河南省致死性家族性失眠症家系的流行病学调查及遗传规律研究

目的 调查致死性家族性失眠症(FFI)家系谱特征及家族发病史;分析病例的临床特点和病理学改变;研究FFI家系的流行病学特征及相关基因遗传规律.方法 通过7代135名家族成员的流行病学调查,了解家族史、家族迁徙史及发病史;对患者及部分家族成员抽取静脉血进行PRNP基因PCR扩增,序列测定和Nsp I酶切鉴定;尸检采集脑组织进行神经病理学检测和Western blot法PrPCc蛋白检测.结果 2例确诊患者临床症状典型;11名家族成员死于相似的神经性疾病;32名家族成员血标本检测,其中11人出现PRNP基因178位密码子点突变(D178N),突变检出率34.38%,第129位密码子为甲硫氨酸;病例脑组织海绵样变性和神经元缺失,可检测到PrPSc蛋白.结论 该家系为FFI家系,病例临床症状典型,病理特征明显.流行病学调查、基因特征分析、神经病理学和Westernblot法检测对确立FFI病例和家系有至关重要的作用.     

河南省致死性家族失眠症家系遗传生物学分析

目的 了解河南省致死性家族性失眠症(FFI)临床表现、致病因子、遗传规律及家族性流行特征,探索预防及控制对策.方法 对河南省FFI家系7代175名家族成员的迁徙史和发病史进行追踪调查分析,采集患者及家族成员静脉血标本进行PRNP基因检测、限制性片段长度多态性(RFLP)NspI酶切分析及序列测定,对死亡患者尸检、采集脑组织进行神经病理学检查和western blot方法检测PrPSc蛋白.结果 2例FFI确诊患者临床症状典型;该FFI家族中死亡的23人中有13人出现与先证者相似的FFI临床症状;90个家族成员血标本检测中出现20个PRNP基因178位密码子突变携带者,129位等位基因为M/M纯合子,突变检出率为22.22%;男女性别比约为1∶1;自先证者祖父辈以来发病年龄有逐渐提前的趋势(遗传早现).结论 该家系FFI家族聚集性发病特点明显,是国内罕见的最大的朊病毒引起FFI发病的家族.     

Familial Creutzfeldt-Jakob disease in Finland: Epidemiological,clinical, pathological and molecular genetic studies

In 1974–1984 30 patients died with a diagnosis of Creutzfeldt-Jakob disease (CJD) in Finland (annual mortality rate of CJD 0.9 per million population for the years 1979–1984). Six of these patients (20%) were familial, all belonging to the same kindred. The pedigree now includes 15 affected members in four generations, and the occurrence of disease is consistent with an autosomal dominant mode of inheritance. The clinical features of CID in this family are in most respects typical of the familial disease described elsewhere. However, the mean age at onset is 47, periodic EEG activity has not been observed, and the mean duration of illness of 27.5 months is longer than usual for either familial or sporadic CJD. Neuropathological examination of brain biopsy and autopsy specimens revealed spongiform change without amyloid plaques, and brain tissue from one patient transmitted disease to a capuchin monkey. In an analysis of the histocompatibility antigens of the family, CJD was not linked with a single haplotype, but at least 12 out of 13 CJD patients shared the HLA antigen A28. Molecular genetic studies disclosed a new G-to-A mutation in codon 178 of the PRNP gene (resulting in a substitution of asparagine for aspartic acid) in the DNA of eight family members with CJD but not in any of ten currently healthy first degree relatives of the patients, or 86 controls. The codon 178 mutation thus seems to co-segregate with CJD in this family. Linkage analysis gave a LOD score value of 3.6.     

