Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome

Kim, Kwang Yeon; Kim, Tae Hyeong; Seong, Moon-Woo; Park, Sung Sup; Moon, Jin Soo; Ko, Jae Sung

doi:10.21203/rs.2.21832/v3

Cited by 2 publications

(9 citation statements)

References 7 publications

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“…Upon reviewing the reported cases, the clinical presentation of DJS as NC is rare, however, our study shows that DJS represents an important disease to consider in the differential diagnosis of NC among the Saudi Arabian population similar to the high frequency reported in the Far-East Asian populations (9)(10)(11)18). The clinical phenotype and biochemical profile (normal or elevated GGT, and high total serum bile acids) of neonatalonset DJS overlap with a broad list of causes of NC, which makes the identification of DJS challenging to clinicians.…”

Section: Discussionsupporting

confidence: 67%

“…The clinical phenotype and biochemical profile (normal or elevated GGT, and high total serum bile acids) of neonatalonset DJS overlap with a broad list of causes of NC, which makes the identification of DJS challenging to clinicians. Notably, some neonates with DJS present with acholic stool and high-GGT cholestasis, a phenotype similar to neonates with BA, and might undergo invasive procedures (liver biopsy and intraoperative cholangiography), a scenario that happened frequently in some reported case series (9,10,19) and in three of our patients as well. Hence, early consideration and prompt diagnosis of DJS is a very important step in the work up of a neonate with cholestasis to avoid subjecting a patient with a benign prognosis to unnecessary invasive and costly evaluation.…”

Section: Discussionmentioning

confidence: 59%

“…The third tool that was frequently employed to diagnose DJS phenotype, before the first molecular characterization of ABCC2 gene in 1997 (1), is liver biopsy. The characteristic histopathological finding of melanin-like pigment deposits in hepatocytes is uncommon in neonates compared with adults (9,10). Thus, the low diagnostic yield and invasiveness of the procedure make liver biopsy an unfavorable diagnostic tool of neonatal-onset DJS, particularly in the era of the advanced molecular genetics and availability of non-invasive methods.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory used different ALT and AST tests during the study period with different normal cut off reference ranges (Table 1), therefore in addition to reporting the absolute values of the transaminases, we calculated the proportion of ALT and AST to the upper limit of normal (ULN). Several previous studies on DJS patients showed that serum ALT levels were typically normal (9)(10)(11)(12)(13)(14). To evaluate the utility of serum ALT level as a biochemical discriminative indicator of DJS, we compared the ALT values in DJS patients with ALT values in other major etiologies contributing to infantile cholestasis in Saudi Arabia.…”

Section: Data Collectionmentioning

confidence: 99%

“…The MRP2, which is located on the canalicular membrane of hepatocytes, is important in excretion of conjugated bilirubin from hepatocytes into the bile (2). 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, particularly 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), however neonatal-onset DJS was rarely reported, and the reports constituted only few case reports and small case series (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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

Al–Hussaini

Alsaleem²,

AlHomaidani³

et al. 2021

Front. Pediatr.

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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.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Data Collectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Al–Hussaini

Alsaleem²,

AlHomaidani³

et al. 2021

Front. Pediatr.

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Pathogenic Novel Heterozygous Variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 Gene, Type 2 Alagille Syndrome Causing Neonatal Cholestasis: A Case Report

et al. 2022

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Patient: Male, newborn Final Diagnosis: Alagille syndrome Symptoms: Cholestasis and/or gallbladder dysfunction Medication: — Clinical Procedure: — Specialty: Genetics • Pediatrics and Neonatology Objective: Unusual clinical course Background: Alagille syndrome (ALGS) is a multisystem hereditary illness with a dominant pattern and partial penetrance. Multiple organ abnormalities can be caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene. Notch receptor 2 (NOTCH2) gene mutations are also uncommon. ALGS is also characterized by deformed or narrowed bile ducts and is notoriously difficult to diagnose due to the wide range of symptoms and absence of unambiguous genotype-phenotype connections. Little is known about ALGS patients who have NOTCH2 mutations. We present a patient who developed progressive liver failure due to a unique pathogenic heterozygous variation of the NOTCH2 gene, c.1076c>T p. (Ser359Phe) chr1: 120512166, resulting in type 2 ALGS. Case Report: A Saudi Arabian newborn with bilateral hazy eyes, ectropion, dry ichthyic skin, normal male genitalia, and bilateral undescended testes was born at 31 weeks. Previous miscarriages, pregnancy-induced maternal cholestasis, fatty liver, or neonatal jaundice were not reported in the family history. He had developed worsening cholestatic jaundice by the third week of hospitalization. The extensive work-up for metabolic, infectious, and other relevant etiologies was negative. Following gram-negative sepsis, he died of multiorgan failure. A NOTCH2 gene mutation explained the phenotypic difference in our situation. Another intriguing observation was the presence of ichthysis and craniosynostosis in ALGS with a NOTCH2 mutation. Conclusions: Cholestasis in newborns can be difficult to diagnose. Next-generation sequencing detects 112 copy number variants in the cholestasis gene panel blood test. More research is needed to understand why NOTCH2 mutations are relatively rare in ALGS.

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Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome

Cited by 2 publications

References 7 publications

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

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

Pathogenic Novel Heterozygous Variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 Gene, Type 2 Alagille Syndrome Causing Neonatal Cholestasis: A Case Report

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