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

Abstract

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.

Clinical and genetic analysis in Chinese children with Alagille syndrome

“…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] .…”

Best practices, challenges and innovations in pediatrics in 2019

“…Recently established laboratory diagnostic techniques have allowed to discover new causes of neonatal cholestasis. In this regard, the group of Pinon and co-workers reported on another syndromic condition characterized by cholestasis, due to a hepatic picture of paucity of intralobular bile ducts combined with renal involvement and paved the way to the inclusion of the hepatocyte nuclear factor-1-beta deficiency as a new condition to be considered in the diagnostic process of the syndromic forms with paucity of intralobular bile ducts [ 57 ].…”

Advances in paediatrics in 2019: current practices and challenges in allergy, endocrinology, gastroenterology, public health, neonatology, nutrition, nephrology, neurology, respiratory diseases and rheumatic diseases

“…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.…”