Quality control for genetic analysis has become more important with a drastic increase in testing volume and clinical demands. The molecular diagnostics division of the Korean Association of Quality Assurance for Clinical Laboratory conducted two trials in 2017 on the basis of molecular diagnostics surveys, involving 53 laboratories. The molecular diagnostics surveys included 37 tests: gene rearrangement tests for leukemia (BCR-ABL1, PML-RARA, AML1-ETO, and TEL-AML1), genetic tests for Janus kinase 2, FMS-like tyrosine kinase 3-internal tandem duplication, FMS-like tyrosine kinase 3-tyrosine kinase domain, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), hearing loss and deafness (GJB2), Avellino (TGFBI), multiple endocrine neoplasia 2 (RET), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, myoclonic epilepsy ragged red fibre, Leber hereditary optic neuropathy, Prader-raderd Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome, apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, and ABO genotyping. Molecular genetic surveys revealed excellent results for most participants. The external quality assessment program for genetic analysis in 2017 proved useful for continuous education and the evaluation of quality improvement.
Achondroplasia ; Acidosis, Lactic ; Angelman Syndrome ; Apolipoproteins ; Brain Diseases ; Breast ; Deafness ; Education ; Epilepsies, Myoclonic ; Fragile X Syndrome ; Gene Rearrangement ; Hearing Loss ; Hepatolenticular Degeneration ; Huntington Disease ; Janus Kinase 2 ; Korea* ; Laboratory Proficiency Testing ; Leukemia ; Li-Fraumeni Syndrome ; Methylenetetrahydrofolate Reductase (NADPH2) ; Molecular Biology ; Multiple Endocrine Neoplasia ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic ; Muscular Dystrophy, Duchenne ; Optic Atrophy, Hereditary, Leber ; Ovarian Neoplasms ; Pathology, Molecular* ; Phosphotransferases ; Quality Control ; Quality Improvement ; Spinocerebellar Ataxias ; Vascular Endothelial Growth Factor Receptor-1

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that identified novel mutations in the ABCB4 gene. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for WD. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3. Ursodeoxycholic acid ameliorates cholestasis in PFIC3, and may help mediate a reduction in hepatic copper content in response to treatment.
Cholestasis ; Cholestasis, Intrahepatic* ; Chromosomes, Human, Pair 7 ; Copper ; Delayed Diagnosis ; Diagnosis* ; Hepatolenticular Degeneration* ; Humans ; Molecular Biology* ; Pathology, Molecular ; Ursodeoxycholic Acid

OBJECTIVETo explore the pathological and clinical characteristics of children with liver diseases by retrospective study on clinical and liver biopsy pathological data of children with liver diseases.

METHODThis retrospective analysis was performed at Beijing No. 302 Hospital among 3 932 children with liver diseases who visited the hospital from January 2001 to December 2012. The kinds of diseases were compared with the results of 1983-2000.

RESULT(1) Liver biopsy was successful in 99.72% (3 932/3 943) of cases of 2001-2012 group, complications occurred in 31 children only. (2) Of the 3 932 cases, 2 647 (67.32%) had hepatitis , non-hepatotropic viral hepatitis and non viral liver disease were seen in 365 cases (9.28%), and 920 cases (23.4%), respectively. Among 2 647 cases with viral hepatitis, 2 115 were hepatitis B (79.90%), 521 hepatitis C (19.69%), 7 were hepatitis A (0.26%) and 4 hepatitis E (0.15%), respectively. (3) In 2001-2012 group, the degrees of inflammatory activity (>G2) of liver were seen in 9.57% (202/2 111) patients with hepatitis B, while 23.57% (132/560) in 1983-2000 group. There was significant difference between the two groups (χ(2)=80.36, P=0.00 ). (4) Significant difference was observed in the rate of non viral liver disease between 2001-2012 group (23.40%, 920/3 932) and 1983-2000 group (9.61%, 98/1 020) (χ(2)=93.46, P=0.00). In 2001-2012 group, including 46 kinds of diseases, which were significantly higher than those of 1983-2000 group (18 kinds). In 2000-2012, the main causes of diseases were liver degeneration (18.26%, 168/920), drug-induced liver injury (13.59%, 125/920), fatty liver (8.80%, 81/920) and liver glycogen accumulation disease (8.70%, 80/920). While in 1983-2000 group, the main causes were liver degeneration (20.41%, 20/98), fatty liver (16.33%, 16/98), glycogen storage disease (10.20%, 10/98) and myopathy (9.18%, 9/98).

CONCLUSIONLiver biopsy in children is safe and feasible. Hepatitis B virus was ranked first in children with liver diseases in 2001-2012 group. The kinds of non viral hepatic disorders had changed and extended.

