Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs

Al–Hussaini, Abdulrahman; Alsaleem, Badr; AlHomaidani, Hamad; Asery, Ali; Alruwaithi, Muhanad; Alameer, Mohammed; Afashah, Waleed; Salman, Bashir Muhammed; Almontashiri, Naif A M

doi:10.3389/fped.2021.741835

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…In fact, the p.Asp482Gly carriers commonly manifest pruritus at an advanced stage and are successfully treated by surgical biliary diversion, whereas P 1 in our study presents an early pruritus at presentation persisting until 16 years of follow‐up despite medical and surgical interventions. This can be in part explained by a polygenic trait involvement particularly by the modifier negative effect of the heterozygous c.2273G > T(p.Gly758Val) variation within the ABCC2 gene previously reported as a causative homozygous pathogenic variant of neonatal‐Dubin–Johnson syndrome (Al‐Hussaini, AlSaleem et al., 2021; Kamal et al., 2022). Moreover, a variable clinical outcome was also shown in PFIC2 patients harboring the same p.Tyr354* truncating variant.…”

Section: Discussionmentioning

confidence: 99%

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low‐GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment

Khabou,

Kallabi,

Abdelaziz

et al. 2023

Annals of Human Genetics

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Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel–target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease‐causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP‐binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide‐binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis‐associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.

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Section: Discussionmentioning

confidence: 99%

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low‐GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment

Khabou,

Kallabi,

Abdelaziz

et al. 2023

Annals of Human Genetics

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“…Two reports were released from Saudi Arabia, one with a large series of 28 genetically proven cases with DJS ( 18 ) and the other one with one non-genetically proven case ( 19 ). Twenty-three out of the 28 patients of Al-Hussaini series had the same mutation detected in our family ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Dubin-Johnson Syndrome Presenting With Infantile Cholestasis: An Overlooked Diagnosis in an Extended Family

et al. 2022

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Dubin-Johnson syndrome (DJS) is an often-missed diagnosis of neonatal cholestasis. We report two patients with DJS, who presented with neonatal cholestasis. The first patient underwent extensive investigations for infantile cholestasis with no definitive etiology reached; the diagnosis of DJS was missed until the age of 14 years old. The diagnosis was confirmed genetically with c.2273G > T, p.G758V mutation in exon 18 of the ABCC2 gene. The 2nd patient is a 7-day-old baby, the son of the 1st patient who gave birth to him at the age of 21 years old. He was diagnosed with DJS at the age of 2 weeks based on normal clinical and laboratory workup apart from direct hyperbilirubinemia. He had the same mutation as his mother in homozygous status. The husband was heterozygous for the same mutation. DJS is one of the often-missed differential diagnoses of neonatal cholestasis. It should be suspected in patients of infantile cholestasis, who have an, otherwise, normal physical examination, and laboratory investigations to avoid unnecessary lengthy, invasive, and expensive workups.

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“…[1][2][3] Although the prevalence of DJS remains low in the global population, certain ethnic groups, particularly Iranian Jews and Japanese, show a higher increase in carrier rates. [4,5] At the heart of DJS is the AR inheritance of mutations in the ABCC2 gene, a key player in the transport of bilirubin and other organic anions from the liver into bile. [6,7] The authors have no funding and conflicts of interest to disclose.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang,

Zuo,

Gao

2024

Medicine

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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.

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Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs

Cited by 4 publications

References 25 publications

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low‐GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low‐GGT intrahepatic cholestasis: Genetic diagnosis and genotype–phenotype correlation assessment

Case Report: Dubin-Johnson Syndrome Presenting With Infantile Cholestasis: An Overlooked Diagnosis in an Extended Family

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

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