Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs
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 clin...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:63138e1366df49149ee0cf1f353929ba2021-11-10T07:17:19ZClinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs2296-236010.3389/fped.2021.741835https://doaj.org/article/63138e1366df49149ee0cf1f353929ba2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fped.2021.741835/fullhttps://doaj.org/toc/2296-2360Background: 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.Abdulrahman Al-HussainiAbdulrahman Al-HussainiAbdulrahman Al-HussainiBadr AlSaleemHamad AlHomaidaniAli AseryMuhanad AlruwaithiMohammed AlameerWaleed AfashahBashir Muhammed SalmanNaif AlmontashiriNaif AlmontashiriFrontiers Media S.A.articleDubin-Johnson syndromeABCC2 geneSaudi Arabianeonatal cholestasisdirect hyperbilirubinemianormal alanine aminotransferasePediatricsRJ1-570ENFrontiers in Pediatrics, Vol 9 (2021) |
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Dubin-Johnson syndrome ABCC2 gene Saudi Arabia neonatal cholestasis direct hyperbilirubinemia normal alanine aminotransferase Pediatrics RJ1-570 |
| spellingShingle |
Dubin-Johnson syndrome ABCC2 gene Saudi Arabia neonatal cholestasis direct hyperbilirubinemia normal alanine aminotransferase Pediatrics RJ1-570 Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Badr AlSaleem Hamad AlHomaidani Ali Asery Muhanad Alruwaithi Mohammed Alameer Waleed Afashah Bashir Muhammed Salman Naif Almontashiri Naif Almontashiri Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| description |
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. |
| format |
article |
| author |
Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Badr AlSaleem Hamad AlHomaidani Ali Asery Muhanad Alruwaithi Mohammed Alameer Waleed Afashah Bashir Muhammed Salman Naif Almontashiri Naif Almontashiri |
| author_facet |
Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Abdulrahman Al-Hussaini Badr AlSaleem Hamad AlHomaidani Ali Asery Muhanad Alruwaithi Mohammed Alameer Waleed Afashah Bashir Muhammed Salman Naif Almontashiri Naif Almontashiri |
| author_sort |
Abdulrahman Al-Hussaini |
| title |
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| title_short |
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| title_full |
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| title_fullStr |
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| title_full_unstemmed |
Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs |
| title_sort |
clinical, biochemical, and molecular characterization of neonatal-onset dubin–johnson syndrome in a large case series from the arabs |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/63138e1366df49149ee0cf1f353929ba |
| work_keys_str_mv |
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