Adolescent ; Biopsy, Needle ; Child ; Child, Preschool ; Female ; Hepatitis B ; pathology ; Hepatitis, Viral, Human ; pathology ; Hepatolenticular Degeneration ; epidemiology ; pathology ; Humans ; Infant ; Liver ; pathology ; Liver Diseases ; pathology ; Liver Function Tests ; Male ; Retrospective Studies

Hypertrophic olivary degeneration resulting from lesions of the dento-rubro-olivary pathway, also called Guillain-Mollaret-triangle, has been described previously in a number of cases. Reports about bilateral hypertrophic olivary degeneration of the inferior olivary nuclei are very limited, and the magnetic resonance imaging findings of hypertrophic olivary degeneration in Wilson disease have not yet been described to the best of our knowledge. Herein, we present the first report of bilateral hypertrophic olivary degeneration diagnosed by magnetic resonance imaging in a patient suffering from Wilson disease.
Diagnosis, Differential ; Hepatolenticular Degeneration/*pathology ; Humans ; Hypertrophy/pathology ; Magnetic Resonance Imaging/*methods ; Male ; Nerve Degeneration/*pathology ; Olivary Nucleus/*pathology ; Young Adult

PURPOSE: To identify the relationship between hemoglobin (Hgb) or hematocrit (Hct) level and dural sinus density using unenhanced computed tomography (UECT). MATERIALS AND METHODS: Patients who were performed UECT and had records of a complete blood count within 24 hours from UECT were included (n=122). We measured the Hounsfield unit (HU) of the dural sinus at the right sigmoid sinus, left sigmoid sinus and 2 points of the superior sagittal sinus. Quantitative measurement of dural sinus density using the circle regions of interest (ROI) method was calculated as average ROI values at 3 or 4 points. Simple regression analysis was used to evaluate the correlation between mean HU and Hgb or mean HU and Hct. RESULTS: The mean densities of the dural sinuses ranged from 24.67 to 53.67 HU (mean, 43.28 HU). There was a strong correlation between mean density and Hgb level (r=0.832) and between mean density and Hct level (r=0.840). CONCLUSION: Dural sinus density on UECT is closely related to Hgb and Hct levels. Therefore, the Hgb or Hct levels can be used to determine whether the dural sinus density is within the normal range or pathological conditions such as venous thrombosis.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cranial Sinuses/pathology/*radiography ; Female ; *Hematocrit ; Hemoglobins/*analysis ; Hepatolenticular Degeneration/complications ; Humans ; Male ; Middle Aged ; Pregnancy ; Pregnancy Complications ; Radiographic Image Interpretation, Computer-Assisted ; Reference Values ; Regression Analysis ; Superior Sagittal Sinus/pathology/*radiography ; Tomography, X-Ray Computed/*methods ; Young Adult

Adenosine Triphosphatases ; genetics ; Alanine Transaminase ; blood ; Cation Transport Proteins ; genetics ; Ceruloplasmin ; metabolism ; Child ; Copper ; blood ; urine ; Copper-transporting ATPases ; Cornea ; pathology ; Diagnosis, Differential ; Genetic Testing ; Hepatolenticular Degeneration ; blood ; diagnosis ; genetics ; metabolism ; Humans ; Liver ; metabolism ; pathology ; Liver Function Tests ; Mutation

The combination of disease-specific human induced pluripotent stem cells (iPSC) and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases. Wilson's disease (WD) is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene. WD affects multiple organs with primary manifestations in the liver and central nervous system (CNS). In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes, we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages. Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B. Combining with directed cell differentiation strategies, we successfully differentiated WD iPSC into hepatocyte-like cells, neural stem cells and neurons. Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells. Hence we established a platform for studying both hepatic and neural abnormalities of WD, which may provide a new tool for tissue-specific disease modeling and drug screening in the future.
Adenosine Triphosphatases ; genetics ; metabolism ; Cation Transport Proteins ; genetics ; metabolism ; Cell Differentiation ; Copper-transporting ATPases ; Hep G2 Cells ; Hepatocytes ; cytology ; metabolism ; Hepatolenticular Degeneration ; metabolism ; pathology ; Humans ; Induced Pluripotent Stem Cells ; cytology ; Mutation ; Neural Stem Cells ; cytology ; metabolism ; Neurons ; cytology ; metabolism ; Sequence Analysis, DNA

OBJECTIVETo reassess the diagnostic value of 24 hour urinary copper excretion in children with Wilson disease (WD).

METHODSFrom July 2005 to June 2007, inpatients over three years old in a pediatric liver center were assigned into WD and non-WD group.

