毛-发-鼻-指(趾)综合征1例并文献复习

目的探讨儿童毛-发-鼻-指(趾)综合征(TRPS)的临床表现、影像学特征及基因特点。方法对2016年9月重庆医科大学附属儿童医院收治的1例TRPS及基因表现进行描述分析,综合文献,归纳TRPS特点。结果 TRPS以毛发稀疏、细软,眉毛外侧稀疏,鼻大,鼻翼扁平,指(趾)节短,指间关节粗大变形为主要临床表现,影像学提示指(趾)骨干骺端膨大、锥形骨骺形成为特点,结合TRPS1基因突变可确诊,本例患儿以关节改变为主要临床表现,毛发稀疏不明显,TRPS1基因分析提示自发突变(c.2732AG,p.N911S)。结论 TRPS诊断可综合临床表现、影像学检查结合基因检查结果明确诊断。     

新无义突变的毛发鼻指（趾）骨综合征1 例报告并文献复习

目的探讨毛发鼻指(趾)骨综合征(TRPS)患儿的遗传学病因。方法回顾分析1例患儿的临床及基因检测资料。结果患儿,男,4岁9个月,自幼喂养困难,多次患手足口病。身材矮小,眉毛、头发稀疏,梨形鼻。骨X片示指骨骨骺呈锥形,部分骨骺提前融合。可乐定激发试验生长激素峰值28.17 ng/mL。高通量测序及Sanger测序方法验证显示,患儿TRPS1基因(NM_014112.4)存在无义变异c.1338CA,P.Tyr446X(杂合),为新生突变,国内外尚未见报道。根据ACMG序列变异解读标准与指南判定为致病变异。结论 TRPS常见特征性矮小。此例患儿TRPS1基因突变位点为首次报道。     

遗传学新技术在发育迟缓患儿病因诊断中的应用价值

目的探讨遗传学新技术在儿童发育迟缓(DD)病因诊断中的应用价值。方法应用常规染色体核型分析、染色体微缺失检测、致病基因突变分析、串联质谱、气相色谱-质谱技术,对儿童保健门诊2013年9月至2014年9月就诊的180例DD患儿进行外周血或尿液分析。结果异常检出率为27.2%(49/180),其中49.0%(24/49)是应用常规染色体核型分析技术确诊:15例为21-三体综合征,9例为其他染色体异常;51.0%(25/49)是应用新近开展的遗传学新技术确诊:14例为染色体微缺失综合征,6例为遗传代谢病,5例为致病基因突变所致。14例染色体微缺失综合征中3例为PraderWilli综合征,天使综合征、22q13缺失综合征、Williams综合征及Smith-Magenis综合征各2例,猫叫综合征、22q11微缺失综合征及1p36缺失综合征各1例;6例遗传代谢病中3例为甲基丙二酸血症;枫糖尿症、酪氨酸血症和戊二酸尿症各1例;5例基因突变中3例为脆性X综合征,2例为德朗热综合征。结论遗传学新技术提高了对DD患儿的病因学诊断;常规染色体检查正常的儿童不能排除染色体微缺失综合征和遗传代谢病。常规染色体核型分析、染色体微缺失检测、基因突变检测、串联质谱及气相色谱-质谱分析在临床应用中具有互补作用,彼此不能完全替代,临床上应根据不同的特殊面容和临床特征,选择相应的遗传学检测技术。     

儿童急性白血病的细胞遗传学研究

目的　 探讨儿童急性白血病的细胞遗传学改变及其临床意义。方法 　用染色体核型分析及姊妹染色单体互换 (SCE)技术检测急性白血病患儿的染色体特征。结果 　患儿外周血或骨髓的染色体核型异常率分别为 31 % ( 9/ 2 9)、74 2 % ( 2 3/31 )。所检测的 1 8名急性白血病患儿的外周血SCE率明显高于对照组 ,P <0 0 0 1。结论 　急性白血病患儿的染色体不稳定性增加 ,说明患儿的DNA受损 ,修复能力减低 ,为基因突变和癌基因激活引细胞癌变提供了条件。因此应尽力减少不良因素对染色体的损伤作用 ,以降低儿童白血病的发病率。     

