Clinical characteristics and follow-up of a newborn with Dubin-Johnson Syndrome: A clinical case report.

BACKGROUND: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive liver disorder, characterized by conjugated hyperbilirubinemia. This case report investigates the clinical characteristics and longitudinal outcomes of a neonate diagnosed with DJS. METHODS: A newborn presented with elevated bilirubin levels and abnormal liver enzyme readings. Comprehensive genetic evaluation was conducted, which included peripheral blood sample collection from the infant and both parents after obtaining informed consent and high-throughput trio exome sequencing was performed. The genetic analysis revealed 2 significant mutations in the ABCC2 gene on chromosome 10: the insertion mutation c.4237(exon30)_c.4238(exon30)ins CT, inherited from the father, and the missense mutation c.517(exon5)G > A, inherited from the mother. Both mutations were classified as pathogenic according to the ACMG 2015 guidelines, indicating a compound heterozygous inheritance pattern. The patient's treatment regimen included phototherapy, which was initiated to address her jaundice upon admission. To support liver function and regulate gut activity, oral ursodeoxycholic acid (20 mg/kg/dose, twice a day) and probiotics were administered. Additionally, a postdischarge medication plan involving a low-dose regimen of phenobarbital (3.5 mg/kg/dose, twice a day) was implemented for 2 weeks. RESULTS: During a 2-year follow-up after discharge, the infant's bilirubin levels significantly decreased, and liver enzymes, including GGT, progressively normalized. CONCLUSION: This case report enhances the understanding of DJS in neonates by emphasizing the clinical ramifications of compound heterozygous mutations within the ABCC2 gene and documenting the evolution of the disease. The gradual normalization of liver function tests suggests potential compensatory mechanisms in response to the genetic abnormalities in neonates with DJS. The correlation between the patient's genetic profile of compound heterozygosity and her milder clinical phenotype warrants attention, suggesting that this specific genetic configuration may be associated with less severe manifestations of the disease. The necessity for long-term follow-up is highlighted, recognizing that intercurrent stress conditions could influence the hepatic profile and potentially exacerbate symptoms. Such sustained observation is crucial to further delineate the genomic and clinical landscape of DJS, offering opportunities to refine prognostic and therapeutic approaches.

Excessive vincristine exposure in a child being treated for acute lymphoblastic leukaemia with underlying Dubin-Johnson syndrome: a case report.

BACKGROUND: Dubin-Johnson syndrome is a rare benign autosomal recessive condition that causes an isolated increase of conjugated bilirubin in the serum. Impaired biliary excretion is due to mutation in the multiple drug-resistance protein 2 gene (MRP2). CASE PRESENTATION: We describe the case of a 4-year-old girl being treated for acute lymphoblastic leukaemia who had a history of conjugated hyperbilirubinaemia and persistently elevated bilirubin levels on initiation of chemotherapy. During treatment for leukaemia, she was diagnosed with Dubin-Johnson syndrome for the underlying condition. Following administration of vincristine at the recommended dose of 1.5 mg/m2, an abnormally high vincristine exposure was observed (AUC > 200 µg/L*h), approximately 3 times higher than previously reported exposures in a comparable clinical setting. Vincristine dose reductions were applied on subsequent cycles of treatment and resulted in markedly reduced drug exposures, within the normal target range. CONCLUSION: This case provided a rare opportunity to assess the impact of MRP2 mutations associated with Dubin-Johnson syndrome on the pharmacokinetics of vincristine and strongly indicates that a marked dose reduction should be recommended. Clinicians should be made aware of the potential for altered drug disposition for agents such as vincristine in patients with this rare genetic condition.

In silico screening and analysis of single-nucleotide polymorphic variants of the ABCC2 gene affecting Dubin-Johnson syndrome.

