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Cureus Aug 2023Gilbert syndrome is a condition of non-hemolytic hyperbilirubinemia without further sequelae or primary laboratory abnormalities. Gilbert syndrome represents the most...
Gilbert syndrome is a condition of non-hemolytic hyperbilirubinemia without further sequelae or primary laboratory abnormalities. Gilbert syndrome represents the most common hereditary disorder of bilirubin metabolism and is frequently identified as the etiology of familial jaundice in clinical medicine. This disorder typically manifests as mild unconjugated hyperbilirubinemia of benign nature. The diagnosis of Gilbert syndrome entails clinical assessment corroborated by the laboratory findings above in the absence of hemolysis or other organic liver diseases. We report a case of a 17-year-old boy who presented to a pediatric clinic with dyspepsia for the management of digestive symptoms, with clinical findings of mild scleral icterus and laboratory findings of isolated indirect hyperbilirubinemia. This case is unique in its subtlety of presentation. It highlights to trainees and experienced physicians the importance of the physical examination and targeted laboratory workup to arrive at the diagnosis of Gilbert syndrome.
PubMed: 37692716
DOI: 10.7759/cureus.43298 -
Frontiers in Genetics 2023Pyruvate Kinase Deficiency (PKD) and Crigler-Najjar syndrome are rare autosomal recessive liver diseases. PKD is caused by homozygous or compound heterozygous mutations...
Pyruvate Kinase Deficiency (PKD) and Crigler-Najjar syndrome are rare autosomal recessive liver diseases. PKD is caused by homozygous or compound heterozygous mutations in the gene, leading to non-spherocytic hereditary hemolytic anemia. On the other hand, Crigler-Najjar syndrome (CNS-II) is characterized by the loss or reduced activity of UDP-glucuronosyltransferase, resulting in elevated levels of unconjugated bilirubin, which is the primary cause of disease manifestation. To date, there have been no reported cases of patients with both conditions. In this case report, we present the unique clinical course of a 15-year-old Chinese patient with both PKD and CNS-II. The patient was admitted for evaluation of hyperbilirubinemia and exhibited yellowish skin color, icteric sclera, and splenomegaly upon physical examination. Extensive laboratory examinations ruled out viral, hemolytic, autoimmune, and inborn or acquired metabolic etiologies of liver injury. Histopathological findings indicated benign recurrent intrahepatic cholestasis (BRIC) and hemosiderosis. Surprisingly, targeted next-generation sequencing (NGS) of the patient's blood did not reveal any mutation sites associated with BRIC. Instead, it identified a novel homozygous pathogenic variant of the gene [c.1276C>T (p.Arg426Trp)] and a rare heterozygous variant of gene [c.-55_-54insAT, c.1091C>T (p.Pro364Leu)]. These findings strongly suggest a diagnosis of PKD and CNS-II in the patient. Treatment with 500 mg/day of ursodeoxycholic acid proved to be effective, rapidly reducing the patient's total bilirubin levels and shortening the symptomatic period. This case highlights the importance of genetic diagnosis in accurately identifying the underlying cause of hyperbilirubinemia, especially in patients with rare hereditary diseases. Furthermore, NGS can provide valuable insights into the genotype-phenotype correlation of PKD and CNS-II.
PubMed: 37671043
DOI: 10.3389/fgene.2023.1229271 -
Cureus Jul 2023Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome in which widespread activation of the immune system causes multi-organ tissue damage. HLH is a serious and...
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome in which widespread activation of the immune system causes multi-organ tissue damage. HLH is a serious and potentially fatal disorder characterized by excessive immune system activation. It is characterized by a dysregulation in natural killer (NK) T-cell function, causing activation of lymphocytes and histiocytes. These cells secrete a large number of inflammatory cytokines and infiltrate various tissues causing multi-organ system failure. The spectrum consists of hereditary or "primary" HLH that comprises genetically heterogeneous conditions, occurring during childhood. The secondary form presents later in life and is associated with several conditions mainly malignancy, autoimmune diseases, viral or bacterial infections, and hematological diseases. Here we present an interesting case in which a 39-year-old patient presented with a complaint of shortness of breath. He was diagnosed with obstructive uropathy in the emergency department and subsequently developed acute liver injury, acute kidney injury, bacteremia, and was diagnosed with HLH with comorbid bacteremia.
PubMed: 37575709
DOI: 10.7759/cureus.41779 -
Cancer Chemotherapy and Pharmacology Oct 2023Dubin-Johnson syndrome is a rare benign autosomal recessive condition that causes an isolated increase of conjugated bilirubin in the serum. Impaired biliary excretion...
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/m, 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.
Topics: Female; Humans; Child; Child, Preschool; Jaundice, Chronic Idiopathic; Vincristine; Multidrug Resistance-Associated Proteins; Multidrug Resistance-Associated Protein 2; Bilirubin; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37452859
DOI: 10.1007/s00280-023-04565-0 -
Saudi Journal of Gastroenterology :... 2023Dubin-Johnson syndrome (DJS) presents during the neonatal period with a phenotype that overlaps with a broad list of causes of neonatal cholestasis (NC), which makes the... (Review)
Review
BACKGROUND
Dubin-Johnson syndrome (DJS) presents during the neonatal period with a phenotype that overlaps with a broad list of causes of neonatal cholestasis (NC), which makes the identification of DJS challenging for clinicians. We conducted a case-controlled study to investigate the utility of urinary coproporphyrins (UCP) I% as a potential diagnostic biomarker.