RESULTS94 patients, including 26 cases in WD and 68 in non-WD group, were enrolled in this study. The median of 24 h urinary copper excretion was 98.5 microg in WD group and 25.8 microg in the non-WD group (Z = -6.111, P equal to 0.000). The area under receiver operator curve (ROC) was 0.909 (95% CI: 0.839-0.979, P equal to 0.000). The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 84.6%, 91.2%, 89.4%, 78.6% and 93.9% respectively using 52.0 ug as a cutoff value, and 50.0%, 97.1%, 84.0%, 86.7% and 83.5% using 100 microg as a cutoff value. The goodness of fitness of 52 microg criteria was significantly higher than 100 microg criteria (kappacoefficient 0.760, 0.541 respectively, P equal to 0.000).

CONCLUSIONComparing to 100, 52 microg of 24 h urinary copper excretion as a cutoff value significantly improves the sensitivity and accuracy for diagnosing WD in children.

Adolescent ; Age Factors ; Ceruloplasmin ; Child ; Child, Preschool ; Copper ; urine ; Female ; Hepatitis ; diagnosis ; pathology ; urine ; Hepatitis A ; diagnosis ; pathology ; urine ; Hepatolenticular Degeneration ; diagnosis ; pathology ; urine ; Humans ; Liver ; pathology ; Male ; Penicillamine ; Predictive Value of Tests ; ROC Curve ; Sensitivity and Specificity ; Time Factors

OBJECTIVE: To determine whether there is a correlation between liver MR findings and the clinical manifestations and severity of liver dysfunction in patients with Wilson's disease. MATERIALS AND METHODS: Two radiologists retrospectively evaluated MR images of the liver in 50 patients with Wilson's disease. The Institutional Review Board approved this retrospective study and informed consent was waived. MR images were evaluated with a focus on hepatic contour abnormalities and the presence of intrahepatic nodules. By using Fisher's exact test, MR findings were compared with clinical presentations (neurological and non-neurological) and hepatic dysfunction, which was categorized by the Child-Pugh classification system (A, B and C). Follow-up MR images were available for 17 patients. RESULTS: Contour abnormalities of the liver and intrahepatic nodules were observed in 31 patients (62%) and 25 patients (50%), respectively. Each MR finding showed a statistically significant difference (p < 0.05) among the three groups of Child-Pugh classifications (A, n = 36; B, n = 5; C, n = 9), except for splenomegaly (p = 0.243). The mean age of the patients with positive MR findings was higher than that of patients with negative MR findings. For patients with Child-Pugh class A (n = 36) with neurological presentation, intrahepatic nodules, surface nodularity, and gallbladder fossa widening were more common. Intrahepatic nodules were improved (n = 8, 47%), stationary (n = 5, 29%), or aggravated (n = 4, 24%) on follow-up MR images. CONCLUSION: MR imaging demonstrates the contour abnormalities and parenchymal nodules of the liver in more than half of the patients with Wilson's disease, which correlates with the severity of hepatic dysfunction and clinical manifestations.
Adolescent ; Adult ; Chi-Square Distribution ; Child ; Child, Preschool ; Female ; Hepatolenticular Degeneration/*diagnosis/pathology ; Humans ; Image Interpretation, Computer-Assisted ; Magnetic Resonance Imaging/*methods ; Male ; Retrospective Studies ; Statistics, Nonparametric

OBJECTIVETo review the clinical features and liver pathology in children with hepatolenticular degeneration.

METHODSClinical manifestations and results of lab tests and liver biopsies of 97 cases diagnosed as hepatolenticular degeneration in Children's Hospital of Fudan University from Jan 1990 to Nov 2006 were reviewed.

RESULTSManifestations of liver malfunction were the most common reason (74%) for their clinic visits. All cases showed liver involvement and nervous system involvement was found in 45%. Positive K-F rings were detected in 63 of 95 cases; ceruloplasmin level was low in 91 of the 94 cases, and 24 hour urinary copper excretion exceeded 100 microg in 25 out of 37 cases who had had this test. Seventeen cases had a liver biopsy. Various levels of inflammation and fibrosis were noted in all 17 biopsies; 8 of the 17 also had steatosis and 3 of the 17 also had glycogen accumulation.

CONCLUSIONLiver abnormality is a consistent feature in children with hepatolenticular degeneration. Corneal K-F rings, serum ceruloplasmin and the 24-hour urinary copper test have limited values for an early diagnosis of the disease. Liver pathology can be a reference in the diagnosis of hepatolenticular degeneration.

Adolescent ; Child ; Child, Preschool ; Female ; Hepatolenticular Degeneration ; diagnosis ; pathology ; Humans ; Liver ; pathology ; Male ; Retrospective Studies