Type I Gaucher disease in children with and without enzyme therapy

This retrospective study describes the course of 56 children with non-neuronopathic Gaucher disease who presented at <16 years and were followed at 6- to 12-month intervals for 3-9 years. Massive splenomegaly and height retardation marked those who required treatment. Enzyme replacement significantly increased hemoglobin levels; platelet counts were divergent at presentation and follow-up, regardless of therapy. Among treated patients there was a significant reduction in liver and spleen index volumes, and a significant increase in height z-scores. None of the children required splenectomy or developed lung involvement. Many patients diagnosed due to large-scale screening were very mildly affected and remain untreated.     

表面活性蛋白C基因突变与儿童间质性肺疾病

表面活性蛋白 C 是唯一在肺泡Ⅱ型上皮细胞中表达的肺表面活性蛋白,其基因突变与儿童间质性肺疾病关系密切。该综述探讨表面活性蛋白 C 基因突变相关儿童间质性肺疾病的发病机制、诊断以及治疗的进展。     

A disease severity scoring system for children with type 1 Gaucher disease

Almost half of patients with Gaucher disease are diagnosed by the age of 10 years, and approximately two thirds are diagnosed by the age of 20 years. Besides symptomatic children, some presymptomatic children are being diagnosed through community screening programs and because of affected siblings. In addition, it is anticipated that in the near future, newborn screening for lysosomal diseases such as Gaucher disease will be introduced in the USA, identifying additional pre/nonsymptomatic children. Currently, there is no severity scoring system for children. A validated disease severity scoring system in the pediatric Gaucher population will be essential for classifying disease severity in these children, monitoring their disease progression, making decisions about when to treat them, and monitoring disease improvement with therapy. A severity scoring system will also be helpful in comparing therapeutic options as new therapies are designed. Therefore, a Pediatric Gaucher Severity Scoring System (PGS3) was devised using expert opinion and validated in 26 patients with type 1 Gaucher disease. The PGS3 correlates well with disease severity in patients at diagnosis and over time. Conclusion: A practical system that will help clinical management, based on signs and symptoms in children with type 1 Gaucher disease, is presented.     

Coagulation abnormalities in type 1 Gaucher disease in children

Gaucher disease is the most prevalent inherited lysosomal storage disorder caused by deficiency of β-glucocerebrosidase enzyme. Clinically, 3 forms of Gaucher disease are recognized, of which type 1 is the mild to moderately severe, slowly progressive, nonneuropathic form. Bleeding disorders in Gaucher disease are believed to be due to thrombocytopenia but there may be additional factors that influence coagulation and fibrinolysis in Gaucher disease patients. The aim of the present work was to study some coagulation parameters in the Egyptian children with type 1 Gaucher disease. Five newly diagnosed patients and another 5 patients on enzyme replacement therapy (ERT) were enrolled in the study. Their coagulation profile, including coagulation factors, was evaluated. The results showed that in newly diagnosed cases factors II and VII were deficient in 40%, factor V was deficient in 20%, and all the cases had low levels of serum fibrinogen. In patients on ERT, factors VII and VIII were deficient in 60%, factor XI was deficient in 40% and factors V, X, and XII were deficient in 20% of cases. In conclusion, Egyptian patients with type 1 Gaucher disease, whether newly diagnosed or receiving enzyme replacement therapy, experience coagulation factor abnormalities regardless the clinical expression of bleeding diathesis. This should be taken into consideration before these patients are subjected to surgery for, e.g., splenectomy, which is common in these patients.     

Type II Gaucher disease: compound heterozygote with RecNciI and L444P mutations

We report the phenotype and genotype of an Indonesian Chinese boy with type II Gaucher disease. He had a unique presentation of recurrent cyanosis from laryngospasm. He was compound heterozygous for L444P/L444P + A456P + V460V. There have been few reports of this heterozygosity and its phenoptype. This genotype-phenotype correlation will be important for physicians in genetic counselling. Type II Gaucher disease in Southeast Asia may not be as rare as was perceived, but may be a condition that is under-reported. The success of our technique together with the results have made it possible for us to perform prenatal diagnosis and carrier detection for the family.     

Immunoglobulin abnormalities and effects of enzyme replacement therapy in children with Gaucher disease

Hyperimmunoglobulinemia is documented in patients with Gaucher disease of all ages. We investigated the frequency of hyperimmunoglobulinemia in 12 pediatric patients with type I and III Gaucher disease and the effects of enzyme replacement therapy on these abnormalities. The incidence of hyperimmunoglobulinemia was 77%, 66%, and 60% at the diagnosis, before and after ERT, respectively. Immunoglobulin G abnormalities were the most commonly seen isotype abnormality. After enzyme replacement therapy normalization of IgA and IgM levels were recorded but decline in IgG levels was less likely to occur. This study indicated the higher frequency of hyperimmunoglobulinemia in pediatric Gaucher patients.     