BACKGROUND AND STUDY AIMS: Dubin-Johnson syndrome (DJS) is a benevolent genetic disorder of the liver with autosomal inheritance. It is a rare disorder characterized by an increase in conjugated bilirubin and anomaly in coproporphyrin clearance. DJS is caused by deleterious mutations in the ABCC2 gene. A polymorphism in the ABCC2 gene causes malfunctions in its ability to regulate the efflux of different organic anions, such as bilirubin, from hepatocytes to the canaliculi. Multidrug resistance protein 2 (MRP2) encoded by the ABCC2 gene is one of the main regulators of the export of bilirubin to respective sites. ABCC2 gene mutations have widely drawn attention in the pathology of DJS in various populations. PATIENTS AND METHODS: The ABCC2 gene was subjected to the National Center for Biotechnology Information (NCBI) database in 2020, and non-synonymous single-nucleotide polymorphisms (nsSNPs) and variants in untranslated regions were studied using different computational servers. SIFT, Protein variation effect analyzer, and PolyPhen-2 were used to retrieve the damaging Single-nucleotide polymorphisms (SNPs); PhD-SNP, SNPs&GO, and Protein Analysis Through Evolutionary Relationships were used to predict the association of nsSNPs with DJS; Mutation3D illustrated the location of variants in the protein; SNAP2, MutPred2, ELASPIC, and HOPE were used to predict the structural and functional effects of these mutations on MRP2; and I-mutant 3.0 and MuPro were used to determine the effects of polymorphism on the function of MRP2. RESULTS: In this study, 18,947 SNPs were screened from the NCBI database, followed by a series of refinement of variants using online available servers. We concluded that 41 ABCC2 gene variants are vital etiological candidates for DJS in humans. These 41 variants had highly damaging effects on the MRP2 protein, which may lead to deficient transportation capacity, thereby affecting the efflux of bilirubin across the canalicular membrane. CONCLUSION: In silico tools are an alternative approach for predicting the target SNPs. Hence, previously unreported variants can be considered strong etiological candidates for diseases related to MRP2.

A case of true vocal fold jaundice.

OBJECTIVES: While jaundice is frequently described in the sclera and skin, there are few reports of true vocal fold jaundice in patients with high bilirubin, and no reports by otolaryngologists in the literature. Here we describe a case of a patient with bilateral true vocal fold jaundice and discuss the potential pathogenesis and implications of this finding. METHODS: A 29-year-old man with history of Dubin-Johnson Syndrome presented with cough and difficulty breathing and was incidentally found to have persistent yellow discoloration of the true vocal folds bilaterally. RESULTS: Videolaryngoscopic exam demonstrated bilateral true vocal fold yellow discoloration with sparing of nearby laryngeal structures on initial presentation and follow-up exam. Direct and total bilirubin levels were found to be elevated. CONCLUSION: A patient with benign Dubin-Johnson Syndrome and elevated total and direct bilirubin was incidentally found to have bilateral vocal fold jaundice. Jaundice and the presence of bilirubin do not appear to cause harm to the function or health of the true vocal folds and may be related to the high concentration of elastin present in the true vocal folds.

Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report.

BACKGROUND: Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy are rare chronic liver disorders. Dubin-Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I and III in the urine. Intrahepatic cholestatic jaundice of pregnancy presents as pruritus, abnormal liver biochemistry and increased serum bile acids. CASE PRESENTATION: A Sri Lankan girl presented with recurrent episodes of jaundice. She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments in the hepatocytes. Urine coproporphyrin examination suggested Dubin-Johnson syndrome. Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin-Johnson syndrome. The gene study of the mother revealed the same missense variant in ABCC2/MRP2 but with a heterozygous status, and in addition a homozygous missense variant p.Val444Ala in the ATP-binding cassette, sub-family B member 11 gene ABCB11 that encodes the bile salt export pump. CONCLUSION: Dubin-Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration. Its early diagnosis prevents repeated hospital admissions and investigations. Knowledge of a well known homozygous variant in ABCB11 gene could help in the management of pregnancy.

Treatment for tuberculosis in a patient with Dubin-Johnson syndrome.

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder characterised by conjugated hyperbilirubinemia resulting from mutations of ABCC2/MRP2 gene. The beneficial effects of ursodeoxycholic acid (UDCA) and rifampicin were found to be complementary in the treatment of cholestatic liver disease secondary to DJS. We present a case of a young woman with tubercular meningitis. She was started on modified antitubercular therapy in view of conjugated hyperbilirubinemia. However, reinitiation of rifampicin resulted in redevelopment of jaundice. Liver biopsy was suggestive of DJS. The patient was started on rifampicin along with UDCA. There was improvement in hyperbilirubinemia and a full course of antituberculous therapy without further worsening of the disorder was possible. This is a rare case of DJS with tuberculosis, showing beneficial effects of rifampicin and UDCA combination therapy, which so far has been considered doubtful. It is uncertain what the level of efficacy of therapy is in various MRP2 gene mutations.

