Quick Search
  Home Journal Information Current Issue Past Issues Services Contact Us  
Vol 13, No 4
Vol 13, No 4 August 2017 ISSN 1708-8569
Review articles
Original articles
Letters to the Editor
Review articles:
Etiology and clinical features of viral bronchiolitis in infancy
  Andrew Fretzayas, Maria Moustaki
Background: Bronchiolitis is a common lower respiratory tract infection in infancy. The aim of this review is to present the clinical profi le of viral bronchiolitis, the different culprit viruses and the disease severity in relation to the viral etiology.
Data sources: Databases including PubMed and Google Scholar were searched for articles about the clinical features of bronchiolitis and its viral etiology. The most relevant articles to the scope of this review were analyzed.
Results: Currently there are two main definitions for bronchiolitis which are not identical, the European definition and the American one. The most common viral pathogen that causes bronchiolitis is respiratory syncytial virus which was identified in 1955; now many other viruses have been implicated in the etiology of bronchiolitis such as rhinovirus, adenovirus, metapneumovirus, and bocavirus. Several studies have attempted to investigate the correlation of bronchiolitis severity with the type of detected virus or viruses. However, the results were not consitent.
Conclusions: For the time being, the diagnosis of bronchiolitis remains clinical. The isolation of the responsible respiratory pathogens does not seem to confer to the prognosis of the disease severity.
  [Abstract] [Full Text] [PDF]  
The emerging role of endoscopic ultrasound for pancreaticobiliary diseases in the pediatric population
  Suril Patel, Jarred Marshak, Fredric Daum, Shahzad Iqbal
Background: Endoscopic ultrasound (EUS) is a useful diagnostic and therapeutic tool in the pediatric population. Given the high accuracy and sensitivity of EUS, it is particularly effective in evaluating pancreaticobiliary disease. Published literature in the use of pediatric EUS is limited. Therefore we aimed to review the current literature for EUS indications, safety, and effectiveness for the pediatric population.
Data sources: English language articles on the use of pediatric endoscopic ultrasound in evaluating pancreaticobiliary diseases were retrieved from PubMed/ MEDLINE.
Results: We analyzed various retrospective studies and case series publications. Data were extrapolated for pediatric patients with pancreaticobiliary diseases.
Conclusions: EUS offers superior imaging. It is comparible to magnetic resonance imaging and/or pancreatic-protocol computed tomography. In the current literature, there are a variety of pancreaticobiliary conditions where EUS was utilized to make a diagnosis. These include recurrent pancreatitis, congenital anomalies, microlithiasis, pancreatic pseudocysts, and pancreatic mass lesions. EUS was shown to be a safe and cost-effective modality with both diagnostic and therapeutic capabilities in the pediatric population. EUS is now increasingly being recognized as a standard of care when evaluating pancreaticobiliary conditions in children.
  [Abstract] [Full Text] [PDF]  
Does probiotic supplementation affect pulmonary exacerbation and intestinal infl ammation in cystic fibrosis: a systematic review of randomized clinical trials
  Zeinab Nikniaz, Leila Nikniaz, Nemat Bilan, Mohammad Hossein Somi, Elnaz Faramarzi
Background: Patients with cystic fibrosis (CF) usually have abnormal intestinal microbiota due to massive exposure to antibiotics. Probiotics could modify the gut microbiota and hence may affect CF management. So the aim of present systematic review was evaluation of the efficacy and safety of probiotic supplementation for the management of cystic fi brosis.
Data sources: We searched PubMed, Science Direct, Google Scholar, Springer Cochrane Library Databases until January 2016 for randomized controlled trials (RCTs) performed in pediatric or adult populations related to the study aim. Key words were selected based on Mesh terms. Based on the Critical Appraisal Skills Programme checklist, eligibility of included articles was evaluated.
Results: Five studies included in this review represent 188 participants with a follow up period ranging from 1 month to 6 months. The results of the included studies supporting the use of probiotics in management of pulmonary exacerbation and intestinal calprotectin in patients with cystic fibrosis. However the level of evidence was limited.
Conclusion: The lack of high quality RCTs makes it impossible to support a general recommendation about the use of probiotics in the treatment of CF pulmonary exacerbation and intestinal inflammation.
