Biliary Anomalies in Patients With HNF1B Diabetes

Kettunen, Juhani; Parviainen, Helka; Miettinen, Päivi J.; Färkkilä, Martti; Tamminen, Marjo; Salonen, Pia; Lantto, Eila; Tuomi, Tiinamaija

doi:10.1210/jc.2017-00061

Cited by 25 publications

(16 citation statements)

References 37 publications

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“…The transcription factor HNF1B is an important regulator of early mouse kidney, liver and pancreas organogenesis ( Coffinier et al, 2002 ; De Vas et al, 2015 ; Gresh et al, 2004 ; Haumaitre et al, 2005 ; Heliot et al, 2013 ; Lokmane et al, 2008 , 2010 ; Massa et al, 2013 ). Heterozygous mutations in the HNF1B gene are the cause of a complex human syndrome known as renal cysts and diabetes (RCAD; OMIM #137920), characterized by early onset of diabetes and developmental abnormalities of the kidney, genital tract and pancreas, as well as a variety of renal, liver, pancreas and biliary dysfunctions ( Clissold et al, 2015 ; Barbacci et al, 2004 ; Bellanné-Chantelot et al, 2004 , 2005; Haldorsen et al, 2008 ; Haumaitre et al, 2006 ; Kettunen et al, 2017 ; Lindner et al, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Niborski

Paces-Fessy

Ricci

et al. 2021

Disease Models &Amp; Mechanisms

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Heterozygous mutations in HNF1B cause the complex syndrome Renal Cysts and Diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remains unclear as mice with heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b-ablation leads to more severe phenotypes.We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor-site. Unlike heterozygous previously characterized, heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic stage E15, originated from glomeruli, early proximal tubules (PT) and intermediate nephron segments, concurrently with a delayed PT differentiation, hydronephrosis and rare genital tract anomalies.Consistently, mRNA-sequencing showed that most down-regulated genes in embryonic kidneys were primarily expressed in early PTs and Henle's Loop and involved in ion/drug transport, organic acid and lipid metabolic processes, while the expression of previously identified targets upon Hnf1b-ablation, including cystic disease genes was weakly or not affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and rarely multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function and fibrosis, and displayed common features with a recently reported urine proteome in a RCAD pediatric cohort. Altogether our results show that HNF1B reduced levels lead to developmental disease phenotypes associated with the deregulation of a subset of its targets. They further suggest that this model represents a unique clinical/pathological viable model of the RCAD disease.

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Section: Introductionmentioning

confidence: 99%

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Niborski

Paces-Fessy

Ricci

et al. 2021

Disease Models &Amp; Mechanisms

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“…The finding that not only PBM but also other congenital malformations are associated more often with fusiform than other CM subtypes is a novel finding and could be related to their different etiopathogenesis (1). CMs may also associate with certain genetic mutations (25,26). Unfortunately, genetic testing results were not systematically registered in the present study.…”

Section: Discussionmentioning

confidence: 86%

Management strategies and treatment results of pediatric choledochal malformations in the Nordic countries

Hukkinen¹,

Björnland

Gatzinsky

et al. 2020

HPB

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Background. Incidence and long-term outcomes of choledochal malformations (CMs) in children remain unclear. Methods. Clinical characteristics, operative details, complications, and follow-up data were collected from eight pediatric surgical centers in Sweden, Norway, Denmark, and Finland, which also answered a questionnaire addressing management practices. Results. During 2000-2017, 126 pediatric CMs were diagnosed, corresponding an incidence of 1:37,400. Diagnostic, treatment, and follow-up practices varied markedly. Of patients with complete clinical data (n=119), 85% and 11% had type I and IV CMs and were managed by open hepaticojejunostomy at median age of 2.5 (interquartile range 0.46-5.8) years. Associated malformations were more common in fusiform and type IV (23%) than cystic CMs (8%, p=0.043). Pancreaticobiliary maljunction was more frequently confirmed in patients presenting with pancreatitis (26% vs. 7%, p=0.005) and with fusiform CMs (56% vs. 25%, p=0.001). Cholangitis/pancreatitis episodes, occurring in 12% during postoperative follow-up of 4.0 (2.0-7.9) years, associated with longer surveillance (OR 1.32, 95% CI 1.13-1.54, p<0.001). However, only two thirds of centers continued follow-up until adulthood. No malignancies were reported. Conclusions. CM incidence was higher than traditionally reported among Western populations. Although open hepaticojejunostomy carries good short-term outcomes, long-term morbidity is noteworthy. Standardized evidence-based management strategies and long-term follow-up are encouraged.

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“…Another report described biliary abnormalities, identified by MRCP, in six patients with HNF1B mutations. Most of them had varying types of bile duct cysts (BDCs) in the extrahepatic bile ducts, with an atypical morphology for any Todani classification [24].…”

Section: Discussionmentioning

confidence: 99%

Not only Alagille syndrome. Syndromic paucity of interlobular bile ducts secondary to HNF1β deficiency: a case report and literature review

Pinon

Carboni

Colavito³

et al. 2019

Ital J Pediatr

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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 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.

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Biliary Anomalies in Patients With HNF1B Diabetes

Abstract: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.

Cited by 25 publications

References 37 publications

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Management strategies and treatment results of pediatric choledochal malformations in the Nordic countries

Not only Alagille syndrome. Syndromic paucity of interlobular bile ducts secondary to HNF1β deficiency: a case report and literature review

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