METHODS
We reviewed our database of 533 cases of NC and identified 28 neonates with disease-causing variants in ATP-binding cassette-subfamily C member 2 (ABCC2) gene "Cases" (Study period 2008-2019). Another 20 neonates with cholestasis due to non-DJS diagnoses were included as "controls." Both groups underwent UCP analysis to measure CP isomer I percentage (%).
RESULTS
Serum alanine aminotransferase (ALT) levels were within the normal range in 26 patients (92%) and mildly elevated in 2 patients. ALT levels were significantly lower in neonates with DJS than in NC from other causes (P < 0.001). The use of normal serum ALT levels to predict DJS among neonates with cholestasis had a sensitivity of 93%, specificity 90%, positive predictive value (PPV) 34%, and negative predictive value (NPV) 99.5%. The median UCPI% was significantly higher in DJS patients [88%, interquartile range (IQR) 1-IQR3, 84.2%-92.7%] than in NC from other causes [67%, (IQR1-IQR3, 61%-71.5%; Confidence interval 0.18-0.28; P< 0.001)]. The use of UCPI% >80% to predict DJS had a sensitivity, specificity, PPV, and NPV of 100%.
CONCLUSION
Based on the results from our study, we propose sequencing of the ABCC2 gene in neonates with normal ALT, presence of cholestasis and UCP1% >80%.
Topics: Humans; Alanine Transaminase; Biomarkers; Cholestasis; Coproporphyrins; Jaundice, Chronic Idiopathic; Infant, Newborn
PubMed: 37313948
DOI: 10.4103/sjg.sjg_480_22 -
Journal of Investigative Medicine High... 2023This case report describes a novel mutation of the gene as a potential pathogenic cause of spherocytosis. A 3-week-old male presented with clinical and laboratory signs...
This case report describes a novel mutation of the gene as a potential pathogenic cause of spherocytosis. A 3-week-old male presented with clinical and laboratory signs consistent with hemolytic spherocytosis, including jaundice, hyperbilirubinemia, anemia, reticulocytosis, negative Coombs test, no ABO or Rh incompatibility, and a peripheral blood smear notable for numerous spherocytes. His laboratory work demonstrated persistent anemia despite daily folate prompting next-generation sequencing which revealed a novel mutation in the gene resulting in a nonfunctioning protein product. Correlation of the genetic finding with clinical presentation may help guide management for this and future patients.
Topics: Infant, Newborn; Humans; Male; Heterozygote; High-Throughput Nucleotide Sequencing; Hyperbilirubinemia; Mutation
PubMed: 37306287
DOI: 10.1177/23247096231180552 -
Journal of the Formosan Medical... Jul 2023Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both...
Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5-32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.
Topics: Adult; Infant, Newborn; Humans; Child; Organic Anion Transporters, Sodium-Independent; Organic Anion Transporters; Liver-Specific Organic Anion Transporter 1; Solute Carrier Organic Anion Transporter Family Member 1B3; Hyperbilirubinemia, Hereditary; Hyperbilirubinemia; Mutation
PubMed: 36964102
DOI: 10.1016/j.jfma.2023.03.003 -
Asian Journal of Surgery Aug 2023
Topics: Humans; Gilbert Disease; Liver Transplantation; Syndrome
PubMed: 36933959
DOI: 10.1016/j.asjsur.2023.02.091 -
The British Journal of Radiology Mar 2023The aim of this study is to demonstrate the role of proton magnetic resonance spectroscopy (1H-MRS) in the detection of brain microstructural changes in patients with...
OBJECTIVE
The aim of this study is to demonstrate the role of proton magnetic resonance spectroscopy (1H-MRS) in the detection of brain microstructural changes in patients with Crigler-Najjar syndrome type-I (CNs-I), and its correlation with demographic, neurodevelopmental and laboratory findings.
METHODS
Prospective study was conducted on 25 children with CNs-I and 25 age and sex-matched children, who served as control. They underwent multivoxel 1H-MRS of basal ganglion at echo time 135-144 ms. N-acetyl aspartate/Creatine (NAA/Cr) and Choline (Ch)/Cr were calculated and correlated with demographic, clinical, and laboratory findings of patients with CNs-I.
RESULTS
There was a significant difference in NAA/Cr and Ch/Cr between patients and controls. The cut-off value for NAA/Cr and Ch/Cr used to differentiate patients from controls were 1.8 and 1.2 with an area under the curve (AUC) of 0.91 and 0.84 respectively. There was a significant difference in MRS ratios between patients with neurodevelopmental delay (NDD) and patients without NDD. The cut-off values for NAA/Cr and Ch/Cr used to differentiate between patients with NDD and patients without NDD were 1.47 and 0.99, with AUC of 0.87 and 0.8 respectively. The NAA/Cr and Ch/Cr were well correlated with family history ( = 0.006 and < 0.001) respectively, consanguinity ( < 0.001 and = 0.001), neurodevelopmental delay ( = 0.001 and = 0.004), serum bilirubin level ( = -0.77, < 0.001), ( = -0.49, = 0.014), phototherapy ( < 0.001 and = 0.32), blood transfusion ( < 0.001 and = 0.001) respectively.
CONCLUSION
1H-MRS can be a useful tool in the detection of neurological changes in patients with CNs-I; NAA/Cr and Ch/Cr parameters are well correlated with demographic, clinical, and laboratory findings.
ADVANCES IN KNOWLEDGE
Our study is the first report on using MRS in assessing neurological manifestations in CNs. 1H-MRS can be a useful tool in the detection of neurological changes in patients with CNs-I.
Topics: Humans; Child; Magnetic Resonance Spectroscopy; Prospective Studies; Crigler-Najjar Syndrome; Brain; Creatine; Aspartic Acid; Choline; Demography
PubMed: 36809151
DOI: 10.1259/bjr.20220433