  [Abstract] [Full Text] [PDF]  
Original articles:
Group B Streptococcus causes severe sepsis in term neonates: 8 years experience of a major Chinese neonatal unit
  Ying Dong, Si-Yuan Jiang, Qi Zhou, Yun Cao
Background: In contrast to industrialized countries, the clinical characteristics of neonatal sepsis caused by Group B Streptococcus (GBS) are largely unexplored in China.
Methods: A retrospective case series study was performed at a high-capacity neonatal unit in Shanghai, China from January 2008 to December 2015. Clinical characteristics of neonates with culture-proven GBS sepsis and antibiotic susceptibility of isolated strains were analyzed.
Results: Forty-three term neonates were included during the study period. The majority (74.4%) had early-onset sepsis with symptoms of respiratory distress. Meningitis was significantly more common in lateonset sepsis than in early-onset sepsis (81.5% vs. 18.8%, P<0.0001). Approximately one third of all patients (n=16) developed severe sepsis, defined as sepsis with organ dysfunctions, and respiratory dysfunction/failure was the most common (32.6%). The in-hospital mortality rate of GBS sepsis was 4.7%. Neonates who progressed to severe sepsis had significantly lower pH level at the onset of symptoms than those who did not (7.260.12 vs. 7.390.05, P=0.006). Treatment of severe GBS sepsis required lots of medical resources including extracorporeal membrane oxygenation. All tested GBS strains were susceptible to penicillin, but the rate of resistance to clindamycin (84.0%) and erythromycin (88.0%) was high.
Conclusions: GBS as a pathogen for neonatal sepsis has been receiving little attention in China. Our data demonstrated that GBS sepsis was likely to be fulminant. Early recognition followed by antibiotics and adequate supportive therapies was critical for successful treatment. Chinese clinicians should be aware of GBS infection when treating neonatal sepsis, especially in the absence of universal maternal GBS screening.
  [Abstract] [Full Text] [PDF]  
Effects of methylprednisolone or immunoglobulin when added to standard treatment with intravenous azithromycin for refractory Mycoplasma pneumoniae pneumonia in children
  Li-Shen Shan, Xin Liu, Xin-Yuan Kang, Fei Wang, Xiao-Hua Han, Yun-Xiao Shang
Background: The prevalence of Mycoplasma pneumoniae pneumonia has increased considerably in recent years. To evaluate the efficacy of combined treatment of azithromycin with intravenous immunoglo-bulin (IVIG) or methylprednisolone in children with refractory Mycoplasma pneumoniae pneumonia (RMPP).
Methods: Children with RMPP were randomly allocated to group A [intravenous azithromycin (IA)+ methylprednisolone], group B (IA+IVIG) or group C (IA alone). Following a 7-day treatment, group C patients were randomly separated into two sub-groups: group C1 (IA+methylprednisolone) and group C2 (IA+IVIG). Temperature, respiratory symptoms and signs were examined. The average febrile period after treatment (F2), average total febrile period (F3), infiltration absorption, atelectasis resolution, pleural effusion disappearance were determined. The levels of C-reactive protein (CRP), D-dimer, and lactate dehydrogenase (LDH) were measured.
Results: Seven days after enrollment, the average F2 after treatment of group A was the shortest. Compared with the control group C, the combined treatment group A and B showed higher rates of infiltration absorption, atelectasis resolution and pleural effusion disappearance, while lower levels of serum CRP, D-dimer and LDH. Fourteen days after enrollment, all children with combined therapy clinically improved, and presented better laboratory results. Group C1 showed shorter F3 and lower levels of CRP and LDH than those of group C2. Overall, group A showed the shortest F3, also has the lowest CRP and LDH.
Conclusions: Azithromycin with IVIG or methylprednisolone was better treatment for children with RMPP than azithromycin alone. IVIG treatment may be beneficial, especially when the efficacy of corticosteroids is insecure, thus could be considered as an alternative of primary therapeutic approaches.
  [Abstract] [Full Text] [PDF]  
Outcomes and risk factors of ventilator-associated pneumonia in neonates
  Anucha Thatrimontrichai, Natthaka Rujeerapaiboon, Waricha Janjindamai, Supaporn Dissaneevate, Gunlawadee Maneenil, Supika Kritsaneepaiboon, Pattama Tanaanantarak
Background: Ventilator-associated pneumonia (VAP) in neonates has been associated with high mortality and poor outcome. This study aimed to compare the incidence, risk factors, and outcomes of VAP and non- VAP conditions in neonates.