外生殖器畸形106例患儿病因分析

目的 分析外生殖器畸形患儿的临床特征并探讨其发病原因,以期提高该病的诊疗水平.方法 收集近几年因外生殖器畸形就诊于上海交通大学医学院附属瑞金医院的106例患儿的资料,总结其临床特征、行染色体核型分析及其他辅助检查.部分患儿抽提外周血基因组DNA进行相关基因突变筛查.结果 (1)106例外生殖器畸形患儿表型多样,从单纯阴蒂肥大/单纯尿道口开口异常,到外生殖器呈间性畸形、性别难辨.染色体核型分析:46,XX 42例(39.6％);46,XY 62例(58.5％);2例(1.9％)染色体核型异常.(2)42例46,XX核型患儿诊断为先天性肾上腺皮质增生症(CAH) 40例(95.2％),肾上腺肿瘤1例(2.4％),另有1例(2.4％)患儿性别决定基因(SRY)阳性.(3)46,XY核型中的53例(85.5％)行5α-还原酶2型基因(SRD5A2)、雄激素受体基因(AR)和类固醇生成因子-1基因(SF-1)突变筛查,发现8例患儿存在SRD5A2突变,存在AR和SF-1突变者各1例.(4)2例染色体异常患儿,1例染色体核型为46,XX/46,XY嵌合型;1例为46,XX/46,XY/46,X.+may.ish(DYZ3+)(DXZ1-)嵌合型.结论 (1)CAH是46,XX核型中呈现外生殖器畸形最常见的病因,少见因素如肾上腺肿瘤、SRY易位等.(2)46,XY核型的外生殖器畸形发病机制复杂,基因突变筛查是明确其病因的最有效方法.(3)染色体异常亦可以引起外生殖器畸形表型.     

12p三体新生儿1例临床及细胞分子遗传学分析

目的探讨12p三体新生儿的临床及细胞分子遗传学特点。方法回顾1例经外周血行淋巴细胞常规G显带染色体核型分析,高通量测序染色体组拷贝数分析(CNV)并经淋巴细胞间期荧光原位杂交(FISH)技术确认的12p三体新生儿的临床资料。结果患儿外周血染色体核型为47,XX,+mar,父母染色体核型均正常;CNV检出患儿12p13.33-p11.1(160 001～34 860 000)区域重复,片段大小为34.7 Mb;外周血淋巴细胞间期FISH显示患儿所有间期细胞核12号染色体短臂均存在3个信号,无嵌合体存在。确诊为12p三体。结论结合临床特征、外周血染色体核型分析、CNV及FISH技术可有效确诊12p三体。     

黏多糖贮积症ⅣA重型2家系患儿的诊治及其同胞的产前诊断

目的分析黏多糖贮积症ⅣA(MPS ⅣA)重型家系患者的临床特点及诊治过程, 探讨MPS ⅣA重型的治疗方法。方法选取郑州大学附属儿童医院2021年8月至2022年4月收治的2例MPS ⅣA重型患儿作为研究对象。回顾性分析以身材矮小、骨骼畸形为主要表现的2个家系患儿的临床表现、生化指标、骨影像学结果等, 取外周血白细胞进行溶酶体酶活性和基因分析, 并对家系2母亲第2次妊娠18周时羊水细胞基因分析进行产前诊断。分别对2家系患儿进行异基因造血干细胞移植。结果两家系患儿均有生长迟缓、关节松弛、鸡胸、膝外翻等MPS ⅣA严重表型临床表现。影像学以骨质密度减低、尺桡骨呈"V"样改变、脊柱生理弯曲异常为主要特点。两家系患儿均有呼吸系统、骨骼系统受累, 视神经可疑受累。患者外周血白细胞溶酶体酶活性分析均显示N-乙酰半乳糖胺-6-硫酸酯酶(GALNS)活性显著降低, 符合MPS ⅣA型。GALNS基因分析显示, 家系1患儿存在c.1019G>A(p.G340D)和c.706C>G(p.H236D)(错义)2个突变, 家系2患儿存在c.425A>G(p.H142R)和c.463G>...     

