儿童肺浆细胞肉芽肿伴肥大性骨关节病1例

患儿女 ,6岁。因运动后气促 2年伴关节肿痛入院。患儿于 2年前开始出现运动后气促明显 ,要蹲下方能缓解 ,随之出现杵状指趾 ,并出现双下肢胫腓骨疼痛 ,双膝关节痛 ,在当地予中药等治疗后疼痛缓解。近 2年来患儿症状无改善 ,门诊拟“肺性骨关节病 ,胸腔积液”收入院。查体 :右肺叩诊音浊 ,呼吸音减弱 ,心律齐 ,左肺呼吸音清。四肢末端见明显杵状指趾 ,双膝、踝关节肿大变形。实验室检查 :血WBC7 94× 10 9/L ,RBC 3 36× 10 12 /L ,Hb 6 4 g/L ,Plt 5 5 1× 10 9/L ,ESR 14 0mm/ 1h ,IgA 4 91g/L (0 33～ 2 0 0g/L) ,IgG33 2 0g/…     

疑似假性肥大性肌营养不良症患儿Dystophin基因缺失突变分析

目的了解中国汉族假性肥大性肌营养不良症(DMD/BMD)患儿基因缺失突变的特点。方法经PCR和20对引物,对964例疑似DMD/BMD患儿Dystophin基因外显子缺失突变类型及断裂点进行检测分析。结果有491例患儿(491/964,51.0%)存在基因缺失突变:其中75例基因缺失突变位于基因5’端区域(15.2%),402例基因缺失突变位于基因中央区域(81.7%),13例基因缺失突变范围跨越了以上两个区域(2.6%)。检测到以50、49、48号外显子缺失突变最为常见。74%患儿的Dystophin基因断裂点位于44～50号内含子,以44号内含子最多(21%)。结论 20对引物的PCR法能够检测超过半数的Dystrophin基因缺失突变,基因中央区缺失是中国汉族DMD/BMD患儿病例的主要基因缺失突变类型。     

HEXA基因纯合变异致Tay-Sachs病1例

目的 分析由HEXA基因纯合变异引起Tay-Sachs病的临床特点及遗传学特征。方法 回顾分析1例Tay-Sachs病患儿的临床资料及基因检测结果。结果 患儿,男,2岁,精神运动发育倒退（4月龄能抬头,7月龄会翻身,8月龄会坐,10月龄左右可发单音节词,14月龄突然不能发单音节词,现不能爬、独自站立、行走）,1岁11月时出现抽搐,反复间断抽搐1月余。全外显子组测序显示HEXA基因（NM＿000520.4）存在c.532C>T(p.R178C)纯合变异,来源于父母,该变异判定为“致病”。HEXA基因（NM＿000520.4）c.532C>T(p.R178C)纯合变异,在东亚人群频率为0,未见文献报道。结论 基因检测有助于Tay-Sachs病的早期诊断,本病例进一步扩展了东亚人群HEXA的基因突变谱。     

中国人家族性腺瘤性患肉病患者结肠腺瘤性患肉病基因的胚系突变

目的 探讨中国人家族性腺瘤性息肉病(familial adenomatous polyposis,FAr)患者的结肠腺瘤性息肉病(adenomatous polyposis coli,APC)基因的胚系突变类型.方法 对9个FAP家系18名成员进行多重连接依赖性探针扩增(multiplex ligation-dependent probe amplification,MLPA)检测APC基因有无大片段缺失.再应用PCR扩增APC基因的15个外显子区域,经变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)对每个扩增片段进行筛查,流出峰异常的片段,经DNA测序验证小片段的改变.结果 9个家系中有3个家系发现有APC基因的胚系突变:家系2为c.3184-3187 del CAhA,家系4为c.5432C＞T,家系9为c.3925-3929 del AAAAG.3种突变中c.5432C＞T在数据库中未见报道.结论 中国人不同的APC基因的胚系突变可引起FAP;无APC胚系突变的FAP患者的发病可能存在其他的机制.     