Methods: We performed a prospective cohort study in a neonatal intensive care unit (NICU) in Thailand from January 2014 to December 2014. All neonatal patients who were ventilated more than 48 hours were enrolled.
Results: There were 128 enrolled patients. The median (inter quartile range) gestational age and birthweight were 35 (30.2, 37.8) weeks and 2380 (1323.8, 3020.0) g. There were 17 VAP patients (19 episodes) and 111 non-VAP ones. The VAP rate was 13.3% or 10.1 per 1000 ventilator days. According to the multivariate analysis, a birthweight less than 750 g [adjusted odds ratio (aOR)=10.75, 95% confidence interval (CI)=2.35-49.16; P=0.002] and sedative medication use (aOR=4.00, 95% CI=1.23-12.50; P=0.021) were independent risk factors for VAP. Compared with the non-VAP group, the median difference in the VAP group yielded a significantly longer duration of NICU stay (18 days, P=0.001), total length of hospital stay (16 days, P=0.002) and higher hospital costs ($5113, P=0.001). The inhospital mortality rate in the VAP and non-VAP groups was 17.6% and 15.3% (P=0.73), respectively.
Conclusions: A neonatal birthweight less than 750 g and sedative medication use were independent risk factors for VAP. Our VAP patients experienced a longer duration of both NICU and hospital stay, and incurred higher hospitalization costs.
  [Abstract] [Full Text] [PDF]  
Allergy march of Chinese children with infantile allergic symptoms: a prospective multi-center study
  Qi Gao, Yi-Xin Ren, Yong-Ge Liu, Lin Ma, Xiao-Hong Gu, Wei-Xi Zhang, Li Liu, Xiao-Jia Zhai, Li Xiang, Kun-Ling Shen
Background: Allergy march refers to progression of allergic diseases from infantile food allergy to the development of asthma and allergic rhinitis (AR). Evidence comes mostly from studies in European countries. This study aimed to investigate allergy march in Chinese children with infantile food protein allergy (FPA) with a special focus on the effect of different formula interventions.
Methods: From 2008 to 2010, 153 infants diagnosed with FPA were recruited in five tertiary hospitals across China. They were randomly treated with amino-acid-based formula or soy-protein-based formula for a period of 3 months. Long-term follow-up was performed when they reached early school age, using questionnaires, physical examinations, and serum-specific immunoglobulin E.
Results: The overall follow-up rate was 73.20%. In patients who reached their early school years, the prevalence of physician-diagnosed AR and asthma were 43.75% and 23.21%, respectively. Only 40% of the subjects remained positive for food sensitizations upon follow-up. Twenty-six subjects receiving aeroallergen screening tests in infancy all proved negative, but upon follow-up, 65.57% were sensitized to aeroallergens (P=0.005). No significant difference between the effects of amino-acid-based formula and soy-protein-based formula on children's allergy march was observed.
Conclusions: A high proportion (47.32%) of Chinese infants with early allergic symptoms developed respiratory allergies by their early school years. Most food-sensitized infants outgrew their condition several years later, but then aeroallergen sensitization often occurred. Amino-acid-based formula showed no advantages over soy protein-based formula with respect to arresting the allergy march.
  [Abstract] [Full Text] [PDF]  
Acute hemorrhagic edema of infancy: the experience of a large tertiary pediatric center in Israel
  Limor Parker, Keren Shahar-Nissan, Liat Ashkenazi-Hoffnung, Liora Harel, Jacob Amir, Omer Trivizki, Efraim Bilavsky
Background: Acute hemorrhagic edema of infancy (AHEI) is a rare leukocytoclastic vasculitis of the small vessels occurring at a young age and considered as a benign self-limited disease. Due to its low prevalence, there are limited data on the presentation and complications of this disease.
Methods: All computerized files of children who were hospitalized at a tertiary pediatric center due to AHEI over a 10 year period were reviewed. Clinical, laboratory and histopathological data were collected.
