evolutionary highly conserved Notch pathway governs many cellular core processes including cell fate decisions. Although it is characterized by a simple molecular design, Notch signaling, which first developed in metazoans, represents one of the most important pathways that govern embryonic development. Consequently, a broad variety of independent inherited diseases linked to defective Notch signaling has now been identified, including Alagille, Adams-Oliver, and Hajdu-Cheney syndromes, CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), early-onset arteriopathy with cavitating leukodystrophy, lateral meningocele syndrome, and infantile myofibromatosis. In this review, we give a brief overview on molecular pathology and clinical findings in congenital diseases linked to the Notch pathway. Moreover, we discuss future developments in basic science and clinical practice that may emerge from recent progress in our understanding of the role of Notch in health and disease.
Topics: Cell Differentiation; Genetic Diseases, Inborn; Humans; Receptors, Notch; Signal Transduction
PubMed: 32060876
DOI: 10.1007/978-3-030-34436-8_9 -
Ophthalmic Genetics Apr 2022: Alagille syndrome (AS) is a multisystem disorder associated with a range of ocular anomalies affecting the anterior and posterior segments. While chorioretinal...
BACKGROUND
: Alagille syndrome (AS) is a multisystem disorder associated with a range of ocular anomalies affecting the anterior and posterior segments. While chorioretinal abnormalities have been reported in Alagille Syndrome, identification of macular dystrophy and detailed clinical and electrophysiologic descriptions are scarce.
MATERIALS AND METHODS
: A retrospective review was conducted to identify patients with a diagnosis of AS and retinal disease who were evaluated in the Division of Pediatric Ophthalmology, Strabismus, and Adult Motility at UPMC Children's Hospital of Pittsburgh. Criteria of AS included biopsy-proven bile duct hypoplasia, presence of major clinical features of AS, and molecular confirmation of the gene.
RESULTS
: This cohort included three patients, two females and one male, diagnosed with -Alagille syndrome. The diagnosis was made before 2 years of life in all patients. The mean follow-up period in our center was 8 years. All patients were found to have retinal pigmentary changes, macular atrophy, choroidal thinning, optic disc anomalies, and progressive decrease in vision. Marked retinal and macular dysfunction were found in electrophysiological studies.
CONCLUSIONS
: Three patients with molecularly confirmed Alagille syndrome demonstrated unusual retinal and macular findings, with two showing progressive vision loss. Due to the rarity of retinal findings in AS and the observed progression of disease in our patients, clinical genetic testing for retinal dystrophies could be completed in two cases. These investigations failed to reveal a separate molecular cause for the observed retinal dystrophy, helping to confirm the association with -related AS.
Topics: Adult; Alagille Syndrome; Atrophy; Child; Eye Abnormalities; Female; Humans; Jagged-1 Protein; Macular Degeneration; Male; Retina; Retinal Dystrophies
PubMed: 34886763
DOI: 10.1080/13816810.2021.2004432 -
Medicina Clinica Mar 2022
Topics: Adult; Alagille Syndrome; Carcinoma, Hepatocellular; Humans; Liver Cirrhosis; Liver Neoplasms
PubMed: 34256939
DOI: 10.1016/j.medcli.2021.06.010 -
International Journal of General... 2023This study aimed to explore the clinical predictors of Alagille syndrome (ALGS) in children and to provide a basis for early diagnosis.
BACKGROUND
This study aimed to explore the clinical predictors of Alagille syndrome (ALGS) in children and to provide a basis for early diagnosis.
METHODS
We retrospectively analyzed the clinical data of 14 children diagnosed with ALGS at the First People's Hospital of Lianyungang City from March 2016 to March 2021 and followed up the children.
RESULTS
Among the 14 patients, 9 (64.28%) had cholestasis, 12 (85.71%) had heart malformations, 13 (92.85%) had characteristic facial features, 2 (14.28%) had pruritus, and 2 (14.28%) had a positive family history. Among the 13 patients who were examined by pediatric ophthalmologists, 3 patients had ocular lesions. Among the 13 patients who underwent spine radiography, 2 had typical butterfly vertebrae. Among the 6 patients with hepatic pathology, 2 had intracellular cholestasis, 2 had reduced or no small bile duct in the portal area, 2 had small bile duct hyperplasia with massive fibrous hyperplasia and extensive inflammatory cell infiltration, and 2 underwent biliary tract exploration. Genetic testing of 12 children with ALGS revealed JAG1 gene mutations in 7 cases and NOTCH2 gene mutations in 2 cases. The abovementioned two mutant genes were not detected in any of the 3 cases. Among the 12 followed-up patients, 7 were in stable condition, 5 underwent liver transplantation, and 1 died of severe pneumonia.
CONCLUSION
Cholestatic liver disease, cardiac malformations, and abnormal facial development are predictors of ALGS in children and can be definitively diagnosed by genetic testing.
PubMed: 36636710
DOI: 10.2147/IJGM.S382430 -
Journal of Clinical Gastroenterology Aug 2023Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed... (Review)
Review
Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.
Topics: Child; Adult; Humans; Biliary Atresia; Alagille Syndrome; Gastroenterologists; Quality of Life; Cholestasis; Cholestasis, Intrahepatic; Bile Acids and Salts
PubMed: 37022007
DOI: 10.1097/MCG.0000000000001850 -
Pediatric Radiology Apr 2018Alagille syndrome is a pediatric multisystem disease with increased prevalence of cerebrovascular disease. The spectrum of cerebrovascular disease in Alagille syndrome...
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.
Topics: Adolescent; Adult; Alagille Syndrome; Cardiovascular Diseases; Cerebral Arterial Diseases; Child; Child, Preschool; Female; Humans; Infant; Male; Neuroimaging; Prevalence; Retrospective Studies
PubMed: 29362841
DOI: 10.1007/s00247-017-4043-2