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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...
Context in source publication
Context 1
... function was impaired (serum creatinine 0.59 mg/dL, es- timated glomerular filtration rate 35 ml/min/1.73m 2 , Chronic Kidney Disease KDIGO stage 3), with metabolic acidosis and tubular proteinuria; he also had polyuria (7 mL/Kg/h) during hospitalization with depressed breg- matic fontanelle. The laboratory tests performed during hospitalization and follow-up are reported in Table 1. ...
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Pediatric patients with liver disease commonly experience itching, also known as pruritus. This symptom may seem to be a mere inconvenience, but can actually significantly affect the quality of life of these patients, including impairing their sleep and worsening their mental health. The cause of itching in liver disease is not fully...
Objective
(s): To assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life (HRQoL) in children with Alagille syndrome ( ALGS).
Study design
This analysis used data from the ICONIC trial, a Phase 2 study with a 4-week double-blind, placebo-controlled, randomized drug withdraw...
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end‐stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase‐to‐platelet ratio index (APRI), Fibrosis‐4 score (FIB‐4), and conjugated bilirubin as biomarkers to ass...
Alagille syndrome (AS) is an autosomal dominant multisystem disorder which can lead to hepatopathy and the development of focal hepatic lesions. The majority of the hepatic lesions are benign, including regenerative nodules, focal hyperplasia, and adenoma. Hepatocellular carcinoma (HCC) is extremely rare in AS, with very few cases reported in the l...
Citations
... Our patient showed early radiological evidence of pancreatic involvement (limited to the pancreatic head) with no signs of pancreatic insufficiency or dysfunction, suggesting the importance of a long-term endocrine follow-up and strict monitoring of pancreatic insufficiency. Mutations or deletions of the HNF1β gene have been described in correlation with different hepatic phenotypes, including NC, adult-onset cholestasis, non-cholestatic liver disease (6)(7)(8)(9)(10)(11)(12)(20)(21)(22), and, more recently, pediatric hepatocellular carcinoma (9,23). The cholestasis resolved in all the described neonatal cases, except for one patient who developed hepatocellular carcinoma (9) and one who required a liver transplantation (12). ...
Neonatal cholestasis can be caused by several conditions, with biliary atresia being the major cause. Genetic and endocrinological etiologies represent other possibilities, with most of them requiring a rapid diagnosis and a specific treatment. We describe a neonatal case of severe cholestasis with low gamma glutamyl transferase in a child presenting with multiple abnormalities, including pituitary stalk interruption syndrome and consequent hypopituitarism. The cholestasis was rapidly resolved with hormone therapy. Genetic analysis showed a de novo 17q chromosome deletion, including the HNF1β gene implicated in liver damage, and this was considered causative of the complex clinical phenotype. Our case highlights the relationship between congenital hypopituitarism and HNF1β gene deletion in 17q12 deletion syndrome as a severe neonatal cholestasis etiology, emphasizing the need to be especially vigilant in cases with associated hypoglycemia. Prompt endocrine evaluation and genetic testing are crucial in neonatal cholestasis to start targeted therapy and long-term monitoring, which could mitigate serious complications.
... 4 In clinical practice, pathogenic HNF1β mutations, including missense mutations, small insertions-deletions, or whole-gene deletions, have been reported to be associated with cholestatic disease with abnormally increased liver enzymes. 5,6 However, the incidence of cholestasis associated with HNF1β mutations is rare, and almost all reported cases have occurred in neonates. Here, we report a case of adultonset cholestasis caused by HNF1β mutation, which exhibited paucity of the portal area in histopathological examination. ...
... 8 To the best of our knowledge, only six cases of cholestasis associated with HNF1β mutations have been reported thus far, and noticeably, all of them have occurred in neonates. 6 Herein, we have presented a case of late-onset diagnosis in an adult patient, thereby contributing to the understanding of this rare disease. A notable clinical characteristic in our case of cholestasis associated with HNF1β mutation was the co-occurrence of renal cysts. ...
Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.
