An activating mutation of the thyrotropin receptor gene in hereditary non-autoimmune hyperthyroidism

The thyroid stimulating hormone (TSH) receptor gene displays a diverse spectrum of activating and inactivating mutations. We report a germline activating mutation M463V of the TSH receptor gene in two siblings with hereditary non-autoimmune hyperthyroidism. The onset of disease in the affected members of the pedigree occurred during childhood or adolescence. The significance of diagnosing activating TSHR mutations lies in therapeutic management and genetic counseling; thyroid ablation is advocated as first line treatment.     

Congenital hyperthyroidism caused by diaplacental exchange of thyrotropin receptor antibodies

We describe the case of a premature baby, extremely small for date whose mother had an untreated hyperthyroidism during pregnancy. Severe symptoms of connatal hyperthyroidism appeared after a latency period of seven days. As the underlying cause we suggest the placental transmission of thyrotropin-receptor-antibodies (TRAb), which were elevated in the mother and the newborn. Main symptoms in the newborn were tachycardia, tachypnea, sweating and diarrhea.     

Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R)

AIM: To identify the molecular defect by which non-autoimmune subclinical hyperthyroidism was caused in a 6-mo-old infant who presented with weight loss. METHODS: Congenital non-autoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor (TSHR) gene. Therefore, the TSHR gene was sequenced directly from the patient's genomic DNA. RESULTS: Molecular analysis revealed a heterozygous point mutation (S505R) in the TSHR gene as the underlying defect. CONCLUSION: A constitutively activating mutation in the TSHR gene has to be considered not only in patients with severe congenital non-autoimmune hyperthyroidism, but also in children with subclinical non-autoimmune hyperthyroidism.     

Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene

Neonatal hyperthyroidism, a rare and serious disorder, occurs in two forms. An autoimmune form associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies, and a non-autoimmune form, resulting from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. To date, 29 separate cases of thyrotoxicosis caused by germline mutations of the TSHR have been documented. These cases have expressed themselves in a range of clinical consequences. This report describes a new case of a newborn with non-autoimmune hyperthyroidism secondary to a constitutively active TSHR mutation (S281N) whose clinical course was complicated by severe respiratory compromise. Typical clinical findings in this disorder are discussed by a review of all previously published cases.     

先天性甲状腺功能减低症汉族儿童的促甲状腺素受体基因失活突变

目的探讨汉族儿童促甲状腺素受体（TSHR）基因失活突变与先天性甲状腺功能减低症（CH）的相关性。方法（1）选择79例CH汉族儿童（亚临床甲减14例,年龄1～5.5岁,男8例,女6例;甲减65例,年龄1.5～6岁,男27例,女38例）为研究对象;100名正常儿童（男40例,女60例,年龄1～8岁）作为对照组。（2）采用PCR和DNA测序技术检测TSHR基因失活突变。结果（1）79例CH患儿中有1例发生复合杂合子突变,其突变位点为（Pro52Thr／Val689Gly）。1例发生杂合子突变,其突变位点为（Gly245Ser）。30例患儿在第10外显子2181位核苷酸处发生C-G转换（GAC→GAG）,使727位密码子天冬氨酸被谷氨酸代替（Asp727Glu）。47例患儿在第7外显子561位核苷酸处发生T-c转换（AAT→AAc）,相应的187位氨基酸（Asn）不发生改变。（2）33例正常对照儿童在第10外显子2181位核苷酸处发生C-G转换;50例正常对照儿童在第7外显子561位核苷酸处发生T-c转换（AAT→AAc）。结论浙江汉族CH患儿TSHR基因有3个杂合子突变位点：（Pr052Thr）、（Gly245Ser）、（Val689Gly）,第10外显子2181位核苷酸处（GAc→GAG）及第7外显子561位核苷酸处（AAT→AAC）存在TSHR基因多态性。     

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.     

腓骨肌萎缩症2S型IGHMBP2基因变异1例

患儿男, 6岁4月龄, 因右下肢跛行5年于2018年2月就诊于郑州大学附属儿童医院康复医学科。主要临床表现为双下肢无力, 右侧显著。腓肠肌肌张力增高, 跟腱反射未引出, 胸部CT平扫示胸椎侧弯畸形, 肌电图示双下肢及右上肢被检神经及肌肉呈神经源性损伤。基因检测示IGHMBP2基因存在c.1202A>G(p.His401Arg)与c.1693G>A(p.Asp565Asn)2个杂合错义变异, 属于复合杂合变异。诊断为腓骨肌萎缩症2S型。     