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。     

FGG基因突变致肝纤维蛋白原贮积症一家系临床表型 病理和基因分析

目的探讨由FGG基因突变所致肝纤维蛋白原贮积症(HFSD)临床特征,报道一汉族家系基因突变类型、治疗情况,提高临床医师对该病的认识。方法采集2019-08-19湖南省儿童医院肝病中心1例FGG基因突变所致HFSD患儿,分析其肝脏穿刺活检、高精度临床外显子检测分析,以及家系资料。结果患儿肝活检术前常规检查发现纤维蛋白原显著降低;肝活检免疫荧光纤维蛋白原染色阳性,磷钨酸-苏木素显示弥漫肝细胞内大量蓝染颗粒样及球性物质,电镜提示肝细胞肿胀,粗面内质网高度扩张,其内充满致密并呈指纹样排列的管状物质。对患儿外周血DNA进行临床医学外显4000致病基因检验和分析,采父母血进行一代验证。检测到FGG基因杂合变异c.1201C>T(p.R401W),验证表明这个变异遗传自父亲。查患儿父亲、母亲、祖母、姑母肝功能、肝脏彩超、凝血功能等,患儿父亲、姑母也存在纤维蛋白原降低情况。结论鉴定出我国汉族1例FGG基因杂合变异c.1201C>T(p.R401W)家系,扩大了HFSD的流行病学数据,进一步验证了HFSD可表现为常染色体显性遗传,且临床表型轻重不等。对于原因不明的慢性转氨酶升高患儿,医务人员应该考虑该病可能,进行肝活检及基因分析可明确诊断。卡马西平治疗或有效。     

CD45+和CD45-儿童急性B淋巴细胞白血病的临床特征分析

目的探讨CD45抗原表达与儿童急性B淋巴细胞白血病(B-ALL)的临床相关性。方法利用多参数流式细胞术(FCM)以CD45/SSC设门对61例B-ALL患儿进行免疫分型检测;采用染色体核型分析和多重巢式RT-PCR技术进行染色体、融合基因分析。结果免疫表型分析显示CD45+组CD13、HLA-DR抗原表达明显高于CD45-组(P<0.05);CD45-组的融合基因主要为HOX11和E2A/PBX1,而CD45+组主要为TEL/AML1、MLL/AF9、HOX11;相关临床参数、染色体核型及疗效比较两组间差异均无显著性(P>0.05)。结论 CD45抗原的表达与否和B-ALL患儿的临床特征、染色体畸变、治疗效果无统计学相关性;CD45+组较CD45-组高表达CD13和HLA-DR。     

An early diagnosis of trichorhinophalangeal syndrome type 1: a case report and a review of literature

Background

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder caused by defects involving the TRPS1 gene. It exhibits distinctive craniofacial, ectodermal and skeletal abnormalities, such as sparse hair, bulbous nasal tip and short deformed fingers, with extremely variable expressivity.

Case presentation

We report the case of a 17?months old girl, who presented growth retardation and dysmorphic features. Postnatal growth was always below ??2 Standard Deviation for both weight and length and physical examination revealed relative macrocephaly, sparse hair, bulbous nasal tip, thin upper lip, protruding ears, prominent forehead, small jaw, and short hands and feet. Patient’s mother shared the same facial features, and presented sparse hair and small hands. The maternal grandfather and two uncles presented short stature, bulbous nasal tip, thin hair, and premature alopecia. Molecular analysis of TRPS1 gene showed a heterozygous c.2086C?>?T;(p.Arg696Ter) mutation both in the patient and her mother, confirming the diagnosis of TRPS, type I.

