Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Mosaic paternal haploidy in a patient with pancreatoblastoma and Beckwith-Wiedemann spectrum.

Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

BACKGROUND/PURPOSE: 45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. PATIENTS AND METHODS: We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. RESULTS: Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4 ± 1.1 to -1.4 ± 0.9 in adulthood (P < 0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. CONCLUSION: The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.

Short tandem repeat analysis for confirmation of uterine non-gestational choriocarcinoma in a postmenopausal Taiwanese woman.

RATIONALE: Rare uterine choriocarcinoma can be differentiated gestational from nongestational choriocarcinoma by using short tandem repeats (STRs). PATIENT CONCERNS: A 56-year-old Taiwanese woman underwent staging surgery because of suspicion of high-grade endometrial cancer. The pathology-confirmed uterine tumor with syncytiotrophoblasts and decidual change of the endometrium was harvested. DIAGNOSIS: Uterine nongestational choriocarcinoma. INTERVENTIONS: The tumor specimen, the patient's blood, and her husband's blood were drawn for STRs analysis using polymerase chain reaction amplification kit. The genotype of the tumor cells was solely maternal and made the diagnosis of uterine nongestational choriocarcinoma. OUTCOME: Adjuvant chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine regimen achieved good response in the patient. The patient is now recurrence-free for 12 months. LESSONS: STRs aid precise classification of rare choriocarcinoma. We encourage using the method to analyze suspicious choriocarcinoma.

Clinical characteristics and long-term outcome of Taiwanese children with congenital hyperinsulinism.

BACKGROUND/PURPOSE: Congenital hyperinsulinism (CHI) is a rare condition causing severe hypoglycemia in neonates and infants due to dysregulation of insulin secretion. This study aimed to review 20 years' experience in the management of Taiwanese children with CHI. METHODS: Between 1990 and 2010, children diagnosed with CHI and followed up at the Pediatric Endocrine Clinic of the National Taiwan University Hospital were enrolled. Their medical records were thoroughly reviewed. RESULTS: In total, 13 patients (8 boys and 5 girls) were enrolled, including six patients with onset of hypoglycemia within 1 month of age and seven patients at 4.0 ± 2.1 months of age. The birth weight standard deviation scores of these two age groups were 4.6 ± 1.8 and 1.4 ± 1.3 standard deviation score, respectively (p < 0.01). Initial intravenous glucose infusion at rates of 22.9 ± 5.3 mg/kg/min and 13.4 ± 5.6 mg/kg/min, respectively, were mandatory to maintain euglycemia in these two groups (p < 0.05). All received pancreatectomy after failure of initial medical treatment. Twelve patients were followed up for a period of 2.5-19.8 years. Eight of them remained euglycemic without any medication and three patients developed diabetes mellitus. Seven of the nine patients who underwent intelligence evaluation had normal mental outcomes. Mental retardation of two patients was too severe to be evaluated. All four patients with mental retardation had a delay in the maintenance of euglycemia, and three of them also had seizure disorder. CONCLUSION: The age at onset of hypoglycemia reflects the severity of CHI. Early diagnosis and appropriate treatment are important for favorable mental outcomes.

Can leflunomide play a role in cytomegalovirus disease prophylaxis besides its antirheumatic effects?

Leflunomide, a disease-modifying antirheumatic drug (DMARD), has shown effectiveness in many autoimmune disorders and can suppress cytomegalovirus (CMV) disease in humans. Thus, it is possible for leflunomide to play a role in CMV prophylaxis or pre-emptive therapy in high-risk patients in addition to its application as a DMARD for autoimmune disorders. We describe two adult patients who developed CMV disease after administration of low-dose leflunomide. One patient was successfully treated with an increasing leflunomide dosage, resulting in a long-term suppression of serum CMV viral load.

Endocrine dysfunction in Taiwanese children with human chorionic gonadotropin-secreting germ cell tumors.

BACKGROUND/PURPOSE: Human chorionic gonadotropin (HCG)-secreting germ cell tumors (GCTs) are rare childhood malignancies with unique clinical manifestations but delayed diagnosis is common. The purpose of this study is to investigate the clinical manifestations and endocrine dysfunction of Taiwanese children with HCG-secreting GCTs. METHODS: From 1991 to 2011, 24 children (19 boys and five girls) with HCG-secreting GCTs were evaluated for their clinical findings and endocrine functions. RESULTS: The mean age at diagnosis of the study patients was 10.8 ± 3.1 years. Of the 24 patients, 20 had central nervous system (CNS) GCTs and four had primary mediastinal GCTs (PMGCTs). The most common pathologic findings were germinomas and mixed type GCTs. The common initial symptoms and signs included polyuria, polydipsia, rapid growth, neurologic deficit,sexual precocity, and growth retardation. There was a delay in diagnosis in about 60% of patients. Diabetes insipidus and hypopituitarism were common endocrine dysfunctions in patients with CNSGCTs. Twelve boys had gonadotropin-independent puberty upon diagnosis, which were related to their high serum ß-hCG levels. None of the five girls had this disorder despite their high serum ß-hCG levels. Three of the four PMGCTs patients had the classic form of Klinefelter syndrome. CONCLUSION: Taiwanese children with HCG-secreting GCTs often have clinical manifestations related to endocrine dysfunction. High index of suspicion is important to avoid delayed diagnosis in these children.