... However, the paucity of Sox9-expressing biliary precursors and mature bile ducts in ΔS6 livers is strikingly similar to other models of RiBi dysfunction in which abnormal organ development stems from a deficiency of specific progenitor cell types due to aberrant translation of critically required transcription factors or signaling effectors that are normally translated at or near threshold levels [64,84,85]. Liver disease in NAIC overlaps with the hepatic component of Alagille syndrome (AGS; OMIM #118450), an autosomal dominant disease caused by mutations in the notch signaling effectors JAG1 or NOTCH2 [86][87][88] or the transcription factor HNF1B [89]. Overlap in hepatic phenotypes is also seen between ΔS6 mice and mice harboring loss-of-function alleles in genes encoding notch pathway signaling components [42, [90][91][92][93] or certain liver-expressed transcription factors [40]. ...
Defective ribosome biogenesis (RiBi) underlies a group of clinically diverse human diseases collectively known as the ribosomopathies, core manifestations of which include cytopenias and developmental abnormalities that are believed to stem primarily from an inability to synthesize adequate numbers of ribosomes and concomitant activation of p53. The importance of a correctly functioning RiBi machinery for maintaining tissue homeostasis is illustrated by the observation that, despite having a paucity of certain cell types in early life, ribosomopathy patients have an increased risk for developing cancer later in life. This suggests that hypoproliferative states trigger adaptive responses that can, over time, become maladaptive and inadvertently drive unchecked hyperproliferation and predispose to cancer. Here we describe an experimentally induced ribosomopathy in the mouse and show that a normal level of hepatic ribosomal protein S6 (Rps6) is required for proper bile duct development and preservation of hepatocyte viability and that its insufficiency later promotes overgrowth and predisposes to liver cancer which is accelerated in the absence of the tumor-suppressor PTEN. We also show that the overexpression of c-Myc in the liver ameliorates, while expression of a mutant hyperstable form of p53 partially recapitulates specific aspects of the hepatopathies induced by Rps6 deletion. Surprisingly, co-deletion of p53 in the Rps6-deficient background fails to restore biliary development or significantly improve hepatic function. This study not only reveals a previously unappreciated dependence of the developing liver on adequate levels of Rps6 and exquisitely controlled p53 signaling, but suggests that the increased cancer risk in ribosomopathy patients may, in part, stem from an inability to preserve normal tissue homeostasis in the face of chronic injury and regeneration.
... Diabetes requiring insulin therapy occurred at an average age of 10 years in 3/5 cases, while 2/5 showed pancreatic hypoplasia with impaired pancreatic exocrine function [60][61][62][63][64]. Moreover, our group has recently described an additional case of a child with high GGT-cholestasis due to a de novo missense pathogenic variant of HNF1B, thus implicating rare mutations in HNF1B in the pathogenetic role in cholestatic liver diseases with increased GGT (Table 2) [65,66]. ...
... Interestingly, a similar clinical/histological liver phenotype was observed in 13 children from 9 unrelated consanguineous families with high GGT cholestatic liver disease, all presenting homozygous damaging variants in kinesin family member 12 (KIF12 ; Table 3) [64,65], a target gene known to be regulated by the HNF1B transcription factor [62]. ...
... HNF1B somatic mutations were observed in several human cancers, among which hepatocellular carcinoma (HCC), confirming further, as previously discussed, its role as an oncogene/tumor suppressor gene [50]. Nevertheless, the association of HCC with germline HNF1B deficiency is largely uncharted [6,65]. However, although at a very low risk, HNF1B deficiency may be associated with HCC, as in some PFIC disorders. ...
The hepatocyte nuclear factor 1β (HNF1B) gene is involved in the development of specialized epithelia of several organs during the early and late phases of embryogenesis, performing its function mainly by regulating the cell cycle and apoptosis pathways. The first pathogenic variant of HNF1B (namely, R177X) was reported in 1997 and is associated with the maturity-onset diabetes of the young. Since then, more than 230 different HNF1B variants have been reported, revealing a multifaceted syndrome with complex and heterogenous genetic, pathologic, and clinical profiles, mainly affecting the pediatric population. The pancreas and kidneys are the most frequently affected organs, resulting in diabetes, renal cysts, and a decrease in renal function, leading, in 2001, to the definition of HNF1B deficiency syndrome, including renal cysts and diabetes. However, several other organs and systems have since emerged as being affected by HNF1B defect, while diabetes and renal cysts are not always present. Especially, liver involvement has generally been overlooked but recently emerged as particularly relevant (mostly showing chronically elevated liver enzymes) and with a putative relation with tumor development, thus requiring a more granular analysis. Nowadays, HNF1B-associated disease has been recognized as a clinical entity with a broader and more variable multisystem phenotype, but the reasons for the phenotypic heterogeneity are still poorly understood. In this review, we aimed to describe the multifaceted nature of HNF1B deficiency in the pediatric and adult populations: we analyzed the genetic, phenotypic, and clinical features of this complex and misdiagnosed syndrome, covering the most frequent, unusual, and recently identified traits.