Results: Twenty-six patients were included in our study, accounting for 0.7 cases per 1000 admissions of children aged 2 years or less. Mean age was 12.9 months. More than two thirds of the children had preceding symptoms compatible with a viral infection. Upon admission, all patients presented with typical findings of a rash and edema. Edema was most profound over the lower extremities (73%). Concomitant viral or bacterial infections were found in six children. Skin biopsy was performed in six patients revealing leukocytoclastic vasculitis. Thirteen children (50%) had systemic involvement including joint involvement (n=9), gastrointestinal hemorrhage (n=4), microscopic hematuria (n=1) and compartment syndrome of the limb (n=1). The latter was diagnosed in a patient with familial Mediterranean fever.
Conclusions: Our largest data series highlighted what is known regarding clinical and histological findings in children with AHEI. However, contrary to what was previously reported, we found a higher rate of systemic involvement. Although AHEI is a rare entity, pediatricians should be familiar with its presentation, management and our reported complications.
  [Abstract] [Full Text] [PDF]  
Pegylated interferon /ribavirin therapy enhances bone mineral density in children with chronic genotype 4 HCV infection
  Ahmed Megahed, Nanees Salem, Abeer Fathy, Tarik Barakat, Mona Abd El Latif Alsayed, Suzy Abd El Mabood, Khaled R Zalata, Ahmed F Abdalla
Background: The impact of chronic hepatitis C (CHC) on bone mineral density (BMD) has been well studied in adults with a relative paucity of data in children, especially concerning effect of treatment with pegylated interferon (PEG-IFN) plus ribavirin (RV). In the current work, we assessed prospectively changes in BMD in children with CHC before, during, and after treatment.
Methods: Forty-six consecutive children with noncirrhotic genotype 4 CHC were subjected to dual-energy X-ray absorptiometry at baseline, 24 weeks, 48 weeks of therapy and 24 weeks after treatment. BMD, bone mineral content (BMC), and Z score of lumbar spine (L2-L4) were reported. Tanner pubertal stage, viral load, liver function tests, serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and liver histopathology were assessed in all included children.
Results: Thirty (65.2%) patients had normal BMD, 10 (21.7%) were at risk for low BMD, and 6 (13.1%) had low BMD for chronological age. Patients with low BMD were significantly older (P=0.001), with higher frequency of delayed puberty than other groups (P=0.002). Baseline densitometric parameters (BMD & BMC) were significantly positively correlated with patients' age, weight, height, body mass index and hemoglobin level; while they were insignificantly correlated with basal viral load, histopathology activity index and fibrosis score. Densitometric parameters improved significantly on PEG-IFN plus RV treatment, this improvement was found to be sustainable 24 weeks after therapy.
Conclusions: Low BMD is detectable in a proportion of CHC children. Antiviral therapy leads to a sustainable increase in BMD.
  [Abstract] [Full Text] [PDF]  
Distal femoral extension and shortening osteotomy as a part of multilevel surgery in children with cerebral palsy
  Matthias C.M. Klotz, Klemens Hirsch, Daniel Heitzmann, Michael W. Maier, Sebastien Hagmann, Thomas Dreher
Background: There are several reports describing an increase in anterior pelvic tilt after hamstring lengthening in children with cerebral palsy (CP). Distal femoral extension and shortening osteotomy (DFESO) is an alternative treatment for correction of flexed knee gait, but investigations analyzing outcome and influence on adjacent joint are few in the literature. The purpose of this study was to analyze the influence of DFESO on knee and pelvis in children with CP. Furthermore, it was of interest if an additional patellar tendon advancement (PA) influences outcome.
Methods: In this retrospective study, 31 limbs of 22 children (GMFCS I-III; mean age: 12.13.1 years), who received DFESO were included and kinematic parameters (knee, pelvis) measured by 3-D-gait analysis were compared before and at least 1 year after surgery (mean follow-up period: 15.6 months).
Results: After surgery, during stance phase minimum knee flexion improved significantly by 20.5 (P<0.001) and mean anterior pelvic tilt increased by 4.0 degrees (P=0.045). In 16 limbs, the postoperative increase in maximum anterior pelvic tilt was more than 5. Limbs who received an additional PA showed the biggest increase in anterior pelvic tilt.
Conclusions: DFESO is an effective method for correction of flexed knee gait in children with CP. Furthermore, the results of this study indicate that DFESO may lead to an increase in anterior pelvic tilt, which may lead to a recurrence of flexed knee gait. In this context, PA seemed to aggravate the effect on the pelvis.