Dubin-Johnson syndrome with multiple liver cavernous hemangiomas: report of a familial case.

Dubin-Johnson syndrome (DJS) is a rare autosomal recessive inheritance disorder of bilirubin metabolism. Herein we reported a complicated but interesting case which is readily resulted in misdiagnosis or an indefinite diagnosis, and this is the first reported familial case of DJS with multiple liver cavernous hemangiomas. A 49-year-old man was referred to our hospital for jaundice and multiple low-density liver masses. Extensive laboratory investigations showed conjugated hyperbilirubinaemia and positive urine bilirubin. Microscopically, lesions were composed of blood-filled vascular channels of various sizes lined by a single layer of flat endothelial cells supported by fibrous tissue. Coarse brown granules presented in the hepatocytes of the liver lobules locating beside the tumor, particularly in the centrilobular hepatocytes, and the granules showed blue-green with Schmorl's reaction lipofuscin staining. Interestingly, one of the patient's six siblings (female) shared the same condition with him. The relationship between DJS and hemangiomas remains unclear, and it might be contributed to some hereditary factors, or probably occurred simultaneously by chance. It was certified that the true reason for the long-term unclear jaundice was DJS, which was presumed clinically to be caused by bile excretion obstacles associated with the hemangiomas. Liver biopsy and histochemical stain may be helpful to identify the reason of jaundice and avoid misdiagnosis or an indefinite diagnosis.

Dubin-Johnson syndrome coinciding with colon cancer and atherosclerosis.

Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress. Dubin-Johnson syndrome is a rare, autosomal recessive, inherited disorder characterized by biphasic, predominantly conjugated hyperbilirubinemia with no progression to end-stage liver disease. The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24. Clinical onset of the syndrome is most often seen in the late teens or early adulthood. In this report, we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A), coinciding with cholestatic liver disease in an 82-year-old male patient. The patient, suffering from advanced atherosclerosis with serious involvement of coronary arteries, developed colorectal cancer with nodal metastases. The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.

[A case of sustained cholestasis caused by acute A viral hepatitis in Dubin-Johnson syndrome].

Dubin-Johnson syndrome is a rare clinical entity. It shows intermittent symptoms such as chronic or intermittent jaundice, abdominal pain, weakness, nausea, vomiting, anorexia and diarrhea. Symptoms are precipitated or aggravated by pregnancy, alcoholism, surgical procedures and intercurrent disease. Chronic idiopathic jaundice is typical of Dubin-Johnson syndrome and its prognosis is good. We describe a case of prolonged cholestasis for more than 10 months caused by acute A viral hepatitis in a patient with Dubin-Johnson syndrome. It is a first report of cholestasis complicated by acute A viral hepatitis in a patient with Dubin-Johnson syndrome.

Severe jaundice due to coexistence of Dubin-Johnson syndrome and hereditary spherocytosis: a case report.

Dubin-Johnson syndrome is a chronic, benign, intermittent jaundice, mostly of conjugated hyperbilirubinemia. The level of bilirubin is not expected to be more than 20 mg/dl in this syndrome. In this article, we report a patient who was evaluated for hyperbilirubinemia and liver function test abnormalities and diagnosed with Dubin-Johnson syndrome coexisting with hereditary spherocytosis. We suggest that other diseases should be investigated if patients with Dubin-Johnson syndrome present with severe hyperbilirubinemia. Dubin-Johnson syndrome accompanied by hemolytic diseases might also have high coproporphyrin levels (as in Rotor's syndrome) than expected in pure Dubin-Johnson syndrome.

[Pleomorphism of the myelin-like bodies in the hepatocytes of patients with Dubin-Johnson syndrome complicated with chronic hepatitis B].

