Che-Sheng Ho

Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988–2004†

Trisomy 18 is the second most common autosomal trisomy in newborns. The birth prevalence of this disorder is approximately 1 in 3,000 to 1 in 8,000, and the life span of the majority of patients is less than 1 year. As information regarding outcome in trisomy 18 is rather fragmentary in the literature, this study is aimed at investigating the survival and natural history of trisomy 18. We also evaluated the survival age and management of trisomy 18 in two different periods, before and after the implementation of National Health Insurance (NHI) program. Thirty‐nine cases of trisomy 18 were collected in Mackay Memorial Hospital in a 17‐year period, from 1988 to 2004. Delivery data, survival age, management before and after the implementation of NHI program, structural defects, image findings and cytogenetic results were analyzed by medical and nurses records. The diagnosis of trisomy 18 was based on the prenatal amniocentesis or postnatal chromosome analysis. Three patients had trisomy 18 mosaicism. Since cardiovascular and central nervous systems are the most common organ systems involved in this disorder, 31 patients received brain ultrasonography and heart ultrasonography for evaluation of their multiple anomalies after admission. All patients except one died in their first year due to severe malformations of the cardiovascular or central nervous systems. The median survival age was 6 days. We found a longer survival with female patients than with male patients (P < 0.05). Implementation of NHI program in the more recent decade of this study period was associated with longer survival of trisomy 18 (P < 0.05). The three most common structural defects were clenched hands (95%), rocker bottom feet (90%), and low set or malformed ears (90%). Low birth weight was present in 90%. By cardiac ultrasonography, the top four heart defects were ventricular septal defect (94%), patent ductus arteriosus (77%) and atrial septal defect (68%). However, ten cases (32%) had complex congenital heart defects. By brain ultrasonography, the most common brain lesion was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%) and choroid plexus cysts (19%). Although most patients with trisomy 18 die within the first few weeks after birth, it is important to recognize that a small but notable percentage of these patients will survive the first year. When prenatal or postnatal decisions need to be made, the possibility of long‐term survival should be included in any discussion to enable families to make the most appropriate decision.

Cerebral perfusion in children with Alice in Wonderland syndrome

Alice in Wonderland syndrome (AIWS) is characterized by visual hallucinations and bizarre perceptual distortions. Technetium-99m hexamethylpropyleneamine tomography (SPECT) brain scans were performed in four patients during the acute stage of AIWS. Two patients were demonstrated to have Epstein-Barr virus infections. One had abnormal (EEG) findings. The visual-evoked potential, cranial CT, and MRI findings were negative. The decreased cerebral perfusion areas in all patients were near the visual tract and visual cortex. All involved some regions of the temporal lobe. In most patients with AIWS, the EEG, CT, and MRI are unable to determine the precise pathologic areas. However, a SPECT brain scan may demonstrate abnormal perfusion areas and explain the clinical presentations.

Clinical characteristics and survival of trisomy 13 in a medical center in Taiwan, 1985-2004.

Background: This study investigated the survival and natural history of trisomy 13 in a series of patients, comparing the management and outcome before and after the implementation of Taiwan’s National Health Insurance program (NHI).

Clinical Manifestations, Laboratory Findings and Complications of Pediatric Scrub Typhus in Eastern Taiwan

BACKGROUND Scrub typhus is a clinically important endemic disease in Taiwan. The aims of this study were to analyze the clinical manifestations, laboratory data and complications of pediatric scrub typhus in eastern Taiwan. PATIENTS AND METHODS We searched medical records for all patients with scrub typhus who were hospitalized between 1992 and 2002 at the Taitung branch of Mackay Memorial Hospital, Taiwan. Records of children under the age of 18 with a confirmed diagnosis were selected for retrospective review. RESULTS During the study period, 145 patients fulfilled the diagnostic criteria for scrub typhus, of whom 106 (73%) were adults and 39 (27%) were children. The mean age of the children was 7.6+/-4.6 years. The most common clinical manifestations of pediatric scrub typhus were fever (n=39; 100%), cough (n=28; 72%), anorexia (72%), eschar (69%), chill (67%) and lymphadenopathy (64%). The most common complications were hepatic dysfunction (77%) and pneumonitis (54%). Three children (8%) required intensive care, but the overall survival rate was 97%. One child died with multi-organ failure within 8 hours after admission. CONCLUSION Scrub typhus should be considered in children with fever and hepatic dysfunction, particularly in those with a history of environmental exposure in an endemic area for scrub typhus. The presence of an eschar offers an important diagnostic clue, but not for all cases. Children with scrub typhus may develop serious complications and may even die if appropriate treatment is not given. Doxycycline is an effective antibiotic for pediatric scrub typhus in Taiwan.

A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family

The autosomal recessive form of type II cutis laxa (ARCL II) is characterized by the appearance of redundant, inelastic skin with wrinkling, an aged look and additional variable systemic involvement including intrauterine growth retardation, failure to thrive, developmental delay, dysmorphism, osseous abnormality, and CNS manifestations. Several genetic defects have been found in patients and families with the clinical manifestations of ARCL II. Recently, mutations in PYCR1 have been linked to cutis laxa with progeroid features. We ascertained two siblings with of ARCL II born to non‐consanguineous parents. Mutation analysis of PYCR1 revealed a novel single‐base deletion (c.345delC) in exon 4 leading to frame‐shift and premature stop of translation. The effect of this mutation results in a strong reduction of PYCR1 expression in skin fibroblasts from affected siblings. These two cases extend the genotypic spectrum of PYCR1‐related ARCL II.