  [Abstract] [Full Text] [PDF]  
Zinc defi ciency in the pediatric age group is common but underevaluated
  Dogus Vuralli, Leyla Tumer, Alev Hasanoglu
Background: Subclinical micronutrient deficiencies have been gradually becoming more important as a public health problem and drawing attention of the health authorities. Today it has been known that detecting and treating people having deficiency symptoms alone is no longer sufficient. It is important to detect and prevent any deficiency before it displays clinical manifestations. Zinc deficiency is one of the most widespread micronutrient deficiencies. In this study, we aimed to evaluate the zinc status and the associated factors in healthy school-age children.
Methods: The study was carried out in schools in Altindag, the district of Ankara. A total of 1063 healthy children, 585 girls and 478 boys, aged 5-16 years were included in the study. Serum zinc, high-sensitivity C-reactive protein levels and white blood cell count were measured. A serum zinc level <65 g/dL was considered as subclinical zinc deficiency for children <10 years of age. For children 10 years of age the cutoffs for serum zinc concentration were set at 66 g/dL for females and 70 g/dL for males. A questionnaire was developed to collect socioeconomic and demographic information of the participants.
Results: The prevalence of subclinical zinc deficiency in children attending the study was detected to be 27.8%. This high ratio showed zinc deficiency was an important health problem in the Altindag district of Ankara, Turkey.
Conclusions: Evaluating the indicators of zinc deficiency such as serum zinc concentration, dietary zinc intake and stunting prevalence, this study is the most comprehensive epidemiological study performed in children in Turkey. This study reveals the high prevalence of subclinical zinc deficiency and indicates that zinc deficiency is a public health concern for the study population.
  [Abstract] [Full Text] [PDF]  
Treatment of pediatric average-risk medulloblastoma using craniospinal irradiation less than 2500 cGy and chemotherapy: single center experience in Korea
  Jong Hyung Yoon, Kyung Duk Park, Hyoung Jin Kang, Hyery Kim, Ji Won Lee, Seung-Ki Kim, Kyu-Chang Wang, Sung-Hye Park, Il Han Kim, Hee Young Shin
Background: Although craniospinal irradiation (CSI) of 2340 cGy plus tumor booster with chemotherapy have been established as a standard treatment of childhood average-risk (AvR) medulloblastoma (MBL) in Western counties, there are a few recent reports in outcomes of AvR MBL using this strategy in Korean and other Asian children. We investigated the outcome of the Korean children with AvR MBL who were treated with CSI <2500 cGy and chemotherapy.
Methods: Between January 2001 and December 2010, clinical characteristics and outcomes of 42 patients who were diagnosed with AvR MBL postoperatively and treated with radiation including CSI <2500 cGy and chemotherapy in Seoul National University Children's Hospital were analyzed.
Results: Their median age was 9 years (range: 3-18.8), and 29 were male. Histological subtypes were classic type in 28 patients, nodular/desmoplastic in 7, and large cell/ anaplastic (LCA) in 7. All the patients received adjuvant radiotherapy (CSI with median 2340 cGy and booster) and multiagent chemotherapy as the first-line treatment. With a median follow-up of 54 months, 12 patients experienced relapse or progression of the tumor. The 3- and 5-year disease-free survival (DFS) rates were 78.0%6.5% and 75.0%6.9%, respectively, and overall survival (OS) rates were 85.3%5.6% and 76.8%6.9%, respectively. The LCA subtype was associated with poorer DFS (P=0.023) and OS (P=0.008), compared with non-LCA subtypes.
Conclusion: The outcomes of children and adolescents with AvR MBL treated with radiation including CSI <2500 cGy and chemotherapy, are compatible to those in Western countries; however, the LCA subtype has a poor outcome with this strategy.
  [Abstract] [Full Text] [PDF]  
Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identifi cation of three novel mutations and in silico structural analysis of the missense mutations
  Souad Ouesleti, Maria Francisca Coutinho, Isaura Ribeiro, Abdehedi Miled, Dalila Saidane Mosbahi, Sandra Alves
Background: Mucopolysaccharidoses type III (MPS III) are a group of autosomal recessive lysosomal storage diseases, caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate: heparan sulfate sulfamidase (SGSH), -Nacetylglucosaminidase (NAGLU), heparan sulfate acetyl- CoA: -glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS).
Methods: In this study, we have performed the molecular analysis of the SGSH, NAGLU and HGSNAT genes in 10 patients from 6 different MPS III Tunisian families.
