Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations Maria Fotoulaki, MD,a Styliani Giza, MD,a Milan Jirsa, MD,b Tassos Grammatikopoulos, MD,c Rosa Miquel, MD,d Prodromos Hytiroglou, MD,e Ioannis Tsitouridis, MD,f A.S. Knisely, MDg

A 27-month-old girl presented with a short history of jaundice initially abstract attributed to drug-induced liver injury. During the preceding 20 days, she had received a 10-day course of cefprozil and 2 doses of a homeopathic preparation of cantharidin for cystitis. Severe conjugated hyperbilirubinemia was present with normal g-glutamyl transpeptidase activity. Liver biopsy aFourth Department of Pediatrics and eDepartment of revealed marked canalicular and hepatocellular cholestasis, with moderate Pathology, Faculty of Health Sciences, School of Medicine, f hepatocellular disarray, as well as evidence of chronicity, including moderate Aristotle University of Thessaloniki and Department of Radiology, Papageorgiou General Hospital of Thessaloniki, portal-tract and perisinusoidal fibrosis. Immunohistochemical studies Thessaloniki, Greece; bCentre for Experimental Medicine, revealed that bile salt export pump expression was preserved, whereas Institute for Clinical and Experimental Medicine, Prague, Czech Republic; cPaediatric Liver, Gastroenterology, and canalicular g-glutamyl transpeptidase expression was largely absent. An Nutrition Centre, and dLiver Histopathology Service, Institute inherited cholestatic disorder was suspected. The entire coding region of of Liver Studies, King’s College Hospital, London, United g ABCB11 Kingdom; and Institut für Pathologie, Medizinische , encoding bile salt export pump, was analyzed. The patient was found Universität Graz, Graz, Austria to be a compound heterozygote for the missense mutation c.3148C.T Dr Fotoulaki evaluated and managed the patient (p.Arg1050Cys) associated with benign recurrent intrahepatic cholestasis clinically, conceived and designed the study, type 2 in the homozygous state and for the nonsense mutation c.3904G.T coordinated and supervised data collection, drafted (p.Glu1302Ter) associated with progressive familial intrahepatic cholestasis the initial manuscript, and reviewed and revised the manuscript; Dr Giza collected and interpreted data type 2. Despite initial improvement with ursodeoxycholic acid, over the and drafted and reviewed the initial manuscript; Dr course of 5 years the patient developed cirrhosis that required liver Jirsa performed molecular studies, analyzed and transplant. Our report emphasizes the need for molecular studies even interpreted the data, and reviewed and critically in patients with putatively “explained” cholestasis to reveal the entire revised the manuscript; Dr Grammatikopoulos evaluated and managed the patient clinically and spectrum of inherited cholestatic disorders. reviewed the manuscript; Dr Miquel performed histologic, histochemical, and immunohistochemical studies, analyzed and interpreted the data, and reviewed the manuscript; Dr Hytiroglou performed Cholestasis may reflect disturbances of We describe a girl with severe histologic and histochemical studies, analyzed and interpreted the data, and reviewed and critically bile-acid homeostasis mediated by cholestasis, initially attributed to drug- revised the manuscript; Dr Tsitouridis performed transport proteins (“transporters”)in induced liver injury (DILI), who proved imaging-studies evaluations, analyzed and hepatocyte and cholangiocyte to be a compound heterozygote for interpreted the data, and reviewed the manuscript; membranes. Conjugated bile acids are PFIC2-associated and BRIC2-associated Dr Knisely performed histologic, histochemical, and ABCB11 mutations. Over 5 years, her immunohistochemical studies, analyzed and secreted into bile by bile salt export interpreted the data, and reviewed and critically pump (BSEP), a transporter at the status evolved from DILI, DIC, and/or revised the manuscript; and all authors approved hepatocyte canaliculus. Variants of the BRIC2 to PFIC2, requiring liver