Conclusions

Clinical phenotype of TRPS can be subtle and the syndrome often remains undiagnosed. A comprehensive clinical examination and an exhaustive family history are crucial to reach the correct diagnosis, which is essential to perform adequate follow-up and timely therapeutic procedures.

     

1个有汗性外胚层发育不良大家系的基因研究

目的 探讨有汗性外胚层发育不良 （HED）的临床特点和分子机制。方法 对1例HED先证者进行其家系5代91人的临床及基因特点研究。抽取家系中7名患者及3名正常对照进行GJB6基因检测。结果 家系5代91人中,HED患者17例,表现为不同程度的指 （趾）甲发育不良、毛发或体毛稀少甚至缺如;家系中男性患者毛发稀少程度重于女性;随着代数增加,指 （趾）甲损害渐减轻。系谱中每一代均有发病者,患者的父母中必有一人发病;男女都可患病;遗传方式为常染色体显性遗传。家系中所有患者的GJB6基因均存在一个杂合错义突变31G→A,家系中无HED临床表现的未检测到此突变。结论 HED为常染色体显性遗传性疾病,以指 （趾）甲发育不良、掌跖角化过度、毛发或体毛稀少甚至缺如为临床特点;男性毛发稀少重于女性;且随着代数的增加,指 （趾）甲损害逐渐减轻。GJB6基因错义突变 （31G→A）是HED的分子机制之一。     

EARS2基因变异致新生儿丘脑脑干受累性脑白质病伴高乳酸血症1例报告并文献复习

目的 探讨丘脑脑干受累性脑白质病伴高乳酸血症的临床表型及基因型.方法 回顾分析1例新生儿丘脑脑干受累性脑白质病伴高乳酸血症患儿的临床资料并复习相关文献.结果 女性患儿,出生26小时,临床表现为反应差、抽搐及顽固性高乳酸血症.患儿于妊娠期时头颅MRI示胼胝体缺如.全外显子测序发现患儿EARS 2核基因第7号外显子c.12...     

Prenatal molecular diagnosis of X‐linked hydrocephalus via a silent C924T mutation in the L1CAM gene

We present a case of a patient whose L1CAM gene in X‐chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X‐linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.     

A Case of Female Pseudohermaphroditism Caused by Aromatase Deficiency

Female pseudohermaphroditism is caused by several etiologies. Here we report a case of aromatase deficiency who showed ambiguous genitalia and maternal virilization during pregnancy. The mother had noticed her own virilization from 16 wk of gestation without androgen exposure and had low urinary estriol levels (5~10 μg/ml at 35 wk of gestation). At birth, the patient presented severe virilization (Prader V), and was assigned as a male with a micropenis and unpalpable testes but the patient had a normal female karyotype and a uterus and cystic ovaries found by magnetic resonance imaging. The patient had a increase in serum 17α-hydroxy progesterone levels (basal 4.9 → 37 ng/ml after a single 0.25 mg/m² infusion of ACTH), but the increase in adrenal androgen was not sufficient to virilize the external genitalia. Dehydroepiandrosterone, 17α-hydroxy pregnenolone and deoxycorticosterone were within the normal ranges. These findings suggested a diagnosis of nonadrenal female pseudohermaphroditism. From the clinical features and biochemical data, we endocrinologically diagnosed her as having an aromatase deficiency. The aromatase gene is now under investigation for definite diagnosis. We finally agreed that aromatase deficiency should be suspected when both the mother and the newborn have been virilized.     

Complete androgen insensitivity syndrome caused by the R855H mutation in the androgen receptor gene