... Indeed, HNF1B-d has been recently suggested to be included in the diagnostic workup of neonatal/infantile cholestasis, and we recently reported a case of paediatric cholestasis with paucity of the interlobular bile ducts and a variable degree of periportal fibrosis due to a pathogenetic variant of HNF1B. 1 Nevertheless, its proper role in liver disease aetiopathogenesis, and particularly its association with paediatric hepatocellular carcinoma (P-HCC), is largely unexplored. ...
Background
Hepatocyte nuclear factor 1B (HNF1B ) is a member of the homeodomain-containing family of transcription factors located on 17q12. HNF1B deficiency is associated with a clinical syndrome (kidney and urogenital malformations, maturity-onset diabetes of the young, exocrine pancreatic insufficiency) and to an underdiagnosed liver involvement. Differently from HNF1A , the correlation between hepatocellular carcinoma (HCC) and germline HNF1B deficiency has been poorly evaluated.
Case report
Here, we report a novel case of a syndromic HNF1B -deficient paediatric patient that developed HCC with unique histopathological features characterised by neoplastic syncytial giant cells, which was observed only in one additional case of paediatric cholestatic liver disease of unknown origin.
Conclusions
Our case highlights the influence of HNF1B deficiency in liver disease progression and its putative association with a rare yet specific HCC histotype. We hypothesised that HCC could be secondary to the repressive effect of HNF1B variant on the HNF1A transcriptional activity.
... Of these, six were novel and included five nonsense pathogenic variants (55.6%), three frameshift pathogenic variants (33.3%), and one splicing pathogenic variant (11.1%). The pathogenic variants were located in the seven exons (6,7,11,12,14,23 and 25) that constitute the coding region of the JAG1 gene. The novel variation of NOTCH2 was the nonsense pathogenic variant c.3928C > T in exon 24. ...
... The most conserved feature of ALGS is bile duct paucity. Liver histology typically reveals a reduction in the concentration of intrahepatic bile ducts (bile duct to portal tract ratio < 0.4) [7]. As few as 60% of patients < 6 months showed paucity, whereas it was commonly found in 95% of infants aged > 6 months [6,8]. ...
Background
Alagille syndrome (ALGS) is a multisystem disorder with variable clinical penetrance. The genes responsible for this disease are JAGGED1 (JAG1) and NOTCH2. Clinical data of this disease are limited in China. The purpose of this study was to enrich the present data of Chinese children with Alagille syndrome by summarizing the clinical characteristics and genetic variations of these cases.
Case summary
From January 2011 to February 2022, 10 children were diagnosed with ALGS. The organs involved in ALGS were as follows: liver (10, 100%); heart (7, 70%); characteristic facial features (7, 70%); skeleton (4, 40%); brain (1,10%) and kidney (3, 30%). Four patients (40%) were small for gestational age. The main clinical manifestations were cholestasis, heart disease, and facial features. The median total bilirubin, direct bilirubin, and total bile acid levels were 138.75 μmol/L (normal, 3.4–20.5 μmol/L), 107.25 μmol/L (normal, 0–8.6 μmol/L), and 110.65 μmol/L (normal, 0.5–10.0 μmol/L), respectively. The median value of gamma-glutamyltranspeptidase was 223 U/L (normal, 9–64 U/L). Six (60%) children had hypercholesteremia. Eight different JAG1 gene variations and one NOTCH2 gene pathogenic variant in the 10 Chinese ALGS patients were identified.