the final manuscript as submitted and agree to be BSEP-encoding gene, ABCB11, that transplant. accountable for all aspects of the work. cause absolute or functional BSEP DOI: https://doi.org/10.1542/peds.2018-2146 deficiency confer susceptibility to Accepted for publication Dec 13, 2018 progressive familial intrahepatic CASE REPORT cholestasis (PFIC) type 2 (PFIC2), A 27-month-old girl with a 6-day To cite: Fotoulaki M, Giza S, Jirsa M, et al. benign recurrent intrahepatic history of jaundice and dark urine, born Beyond an Obvious Cause of Cholestasis in cholestasis (BRIC) type 2 (BRIC2), and to nonconsanguineous parents after an a Toddler: Compound Heterozygosity for ABCB11 Mutations. Pediatrics. 2019;143(5):e20182146 drug-induced cholestasis (DIC).1 unremarkable first pregnancy, was

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 143, number 5, May 2019:e20182146 CASE REPORT referred for care. She had experienced interpreted as indicating subclinical nonsense mutation, c.3904G.T palmar pruritus from infancy. A chronicity. BSEP expression was (HGMD identifier CM081484), which lower–urinary tract infection with preserved (Fig 2B), whereas is predicted to introduce a premature Escherichia coli, diagnosed 20 days canalicular expression of GGT, an stop codon at p.1302 (p.Glu1302Ter). earlier, had been treated with oral ectoenzyme, was nearly absent The paternal mutation has been cefprozil (30 mg/kg per day) for 10 (Fig 2C). Expression of the found in BRIC2.2 The maternal days. Because dysuria persisted, she transporter multidrug mutation has been found in PFIC2.3 received 2 doses of oral cantharidin resistance–associated protein 2 was Given 2 pathogenic mutations in homeopathically compounded preserved but with displacement to trans, we did not at that time (“cantharis,” 200 mg each, 2 days basolateral aspects of hepatocytes sequence ATP8B1. Exomic sequencing apart). She developed jaundice 5 days (Fig 2D), a nonspecific phenomenon that included ATP8B1 was, however, after the first dose. Her personal and in cholestasis. Another ectoenzyme, undertaken subsequently. family history were otherwise alanyl aminopeptidase, and unremarkable. Examination revealed a structurally similar molecule On follow-up, hyperbilirubinemia icterus, scratch marks, and without enzymatic activity, biliary subsided without resolving. When the hepatomegaly. Laboratory glycoprotein (carcinoembryonic parents withdrew UDCA on their investigations revealed a normal antigen), were well expressed along own, pruritus reappeared. Three hemogram and international bile canaliculi (not shown). similar exacerbations of cholestasis normalized ratio (0.85), elevated total were recorded approximately once The child’s jaundice deepened. On the bilirubin and direct bilirubin values per year. No triggering events were ninth day of hospitalization, (19 and 10.13 mg/dL, respectively), identified. ursodeoxycholic acid (UDCA) was elevated aspartate transaminase begun, with gradual improvement activity (113 IU/L), and normal After 2 years lost to our care, the seen (total bilirubin 8.73 mg/dL and alanine transaminase and g-glutamyl patient was hospitalized again, direct bilirubin 6.32 mg/dL after 1 transferase (GGT) activity (46 and 7 5 years after the original month). IU/L, respectively). Serum copper and presentation. Jaundice, pruritus, and ceruloplasmin, urine copper, and Mutation in ATP8B1 or ABCB11 was hepatomegaly were apparent, with serum a-1-antitrypsin values all considered because cholestasis conjugated hyperbilirubinemia, were normal. No evidence for associated with mutation in either is elevated transaminase activity and hepatotropic-virus infection or generally not partnered with elevated international normalized ratio values, autoimmunity was found. Abdominal serum GGT activity. Bland canalicular hypoalbuminemia, and pancytopenia ultrasonography and MRI revealed cholestasis characterizes ATP8B1 ascribed to hypersplenism. MRI no abnormality. DILI caused by disease; this patient, however, had results confirmed hepatomegaly, with