一例13号环状染色体综合征患儿的临床及遗传学分析

患儿,女,5个月,因生长发育迟缓就诊,体格检查发现体格发育落后,特殊面容（小头畸形、眼距宽、耳位偏低、鼻梁扁平、短人中）以及一侧小阴唇缺失。外周血染色体核型为46,XX,r（13）（p11q33）[82]/45,XX,-13[10]/46,XX,r（13;13）（p11q33;p11q33）[8];微阵列比较基因组杂交（aCGH）检测显示13q11q33.2区域和13q33.2q34区域分别有87.5 Mb的重复和8.2 Mb的缺失;荧光原位杂交（FISH）显示13号环状染色体长臂末端缺失。诊断为13号环状染色体综合征。该综合征临床表型多变,主要与染色体区带中遗传物质丢失的数量、部位以及不同核型嵌合比例不同等密切相关。     

一例15号额外标记染色体致智力障碍、难治性癫癎伴中枢性性早熟患者的临床及遗传学分析

15号额外标记染色体是一种罕见的染色体异常,本文报道1例15号额外标记染色体患儿,就其临床诊治经过及遗传缺陷进行研究。患儿,女,9岁半,自幼智力、运动发育落后,7岁出现乳房发育,8岁半出现癫癎发作：发作形式多样,多种抗癫癎药物控制欠佳,头颅磁共振未见异常,脑电图提示癎样放电频繁。采用G显带核型分析、荧光原位杂交（FISH）、甲基化多重连接依赖性探针扩增技术（甲基化MLPA）和微阵列比较基因组杂交（array-CGH）等多种遗传学检测手段,明确患儿存在新生的15q重复：15q11-13区域母源性拷贝数复制增加,基因组重排的形式为47,XX,+inv dup （15）（pter→q13：q13→pter）。15q11-13区域拷贝数复制增加与智力障碍、难治性癫癎伴中枢性性早熟临床表现密切相关。建议对于不明原因智力障碍伴癫癎患儿进行高分辨染色体核型分析。     

以身材矮小为突出表现的环状4号染色体1例报告及文献复习

目的探讨环状4号染色体病例的临床表型及发病机制。方法回顾分析1例以身材矮小为主要表现的环状4号染色体患儿的临床资料,并复习相关文献。结果女性患儿,10岁11个月,因身材矮小就诊,有颈蹼、乳头间距大,无明显智力障碍和其他畸形,生长激素分泌正常。染色体核型分析提示为环状4号染色体46,XX,r(4)(p16q35)。结论矮小症患儿需警惕环状染色体可能,染色体核型分析有助于确诊。     

以身材矮小为突出表现的环状 4 号染色体 1 例报告及文献复习#br#

目的探讨环状4号染色体病例的临床表型及发病机制。方法回顾分析1例以身材矮小为主要表现的环状4号染色体患儿的临床资料,并复习相关文献。结果女性患儿,10岁11个月,因身材矮小就诊,有颈蹼、乳头间距大,无明显智力障碍和其他畸形,生长激素分泌正常。染色体核型分析提示为环状4号染色体46,XX,r(4)(p16q35)。结论矮小症患儿需警惕环状染色体可能,染色体核型分析有助于确诊。     

6号环状染色体致隐匿性阴茎1例报告及文献复习

目的探讨6号环状染色体片段缺失与临床表型的关系。方法报道1例因隐匿性阴茎就诊男性患儿,通过常规染色体核型和全基因组染色体微阵列芯片技术,分析缺失片段位置及包含基因与临床表型的关系;同时进行文献复习。结果患儿染色体核型分析结果为6号环状染色体,全基因组染色体微阵列芯片检测发现,6号染色体短臂和长臂末端均存在缺失,del6p25.3p25.1.seq[GRCh37/hg39](204909-4210858)×1,del6q27.seq[GRCh37/hg39](170438227-170898549)×1,短臂p25区域缺失4.01 Mb,包含DUSP22、IRF4、EXOC2、HUS1B、LOC285768、FOXQ1、FOXF2、FOXC1等30个基因,而长臂6q27区域发生0.46 Mb缺失,包含LOC154449、DLL1、FAM120B、PSMB1、TBP、PDCD2等7个基因。分析比较本例患儿和文献报道的6号环状染色体病例,发现所有患儿均存在神经或生长发育障碍,但仅本例和另1例患儿有生殖道畸形。结论 6号环状染色体患者的临床表型与染色体缺失部位、缺失片段大小以及环状染色体稳定性密切相关。     