OBJECTIVE: To explore characteristics of the myelin-like bodies in the hepatocytes of patients with Dubin-Johnson syndrome (DJS) complicated with chronic hepatitis B (CHB). METHODS: 11 cases of DJS complicated with CHB and 5 cases DJS without CHB were studied clinicopathologically. The hepatocyte ultrastructure was observed with transmission electron microscope and taken photos. The data were compared and analyzed using Fisher's Exact Test. RESULTS: Deposition of myelin-like bodies can be observed in the hepatocytes of DJS patients with CHB but can not in DJS patients without CHB. The morphology of pigment varys. The electron density and volume of pigment in DJS patients with CHB can be classified into five types: brights (2/11,18.2%), reticulation (1/11, 9.1%), punctiform (6/11, 54.5%), abnormity (1/11, 9.1%) and primary type (1/11, 9.1%). The myelin-like bodies in the hepatocytes of patients with DJS are high density and round with membrance (we named it as primary type) (5/5, 100%). CONCLUSIONS: The myelin-like bodies in the hepatocytes of DJS patients with CHB possess special pleomorphism and may have important diagnostic value.

Hepatectomía derecha extendida por colangiocarcinoma intrahepático en un paciente con síndrome de Dubin-Johnson / Hepatectomy for cholangiocarcinoma in one patient with Dubin Johnson syndrome

Dubin-Johnson syndrome (SDJ) is a rare benign autosomal recessive congenital disease that causes jaundice. We report a 71 years old male with a Dubin Jonson syndrome diagnosed at the age of 40. On a ultrasound examination and magnetic resonance imaging, a liver tumor was found, that was excised. The pathology report showed a cholangiocarcinoma. During the postoperative period, the patient had a hyperbilirubinemia that subsided slowly. There are reports of hyperbilirubinemia of difficult management after hepatectomy in patients with Dubin-Johnson syndrome.

El síndrome de Dubin-Johnson (SDJ) es una patología benigna, familiar, con carácter autosómico recesivo y de aparición poco frecuente. Consiste en un defecto en la excreción hepática de la bilirrubina conjugada que permite su entrada al canalículo biliar, manifestando un cuadro clínico de ictericia silente. La asociación de esta enfermedad con colangiocarcinoma intrahepático es excepcional, siendo difícil la sospecha precoz de este diagnóstico y también el manejo de la ictericia postoperatoria. El objetivo de este trabajo es describir un caso clínico con estas características y revisión de la literatura existente. Se presenta a un paciente de sexo masculino de 71 años de edad, con antecedente de síndrome de Dubin-Johnson diagnosticado a los 40 años. Asintomático, en exámenes de rutina se encuentra un tumor hepático en la ecotomografía abdominal, que luego se corrobora en la TAC y RNM, mide aproximadamente 10 cm de diámetro, de ubicación central y derecho. Resto de estudio no muestra diseminación. Se realiza laparoscopia diagnóstica y ecografía intraoperatoria confirmando lo visto por imágenes, y se decide convertir a laparotomía para efectuar hepatectomía derecha extendida. Biopsia rápida y diferida informan colangiocarcinoma. Evoluciona favorablemente en el postoperatorio, con hiperbilirrubinemia sostenida de lenta resolución. La asociación de hepatectomía con síndrome de Dubin-Johnson es de muy baja frecuencia, existiendo poca literatura al respecto. Se ha descrito que la hiperbilirrubinemia en el postoperatorio es de difícil manejo, sin embargo, en este caso el paciente evolucionó favorablemente sin necesidad de alguna terapia específica.

Dubin-Johnson syndrome.

A young man presented with recurrent episodes of mild jaundice. Apart from conjugated hyperbilirubinemia, other liver function tests were always normal. Clinical suspicion of Dubin-Johnson syndrome was raised. Liver biopsy showed diffuse deposition of coarse granular dark brown pigment in hepatocytes. Dubin-Johnson syndrome is a benign condition, which results from a hereditary defect in biliary secretion of bilirubin pigments, and manifests as recurrent jaundice with conjugated hyperbilirubinemia. The defect is due to the absence of the canalicular protein MRP2 located on chromosomes 10q 24, which is responsible for the transport of biliary glucuronides and related organic anions into bile. No treatment is necessary and patients have a normal life expectancy.

Dubin-Johnson syndrome with systemic lupus erythematosus: a case report.

BACKGROUND: Dubin-Johnson syndrome (DJS) is a rare clinical entity. We describe a case of DJS complicated by systemic lupus erythematosus (SLE). METHODS: A case of congenital hyperbilirubinemia with SLE was evaluated systematically including review of history, physical examination for the stigmata of chronic liver disease, and other investigations. RESULT: Liver biopsy revealed a black liver with preserved architecture suggestive of DJS. CONCLUSIONS: SLE may develop in DJS. The relationship between DJS and SLE in this case is most likely a chance occurrence.