Conclusion
Cholestasis was the most common initial presenting symptom in Chinese ALGS pediatric patients. Pathogenic variants in JAG1 and NOTCH2 are the primary mutations in Chinese children with ALGS, but we had our own unique variant spectrum. ALGS should be considered for cholestasis in infants and young children, especially those with multiorgan abnormalities.
... Liver biopsy results can be confusing when diagnosing ALGS. Hence, a newborn with HNF1 deficit due to a mutation in the HNF1 gene [39] or a KDM6A gene mutation has been reported to have cholestasis because of a lack of interlobular bile ducts, which is a classic sign of ALGS [40]. JAG1 mutations account for the majority of reported mutations, with NOTCH2 accounting for approximately 1% to 3% [41,42]. ...
Patient: Male, newborn
Final Diagnosis: Alagille syndrome
Symptoms: Cholestasis and/or gallbladder dysfunction
Medication: —
Clinical Procedure: —
Specialty: Genetics • Pediatrics and Neonatology
Objective
Unusual clinical course
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.
... Twenty-three cases with karyotypic abnormalities were identified ( and HSPA9. 73,74,76,81,83 Eighteen additional cases of known syndromes without current known genes were identified in association with non-isolated hemivertebra (Table S1). These included three cases of lumbocostoverteb- and was reported as normal in all, with two cases that also reported normal chromosomal microarray, 91 and one case of negative exome sequencing. ...
Hemivertebra is a congenital vertebral malformation caused by unilateral failure of formation during embryogenesis that may be associated with additional abnormalities. A systematic review was conducted to investigate genetic etiologies of non‐isolated hemivertebra identified in the fetal, neonatal, and infant periods using PubMed, Cochrane database, Ovid Medline, and ClinicalTrials.gov from inception through May 2022 (PROSPERO ID CRD42021229576). The Human Phenotype Ontology database was accessed May 2022. Studies were deemed eligible for inclusion if they addressed non‐isolated hemivertebra or genetic causes of non‐isolated hemivertebra identified in the fetal, neonatal, or infant periods. Cases diagnosed clinically without molecular confirmation were included. Systematic review identified 23 cases of non‐isolated hemivertebra with karyotypic abnormalities, 2 cases due to microdeletions, 59 cases attributed to single gene disorders, 18 syndromic cases without known genetic etiology, and 14 cases without a known syndromic association. The Human Phenotype Ontology search identified 49 genes associated with hemivertebra. Non‐isolated hemivertebra is associated with a diverse spectrum of cytogenetic abnormalities and single gene disorders. Genetic syndromes were notably common. Frequently affected organ systems include musculoskeletal, cardiovascular, central nervous system, genitourinary, gastrointestinal, and facial dysmorphisms. When non‐isolated hemivertebra is identified on prenatal ultrasound, the fetus must be assessed for associated anomalies and genetic counseling is recommended.
... Interestingly, a target gene upregulated by NOTCH signalling is HNF1B, having a vital role in the differentiation of hepatoblasts into ductal plate cells and the inclusion of the developing duct into the portal space. Moreover, HNF1B downregulation and mutations in HNF1B have been associated with neonatal or late-onset cholestasis and with common cancers, including endometrial, prostate, ovarian, hepatocellular, renal and colorectal tumours [139]. FXR is one of the most studied BAs receptors regulating the BAs synthesis, metabolism and intestinal reuptake. ...
Abstract: The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC
genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
... A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. Pinon et al. reported a novel case of 5-week-old boy affected by paucity of interlobular bile ducts due to an HFN1β defect [96]. He was admitted for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination, characterized by cholestatic disease, hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, paucity of interlobular bile ducts at liver biopsy, thus the diagnosis of Alagille syndrome (AGS) was considered, but excluded. ...
We highlight the main developments that have been published during the first semester of the last year in the Italian Journal of Pediatrics. We have carefully chosen information from numerous exciting progresses issued in the Journal in the field of allergy, endocrinology, gastroenterology, neonatology, nutrition, nephrology, neurology, public health, respiratory diseases and rheumatic diseases. The impact on the care of patients has been placed in the broader context of studies that appeared in other journals. We think that many observations can be used directly to upgrade management of patients.