Revised recommendations for the management of Gaucher disease in children

Gaucher disease is an inherited pan-ethnic disorder that commonly begins in childhood and is caused by deficient activity of the lysosomal enzyme glucocerebrosidase. Two major phenotypes are recognized: non-neuropathic (type 1) and neuropathic (types 2 and 3). Symptomatic children are severely affected and manifest growth retardation, delayed puberty, early-onset osteopenia, significant splenomegaly, hepatomegaly, thrombocytopenia, anemia, severe bone pain, acute bone crises, and fractures. Symptomatic children with types 1 or 3 should receive enzyme replacement therapy, which will prevent debilitating and often irreversible disease progression and allow those with non-neuropathic disease to lead normal healthy lives. Children should be monitored every 6 months (physical exam including growth, spleen and liver volume, neurologic exam, hematologic indices) and have one to two yearly skeletal assessments (bone density and imaging, preferably with magnetic resonance, of lumbar vertebrae and lower limbs), with specialized cardiovascular monitoring for some type 3 patients. Response to treatment will determine the frequency of monitoring and optimal dose of enzyme replacement. Treatment of children with type 2 (most severe) neuropathic Gaucher disease is supportive. Pre-symptomatic children, usually with type 1 Gaucher, increasingly are being detected because of affected siblings and screening in high-prevalence communities. In this group, annual examinations (including bone density) are recommended. However, monitoring of asymptomatic children with affected siblings should be guided by the age and severity of manifestations in the first affected sibling. Treatment is necessary only if signs and symptoms develop. Conclusion: Early detection and treatment of symptomatic types 1 and 3 Gaucher disease with regular monitoring will optimize outcome. Pre-symptomatic children require regular monitoring. Genetic counseling is important.     

HLA phenotypes in children with Duchenne muscular dystrophy and their gene carrier mothers

Typing of HLA A, B and C locus antigens was carried out and the frequency distribution calculated in 32 hemizygous children affected by DMD, in 11 mothers who were either obligatory gene carriers or had increased CPK activity, and in 222 healthy blood donors. For typing peripheral blood lymphocytes and the standard NIH lymphocytotoxicity test were used. The HLA-B7 antigen had a tendency to be more frequent, being 31% in the group of hemizygous children with DMD as against 13.5% in the control group (p less than 0.04). In the gene carrier mothers the frequency of HLA-B7 was 36% (p less than 0.12). In the group of DMD hemizygotes the HLA-Aw24 antigen showed a tendency to higher frequency (p less than 0.05).     

MEFV gene mutations in Turkish children with juvenile idiopathic arthritis

Mutations of the Mediterranean fever (MEFV) gene, which encodes pyrin protein, leads to familial Mediterranean fever (FMF) and a connection between MEFV mutations and rheumatic diseases has been suggested. The aim of this study was to explore the frequency and clinical significance of MEFV mutations in children with juvenile idiopathic arthritis (JIA). In this study, children with JIA, who had no typical symptoms of FMF, were screened for the mutations in exons 2 and 10 of the MEFV gene by direct sequencing. A total of 96 children, 56 girls (58.3 %), with a median age of 11 years (2–18 years) were included. Patients were classified according to JIA subgroups as oligoarthritis in 43 (44.8 %), rheumatoid factor-negative polyarthritis in 22 (22.9 %), rheumatoid factor-positive polyarthritis in 2 (2.1 %), systemic arthritis in 12 (12.5 %) patients, enthesitis-related arthritis in 16 (16.7 %), and psoriatic arthritis 1 (1.04 %). A total of 31 children (32.3 %) had MEFV mutations: 25 heterozygous, 2 homozygous, and 4 compound heterozygous. There were 22 (11.4 %) exon 10 mutations (M694V, R761H, K695R, V726A, R653H) and 15 (7.8 %) exon 2 mutations (E148Q, G304R, E148V, T267I). The allele frequencies of MEFV mutations were found to be 19.27 %, which is higher than the general population [p?=?0.03, (odds ratio (OR):1.93, 95 % confidence interval (CI): 1.09–3.41)]. MEFV mutation carrier rates were significantly higher in antinuclear antibody (ANA) negative than in ANA positive patients [p?=?0.01, (OR: 0.25, 95 % CI: 0.085–0.74)] and in males than in females [p?=?0.001, (OR: 0.197, 95 % CI: 0.078–0.495)]. Also, there was a statistically significant difference between the MEFV mutation carrier rates and the subgroups of JIA (p?=?0.005). Conclusion: These findings suggest that mutations of the MEFV gene may be responsible for rheumatic diseases other than FMF, and patients with JIA especially males, ANA negatives, and ERA subgroups should be screened for MEFV gene mutations in countries where FMF is frequent.     