Clinical characteristics of central diabetes insipidus in Taiwanese children.

BACKGROUND/PURPOSE: Data on the clinical features of children with central diabetes insipidus (CDI) are lacking in Taiwan. This study investigated the clinical manifestations and etiology of CDI in Taiwanese children. METHODS: From 1983 to 2012, 62 children with permanent diabetes insipidus were enrolled in the study. They were diagnosed at the Department of Pediatrics of National Taiwan University Hospital. Their medical records were thoroughly reviewed and their clinical symptoms and signs, laboratory data, and etiologies were analyzed. RESULTS: The patients' median age at diagnosis was 10 years and the median interval between initial manifestations and diagnosis was 0.5 years. The most common symptoms and signs were polyuria, polydipsia, nocturia, and growth retardation. Most patients had low urine osmolality and elevated plasma osmolality on diagnosis. Absence of a posterior pituitary hyperintense signal and thickening of the pituitary stalk were common findings on magnetic resonance imaging. Approximately 80% of the patients had anterior pituitary hormone deficiency and all patients had growth hormone deficiency. Approximately 60% of patients had intracranial lesions, the most common causes of which were germ cell tumor and Langerhans cell histiocytosis. Two patients were initially believed to have idiopathic CDI but intracranial lesions were detected during the follow-up period. CONCLUSION: Because a delayed diagnosis of CDI is common in Taiwanese children, a high index of suspicion is important. The underlying etiology of CDI in children may not initially be obvious. Long-term surveillance is therefore necessary, especially for the early detection of evolving treatable intracranial lesions.

Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation.

UNLABELLED: Alteration of cell surface proteolysis has been proposed to play a role in liver fibrosis, a grave complication of biliary atresia (BA). In this study we investigated the roles of hepatocyte growth factor activator inhibitor (HAI)-1 and -2 in the progression of BA. The expression levels of HAI-1 and -2 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI-1 and -2 were coexpressed in cells involved in ductular reactions. In other selective cholangiopathies, ductular cells positive for HAI-1 or HAI-2 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up-regulated expression of HAI-1 and -2 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase-2 inhibitor. Conditioned media from cell lines stably overexpressing HAI-1 or HAI-2 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI-1 and -2 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI-1 and -2 in cholangiopathies by exploring their functions in fetal liver cells. Knockdown of HAI-1 or HAI-2 promoted bidirectional differentiation of hepatoblast-derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen-activated protein kinase kinase 1, and phosphatidylinositol 3-kinase signaling pathways were involved in hepatic differentiation enhanced by HAI-2 knockdown. CONCLUSION: HAI-1 and -2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation; they could be investigated as disease markers and potential therapeutic targets.

Cushing's disease in children: report of three cases.

Cushing's disease is rare in children and adolescents. We report the clinical presentations of three children with Cushing's disease. All three exhibited the typical symptoms and signs of weight gain and growth retardation. Tw o also demonstrated personality changes, hypertension and hypokalemia, the last of these being rarely reported in patients with Cushing's disease. Lack of diurnal changes in serum cortisol levels was the most common biochemical finding. Serum cortisol levels were suppressed by low-dose dexamethasone in one patient, which is not typical for patients with Cushing's disease. Imaging studies are essential for localizing the tumor. Transsphenoidal surgery remains the treatment of choice, and pituitary irradiation should be considered for those patients whose tumors cannot be totally removed. Careful follow-up of these patients with awareness of the possibilities of relapse and the complications of hypopituitarism is indicated.

Analysis of cases of sexual assault presenting at a medical center in Taipei.

OBJECTIVE: Sexual assault is a form of interpersonal violence with significant consequential health problems. The purpose of this study was to describe the characteristics of the victims, assaults, and associated physical and psychologic trauma of sexual assault cases in Taipei. MATERIALS AND METHODS: Data were retrospectively collected from the medical records of sexual assault victims who visited the emergency department of a medical center in Taipei from 1991 to 2003. The characteristics of the victims, assaults, and factors associated with general body and genital trauma were analyzed. RESULTS: There were 114 sexual assault victims, including 107 females and seven males, aged from 3 to 49 years (mean, 17.9 years). Overall, 72.3% of victims had evidence of physical trauma. Genital/anal injuries (53.3%) occurred more often than general body trauma (41.0%). The presence of general body injuries was positively associated with physical examination within 72 hours, and negatively associated with a victim age younger than 18 years. Genital/anal lesions were significantly more common in victims without prior sexual intercourse. CONCLUSION: The results of physical examination in sexual assault victims were related to early examination, age, and sexual experience.

Asymptomatic thymic carcinoma with solitary hepatic metastasis detected by fluorodeoxyglucose positron emission tomography.