Results: In the SGSH gene, two mutations were identified: one novel (p.D477N) and one already described (p.Q365X). In the NAGLU gene, two novel mutations were discovered (p.L550P and p.E153X). For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations. Finally, in HGSNAT gene, we found the splicesite mutation c.234+1G>A that had already been reported as relatively frequent in MPS IIIC patients from countries surrounding the basin of the Mediterranean sea. Its presence in two Tunisian MPS IIIC families points to the hypothesis of its peri Mediterranean origin. With the exception of the c.234+1G>A mutation, that was identified in two unrelated MPS IIIC families, the other identified mutations were family-specific and were always found in homozygosity in the patients studied, thus reflecting the existence of consanguinity in MPS III Tunisian families.
Conclusions: Three novel mutations are reported here, further contributing to the knowledge of the molecular basis of these diseases. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to an improvement in genetic counseling.
  [Abstract] [Full Text] [PDF]  
Eight novel MUT loss-of-function missense mutations in Chinese patients with isolated methylmalonic academia
  Lian-Shu Han, Zhuo Huang, Feng Han, Yu Wang, Zhu-Wen Gong, Xue-Fan Gu
Background: Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT). This study aimed to verify whether missense mutations in MUT in Chinese patients affect the stability and enzymatic activity of MCM.
Methods: Eight Chinese patients were identified with novel mutations. Plasmids carrying the wild-type and mutated MUT cDNA were constructed and transfected into HEK293T cells for functional analyses. The expression and activity of MCM were determined by western blot and ultra-performance liquid chromatography, respectively.
Results: All patients had high levels of blood propionylcarnitine and urinary methylmalonyl acid. By the end of the study, two patients were lost to follow-up, three died, and three survived with mental retardation. Compared to the wild-type protein, the expression levels of all missense mutations of in vitro MCM protein were decreased (P<0.05) except those for I597R, and the MCM activity of the mutations was reduced in a permissive assay.
Conclusion: The missense mutations L140P, A141T, G161V, W309G, I505T, Q514K, I597R and G723D affected the stability and enzymatic activity of MCM, indicating that they had a disease-causing capacity.
  [Abstract] [Full Text] [PDF]  
Identifi cation of two novel mutations in the ATP7B gene that cause Wilson's disease
  Hong-Wen Zhu, Zhong-Bin Tao, Gang Su, Qiao-Ying Jin, Liang-Tao Zhao, Jia-Rui Zhu, Jun Yan, Tian-Yu Yu, Jie-Xian Ding, Yu-Min Li
Background: Wilson's disease is an autosomal recessive disorder characterized by liver disease and/or neurologic deficits due to copper accumulation and is caused by pathogenic mutations in the ATP7B gene.
Methods: Two unrelated Chinese patients born to nonconsanguineous parents who were diagnosed with earlyonset Wilson's disease. DNA sequencing and bioinformation analysis were conducted.
Results: We have identified four mutations in two family trios, of which two were novel, namely, c. 3028A>G (p. K1010E) and c.3992T>G (p.Y1331X), in each patient.
Conclusions: Gene testing is playing an important role in diagnosis of Wilson's disease. The early-onset of Wilson's disease is apparently not associated with P-ATPase domain in the ATP7B protein. Our findings further widen the spectrum of mutations involving the ATP7B gene.
