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Italian Journal of Pediatrics Feb 2019paucity 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... (Review)
Review
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.
Topics: Alagille Syndrome; Cholestasis, Intrahepatic; Hepatocyte Nuclear Factor 1-beta; Humans; Infant; Male
PubMed: 30791938
DOI: 10.1186/s13052-019-0617-y -
Human Mutation 2001We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 (JAG1). This data has been published by seven different laboratories in... (Review)
Review
We have summarized data on 233 Alagille syndrome patients reported with mutations in Jagged1 (JAG1). This data has been published by seven different laboratories in Europe, the United States, Australia, and Japan. Mutations have been demonstrated in 60-75% of patients with a clinically confirmed diagnosis of Alagille syndrome. Total gene deletions have been reported in 3-7% of patients, and the remainder have intragenic mutations. Seventy two percent (168/233) of the reported mutations lead to frameshifts that cause a premature termination codon. These mutations will either lead to a prematurely truncated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty three unique missense mutations were identified (13% of mutations). These were clustered in conserved regions at the 5' end of the gene, or in the EGF repeats. Splicing consensus sequence changes were identified in 15% of patients. A high frequency of de novo mutations (60-70%) has been reported. The spectrum of mutations identified is consistent with haploinsufficiency for JAG1 being a mechanism for Alagille syndrome.
Topics: Alagille Syndrome; Animals; Calcium-Binding Proteins; Diseases in Twins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mutation; Proteins; Serrate-Jagged Proteins; Twins, Dizygotic
PubMed: 11139239
DOI: 10.1002/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T -
Ryoikibetsu Shokogun Shirizu 1995
Review
Topics: Alagille Syndrome; Diet Therapy; Humans; Prognosis; Vitamins
PubMed: 8749543
DOI: No ID Found -
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 -
Current Opinion in Cell Biology Feb 2024Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged... (Review)
Review
Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.
Topics: Humans; Alagille Syndrome; Serrate-Jagged Proteins; Membrane Proteins; Calcium-Binding Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein
PubMed: 38194749
DOI: 10.1016/j.ceb.2023.102302 -
Clinics and Research in Hepatology and... Jun 2012Alagille syndrome is an embryofoetopathy, due to mutations in the gene JAG1. It is autosomic dominant with variable expressivity, or sporadic. Neonatal cholestasis is a...
Alagille syndrome is an embryofoetopathy, due to mutations in the gene JAG1. It is autosomic dominant with variable expressivity, or sporadic. Neonatal cholestasis is a main feature, due to the paucity of intrahepatic bile ducts. It can rarely develop into cirrhosis, but be responsible for a disabling pruritus and xanthomas. The other features are a peculiar facies, cardiac abnormalities, butterfly vertebrae, and ocular embryotoxon. The prognosis depends on the severity of the liver and heart diseases. Hepatocarcinoma has been reported.
Topics: Alagille Syndrome; Avitaminosis; Bile Ducts, Intrahepatic; Biliary Tract Surgical Procedures; Calcium-Binding Proteins; Diet; Humans; Incidence; Infant; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver Transplantation; Membrane Proteins; Mutation; Prognosis; Pruritus; Serrate-Jagged Proteins
PubMed: 22521120
DOI: 10.1016/j.clinre.2012.03.019 -
Clinica Chimica Acta; International... Oct 2021Alagille syndrome (ALGS) is a rare multisystem disorder caused by mutations in the JAG1 or NOTCH2 gene. However NOTCH2 gene mutations were rarely found in the Alagille...
BACKGROUND
Alagille syndrome (ALGS) is a rare multisystem disorder caused by mutations in the JAG1 or NOTCH2 gene. However NOTCH2 gene mutations were rarely found in the Alagille patients. Little is known about the clinical and pathological profiles about Alagille patients with NOTCH2 mutation.
CASE REPORT
Our case described a 16-year-old female patient manifesting as recurrent jaundice and abnormal liver function from the second week of her birth. She presented a butterfly vertebrae and typical facial features including a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with bulbous tip. Pathogenic heterozygous c.5857 C > T variant in NOTCH2 gene was found. Her liver biopsy featured by a disorder liver structure with cholestasis and fibrosis in portal area, which is different from typical bile duct paucity reported in JAG1 deficient patients.
RESULTS
A diagnosis of ALGS was made. The patient was treated with ursodeoxycholic acid and compound embryonic bovine liver extract tablets and infusion of human serum albumin to improve her clinical and pathological symptoms.
CONCLUSION
Since Alagille patients with NOTCH2 mutations have been rarely reported, our case will highlight the clinical and pathological profiles of these patients.
Topics: Adolescent; Alagille Syndrome; Animals; Cattle; Female; Humans; Jagged-1 Protein; Mutation; Receptor, Notch2; Ursodeoxycholic Acid
PubMed: 34332988
DOI: 10.1016/j.cca.2021.07.026 -
Journal of Gastrointestinal Cancer Sep 2020
Review
Topics: Adolescent; Alagille Syndrome; Carcinoma, Hepatocellular; Child; Child, Preschool; End Stage Liver Disease; Female; Follow-Up Studies; Hepatectomy; Humans; Incidental Findings; Infant; Jagged-1 Protein; Liver; Liver Neoplasms; Liver Transplantation; Male; Mutation; Receptor, Notch2; Retrospective Studies; alpha-Fetoproteins
PubMed: 32180165
DOI: 10.1007/s12029-020-00391-2 -
BMJ Case Reports May 2020Alagille syndrome (AGS) is a multisystem disorder classically involving liver and heart failure, characteristic vertebral and facial features and ocular abnormalities....
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.
Topics: Alagille Syndrome; Child; Female; Humans; Male; Tooth Demineralization
PubMed: 32475824
DOI: 10.1136/bcr-2020-234689 -
Nature Reviews. Nephrology Jul 2013Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling... (Review)
Review
Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease.
Topics: Alagille Syndrome; Calcium-Binding Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Kidney Diseases; Membrane Proteins; Receptor, Notch2; Serrate-Jagged Proteins; Signal Transduction
PubMed: 23752887
DOI: 10.1038/nrneph.2013.102