含有二个PHD型锌指域的新基因内的突变可导致自身免疫病—APECED

自身免疫增多内分泌病变—念珠菌病—外胚层营养不良（ＡＰＥＣＥＤ）是唯一一个单基因背景且位于ＭＨＣ外的自身免疫病。ＡＰＥＣＥＤ病的生化缺陷目前还不清楚。芬兰和日本的二个研究小组几乎同时完成了ＡＰＥＣＥＤ基因的定位克隆,认为ＡＩＲＥ基因突变是ＡＰＥＣＥＤ的致病原因,他们的研究为探索自身免疫病的分子基础提供了工具。     

NF1基因新突变及我国首例NF1基因拷贝数目变异报道

 目的:对2例散发性1型神经纤维瘤患者进行致病基因NF1编码序列的突变筛查以及拷贝数变异(copy number variation,CNV)研究,寻找致病性突变。方法:PCR扩增NF1基因的编码区及外显子-内含子交界区,对产物进行直接测序。在50例正常对照中进行新发现突变位点的测序分析,以排除多态性。用多重连接探针扩增技术(MLPA)对患者进行NF1基因CNV的检测,并对证实有NF1拷贝缺失的患者进行长片段PCR,以找寻断裂点。结果:患者S736于NF1基因检测到一个国际上尚未报道的新突变：c.6345_6346 ins G (p.Leu2116Alafs*4),患者父母均不携带此突变,故此突变为一个de novo突变。该突变使开放阅读框移位,提前引入终止密码子,导致蛋白质分子的截断,以致部分犰狳式褶皱(ARM-type fold)结构域丢失。在另一患者S743中检测到一个包含整个NF1基因的大片段缺失,缺失区域为1.3～1.9 Mb,但断裂点尚不明,此为我国首例NF1基因拷贝数目变异的报道。结论: 患者NF1基因的de novo突变及CNV是引起这2例1型神经纤维瘤发病的分子机制,这些发现可用于临床1型神经纤维瘤的分子诊断。     

原发性色素性结节状肾上腺皮质病1例

患者女性,36岁,因高血压5年伴向心性肥胖2年就诊,影像学检查示左侧肾上腺皮质增生,2020年12月12日我院门诊以左侧肾上腺皮质增生、皮质醇增多症收入院.查体:血压170/110 mmHg,呈向心性肥胖,满月脸,水牛背,多血质面容,多毛,痤疮,腹部及大腿内侧见紫纹.患者亲属中无类似家族史.实验室检查:血钾3. 1 m...     

家族性腺瘤性息肉病一家系调查及APC基因胚系突变分析

目的 探讨家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)家系调查及高危亲属基因筛查的意义,报道云南省一FAP家系发病相关基因APC基因的胚系突变结果.方法 查阅对2001年昆明医学院第一附属医院1例FAP患者病例,电话联系及登门随访进行其家系调查,绘制家系图谱.抽取该家系成员外周静脉血提取DNA,利用PCR方法扩增APC基因,应用DNA自动测序仪进行测序.结果 该家系三代共计9人,成员Ⅰ1、Ⅱ1、Ⅱ2、Ⅱ3、Ⅱ4、Ⅲ2、Ⅲ3、Ⅲ48人检出APC基因胚系突变c.3587C>A(S1196X),其中Ⅱ2、Ⅱ2、Ⅱ4、Ⅲ2、Ⅲ3经肠镜检查证实有结直肠多发息肉,Ⅲ4未检出息肉,为基因突变携带者.结论 通过家系调查对高危亲属进行基因筛查可以发现早期患者,尤其是无临床表现的FAP基因突变携带者,以早期进行医学干预及预防性手术治疗,降低FAP的癌变率、病死率;APC基因c.3587C>A(S1196X)胚系突变是引起该家系FAP患者发病的原因.     

儿童淋巴瘤患者EBV-LMP1基因C末端30bp缺失突变检测

目的 研究儿童淋巴瘤来源的EBV-LMP1基因C末端30 bp缺失突变情况并分析其意义.方法 应用巢式聚合酶链反应技术(Nested-PCR)扩增免疫组化检测EBV-LMP1或原位杂交检测EBV.EBERS阳性的霍奇金淋巴瘤、非霍奇金淋巴瘤和淋巴结反应性增生病理标本中EBV-LMP1基因,并进行序列分析.结果 EBV-LMP1羧基端30 bp缺失的del-LMP1的检出率在霍奇金淋巴瘤、非霍奇金淋巴瘤和淋巴结反应性增生分别为11/25、3/8和5/15,三组间差异无统计学意义(P=0.793,X2=0.463).经序列分析发现,所扩增的EBV-LmP1基因型可分为三个亚型:B95.8、China1和China2.结论 EBV羧基端30 bp缺失的del-LMP1基因型广泛存在EBV阳性的儿童霍奇金淋巴瘤、非霍奇金淋巴瘤和淋巴结反应性增生病例中,与疾病本身没有关系.儿童来源的EBV-LMP1基因型主要可分为B95.8、China1和China2三个亚型.     