1例编码细胞色素b558的gp91phox亚基氨基酸错义突变导致的X-连锁慢性肉芽肿病家系研究

目的 对1例X-连锁慢性肉芽肿病（X-CGD）家系进行临床表型和基因突变分析，揭示X-CGD的发病机制。方法 根据患儿临床症状、体征及四唑氮蓝试验（NBT）分析诊断，采集家系成员外周血抽提基因组DNA，扩增CYBB基因并检测基因突变。结果 ①NBT显示，患儿未刺激组、大肠埃希杆菌内毒素刺激组及佛波乙酸酯刺激组中，中性粒细胞NBT还原率为0，患儿母亲的分别为4％，10％，25％。患儿父亲分别为2％，97％，97％，结合患儿临床症状、体征初步确诊为X-CGD；②基因突变分析显示，先证者位于Xp21．1编码NADPH细胞色素b558的gp91^phox亚基的CYBB基因第9外显子第949位的碱基由T突变为A，由此引起编码序列第312个氨基酸错义突变为Met312Lys，患儿母亲及姐姐均存在同位点基因突变，但患儿父亲CYBB基因无突变，证实该错义突变来源于母系。结论 CYBB基因氨基酸错义突变，是引起该家系X-CGD的原因。     

非综合征性耳聋家系的临床分析与基因检测

目的:探讨母系遗传氨基糖甙类抗生素致聋家系的临床表型与基因突变的关系。方法:收集贵州省遵义地区不同民族的6个母系遗传非综合征性耳聋家系的临床资料及血液样本,经PCR-RFLP及测序技术检测线粒体DNA 1555G、3243G、7445G突变,并通过对各家系线粒体DNA高变区序列测定及编码区限制性片段多态性分析以划分单倍型类群。结果:经酶切及测序证实其中4个家系存在线粒体DNA 1555G突变,但未发现线粒体DNA 3243G、7445G突变。6个耳聋家系分别属于A、D6、D、G、B5 a及M*单倍型。结论:该地区线粒体DNA 1555G突变引起氨基糖甙类抗生素高度敏感致聋的家系发生率较高,提示线粒体DNA 1555G突变检测有一定的临床应用价值。     

Differences and similarities of postprandial lipemia in rodents and humans

Background

Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328).

Findings

Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04).

Conclusions

This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.     

人感染禽流感家庭聚集性病例研究进展

1997年以来,全球多个国家相继出现人感染H5N1禽流感家庭聚集性病例,随后中国局部地区也陆续报告了人感染H7N9禽流感相关病例。目前存在的人传人的现象是有限非持续的,具体的人际间传播途径与方式并不清楚且尚无证据证实上述2种病毒可以在人间持续传播。家庭聚集性病例多发生在与禽类接近或接触的人群中,可能存在的遗传易感性以及个体间受体表达的差异增加了家庭成员感染禽流感病毒的风险。随着人感染H5N1与H7N9禽流感病毒的持续流行以及病毒自身变异的发生,不排除其获得对人类的适应性突变可能性。人感染H7N9病例中未检测出的症状轻微感染者可能会引起更难以控制的人际间流行。本文将从人感染H5N1、H7N9病毒家庭聚集性病例的流行病学特征、传播模式以及传播能力等方面进行系统阐述,为今后禽流感疫情的防控提供一定的科学依据。     

原发性先天性淋巴水肿一家系随访分析

目的探讨我国原发性先天性淋巴水肿（primary congenital lymphoedema,PCL）,也称为Milroy病的临床特征。方法通过诊断收集国内PCL一家系,并对受累者全面检查,建立了完善的家系谱和该病详细的临床资料。结合其临床资料和国内外文献对该病进行分析总结。结果该家系4代48位成员,受累者为11例,男性3例,女性8例,患者年龄为3-85岁;出生即发病的为10例,呈缓慢性持续性病态,病灶分布如下：双下肢1例、双下肢和右上肢1例、左上肢1例、右下肢3例、左下肢3例、双足背2例,病变范围超过膝关节2例,伴右手皮肤癌1例,伴双足大拇指甲上跷1例;早期自愈2例。结论遗传学分析表明,国内PCL家系表现为常染色体显性遗传,女性发病率高,受累部位分布具有多样性和局限性特点,多为单侧下肢受累,偶见上肢水肿,并可发生皮肤癌变;临床上提高对该病的认识,并积极进行早期治疗干预,有助于改善预后。     

Clinical findings and diagnosis in genetic prion diseases in Germany

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.     