Autopsy case of Dubin-Johnson syndrome with pneumonia and abetalipoproteinemia-like lipid profile.

We report the autopsy of a 79-year-old Japanese woman with Dubin-Johnson syndrome accompanied by pneumonia, an abetalipoproteinemia-like lipid profile and acanthocytosis. On admission, physical examination of the patient revealed malnutrition. Blood tests revealed marked inflammatory changes and mild liver dysfunction. Chest X-ray indicated bilateral pneumonia. Total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride levels were 89 mg/dL, 5 mg/dL and 6 mg/dL, respectively. Peripheral blood smears revealed numerous acanthocytes. Despite the administration of antibiotics and nutritional support, the patient died. Autopsy revealed a black liver, atrophy of fat tissue on the mesentery, and pneumonia with bilateral pleural effusion. We believe that the abetalipoproteinemia-like lipid profiles in this case were caused by malnutrition and the inflammatory changes rather than the direct effects of Dubin-Johnson syndrome. We base this conclusion on the following three findings: 1) the patient's lipid profile before hospitalization was in the normal range, 2) her serum LDL cholesterol and triglyceride levels gradually increased after nutritional support began, and 3) blood tests revealed marked inflammatory changes (C-reactive protein 9.0 mg/dL; interleukin-6 16.4 pg/mL). This case provides important information that enhances our understanding of lipid metabolism under conditions of malnutrition and inflammation.

Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert's and Dubin-Johnson syndrome.

BACKGROUND & AIMS: Dubin-Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canalicular transporter for conjugated bilirubin. Gilbert's syndrome is recessively inherited, unconjugated hyperbilirubinemia caused by decreased conjugation rate of bilirubin associated mostly with homozygous A(TA) 7 TAA variant of the TATAA-box in the UGT1A1 gene promoter. Our aim was to establish the molecular diagnosis in a 3-year-old male with atypical, intermittent, predominantly unconjugated, hyperbilirubinemia. METHODS: 99m Tc-HIDA cholescintigraphy was used for imaging the biliary tree. Expression of ABCC2/MRP2 protein in hepatocytes was investigated immunohistochemically. UGT1A1 and ABCC2/MRP2 genes were sequenced from genomic DNA, and the mutations were verified by fragment analysis, sequencing the cloned exons, and restriction fragment length polymorphism. RESULTS: Cholescintigraphy revealed delayed visualization of the gallbladder. A brown granular lipopigment differing from melanin-like pigment reported in Dubin-Johnson syndrome was present in hepatocytes, but, otherwise, liver histology was normal. ABCC2/MRP2 protein was not detected on the canalicular membrane of hepatocytes, and 2 novel mutations were found in the ABCC2/MRP2 gene: a heterozygous in-frame insertion-deletion mutation 1256insCT/delAAACAGTGAACCTGATG in exon 10 inherited from the father and a heterozygous deletion 4292delCA in exon 30 inherited from the mother. In addition, the patient was homozygous for -3279T>G and A(TA) 7 TAA mutations in the UGT1A1 gene promoter. CONCLUSIONS: Our patient represents a case of digenic mixed hyperbilirubinemia-a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes.

Hepatocellular carcinoma in a case of Dubin-Johnson syndrome treated successfully with a central bilateral segmentectomy.

A 72-year-old woman with hepatocellular carcinoma and HCV cirrhosis combined with Dubin-Johnson syndrome was successfully treated by a central bilateral segmentectomy. While the preoperative serum bilirubin level is one of the established criteria for determining the indications for a hepatic resection, it is not effective for HCV cirrhosis cases associated with Dubin-Johnson syndrome. Postoperative hyperbilirubinemia may be cured without special treatment such as bilirubin absorption or plasma exchange, but such patients must be carefully observed to ensure that liver failure does not occur.

Association of Dubin-Johnson syndrome and portal vein thrombosis.

Dubin-Johnson syndrome is neither complicated by liver cell necrosis nor associated with portal hypertension. We report a 22-year-old man who had recurrent episodes of jaundice (conjugated hyperbilirubinemia) because of Dubin-Johnson syndrome and portal hypertension secondary to portal vein thrombosis. The relationship between Dubin-Johnson syndrome and portal vein thrombosis in this case is most likely a chance occurrence.