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Case Report
 
HNF1B Mutation: A Rare Cause of Syndromic Biliary Hypoplasia and Neonatal Cholestasis
Keywords :
Ashok Goyal, Vignesh Vinayagamoorthy, Moinak Sen Sarma, Ujjal Poddar, Anshu Srivastava
Department of Paediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, India.



Corresponding Author
:
Dr Moinak Sen Sarma
Email: moinaksen@yahoo.com


DOI: http://dx.doi.org/10.7869/tg.655

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Hepatocyte nuclear factor 1-beta (HNF1B) is a transcription factor ubiquitously expressed in the fetus (kidney, liver, bile ducts, thymus, genital tract, pancreas, lung, and gut). It is an important factor of embryogenesis of many organs. Mutations in this protein are known to predominantly affect the genitourinary tract (renal cysts) and pancreas (maturity-onset diabetes of the young type 5 and exocrine insufficiency). In humans, heterozygous mutations of HNF1B are responsible for a dominantly inherited disease with both renal and extra renal phenotypes.1,2 Most of the HNF1B variants are de novo whole gene deletions. Hepatic manifestations can range from neonatal cholestasis to non-cholestatic liver impairment. Neonatal cholestasis has not been reported commonly and may mimic many other conditions. Here we report a 2-month-old boy with HNF1B deletion presenting with neonatal cholestasis, facial dysmorphism and an affected sibling. 

Case Report

Sixty day old boy (post conceptional age 45 weeks), third born of a non-consanguineous marriage was referred with progressive jaundice, high coloured urine, pigmented stools and poor weight gain. There were no other systemic complaints. Development and immunisation were appropriate for age. General physical examination of the index child showed gross facial dysmorphism (Figure 1) and soft hepatomegaly (liver span 7 cm). Bones, spine and other systems were normal. Anthropometric parameters Z scores were weight for age -3.7, length for age -4.2, weight for length 0.4 & head circumference 37cm (normal for length). 



The first male sibling had neonatal cholestasis, pale stools, ventricular septal defect, hypospadiasis and a similar facial dysmorphism. Liver histology showed bridging fibrosis, bile ductular proliferation, portal tract expansion and ductal plate malformation. Surgical findings were suggestive of type III extrahepatic biliary atresia and he underwent a portoenterostomy in another tertiary referral hospital. Post-surgery, the sibling died at 5th month of life with worsening liver functions. Second male sibling aged 1.5 year old and both parents were asymptomatic for any disease.  Other family members in the second generation were affected with liver or urogenital abnormalities (Figure 2). 




In the index case, complete blood counts, renal function test, arterial blood gas, blood sugars and urine routine microscopy were normal. Liver function tests showed total/direct serum bilirubin 12.1/6.6 mg/dL, serum aspartate aminotransferase 262 U/L, serum alanine aminotransferase 97 U/L, total protein 5.3 g/dL, albumin 3.8 g/dL, alkaline phosphatase 639 U/L, gamma glutamyl transferase 1005 U/L, international normalized ratio (INR) 1.02. Abdominal ultrasonography showed small sized (8 mm) gallbladder, non-visualised common bile duct and multiple small cysts in bilateral kidneys. Two dimensional cardiac echocardiogram, X-ray dorso-lumbar spine & direct ophthalmoscopy were normal. Liver histology showed distortion of lobular architecture with occasional portal tract expansion and paucity of inter-lobular bile ducts with bile duct to portal tract ratio of 0.2 (normal 0.9-1.8). Electron microscopy of liver biopsy showed maintained architecture and reduced number of peroxisomes. Whole exome sequencing showed heterozygous mutation in Exon 1c.73G>T (p.Val25Leu) of HNF1B gene. Nutritional support and multivitamin supplementation was provided to which growth parameters improved. At 180 days follow-up, the liver and renal function test showed no worsening. 

Discussion

Mutations in HNF1B are associated with a wide array of clinical phenotypes without a clear genotype-phenotype association. Till date, around 230 mutations in HNF1B have been described3.  HNF-1 is expressed in embryonic liver and biliary apparatus and has been shown to be important in hepatobiliary morphogenesis in conditional knockout mice models. These mice presented with severe jaundice caused by abnormalities of the gall bladder and intrahepatic bile ducts4,5. It has also been shown that HNF-1 controls the genes that are involved in bile acid transport and metabolism5,6. Hepatic manifestation of HNF1B mutation may mimic features of other multisystemic syndromes such as Alagille (AGS) and Zellweger spectrum disorders. Mild liver dysfunction is known. Neonatal onset cholestatic form represents a severe hepatic phenotype. Our index patient presented with persisting cholestasis which was consistent with the known hepatic phenotype. The sibling had a documented atretic biliary system requiring portoenterostomy. This feature has not been reported so far in humans. Another atypical feature was the facial dysmorphism in the both siblings. Kitanaka et al. reported a novel mutation (H153N missense mutation) in HNF1B where patient presented with neonatal cholestasis, liver dysfunction and diabetes mellitus7. The natural history of cholestasis is variable though most patients show improvement by first birthday8. Ductopenia on liver biopsy in syndromic child can mimic features seen in AGS. Therefore, HNF1B mutation should be taken into consideration as one of the underlying causes of syndromic biliary hypoplasia. Long term follow-up in the index patient needs to be seen.

References
  1. Bellanné-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med 2004;140: 510-517.
  2. Bingham C, Hattersley AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant 2004;19:2703-2708.
  3. Stenson PD, Mort M, Ball EV, et al. The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–677. 
  4. Coffinier C, Barra J, Babinet C, Yaniv M. Expression of the vHNF1/ HNF1 homeoprotein gene during mouse organogenesis. Mech Dev 1999; 89:211– 213.
  5. Coffinier C, Gresh L, Fiette L, et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1. Development 2002; 129:1829–1838. 
  6. Shih DQ, Bussen M, Sehayek E, et al. Hepatocyte nuclear factor-1 is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet 2001; 27:375–382. 
  7. Kotalova R, Dusatkova P, Cinek O, et al. Neonatal cholestasis and HNF1B gene deletion World J Gastroenterol 2015; 21: 2550-2557.
  8. Clissold RL, Shaw-Smith C, Turnpenny P, et al. Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder. Kidney Int. 2016; 90:203–211.