15q11.2-13.2微重复四倍体综合征1例并文献复习

目的 采用分子遗传学技术分析1例常规染色体核型拟诊为21/22三体的发育迟缓伴孤独症患儿,明确遗传学诊断。方法 收集患儿及其父母的外周血标本,常规提取基因组DNA,应用高分辨染色体核型分析（400-550带）检测患儿及其父母的染色体数目及结构,微阵列比较基因组杂交技术(array-CGH)筛查患儿的全基因组拷贝数变异,以荧光原位杂交技术（FISH）对异常的基因拷贝进行染色体精确定位和定量。结果 女,2岁,发育迟缓伴孤独症样表现。外侧眼角下垂、内眦赘皮。常规染色体核型检查（320带）分别为47,XX,+22和47,XX,+21。高分辨染色体核型分析显示,该患儿携带额外标记染色体（SMC）,核型为47,XX,+mar dn,尚不能确定是否为21/22三体携带者,患儿父亲高分辨率核型染色体分析提示为46,XY,母亲为46,XX,提示患儿携带SMC为新生突变。array-CGH检测显示15q11.2-13.2区域微重复（chr15:22684529-30730543,8.0 Mb,hg19）。FISH验证该SMC来源于15号染色体,由15q11.2-13.2区域二倍体及双着丝粒组成。患儿最终诊断为15q11.2-13.2微重复四倍体综合征。复习文献报道的15q11.2-13.2拷贝数增加病例的临床表型,微重复四倍体综合征的主要表型有智力低下/发育迟缓（100％）、肌张力低下（92.9％）、孤独症/孤独症样表现（71.4％）和癫痫（61.5％）等。结论 15q11.2-13.2微重复四倍体综合征是患儿发生精神发育迟滞伴孤独症的遗传学基础,array-CGH能够快速、准确地检测基因组的微小失衡。     

矮身材女性患儿染色体核型分析及其临床意义

目的　了解女性矮身材与染色体核型之间的关系。方法　对 2 6 1例矮身材的女性患儿常规制备外周血淋巴细胞G显带标本 ,进行染色体核型分析 ,必要时做C带、高分辨G显带分析。根据临床表现将患儿分为两组 :A组为单纯生长落后组 92例 ;B组为疑诊Turner综合征组 16 9例。结果　两组的染色体核型 ,A组 :4 6 ,XX(n =82 ) ;4 5 ,X(n =5 ) ,4 5 ,X/ 4 6 ,XX(n =1) ;4 5 ,X/ 4 6 ,X ,i(Xq) (n =1) ;4 5 ,X/ 4 6 ,X ,mar(n =1) ;4 6 ,X ,del(X) (q12 ) (n =1) ;4 6 ,XX ,t(5 ,11) (5p11p ;5 q11q) (n =1)。B组 :4 6 ,XX(n =75 ) ;4 5 ,X(n =4 8) ;4 6 ,X ,i(Xq) (n =16 ) ;4 5 ,X/ 4 6 ,X ,i(Xq) (n =6 ) ;4 5 ,X/ 4 6 ,X ,mar(n =7) ;4 5 ,X/ 4 6 ,XX(n =2 ) ;4 5 ,X/ 4 6 ,X ,r(X) (n =1) ;4 6 ,XX/ 4 6 ,X ,i(Xq) (n =1) ;4 5 ,X/ 4 6 ,X ,del(X) (q12 ) (n =1) ;4 6 ,XX/ 4 6 ,X ,del(X) (q2 2 q2 4 ) (n =1) ;4 6 ,X ,del(Xp) (n =4 ) ;4 6 ,X ,del(Xq) (n =2 ) ;4 6 ,X ,dir　dup(X) (q2 3→q2 5 ) (n =1) ;4 7,XXX(n =3) ;4 5 ,X/ 4 6 ,XY(n=1)。A、B两组患儿的年龄及染色体核型异常者的年龄比较有显著性差异。结论　①矮身材的女性患儿染色体异常多见 ,故对矮身材的女孩应常规做染色体核型分析 ,以排除染     

Phelan-McDermid综合征临床及微阵列比较基因组杂交芯片技术分析

目的探讨Phelan-McDermid综合征的临床表现及微阵列比较基因组杂交芯片技术(array CGH,aCGH)结果。方法回顾性分析1例Phelan-McDermid综合征患儿的临床资料;采用常规G显带分析染色体核型,运用aCGH检测全染色体微小改变。结果患儿染色体核型示正常女性核型,未发现染色体数目及结构异常;aCGH分析发现Chr22q13.2-qter缺失,并排除其他染色体微改变;确诊为Phelan-McDermid综合征。结论通过典型的临床表现和染色体微改变相关实验室检查可确诊Phelan-McDermid综合征;aCGH技术对于筛查该病并排除其他染色体微改变最有意义。     