Outcome of preterm infants with postnatal cytomegalovirus infection via breast milk: A two-year prospective follow-up study

AbstractApproximately 15% of preterm infants may develop postnatal cytomegalovirus (CMV) infection from seropositive mothers via breast milk and are at risk for neurological sequelae in childhood. The aims of this study were to assess the effects and outcomes on growth, neurodevelopmental status, and hearing in very low birth weight (VLBW) premature infants with postnatal CMV infection via breast milk at the corrected age of 12 and 24 months.The prospective follow-up study population comprised all living preterm children (n = 55) with a birth weight ⩽1500 g and gestational age of ⩽35 weeks, who had been participated in our “postnatal CMV infection via breast milk” studies in 2000 and 2009, respectively. The cohort of children was assessed at 12 and 24 months. Clinical outcomes were documented during hospitalization and after discharge. Long-term outcomes included anthropometry, audiologic tests, gross motor quotient, Infant International Battery, and neurodevelopmental outcomes; all were assessed at postcorrected age in 12 and 24 months during follow-up visits.Of the 55 infants enrolled in the study (4 noninfected infants were excluded because their parents did not join this follow-up program later), 14 infants postnatally acquired CMV infection through breast-feeding (infected group) and were compared with 41 infants without CMV infection (control group). No significant differences were observed between the groups with regard to baseline characteristics, clinical outcomes, anthropometry, or psychomotor and mental development on the Bayley scale of infant development. None of the infants had CMV-related death or permanent sensorineural hearing loss.Transmission of CMV from seropositive mother via breast milk to preterm infants does not appear at this time to have major adverse effects on clinical outcomes, growth, neurodevelopmental status, and hearing function at 12 and 24 months corrected age.

Evolving trends of neonatal and childhood bacterial meningitis in northern Taiwan

BACKGROUND The epidemiology of bacterial meningitis varies in different areas, age groups, and times. To know the trend of neonatal and childhood bacterial meningitis in northern Taiwan, we performed this 29-year-long assessment. METHODS Eligible patients were aged 18 years or younger, hospitalized in Mackay Memorial Hospital between 1984 and 2012, and proven by positive cerebrospinal fluid bacterial cultures. Analysis included the patient numbers and pathogens in different age groups, periods, complications, and outcomes. RESULTS Males were predominant in all the age groups through the years. Almost half of the patients were in the neonatal period. Patient numbers went up in the early study period and declined after 1993-1997. Group B Streptococcus and Escherichia coli were the most common pathogens in neonates, whereas in childhood were Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Patient numbers of Group B Streptococcus, S. pneumoniae, and Hib meningitis declined in the late study period, but E. coli meningitis increased. The mortality rate decreased but sequela rate increased. Among the four most common pathogens, S. pneumoniae had the worst outcome and had highest mortality rate. All Hib meningitis patients survived, but their sequela rate was the highest. CONCLUSION This study provides an epidemiological data on trends of neonatal and childhood bacterial meningitis in northern Taiwan during the past 29 years, including male and neonatal predominance, decrease of total patient number in recent years, change of major pathogens, and declined mortality but raised morbidity.

Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome

De Barsy syndrome (DBS) is characterized by progeroid features, ophthalmological abnormalities, intrauterine growth retardation, and cutis laxa. Recently, PYCR1 mutations were identified in cutis laxa with progeroid features. Herein, we report on a DBS patient born to a nonconsanguineous Chinese family. The exceptional observation of congenital glaucoma, aortic root dilatation, and idiopathic hypertrophic pyloric stenosis in this patient widened the range of symptoms that have been noted in DBS. Mutation analysis of PYCR1 revealed compound heterozygous PYCR1 mutations, including a p.P115fsX7 null mutation allele and a second allele with two missense mutations in cis: p.G248E and p.G297R. The effect of mutation results in a reduction of PYCR1 mRNA expression and PYCR1 protein expression in skin fibroblasts from the patient. The findings presented here suggest a mutation screening of PYCR1 and cardiovascular survey in patients with DBS.

Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy

Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the treated twitcher mice was significantly prolonged and their neurobehavioral performance was improved. Taken together, our findings underscore the complexity of cerebellar neurodegeneration in GLD and highlight the potential effectiveness of gene therapy in mitigating neuropathological deficits in GLD and other neurodegenerative disorders in which Purkinje cells are involved.

Technetium-99m-HmPAO brain SPECT in infantile Gaucher's disease

The authors report serial technetium-99m hexamethylpropylene-amine-oxime brain single photon emission computed tomography (SPECT) findings in two infants with Gauchers disease type 2. Detailed neurologic and laboratory examinations, including bone marrow biopsies and enzymatic assays, were described. Serial brain magnetic resonance imaging studies in one patient illustrated the progressive cerebral atrophy in the frontal and temporal lobes. The SPECT in both cases demonstrated positive findings of initial scattered hypoperfusion, with extending to hypoperfusion of the entire cerebrum after 4 months of clinical deterioration. These changes in the SPECT findings may reflect progressive degeneration of the cerebrum in Gauchers disease type 2. Brain SPECT may provide useful information on cerebral flow and metabolic distribution corresponding to the neurologic deficits of neuronopathic Gauchers disease.