NKX2.5基因和TBX5基因在先天性心脏病试管婴儿中的突变检测

目的探讨患先天性心脏病的试管婴儿与自然受孕儿间是否存在NKX2.5基因和TBX5基因突变差异。方法应用聚合酶链反应结合DNA测序技术,对68例试管婴儿先天性心脏病患儿和98例自然受孕先天性心脏病患儿的NKX2.5基因编码区1、2和TBX5基因编码区4、5、8进行突变检测。结果在患先天性心脏病的试管婴儿与自然受孕儿中,均发现NKX2.5基因编码区1中第63位碱基发生突变(c.63AG),该位点基因型及等位基因频率的分布在两组间差异无统计学意义。NKX2.5基因编码区2和TBX5基因编码区4、5、8未检测到突变。结论先天性心脏病的试管婴儿与自然受孕儿间NKX2.5基因和TBX5基因突变无差异,推测辅助生殖技术并未引起NKX2.5基因和TBX5基因突变。     

Interleukin‐4 receptor polymorphisms in asthma and allergy: relation to different disease phenotypes

Aim: Inheritance and genetic factors are supposed to influence susceptibility to asthma and allergy. We tested if single nucleotide polymorphisms (SNPs) in the IL4R gene were associated with susceptibility to such diseases, or if they were related to the phenotypic presentation of asthma and allergic rhinoconjunctivitis (ARC). Methods: Three hundred and nine 12‐ to 13‐year‐old children were included. Six SNPs in the IL4R were analysed in response to current allergic disease, and to presentation of specific asthma and ARC phenotypes. Questionnaires were used to determine allergic disease status, and skin prick tests to evaluate sensitization to common airborne allergens. Results: Less eczema was seen in individuals with the AA‐genotype of rs2057768, and less ARC among those with the AA‐genotype of rs2107356, especially ARC associated with sensitization to pollen. The AA‐genotype of rs2057768 and the TT genotype of rs3024632 were associated with a specific asthma phenotype. Conclusion: Variations within the IL4R gene are associated with allergic diseases in children, preferably with eczema and disease phenotypes of ARC and asthma.     

Serum concentrations of CCR4 ligands in relation to clinical severity of atopic dermatitis in Egyptian children

T helper 2 (Th2) lymphocytes, the key effector cells in pathogenesis of atopic dermatitis (AD), express CCR4 receptors. CCR4 ligands (macrophage-derived chemokine ‘MDC’ and thymus and activation-regulated chemokine ‘TARC’) direct trafficking and recruitment of Th2 cells into lesional skin in AD. These chemokines appear to be useful inflammatory markers for assessing severity of AD in adults. However, the same results have not been replicated in children. Therefore, we were stimulated to elucidate the expression of CCR4 ligands in children with AD and their relation to clinical disease severity. To investigate this, serum concentrations of CCR4 ligands were determined in 60 children, of whom 30 had AD and 30 were healthy matched subjects. Patients were classified into mild (n = 8), moderate (n = 12) and severe (n = 10) according to the objective scoring AD (obj-SCORAD) index. Serum concentrations of MDC and TARC were significantly increased in children with AD (2697 ± 982.6 pg/ml and 945.5 ± 494.7 pg/ml, respectively) compared with controls (357.2 ± 233.2 pg/ml and 214.2 ± 116.6 pg/ml, respectively, p < 0.0001). Serum levels of both chemokines went hand in hand with disease severity as they were significantly higher in severe than moderate and in moderate than mild AD. In addition, they correlated positively with obj-SCORAD (r = 0.99 for both, p < 0.0001). Furthermore, both chemokines had significant positive correlations to blood eosinophil counts and serum immunoglobulin E. In conclusion, serum CCR4 ligands may be useful inflammatory markers for assessing AD severity in children. Further studies may pave way for CCR4 ligands antagonism among the adjuvant therapeutic strategies of AD.     

Duchenne肌营养不良患儿的智力特点及与基因突变关系初步探讨

目的：了解国内Duchenne肌营养不良（DMD）患儿智力水平及智力低下的比例,初步探讨DMD患儿智力的结构特点及与基因突变类型的关系。方法：选择2009年1月至2011年3月的102例DMD患儿,其中84例患儿通过多重连接依赖式探针扩增（MLPA）方法进行DMD基因检测。102例DMD患儿中,选择≥6岁的50例DMD患儿作为DMD组;另选取50例年龄、性别与DMD组匹配的健康体检儿童作为对照组。采用韦氏智力量表对两组儿童进行智力及智力结构分析。结果：102例DMD患儿的平均智商为84±21,其中30例（29.4%）总智商低于70。DMD组患儿总智商、言语智商、操作智商及其11项分测验得分均显著低于对照组（P<0.01）。其中DMD基因56-79号外显子突变患儿的智商最低(59.3±11.9),另外,45-55号外显子突变患儿的智商(88.6±1.9) 明显低于1-29号(97.5±9.6)和30-44号(102.8±3.8)外显子突变的患儿（P<0.01）。结论：DMD患儿的总智商、言语智商、操作智商均显著低于正常儿童。DMD患儿智力低下与基因突变存在联系。     

HLA in Egyptian children with biliary atresia

We studied the human leukocytes antigens in 18 Egyptian children with biliary atresia (BA) without extrahepatic congenital malformations. There was a significant increased frequency of both B8 and DR3 (83.3% and 94.4% in patients with BA compared with 6.5% and 14.9% in the general population, respectively). Ten patients had the B8/DR3 haplotype. Our results support the hypothesis that genetic factors may play a role in susceptibility to BA.