Pallister-Killian综合征1例临床及细胞分子遗传学分析

目的探讨Pallister-Killian综合征(PKS)的细胞分子遗传学特点。方法采集患儿外周血标本进行G显带染色体核型分析,单核苷酸多态性-微阵列芯片(SNP array)技术鉴定异常片段来源,运用荧光原位杂交(FISH)技术加以确认。结果女性患儿,8月龄,因精神运动发育迟缓就诊。出生后有喂养困难、肌张力低下、面容异常、后发际线低、足部畸形、双耳听力未过关等临床表现。外周血染色体G显带核型为mos 47,XX,+mar[18]/46,XX[82];芯片分析结果发现患儿12号染色体短臂嵌合重复,提示为12 p四体嵌合体;FISH检测显示有48%的细胞有4个12 p信号。结论根据临床表现,常规外周血染色体核型分析结合SNP-array及FISH检测诊断PKS。     

中国Phelan-McDermid综合征1例患儿的临床及分子遗传学分析

目的 对1例不明原因的生长过快、发育迟缓患儿进行临床特征及基因诊断分析.方法 描述患儿临床特点;实验室检查采用常规G显带分析染色体核型,进一步通过多重连接依赖探针扩增(MLPA)对微小缺失片段进行拷贝数变异(CNVs)检测,同时应用比较基因组杂交芯片技术(array CGH)检测全染色体微小改变,并采用荧光原位杂交技术(FISH)对新发现的缺失片段进行实验验证.结果 1.患儿,男,1.5岁,宽额,尖下巴,生长过快,全面的发育迟缓,语言发育障碍、孤独症样表现.2.常规G带染色体核型示46,XY,MLPA结果显示患儿22q13段的SHANK3基因的9～23外显子及ACR、RABL2B基因的杂合性缺失,比较基因组杂交芯片分析证实22q13段杂合性缺失,并排除其他染色体的微改变,FISH进一步证实22q13段的缺失.结论 根据临床表现,结合各项实验室检查结果可诊断患儿为Phelan-McDermid综合征;针对性的CNVs适宜采用MLPA技术,而array CGH更宜作为全染色体CNVs的筛查.     

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

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孤独症谱系障碍(autistic-spectrum disorders,ASDs)近年来患病率逐年攀升至1%左右,其症状往往伴随终生,成为严重威胁儿童健康和发展的神经发育性疾患;注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)是儿童期最常见的精神障碍,国内报道患病率为4.13%～5.83%,其症状可延续至青少年期,甚至到成年期[1]。这两类精神障碍在成年期的临床表现、共患病、治疗策略和预后与儿童期有哪些不同呢?本文通过回顾相     

EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.     

Infiltrations of Epstein-Barr virus-carrying cells in granular lymphocyte-proliferative disorders corresponding to chronic active Epstein-Barr virus infection

A 21-year-old man with granular lymphocyte-proliferative disorders (GLPD) associated with chronic active Epstein-Barr virus (EBV) infection is described. Chromosomal analyses revealed several clonal abnormalities and two of them were mainly repetitious. High copy numbers of monoclonal EBV genome were also detected in the proliferative large granular lymphocytes (LGLs), indicating the monoclonal expansion of EBV-infected LGLs. The patient had an indolent course for several years, and there was no evidence of infiltrations of his bone marrow until the end stage. At autopsy, microscopic studies revealed marked infiltrations of LGL in the liver and spleen, and the infiltrating cells were NK-cell immunophenotype. The infiltrated LGLs showed latency I.     

LUTEINIZING HORMONE RECEPTOR MUTATIONS IN DISORDERS OF SEXUAL DEVELOPMENT AND CANCER

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.     

Personality profiles and heart rate variability (vagal tone) in children with recurrent abdominal pain

The aim of the study was to explore psychological factors and autonomic activity in children with recurrent abdominal pain and to compare them with those in a control group of healthy children. The Personality Inventory for Children was used for assessment of developmental, emotional and psychosocial factors in 25 children with recurrent abdominal pain (age, 7-15 y). Parasympathetic and sympathetic functions in these children and in 23 healthy control subjects (age, 7-13 y) were also investigated, non-invasively using a computerized polygraph. Vagal tone (parasympathetic function) was indexed by calculation of respiratory sinus arrhythmia in beats/min. Skin conductance (sympathetic function) was recorded by the constant current method. On the Personality Inventory for Children, 16 patients had high scores on somatic concern. Several patients had scores in the clinical range for depression, withdrawal and anxiety, but the mean scores for these personality profile scales were well within the normal range of healthy children. Interestingly, there was a spike on the L (Lie)-scale for most of the patients and 15 patients had scores above or close to the clinical cut-off value. As compared with the scores in healthy children, vagal tone and sympathetic tone were normal. Conclusion: Many children with recurrent abdominal pain have scores in the clinical range for depression, withdrawal, anxiety and L-scale indicating coping problems, denial and a trend towards somatic concern that may contribute to the evolution of abdominal pain. Autonomic nerve activity was not disturbed in these children.     