Thymic carcinoma is a rare anterior mediastinal malignancy. Most patients present initially with chest pain, cough or dyspnea. Asymptomatic patients account for less than one third of the total cases. Thymic carcinoma is aggressive and tends to metastasize to the lymph nodes, lungs, and bones, and less commonly to the liver, spleen, brain, and adrenal glands. We present a 49-year-old man who received abdominal ultrasound and magnetic resonance imaging for a health checkup, during which, a necrotic hepatic tumor was found incidentally. Fluorodeoxyglucose (FDG) positron emission tomography was performed to search for the primary site of malignancy, and lobulated FDG hypermetabolic lesions in the anterior mediastinum were found. The diagnosis of thymic carcinoma with liver metastasis was then confirmed after morphological and immunohistochemical studies of hepatic and mediastinal biopsy specimens.

Adult progressive intrahepatic cholestasis associated with genetic variations in ATP8B1 and ABCB11.

Severe intrahepatic cholestasis with low serum gamma-glutamyltranspeptidase (gamma-GT) activity is exceptionally rare in adult patients, and its association with multi-genetic alterations of bile salt transporters has not been reported. We investigated a 25-year-old man presenting with a four-year history of jaundice. Laboratory and radiographic examinations revealed clinical pictures of progressive intrahepatic cholestasis with low gamma-GT. Serial liver histopathology demonstrated cirrhosis resulting from progressive persistent cholestatic injury. Genetic sequencing studies for the entire coding exons of ATP8B1 and ABCB11 uncovered a heterozygous missense mutation 1798 C->T (R600W) in ATP8B1, and a homozygous nucleotide substitution 1331 T->C (V444A) in ABCB11. In conclusion, this is a rare case of adult onset progressive intrahepatic cholestasis with low gamma-GT associated with heterozygous ATP8B1 mutation and homozygous ABCB11 polymorphism. Further studies are necessary to investigate the impact of heterozygous R600W mutation and whether other cholestatic disorders are multi-genetic.

Human parvovirus b19 infection in patients with coronary atherosclerosis.

BACKGROUND AND AIMS: The identification of possible pathogens for an infectious etiology of atherosclerotic coronary artery disease (CAD) is an expanding field. The present study was undertaken to explore the role of parvovirus B19, a potent infectious agent. METHODS: A total of 565 patients were analyzed (90 patients with CAD, and 475 controls). Serologic analysis for human paravovirus B19 (B19) specific IgM and IgG was carried out in all patients. In addition, tissue specimens were obtained from five patients who received heart transplants. Direct in situ polymerase chain reaction (PCR) and immunocytochemistry were performed in the samples to localize B19 DNA. RESULTS: Enzyme immunoassay showed that the seropositive rate of anti-B19 IgG in patients with CAD was 1.5- to 2.7-fold more frequent than in healthy controls. Clinical characteristics did not affect the prevalence of seropositivity for B19. However, anti-B19 IgM and B19-specific DNA were not detected in healthy or individuals with CAD. Furthermore, nonradioactive in situ PCR found that the majority of B19-specific DNA was located in the endothelial cells of the thickened intima. CONCLUSIONS: Our results first demonstrate a seroepidemiological and histopathological association between chronic B19 infection and CAD, suggesting that B19 infection may have a potential role in the pathogenesis of coronary atherosclerosis.

Malignant prolactinoma with craniospinal metastasis in a 12-year-old boy.

The authors report the clinical features of and imaging studies on a rare case of pediatric malignant prolactinoma. A 12-year-old boy presented with ataxia, blurred vision, and consciousness disturbance. He had received transcranial surgery and adjuvant radiotherapy. However, the tumor regrew with craniospinal metastasis 16 months after the operation. The relevant literature was reviewed regarding the clinical presentation, pathogenesis, treatment approaches, and prognosis of malignant prolactinoma.

Rhabdomyolysis: magnetic resonance imaging and computed tomography findings.

OBJECTIVE: Our purpose was to describe the magnetic resonance (MR) imaging and computed tomography (CT) findings in patients with rhabdomyolysis. METHODS: The medical records and imaging studies of 10 patients (5 males, 5 females; age range, 14-60 years; mean age, 28.3 years) with rhabdomyolysis were retrospectively reviewed. Magnetic resonance imaging was available in 9 patients and CT in 2 patients. RESULTS: Two distinct imaging types of rhabdomyolysis were observed. For type 1 rhabdomyolysis (n = 2), the affected muscles revealed homogeneously isointense to hyperintense on T1-weighted, homogeneously hyperintense on T2-weighted and short-tau inversion recovery (STIR) images, and homogeneously enhanced on contrast-enhanced MR images. For type 2 rhabdomyolysis (n = 8), the affected muscles revealed homogeneously or heterogeneously isointense to hyperintense on T1-weighted images, heterogeneously hyperintense on T2-weighted and STIR images, heterogeneously hypodense on CT images, and rim enhanced on contrast-enhanced MR and CT images with the presence of a specific presentation, named as the "stipple sign." CONCLUSIONS: Rhabdomyolysis is a clinical and biochemical syndrome comprising 2 distinct imaging types. Homogeneous signal changes and enhancement in the affected muscles advocate type 1 rhabdomyolysis. The stipple sign is helpful in demonstrating the areas of myonecrosis in type 2 rhabdomyolysis and, together with clinical and laboratory presentations, in reaching the correct diagnosis.