cefprozil or cantharidin was substantial lobular disarray. That nodularity and periportal edema, considered, although published BSEP was expressed was consonant splenomegaly, and gallbladder sludge reports were lacking. with age at presentation with icterus and stones. Esophageal variceal because the absence of BSEP rupture prompted referral for living- Liver biopsy revealed marked expression characterizes PFIC2, related liver transplant, on which canalicular and hepatocellular which manifests in infancy. Thus, molecular analysis results confirmed cholestasis with moderate ABCB11 was clinically and the ABCB11 mutations previously hepatocellular disarray, portal-tract histopathologically the initial identified and revealed fibrosis, and perisinusoidal fibrosis candidate for Sanger sequencing (the heterozygosity for the ABCB11 (Fig 1 A–C). Portal tracts and lobules technique then available). Analysis of variant c.1331T.C (p.Val444Ala), were inflamed. Interlobular bile ducts its entire coding region revealed which is known to reduce BSEP appeared unremarkable; ductular compound heterozygosity for 2 expression, and the unusual TJP2 reaction was minimal. Orcein staining known pathogenic mutations: (tight junction protein 2) variant disclosed scant metallothionein a paternal missense mutation, c2732A.G (p.Tyr911Cys) (GenBank deposits in periportal hepatocytes. On c.3148C.T (GenBank Single Single Nucleotide Polymorphism immunohistochemical study, many Nucleotide Polymorphism Database Database identifier rs780609130; hepatocytes marked ectopically for identifier rs72549398; Human Gene HGMD identifier CM154706), the cholangiocyte-associated antigen Mutation Database [HGMD] which was of uncertain pathogenicity. cytokeratin 7 (Fig 2A). Like identification CM042275), which is The explanted liver was cirrhotic metallothionein deposits, such predicted to cause the without malignancy. At this writing, marking is generally observed in nonsynonymous amino-acid change 2 years after transplant, the child prolonged cholestasis and thus p.Arg1050Cys, and a maternal is well.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 FOTOULAKI et al FIGURE 1 Histologic findings: liver-biopsy specimen (all magnifications of original images). A, Moderate hepatocellular disarray with cholestasis, cytoplasmic swelling, and cell plate thickening. An apoptotic hepatocyte is seen (short arrow). Bile-duct profiles (long arrows) are preserved in a portal tract (hematoxylin and eosin; 3200). B, Prominent canalicular cholestasis (arrows; bile plugs) accompanied by hepatocellular swelling and anisocytosis (hematoxylin and eosin; 3400) in this centrilobular region. C, Reticulin stain demonstrating fibrosis of portal tracts, both in isolation (short arrow) and with extension perisinusoidally (long arrow) into the lobule (340).

DISCUSSION expression and function is under cholestasis per se. Thus, events 4 When cholestasis occurs in active study, correlations among recapitulated the spectrum of BSEP- combination with normal GGT values, clinical-chemistry, histopathologic, related liver disease, from DILI and genetic findings are not generally manifest as DIC through BRIC2 to to suspect inherited disorders is sought in patients with DILI and/or PFIC2. important. This 27-month-old girl DIC. In our patient, chronic presented with severe cholestasis, cholestasis could be ascribed to Familial intrahepatic cholestasis originally thought to represent DILI, compound heterozygosity for includes disorders of reduced bile and persistently low GGT activity. pathogenic mutations in ABCB11, flow without anatomic obstruction, Although DILI associated with with drug exposure being a trigger of viz, progressive familial intrahepatic alterations in canalicular-transporter rather than causing acute intrahepatic cholestasis (PFIC), BRIC, and