A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: Evidence from pedigree segregation analysis

We have previously reported a large Israili-Arab pedigree with sensorineural deafness possibly determined simultaneously by two loci-one mitochondrial, and one autosomal recessive. This was analyzed by extending classic segregation analysis methods to the many nuclear families derived from the maternal line pedigree. Here we expand this pedigree and extend our analysis by using the regressive models for segregation analysis on the entire pedigree. The corresponding REGD computer program was utilized and the marrying-in males' and paternal line members' affection statuses were assigned as unknown to accommodate the exclusive maternal transmission pattern. For the autosomal locus, a simple autosomal recessive (q = 0.52) model with a nearly complete penetrance (0.93) was found to be the regressive models to test the hypothesis of mitochondrial mutation occurred in a heteroplasmic distribution in the family members, this could not explain the familial aggregation in this pedigree, and an autosomal recessive locus is still required. These results provide further support for the concept that the sensorineural deafness occurring in this large Israeli-Arab pedigree results from simultaneous involvement of two genes at two different loci, one mitochondrial and likely homoplasmic, and the other autosomal and recessive. © 1993 Wiley-Liss. Inc.     

A Pedigree of Congenital Optic Atrophy Embracing Sixteen Affected Cases In Six Generations: (Section of Ophthalmology)

A family including six generations and 31 individuals is described. Sixteen were affected with congenital optic atrophy; in ten of these the condition has been verified by expert examination. Out of the sixteen, ten were males and six females, a sex-incidence differing considerably from that in Leber''s disease. In our pedigree, inheritance is dominant and is always through an affected mother, never through an unaffected mother or through the father. In typical Leber''s disease it is through an unaffected mother, i.e. it is recessive.In the family now described, the optic atrophy appears to be stationary. In all the cases that have been seen the discs are white, with well-defined margins and no filling-in of the central cups, even in those cases that retain some useful vision. Instead of a central scotoma as in Leber''s disease, there is peripheral restriction, in some cases severe, but in others only slight. No ring or paracentral scotoma or any colour scotoma have been demonstrated. Except the atrophic discs there are no definite ophthalmoscopic changes. Nystagmus is either constant or intermittent in nearly all the cases. No other congenital anomalies have been noted, either in the affected or the unaffected members of our pedigree, or are known to exist in any relatives. There is no consanguinity which might be a factor in the causation.There are several recorded pedigrees of family optic atrophy differing from Leber''s disease in some respects, but the only ones at all resembling ours are those of (1) J. M. Griscom and (2) Rampoldi. In (1) eight males and six females included in three generations had optic atrophy dating from early childhood. The inheritance was dominant but was through an affected father. In (2) seven members of a pedigree of four generations are presumed to have had optic atrophy inherited directly from an affected father in two cases, and from an affected mother in four.Taken together, these instances suggest that there may exist a form of congenital or family optic atrophy in which inheritance is of the dominant type, which in some families is transmitted through the father only, in others through the mother, and in others sometimes through the father and sometimes through the mother.     

Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999

In April 1999, isolation of avian influenza A (H9N2) viruses from humans was confirmed for the first time. H9N2 viruses were isolated from nasopharyngeal aspirate specimens collected from two children who were hospitalized with uncomplicated, febrile, upper respiratory tract illnesses in Hong Kong during March 1999. Novel influenza viruses have the potential to initiate global pandemics if they are sufficiently transmissible among humans. We conducted four retrospective cohort studies of persons exposed to these two H9N2 patients to assess whether human-to-human transmission of avian H9N2 viruses had occurred. No serologic evidence of H9N2 infection was found in family members or health-care workers who had close contact with the H9N2-infected children, suggesting that these H9N2 viruses were not easily transmitted from person to person.     

一起医院同事混合家庭成员感染新冠肺炎事件的调查

 目的 分析某医院新型冠状病毒肺炎（COVID-19）医护人员病例及家庭关联病例的流行病学特征,为制定防控策略提供参考。方法 采用描述流行病学方法,分析该医院的4起聚集性疫情病例的三间分布、临床特点、接触史等。结果 该医院共有14例医务人员病例,并关联11例家庭成员病例。所有病例年龄的中位数为38（23~76）岁,病例男女性别比为0.79：1。所有病例的最短潜伏期中位数为4（0~9）d,最长潜伏期中位数为7（3~14）d。所有病例发病至就诊间隔日数为2（0~9）d,其中医护人员病例为1.5（0~8）d,家庭病例为3（1~9）d。4起COVID-19聚集性疫情的首例病例均与武汉相关。结论 该事件由4起COVID-19聚集性疫情组成,其中3起为家庭成员传播,1起为医院同事混合家庭成员传播。     