Complete androgen insensitivity syndrome (CAIS) is characterized by a completely female phenotype in a 46,XY individual and is caused by mutations in the androgen receptor (AR) gene. A 5 year-old girl presented with bilateral hernia and was noted to have bilateral testes. She had a 46,XY karyotype and was diagnosed with CAIS. To identify the underlying mutation, the exons 2 to 8 of the AR gene were amplified by PCR using sets of known primers and reaction conditions. The results of the mutational analysis for the AR showed the presence of the R855H mutation; her mother was found to be heterozygous and both her 46,XX sister and her aunt had a normal AR gene. This mutation, is the result of a guanine to adenine transition in codon 855 at position 2926 in exon 7 of the AR gene, which causes an alteration of the coding nucleotide triad from CGC to CAC, which subsequently causes the substitution from arginine to histidine in the amino acid sequence of the receptor protein molecule. The same mutation has been reported to cause variable phenotypic expression, which could be explained by the presence of additional co-activating factors modifying the biological activity of the AR. The identification of an AR mutation in a girl with CAIS provides important information, because of the syndrome's genetic heterogeneity. This report emphasizes the fact that genetic determinants outside the coding sequence of the AR can influence the function of the AR protein molecule. Phenotypic expression of the mutation may be used for the construction of maps of functional domains of the AR.     

NRAS基因突变致系统性红斑狼疮1例并文献复习

摘要 目的：报告1例NRAS基因突变致系统性红斑狼疮（SLE）的临床特征,提高对NRAS基因突变表型谱的认识。方法：收集患儿的临床资料,包括病史特点、相关实验室检查和家族史等。采用外显子捕获的方法对患儿及其父母进行全外显子高通量测序,并进行生物信息学分析,通过Sanger测序对高通量测序结果进行验证。进行相关文献复习。结果：先证者,男,2.6岁,1岁后反复出现发热、外周血PLT和RBC计数下降;2.6岁时出现皮疹、左膝关节肿痛,有轻度蛋白尿,抗核抗体和抗ds-DNA抗体等多种自身抗体阳性。患儿无明显面容异常,其他脏器无畸形。测序发现NRAS基因c.38G>A （p.G13D）杂合突变,其父母均未携带,为新发突变。Sanger法验证了上述高通量测序结果。c.38G>A突变为已报道的致病性突变。结论：本研究显示生殖细胞NRAS基因突变患儿可仅有SLE表型,进一步丰富了NRAS基因突变表型谱。     

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.     

LMNA 相关的先天性肌营养不良症1 例报告并文献复习

目的探讨LMNA相关的先天性肌营养不良症的临床特征和诊断。方法回顾1例LMNA基因突变引起的肌营养不良症病例的临床资料,并复习相关文献。结果患儿,女,8个月,临床表现为抬头乏力、眼睑下垂、运动发育迟缓。检测患儿及其父母、姐姐的LMNA基因,显示患儿存在杂合突变c.94-96 del AAG(p.K32del),确诊为LMNA突变引起的肌营养不良。患儿父母及姐姐均未发现LMNA基因突变。文献检索显示,LMNA相关的先天性肌营养不良症患儿80%以上以抬头乏力为主要表现,并且可能交叉重叠存在肢体近端肌无力、运动发育迟缓、轴向肌无力。结论 LMNA基因分析有助于早期诊断先天性肌营养不良。     

SURF1基因突变导致Leigh综合征家系1例

Leigh综合征是一种由于线粒体氧化磷酸化障碍所导致的严重退行性脑病。常染色体SURF1基因突变所致细胞色素C氧化酶缺乏是导致Leigh综合征的常见原因,国外已报道多种突变类型。该研究回顾了1例SURF1基因604G>C杂合性错义突变所致中国人Leigh综合征患者及其家系的临床与遗传学特点。患者,女, 9个月起病,表现为喂养困难,营养不良,进行性运动倒退,肌张力低下,眼震。17个月时来院就诊, 23个月时死于呼吸衰竭。脑MRI显示双侧基底节对称性损害,脑干、小脑萎缩。聚合酶链式反应扩增SURF1基因的全部外显子,进行序列测定及限制性片断长度多态性分析均显示患者及其母亲、舅舅的SURF1基因的外显子7存在一个604G>C杂合性错义突变,其父亲及正常对照的相关外显子序列未发现异常。该研究首次报道了1例中国人群中由于SURF1基因604G>C杂合性错义突变导致的Leigh综合征及其家系,不仅明确了病因,亦将有助于今后对患者家系的遗传咨询。