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 143, number 5, May 2019 3 FIGURE 2 Immunohistochemical findings: biopsy specimen (all with diaminobenzidine chromogen and hematoxylin counterstain; all magnifications of original images). A, Many hepatocytes mark ectopically for cytokeratin 7. Expression of this antigen is normally found only in cholangiocytes (arrow; bile-duct radicle within portal tract), although here, nearly every cell in the lobule is decorated (3100). B, Preserved canalicular immunoreactivity for BSEP (3200). C, No canalicular marking for GGT present (arrows; bile plugs). Compare this with the insert: normal control (3200). D, Canalicular immu- noreactivity for multidrug resistance–associated protein 2 preserved but with displacement to basolateral aspects of hepatocytes. Compare the relatively crisp marking for BSEP (Fig 2B) found in a parallel section. Note giant cell change and multinucleation at several sites (3200). intrahepatic cholestasis of pregnancy BRIC (mild and transitory) and PFIC Unlike most cholestatic conditions, (ICP). Until recently, PFIC was (severe and permanent).7,8 ICP is PFIC1, BRIC1, PFIC2, BRIC2, and PFIC4 classified into 3 types5; a fourth BRIC triggered by hormonal shifts are characterized by normal or near- variant is newly distinguished.6 These in gestation; all 4 genes may normal GGT values. GGT activity in are associated with mutations in contribute.9,10 ICP overlaps with DIC PFIC3 is high; intermittently manifest ATP8B1 (PFIC1), ABCB11 (PFIC2), in which exogenous hormones disease is, oddly, not referred to as ABCB4 (PFIC3), and TJP2 (PFIC4). are implicated, such as those in BRIC3. Within low-GGT familial Mutations in ATP8B1 and ABCB11 can contraceptive agents. How intrahepatic cholestasis, ABCB11 disease also result in milder phenotypes paraneoplastic cholestasis exhibits higher transaminase activity (BRIC1 and BRIC2, respectively).2 (Stauffer syndrome)11 reflects than does ATP8B1 disease,13,14 However, intermediate phenotypes genetic constitution is poorly as does TJP2 disease (personal form a continuum between understood.12 observations).

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 FOTOULAKI et al In our patient, transaminase expressed along bile canaliculi in associated with cholestatic disorders, elevations and histopathologic PFIC2 supports this hypothesis. as in our patient. Case descriptions features suggested ABCB11 rather Alternatively, disordered trafficking of will help to elucidate the full than ATP8B1 as being likely mutated ectoenzymes, such as GGT, to the spectrum of inherited cholestasis and (severe TJP2 disease had not been canalicular membrane (as in permit terminology that meaningfully defined when she was first microvillus inclusion disease addresses genetic defects and evaluated). Compound heterozygosity [personal observations] or clinicopathologic features. for 2 known pathogenic ABCB11 arthrogryposis–renal- – mutations was found. Homozygosity dysfunction cholestasis ACKNOWLEDGMENTS for the paternal mutation c.3148C.T syndrome17,18) or abnormal underlay BRIC2 in 2 adult sisters.2 composition of the canalicular We thank Prof R. J. Thompson (King’s Expression of BSEP was not assessed membrane (as in ATP8B1 disease19) College London) for access to findings histopathologically, but in vitro assay may abrogate canalicular GGT from genetic study as well as for yielded predominantly immature expression, without which serum GGT helpful discussions and M. Neroldová BSEP.15 The maternal mutation activity remains low. We expect that and V. Stránecký for processing c.3904G.T is recorded in the BSEP in our patient was dysfunctional and interpreting exome- compound heterozygous state in 3 because biomarkers reflected sequencing data. unrelated patients with PFIC2.3 hepatocellular injury, which we Among them, 2 were heterozygotes ascribe to retention of bile salts . for splice site mutations (c.2178+G within hepatocytes. Heterozygosity ABBREVIATIONS A and c.611+1G.A). Neither for the TJP2 mutation found is, we expressed BSEP. In the third, who think, likely noncontributory to BRIC: benign recurrent was a heterozygote for the missense cholestasis; it has been reported in intrahepatic cholestasis mutation c.890A.G (p.Glu297Gly), the homozygous form in an adult BRIC1: benign reccurent BSEP expression was scant. That our patient with deafness20 but without intrahepatic cholestasis patient expressed clinical liver disease (X. Gu, PhD, type 1 immunohistochemically personal communication, 2018), BRIC2: benign recurrent demonstrable BSEP indicates suggesting limited pathogenicity. We intrahepatic cholestasis functional rather than absolute BSEP can offer no explanation based on type 2 deficiency, as with combinations of ABCB11 or TJP2 mutation for the BSEP: bile salt export pump other ABCB11 mutations in patients deficiency of GGT expression while 2 DIC: drug-induced cholestasis with intrahepatic cholestasis.15 other canalicular species similar in DILI: drug-induced liver injury GGT: g-glutamyl transferase When our patient received UDCA, cell-membrane attachment, biliary HGMD: Human Gene Mutation clinical and biomarker status glycoprotein, and alanyl Database improved, but she was not freed from aminopeptidase, were unremarkably ICP: intrahepatic cholestasis of disease: episodes of cholestasis expressed. PFIC2, with unremarkable pregnancy recurred, and cholelithiasis and canalicular GGT expression, is PFIC: progressive familial cirrhotic hepatomegaly developed, clinically a steady state. DIC and/or fl intrahepatic cholestasis with portal hypertension manifested BRIC, by contrast, are in ux during PFIC1: progressive familial as splenomegaly, hypersplenism, and onset and again during resolution. fi intrahepatic cholestasis variceal hemorrhage, requiring liver Perhaps transient de ciency of GGT type 1 transplant. She moved from DIC and/ expression is usual in BRIC2; the PFIC2: progressive familial or BRIC to PFIC. point has not been studied. GGT handling in the cholestatic liver intrahepatic cholestasis Two mechanisms explain failure of clearly awaits investigation. type 2 GGT values to rise despite conjugated PFIC3: progressive familial hyperbilirubinemia.16 GGT at the intrahepatic cholestasis CONCLUSIONS canalicular membrane gains access to type 3 plasma when leached by bile salts Inherited disorders should be PFIC4: progressive familial into bile that seeps between damaged considered in cholestasis with normal intrahepatic cholestasis hepatocytes into the space of Disse. If GGT activity even when the clinical type 4 bile lacks bile salts, as in ABCB11 history suggests DILI and/or DIC. TJP2: tight junction protein 2 disease, GGT activity in serum Molecular diagnostics can reveal UDCA: ursodeoxycholic acid remains low. That GGT is normally novel combinations of mutations

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 143, number 5, May 2019 5 Address correspondence to Maria Fotoulaki, MD, Fourth Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, 56403 Thessaloniki, Greece. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Jirsa was supported by the Ministry of Health of the Czech Republic (grant NV18-06-00032); the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES 1. de Lima Toccafondo Vieira M, Tagliati 8. Lam CW, Cheung KM, Tsui MS, Yan MS, severe FIC1 and BSEP deficiencies. CA. Hepatobiliary transporters in drug- Lee CY, Tong SF. A patient with novel J Hepatol. 2010;53(1):170–178 induced cholestasis: a perspective on ABCB11 gene mutations with phenotypic 15. Byrne JA, Strautnieks SS, Ihrke G, et al. the current identifying tools. Expert transition between BRIC2 and PFIC2. Missense mutations and single Opin Drug Metab Toxicol. 2014;10(4): J Hepatol. 2006;44(1):240–242 nucleotide polymorphisms in ABCB11 581–597 9. Dixon PH, Sambrotta M, Chambers J, impair bile salt export pump 2. van Mil SW, van der Woerd WL, van der et al. An expanded role for processing and function or disrupt pre- Brugge G, et al. Benign recurrent heterozygous mutations of ABCB4, messenger RNA splicing. Hepatology. intrahepatic cholestasis type 2 is ABCB11, ATP8B1, ABCC2 and TJP2 in 2009;49(2):553–567 intrahepatic cholestasis of pregnancy. caused by mutations in ABCB11. 