Overcoming surfactant inhibition with polymers

Inhibition of the function of pulmonary surfactant in the alveolar space is an important element of the pathophysiology of many lung diseases, including meconium aspiration syndrome, pneumonia and acute respiratory distress syndrome. The known mechanisms by which surfactant dysfunction occurs are (a) competitive inhibition of phospholipid entry into the surface monolayer (e.g. by plasma proteins), and (b) infiltration and destabilization of the surface film by extraneous lipids (e.g. meconium-derived free fatty acids). Recent data suggest that addition of non-ionic polymers such as dextran and polyethylene glycol to surfactant mixtures may significantly improve resistance to inhibition. Polymers have been found to neutralize the effects of several different inhibitors, and can produce near-complete restoration of surfactant function. The anti-inhibitory properties of polymers, and their possible role as an adjunct to surfactant therapy, deserve further exploration.     

How well are we doing? – Metabolic control in patients with diabetes

OBJECTIVE: To compare the present level of metabolic control in children and adolescents with insulin-dependent diabetes mellitus (IDDM) attending Brisbane paediatric diabetes clinics with published overseas data. METHODOLOGY: Blood HbA1c concentrations, population characteristics, current treatment practices and short-term complications were recorded in all patients, aged 19 years and under, attending the diabetes clinics of the two Brisbane Children's Hospitals or the private practice of one of the authors (MJT) in the first quarter of 1998. RESULTS: Two hundred and sixty-eight patients were assessed (M/F 142/126). Ages ranged from 1 to 19 years (mean 11. 2 years); duration of IDDM was 0-16 years (mean 4.4 years); and 141 (53%) were pubertal. Of those aged less than 13 years, only 4% had more than two injections daily. Insulin doses (U/kg/day) rose with increasing age. Larger doses were required in regimens involving more than two injections per day than those involving one to two injections per day. Ketoacidosis or severe hypoglycaemia in the last 3 months were reported in eight (2.7%) and 17 (6.3%) of patients, respectively. Mean HbA1c (+/- SD) was 8.6 +/- 1.4% (range 5.2-14.0%), with 33% of children having a HbA1c concentration < 8%. HbA1c concentrations were significantly related (P < 0.05) to insulin dose and to duration of diabetes, but not to severe hypoglycaemia, ketoacidosis, age, frequency of injections, or number of clinic visits per year. Mean HbA1c concentration was significantly higher (P < 0.05) in those children in puberty (8.7 +/- 1.5%) than in those not in puberty (8.5 +/- 1.2%). CONCLUSION: Only 33% of patients had a HbA1C concentration less than 8% and 6.3% had a severe hypoglycaemic episode in the 3 months. These results are similar to published overseas data.     

MAINTENANCE OF DIFFERENTIATED FUNCTION OF THE SURFACTANT SYSTEM IN HUMAN FETAL LUNG TYPE II EPITHELIAL CELLS CULTURED ON PLASTIC

We report a simplified culture system for human fetal lung type II cells that maintains surfactant expression. Type II cells isolated from explant cultures of hormone-treated lungs (18-22 wk gestation) by collagenase + trypsin digestion were cultured on plastic for 4 days in serum-free medium containing dexamethasone (Dex, 10 nM) + 8-bromo-cAMP (0.1 mM) + isobutylmethylxanthine (0.1 mM) or were untreated (control). Surfactant protein (SP) mRNAs decreased markedly in control cells between days 1 and 4 of culture, but mRNA levels were high in treated cells on day 4 (SP-A, SP-B, SP-C, SP-D; 600%, 100%, 85%, 130% of day 0 content, respectively) . Dex or cAMP alone increased SP-B, SP-C, and SP-D mRNAs and together had additive effects. The greatest increase in SP-A mRNA occurred with cAMP alone. Treated cells processed pro-SP-B and pro-SP-C proteins to mature forms and had a higher rate of phosphatidylcholine (PC) synthesis (2-fold) and higher saturation of PC (~34% versus 27%) than controls. Only treated cells maintained secretagogue-responsive phospholipid synthesis. By electron microscopy, the treated cells retained lamellar bodies and extensive microvilli. We conclude that Dex and cAMP additively stimulate expression of surfactant components in isolated fetal type II cells, providing a simplified culture system for investigation of surfactant-related, and perhaps other, type II cell functions.