Abstract
Background: There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe.Objectives: In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS.Methods: We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in ABCC2 gene.Results: Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3–6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5–14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes (p < 0.001). The median urinary coproporphyrin I% was 88% (IQ1–IQ3 = 84.2–92.7%). We identified four homozygous variants in the ABCC2 gene (from 22 unrelated families), one splicing variant (c.3258+1G>A; p.?), and three were missense variants; two of which were novel missense variants [c.1594G>A (p.Glu532Lys) and c.2439G>C (p.Lys813Asn)]. The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families).Conclusions: Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with “founder effects.” Identification of the predominant ABCC2 variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.
Highlights
Dubin–Johnson syndrome (DJS) is a rare cause of neonatal cholestasis. It results from variants in the ATP-binding cassettesubfamily C member 2 (ABCC2) gene leading to absent, reduced expression, or impaired function of a transporter protein known as multidrug resistance-associated protein 2 (MRP2) [1]
From 2008 to 2019, 22 unrelated Saudi families with a total of 28 cases with neonatal cholestasis (NC) were diagnosed with DJS, DJS accounted for 5.3% (28/533) of the causes of infantile cholestasis in our center
The typical patients with neonatal-onset DJS are likely to be full-term, well looking neonates who manifest with normal alanine transaminase (ALT) cholestasis since the 1 week of life, which resolves within 3–6 months of age, followed by a benign course that could be punctuated by recurrent episodes of jaundice on long term follow-up, and a direct bilirubin that do not normalize between episodes
Summary
Dubin–Johnson syndrome (DJS) is a rare cause of neonatal cholestasis. It results from variants in the ATP-binding cassettesubfamily C member 2 (ABCC2) gene leading to absent, reduced expression, or impaired function of a transporter protein known as multidrug resistance-associated protein 2 (MRP2) [1]. Since molecular characterization of the first ABCC2 gene variant responsible for DJS in 1997 [1], several variants of ABCC2 gene were identified in DJS patients from different populations and ethnicities, from Far-East Asia (Japan, Taiwan, Korea, and China), Israel (Iranian and Moroccan Jews), and Europe [3,4,5,6,7,8,9,10,11,12,13,14] Most of these studies included children and adults [3,4,5,6,7,8], neonatal-onset DJS was rarely reported, and the reports constituted only few case reports and small case series [9,10,11,12,13,14]. There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), from Far-East Asia, Iranian and Moroccan Jews, and Europe
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