16. Knisely AS, Gissen P. Trafficking and – Sci Rep. 2017;7(1):11823 Gastroenterology. 2004;127(2):379 384 transporter disorders in pediatric 3. Strautnieks SS, Byrne JA, Pawlikowska 10. Vitale G, Gitto S, Raimondi F, et al. cholestasis. Clin Liver Dis. 2010;14(4): L, et al. Severe bile salt export pump Cryptogenic cholestasis in young and 619–633 adults: ATP8B1, ABCB11, ABCB4, and deficiency: 82 different ABCB11 17. Gissen P, Johnson CA, Morgan NV, et al. TJP2 gene variants analysis by high- mutations in 109 families. Mutations in VPS33B, encoding throughput sequencing. Gastroenterology. 2008;134(4): a regulator of SNARE-dependent J Gastroenterol. 2018;53(8):945–958 1203–1214 membrane fusion, cause 4. Zollner G, Thueringer A, Lackner C, 11. Barta SK, Yahalom J, Shia J, Hamlin PA. arthrogryposis-renal dysfunction- Fickert P, Trauner M. Alterations of Idiopathic cholestasis as cholestasis (ARC) syndrome. Nat Genet. – canalicular ATP-binding cassette a paraneoplastic phenomenon in 2004;36(4):400 404 Hodgkin’s lymphoma. Clin Lymphoma transporter expression in drug-induced 18. Cullinane AR, Straatman-Iwanowska A, Myeloma. 2006;7(1):77–82 liver injury. Digestion. 2014;90(2):81–88 Zaucker A, et al. Mutations in VIPAR 12. Blackmore L, Knisely AS, Hartley JL, cause an arthrogryposis, renal 5. van Mil SW, Houwen RH, Klomp LW. et al. Polymorphisms in ABCB11 and dysfunction and cholestasis syndrome Genetics of familial intrahepatic ATP8B1 associated with development of phenotype with defects in epithelial cholestasis syndromes. J Med Genet. severe intrahepatic cholestasis in polarization [published correction 2005;42(6):449–463 Hodgkin’s lymphoma. J Clin Exp Hepatol. appears in Nat Genet. 2011;43(3):277]. 6. Sambrotta M, Strautnieks S, Papouli E, 2013;3(2):159–161 Nat Genet. 2010;42(4):303–312 et al; University of Washington Center 13. Davit-Spraul A, Fabre M, Branchereau S, 19. Paulusma CC, Groen A, Kunne C, et al. for Mendelian Genomics. Mutations in et al. ATP8B1 and ABCB11 analysis in 62 Atp8b1 deficiency in mice reduces TJP2 cause progressive cholestatic liver children with normal gamma-glutamyl resistance of the canalicular – disease. Nat Genet. 2014;46(4):326 328 transferase progressive familial membrane to hydrophobic bile salts 7. van Ooteghem NA, Klomp LW, van Berge- intrahepatic cholestasis (PFIC): and impairs bile salt transport. Henegouwen GP, Houwen RH. Benign phenotypic differences between PFIC1 Hepatology. 2006;44(1):195–204 and PFIC2 and natural history. recurrent intrahepatic cholestasis 20. Gu X, Guo L, Ji H, et al. Genetic testing Hepatology. 2010;51(5):1645–1655 progressing to progressive familial for sporadic hearing loss using intrahepatic cholestasis: low GGT 14. Pawlikowska L, Strautnieks S, targeted massively parallel sequencing cholestasis is a clinical continuum. Jankowska I, et al. Differences in identifies 10 novel mutations. Clin J Hepatol. 2002;36(3):439–443 presentation and progression between Genet. 2015;87(6):588–593

Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 FOTOULAKI et al Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations Maria Fotoulaki, Styliani Giza, Milan Jirsa, Tassos Grammatikopoulos, Rosa Miquel, Prodromos Hytiroglou, Ioannis Tsitouridis and A.S. Knisely Pediatrics originally published online April 23, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2019/04/19/peds.2 018-2146 References This article cites 20 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2019/04/19/peds.2 018-2146#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Gastroenterology http://www.aappublications.org/cgi/collection/gastroenterology_sub Hepatology http://www.aappublications.org/cgi/collection/hepatology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations Maria Fotoulaki, Styliani Giza, Milan Jirsa, Tassos Grammatikopoulos, Rosa Miquel, Prodromos Hytiroglou, Ioannis Tsitouridis and A.S. Knisely Pediatrics originally published online April 23, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2019/04/19/peds.2018-2146

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 28, 2021