Severe coinfection with seasonal influenza A (H3N2) virus and Staphylococcus aureus--Maryland, February-March 2012

On March 5, 2012, the Maryland Department of Health and Mental Hygiene (DHMH) and the Calvert County Health Department were notified of three deaths following respiratory illness among members of a Maryland family. One family member (patient A) experienced upper-respiratory symptoms and died unexpectedly at home. Two others (patients B and C) sought medical care for fever, shortness of breath, and cough productive of bloody sputum and died during their hospitalizations. All three family members had confirmed infection with seasonal influenza A (H3N2) virus. Patients B and C had confirmed coinfection with methicillin-resistant Staphylococcus aureus (MRSA), which manifested in both patients as MRSA pneumonia and bacteremia. DHMH and the Calvert County Health Department, in collaboration with the District of Columbia Department of Health, local hospitals, and CDC, conducted an investigation to determine the cause of the illnesses and identify additional related cases. Three additional family members with influenza were identified, two of whom were confirmed to have influenza A (H3N2) and required hospitalization, but neither was coinfected with MRSA, and both recovered. Influenza vaccination remains the best method for preventing complications from influenza; when influenza infection is suspected, treatment with influenza antiviral agents is recommended in certain cases. In addition, when high clinical suspicion for serious S. aureus coinfection exists, empiric coverage with antibiotics, including those with activity against methicillin-resistant strains, should be instituted.     

Allelic variation of msp-3α gene in Plasmodium vivax isolates and its correlation with the severity of disease in vivax malaria

Malaria is a global socio-economic burden of which Plasmodium vivax contributes for about 70–80 million cases on an annual basis worldwide and 60–65% cases in India. Diversity observed in highly polymorphic Merozoite Surface Protein-3α (msp-3α) encoded by MSP-3 gene family, has been used efficiently for genotyping of P. vivax infection. This study aims to correlate the severity of clinical symptoms with parasite load, genotype of P. vivax and multiplicity of infection. Based on clinical symptoms classification, 31 (67.9%) out of 46 cases were found to be severe while 15 (32.6%) were non-severe and correlation of the severity of vivax infection with parasite load was not observed. Analysis of msp3-α allele genotype showed that out of 31 severe cases, 19 (61.2%) were single-clone infection cases whereas 12 (38.7%) were multi-clone infections. Similarly, out of 15 non-severe cases, 9 (60%) were single clone and 6 (40%) were multi-clone infections indicating the absence of a correlation between the multiplicity of infection and disease severity. Allele frequency observed was 65.9%, 23.4%, 23.4%, and 28.2% for allele A, B, C and D, respectively. An important finding was the greater distribution of allele D than alleles B and C, which has been reported as a rare allele otherwise. Further, of 13 cases with allele D, 76.9% (10/13) cases were severe. This study showed the absence of a correlation between the severity of clinical symptoms with parasite load and multiplicity of infection but at the same time drives a possibility of severe vivax malarial symptoms to have an association with the persistence of allele D in the population. This upon exploration can lead to the development of a target in detection of severe cases of malaria.     

Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.     

Description of a large pedigree with an adverse lipoprotein cholesterol phenotype: the Bogalusa Heart Study

A large pedigree (N = 356) with a high prevalence of heart disease and associated adverse lipoprotein phenotype was studied. The adverse lipoprotein phenotype is characterized by both low levels of high-density-lipoprotein cholesterol (HDL-C) alone (16.3%) and in combination with other adverse lipoprotein levels (12.8%). In all, 44.2% of all pedigree members had at least one adverse lipoprotein level. Analysis of mating types showed that all lipids and lipoproteins possess familial clustering with 25-36% of offspring above median levels when both parents had levels below the median, while 67-83% had levels above the median when both parents had levels above the median. Using adjusted lipid and lipoprotein levels, a statistically significant linear trend was found between the degree of relationship to pedigree members with heart disease, and both the low-density-lipoprotein cholesterol/high-density-lipoprotein cholesterol (LDL-C/HDL-C) ratio (P less than .05), and the very-low-density-lipoprotein cholesterol (VLDL-C; P less than .01) level. A similar analysis using the prevalence of adverse lipoprotein levels as the dependent variable and degree of relationship to heart diseased pedigree numbers as the independent variable showed significant (P less than .05) relationships with VLDL-C and the LDL-C/HDL-C ratio. Further genetic analyses of this pedigree may reveal genetic mechanisms responsible for the familiality of lipoprotein levels in this pedigree.     