A novel mutation in the HPGD gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family

Primary hypertrophic osteoarthropathy (PHO) is a congenital multisystemic entity characterized by three major clinical symptoms: pachydermia, periostosis, and digital clubbing. Recently it has been reported that pathogenic mutations in two genes are known to be associated with PHO: HPGD and SLCO2A1. In the present study, a five‐generation consanguineous Pakistani family harboring primary hypertrophic osteoarthropathy in autosomal‐recessive pattern was ascertained. Whole genome single nucleotide polymorphisms (SNPs) genotyping and sequence analysis revealed a novel homozygous missense mutation (c.577T?C) of the human HPGD gene in all affected members of the family. The study presented here demonstrate the first case of primary hypertrophic osteoarthropathy reported in Pashtun population.     

A novel homozygous mutation in the SLCO2A1 gene causing pachydermoperiostosis: Efficacy of hydroxychloroquine treatment

Pachydermoperiostosis (PDP), otherwise known as primary hypertrophic osteoarthropathy, is characterized by digital clubbing, pachydermia and subperiosteal new bone formation. Joint pain, polyarthritis, cutis verticis gyrata, seborrhea, and hyperhidrosis are frequently associated to this condition. We report a 17‐year‐old boy presented with pain and swelling of knees and ankles, and progressive thickening of skin face with seborrhea from about 4 years. At the admission he also showed digital clubbing of both hands and feet and palmoplantar hyperhidrosis. We hypothesized PDP and molecular analysis confirmed diagnosis showing a novel mutation in a homozygous state in the SLCO2A1 gene coding for prostaglandin transporter. He started therapy with hydroxychloroquine with a great improvement in joint pain and skin conditions. This is the first reported case of PDP who was successfully treated with hydroxychloroquine, with effects not only on arthralgia but also, surprisingly, on skin conditions.     

A novel point mutation of the androgen receptor (F804L) in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis

Androgen-insensitivity syndrome (AIS) is a major cause of male pseudohermaphroditism (MPH). Although AIS is usually reported as a monogenic disease resulting from androgen receptor (AR) mutations, on rare occasions it has been observed as part of a multiple congenital anomaly syndrome. We report here a patient who was the first newborn girl of an unrelated couple. Shortly after birth, the diagnoses of congenital glaucoma and pyloric stenosis were made. A detailed history of the father's family revealed that nine members presented glaucoma before 40 years of age. Clinical and ultrasound evaluation showed two inguinal testes, with female external genitalia and no Mullerian derivatives. The patient had a 46,XY karyotype, good testicular response to gonadotrophin stimulation and a remarkably high T : dihydrotestosterone ratio. Sequencing of the five exons of the 5alpha-reductase type 2 gene (SRD5A2) was normal. Conversely, a de novo point mutation was found in exon 6 of the AR gene, resulting in an F804L substitution, which has never been described previously. To our knowledge, the association of complete AIS, congenital glaucoma and pyloric stenosis has also never been reported previously.     

A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)

Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.     

A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient

Congenital leptin deficiency is a rare recessive genetic disorder resulting in severe hyperphagia and early onset obesity. It is caused by mutations in the LEP gene encoding leptin. To date, only two mutations have been identified in the LEP gene, Δ133G and R105W. We present the third reported mutation identified in an Egyptian patient with very low serum leptin levels and severe early onset obesity (BMI = 51). Direct sequencing of the coding region of the LEP gene revealed a novel homozygous missense mutation, N103K. The N103K mutation was not found in 100 alleles from 50 unrelated Egyptian normal-weight control subjects using polymerase chain reaction and restriction fragment length polymorphism analysis. In conclusion, this study presents the third reported mutation of the LEP gene and will provide further insight into the physiologic role of leptin in human obesity.