  [Abstract] [Full Text] [PDF]  
Letters to the Editor:
Mutation analysis and prenatal diagnosis of
  Patra Yeetong, Kanya Suphapeetiporn, Vorasuk Shotelersuk
Griscelli syndrome type 2 (GS2; OMIM#607624) is a rare autosomal recessive disorder characterized by hypomelanosis with immunologic abnormalities and haemophagocytic lymphohistocytosis.[1] Neurological manifestations were reported in 67% of GS2 patients.[2] It is caused by mutations in the RAB27A gene.[3] The RAB27A gene encodes Rab27a, a member of the small GTPase superfamily, involved in vesicular fusion and trafficking.[3] Mutations in the MYO5A, RAB27A, or MLPH genes cause GS1, GS2 or GS3, respectively. It has been demonstrated that the tripartite protein complex (Rab27a/ melanophilin/myosin Va) in melanocytes is needed for capturing mature melanosomes for transferring to keratinocytes.[4]
In this study, we report a Thai boy who was admitted to King Chulalongkorn Memorial Hospital for the first time at two years of age because of recurrent fever. He was the fi rst child born to non-consanguineous parents. Hepatosplenomegaly was first noted at the age of 9 months. On physical examination, he was found to have silvery-gray hair and eyebrows, pale conjunctivae and hepatosplenomegaly with the liver edge palpable 7 cm below the right costal margin (span: 12 cm) and the spleen palpable 5 cm below the left costal margin. Lab investigation showed large clumps of pigment in the hair shafts seen under the light microscope (Fig. A), pancytopenia (haemoglobin B: 9.4 g/dL; white blood cell count: 4450 mm3; platelet count: 20 000 mm3), normal to slightly high immunoglobulin levels [IgG: 637.4 mg/dL (380-950 mg/dL); IgM: 143.6 mg/dL (28-112 mg/dL); IgA: 108.7 mg/dL (18-110 mg/dL); total IgE: 79.7 IU/mL (0-60 IU/mL)]. Bone marrow aspiration revealed hypercellular marrow, increased normally matured megakaryocytes, and increased histiocytes. Flow cytometry showed total T cells (CD3) of 3386 cells/mm3 (72%; CD4 18% and CD8 42%), B cells (CD19) 15% and natural killer cells (CD16 & 56) 8%. Chest X-ray showed diffuse granular infiltration. At the age of three years, he developed ataxia and refused to walk. Magnetic resonance imaging of the brain showed almost symmetrical white matter lesions involving bilateral cerebellar hemispheres and parietooccipital regions.
After informed consent, genomic DNA and total RNA was isolated from peripheral leukocytes. Direct sequencing of polymerase chain reaction (PCR)- amplified complementary DNA representing the entire coding regions of RAB27A was performed. It revealed that the patient was compound heterozygous for two novel mutations, c.109A>T (p.K37X) and c.318T>G (p.S106R) (Fig. B). Genomic DNA was amplified and sequenced, confirming the existence of both mutations.
His conditions worsened and bone marrow transplantation using an unrelated donor was performed at the age of four years. He passed away a few weeks after the transplantation due to sepsis.
Identification of the disease-causing mutation has enabled more accurate genetic counseling. Five years after the proband passed away, the parents decided to have another child and requested a prenatal diagnosis. At 16 weeks of gestation, genomic DNA was isolated from amniocytes. PCR-restricted fragment length polymorphisms primers were used to specifically amplify exons 2 and 4 of the RAB27A gene. The PCR products were examined for the p.K37X and p.S106R mutations by restriction enzyme digestion using DdeI and BanI, respectively. The result revealed that the fetus carried the p.K37X, but not the p.S106R (Fig. C), suggesting that the fetus would be unaffected with GS2. The mother continued her pregnancy and gave birth to a healthy child.
We reported the first patient with GS2 in Thailand. To our knowledge, in Asia, only Turkish, Iranian, Jordanian, Indian and Pakistani descents were reported for GS2 mutations.[5-7] Our patient had silvery-gray hair and eyebrows with immunological defects which could help distinguish GS2 from other types. The hair shaft revealed the large irregular clumping of pigment which distributed around medulla when compared to normal hair. There was no difference between the characteristic of our Thai patient's hair shaft and other Asian's hair shaft.[8] The onset of the accelerated phase of our proband was within the previously observed range which was from the infancy to teens.[2] Serum triglyceride level of our patient was within a normal range while most reported patients had a high level of triglycerides.[9] At least 16 patients with GS2 were reported to undergo hematopoietic stem cell transplantation and all of them survived.[2,4,5,7,10]
The p.K37X is expected to be degraded by nonsensemediated mRNA decay and the p.S106R changes a neutral polar serine to a basic polar arginine. ClustalX 1.83 software showed that serine at the 106 position of RAB27A was evolutionary conserved among all species available in the database (Fig. D). Polymorphism phenotyping-2 (http://genetics.bwh.harvard.edu/pph2/) and sorting intolerant from tolerant (http://sift.jcvi. org/) predicted that it was "probably damaging" and "deleterious", respectively. In addition, it was absent in 250 unrelated Thai controls.
In conclusion, we found two novel mutations in the RAB27A gene in a Thai boy with GS2. The identified mutations enabled us to perform a prenatal diagnosis for the subsequent pregnancy. The fetus was found to carry only one mutation. We reported the first case of a successful prenatal diagnosis for GS2.