河南省首例人感染H7N9禽流感病例的流行病学调查

[目的]通过对1例人感染H7N9禽流感病毒患者的调查分析,为人感染H7N9禽流感的科学防控提供依据。[方法]采用流行病学调查方法,调查病例的发病经过、可能的感染来源、传播途径及暴露因素等,医学观察患者的密切接触者,同时对患者进行临床诊治、实验室检测。[结果]确诊1例人感染HTN9禽流感病毒,经救治后痊愈出院。患者有明确的活禽接触史,咽拭子检测H7N9禽流感病毒核酸阳性。患者的密切接触者中均未发现异常临床表现。通过扩大监测流感病例160例和职业人群858例,均未发现H7N9禽流感病毒核酸阳性。当地活禽交易市场鸡咽拭子标本检出2份H7N9禽流感病毒核酸阳性,阳性鸡来源于外省。[结论]活禽暴露是人感染H7N9禽流感病毒的关键风险因素,暂无证据人传人,未发现人群隐性感染和轻症病例。仍需开展扩大监测和流行病学调查,以完善对感染谱的认识。     

Clinical, microbiological, and therapeutic aspects of Nocardia sp. infections in the Bordeaux hospital from 1993 to 2003

ObjectiveOur goal was to describe the epidemiological, clinical, and microbiological characteristics of nocardiosis in the Bordeaux teaching hospital, between January 1, 1993 and December 31, 2003.DesignsThe retrospective study included patients examined between January 1, 1993 and December 31, 2003 in whom a Nocardia bacterium had been identified from a biological sample.ResultsTwenty-four out of 30 Nocardia sp. strains identified during the study period were classified as colonizing strains. 19 patients presented with risk factors for nocardiosis. Nocardia asteroïdes were found in 22 samples, mainly from pulmonary samples. 11 cases of infection due to Nocardia sp. were reported during the study period. Immunosuppression was reported in 7 cases. The clinical forms were not specific. The species incriminated belonged to the N. asteroïdes complex in 8 cases. Treatment consisted in a combination of 2 or 3 molecules including cotrimoxazole for an average duration of 9 months. 9 patients recovered.ConclusionsThe variability of clinical presentation and the lack of standard identification methods delayed the diagnostic. The treatment is not well defined. Clinical strains should be reported to the reference laboratory and prospective studies are necessary.     

Children with acute rheumatic fever and acute poststreptococcal glomerulonephritis and their families in a subtropical zone: a three-year prospective comparative epidemiological study

Over a period of three years (December 1980 through November 1983) the incidence and epidemiological features of acute rheumatic fever (ARF) and acute poststreptococcal glomerulonephritis (AGN) were studied prospectively in two regional hospitals in Kuwait serving a childhood population of 225,000. The study included 146 children with ARF and 256 family members and 125 children with AGN and 199 family members. The annual incidence of ARF and AGN were 19.6 and 17.8 respectively per 100,000 childhood population (7.3 and 6.7 respectively per 100,000 total population). Both diseases occurred sporadically throughout the year with a similar peak in winter. The clinical profile of ARF was essentially similar to that reported from temperate climates, and AGN followed mainly throat infections. Microscopic haematuria was detected in ten ARF family members (4%) and in 20 AGN family members (10%). Haematuria and low C3 were found in two (0.8%) and in seven (3.5%) ARF and AGN family members respectively. Of the nine family members with subclinical nephritis the group C streptococcus was isolated from three (33%). The geometric mean titre (GMT) of antistreptolysin O (ASO) and of antihyaluronidase (AH) in ARF and AGN patients were markedly elevated. Although the median age of ARF and AGN family members were 13 and 15 years respectively, yet the GMT of ASO and AH in the family members were slightly higher than those of the normal childhood population.