  [Abstract] [Full Text] [PDF]  
Crohn's disease with anorectal stenosis
  Darja Urlep, Rok Orel
Anorectal stenosis (ARS) is a rare complication of Crohn's disease (CD) and a risk factor for both fecal diversion (FD) and proctectomy,[1,2] especially in patients who failed anti-tumor necrosis factor- (anti-TNF) therapy.[3,4] Herein, we presented a case of a 17-year-old female diagnosed with CD at age 7, with inflammation located in the small bowel and colon (Paris classification: L3L4b). Due to corticosteroid dependency, infl iximab with concomitant azathioprine was introduced at age 9 and discontinued two years after, because of the appearance of a 3 cm tumor-mass, which resembled a lymphoma, in the oral cavity. The histopathologic examination confirmed orofacial granulomatosis. The therapy with anti-TNF agent (adalimumab) was continued. While treated with adalimumab and azathioprine, she presented with symptoms of ileus at the age of 14. The cause of the obstruction was ARS (4 cm in length), impassable by the coloscope, which was resolved by endoscopic balloon dilatation (EBD). The dose of adalimumab was increased to 80 mg per week and azathioprine was continued. Despite this therapy, she needed EBD every 3-5 months because of repeated obstructive ARS. She suffered from extreme fatigue and was not able to attend school. Pediatric Crohn's disease activity index (PCDAI) was 45. At that time, surgical therapy with FD was planned. Colonoscopy revealed severe proctitis with ARS and a simple endoscopic score for CD (SES-CD) of 11 in the rectum (Fig. A). However, a trial with vedolizumab (VDZ) was started prior to surgical therapy at age 16. The response to VDZ was assessed at week 10; she was in clinical remission (PCDAI=5), feeling energetic and again able to attend school. Colonoscopy revealed a dramatic endoscopic improvement (Fig. B) with SES-CD of 3.
The management of CD with ARS is challenging. Our patient had failed anti-TNF therapy, therefore a trial involving the biologic agent VDZ with a different mechanism of action was a logical treatment option. VDZ is a selective monoclonal antibody against 47-integrin, which targets leukocyte trafficking in the gastrointestinal tract (GIT).[5] VDZ has not been approved for use in pediatric CD, although there are clinical trials that report its effectiveness and safety in adult CD.[6] Our case demonstrates that VDZ may represent a viable treatment option in severe pediatric CD patients with refractory ARS intended for surgical therapy. After one year of the VDZ therapy, our patient remains in clinical and endoscopic remission without the need for EBD or surgical treatment.
Darja Urlep, Rok Orel Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, University Medical Center, Bohoričeva 20, 1000 Ljubljana, Slovenia Email: darja.urlep@kclj.si
1 Galandiuk S, Kimberling J, Al-Mishlab TG, Stromberg AJ. Perianal Crohn disease: predictors of need for permanent diversion. Ann Surg 2005;241:796-801.
2 Brochard C, Siproudhis L, Wallenhorst T, Cuen D, d'Halluin PN, Garros A, et al. Anorectal stricture in 102 patients with Crohn's disease: natural history in the era of biologics. Aliment Pharmacol Ther 2014;40:796-803.
3 Singh S, Ding NS, Mathis KL, Dulai PS, Farrell AM, Pemberton JH, et al. Systematic review with meta-analysis: faecal diversion for management of perianal Crohn's disease. Aliment Pharmacol Ther 2015;42:783-792.
4 Strong S, Steele SR, Boutrous M, Bordineau L, Chun J, Stewart DB, et al. Clinical practice guideline for the surgical management of Crohn's disease. Dis Colon Rectum 2015;58:1021-1036.
5 Bryant RV, Sandborn WJ, Travis SP. Introducing vedolizumab to clinical practice: who, when, and how? J Crohns Colitis 2015;9:356-366.
6 Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013;369:711-721. doi: 10.1007/s12519-017-0038-1
  [Abstract] [Full Text] [PDF]  
roger vivier bags 美女 美女

Home  |  Journal Information  |  Current Issue  |  Past Issues  |  Journal Information  |  Contact Us
Children's Hospital, Zhejiang University School of Medicine, China
Copyright 2007  www.wjpch.com  All Rights Reserved Designed by eb