COG6基因新突变致新生儿期起病的先天性糖基化障碍1例并文献复习

目的：诊断1例COG6基因复合杂合突变所致的先天性糖基化障碍（CDG）,为CDG患儿的的早期诊断、制定干预措施和结局预测提供依据。方法： 总结1例携带有COG6复合杂合突变的CDG患儿的临床表型、家系sanger验证信息、影像学表现、实验室检查和随访信息,对COG6及其他Golgi复合体（COG）基因突变所致CDG的疾病表型行文献复习。结果：患儿因早产、生后反复气促吐沫1月余就诊,主要表现为不明原因反复高热伴肝酶异常,皮肤少汗,异常面容,并存在心、肺、肾、凝血和神经系统异常。行核心家系全外显子组检测发现COG6基因复合杂合突变c.511C>T （p.R171X）和c.540G>A （p.E180E）,c.511C>T 来源于母亲,是人类基因突变数据库（HGMD）已报道的CDGⅡ型的致病突变;c.540G>A 来源于父亲,为新发突变。汇总专业版HGMD已报道的COG6-CDG 患儿9例加本文1例共10例表型（CDGⅡ型）,异常面容,可表现为肝、皮肤、心脏、肾脏、骨骼、关节、凝血、免疫、神经系、听力和视觉异常或其他畸形等,多数患儿生长发育迟缓,预后不良,5例病死,存活者均进展为严重肝功能障碍伴反复感染。比COG-CDG其他亚型,临床表现更丰富、病情偏重且预后差。结论：新生儿期表现为不明原因高热伴肝酶异常,皮肤少汗,肌张力异常,或存在心、肾、免疫和凝血等多器官和系统功能异常的患儿,应高度怀疑COG6-CDG,此类患儿多数生长发育迟缓,预后不良,新生儿期通过基因测序可早期诊断。     

NPHS1基因Fin-minor突变致中国先天性肾病综合征2例报道并文献复习

目的总结2例先天性肾病综合征芬兰型NPHS1基因Fin-minor突变患儿临床资料,提高对该病的认识。方法报道2例先天性肾病综合征患儿的临床特点。对可能致病基因NPHS1、NPHS2、PLCε1、LAMB2、COQ2和LMX1B外显子和WT1基因第8、9外显子,以及外显子相邻附近区域进行直接测序。对该家系相关成员进行NPHS1基因外显子及附近调控区域直接测序,分析突变位点,并文献综述。 结果2例患儿均于出生后1个月内起病,临床表现为肾病综合征。血清病原学检查均为阴性。家系调查未发现家族中有类似疾病的成员。NPHS1、NPHS2、PLCε1、LAMB2、COQ2、LMX1B和WT1基因分析发现,2例患儿存在双NPHS1基因杂合突变,未发现其他基因有致病性突变。1例患儿为NPHS1基因的p.R1109X（c. 3325C>T ,Fin-minor）和IVS26DS-2A>T杂合突变,IVS26DS-2A>T剪切突变为首次报道,其父亲携带IVS26DS-2A>T,其母亲携带p.R1109X。1例患儿为NPHS1基因的p.R1109X （c. 3325C>T ）和p.A1160X （c.3478C>T）杂合突变,其母亲携带p.R1109X突变,未发现p.A1160X突变,其父亲拒绝行NPHS1基因分析。以上发现的突变在100例正常人群中未发现。 结论中国先天性肾病综合征儿童不仅有NPHS1基因突变,而且有经典的Fin-minor突变,为国内首报。本研究新发现的IVS26DS-2A>T剪切突变丰富了NPHS1基因突变谱。     

SZT2基因突变所致儿童难治性癫痫3例报告

目的报道3例SZT2基因突变所致难治性癫痫患儿的临床表现及预后。方法分析总结3例SZT2基因突变所致难治性癫痫患儿的临床资料及随访结果。结果男2例,女1例,分别于4月龄、10月龄及18月龄时出现难治性癫痫,伴有智力运动发育落后、特殊面容(高前额、睑裂下斜、眼睑下垂、弓形眉)、四肢肌张力低下、头围增大等,均有严重的癫痫性脑病表现,其中1例男性患儿(10月龄发病)因反复惊厥死亡。3例患儿基因检测结果均提示SZT2基因突变。结论对无明显诱因出现难治性癫痫伴有智力运动发育落后的患儿应尽早完善基因检测,以明确诊断。     

先天性心脏病GATA4基因突变研究进展

GATA4基因突变在先天性心脏病患儿中较为常见.目前为止,已发现超过120个突变位点,其中在室间隔缺损、房室间隔缺损或法洛四联症患者中多见,但突变基因型与临床表型间的关系至今仍未阐明.该文总结了在人类先天性心脏病中已发表的GATA4基因突变位点,并绘制出功能性改变的基因突变图谱.     

Follow-up of a child with congenital chloride diarrhoea caused by a novel mutation

Congenital chloride diarrhoea (CLD) is a rare autosomal recessive disease with chronic secretory diarrhoea and a need for lifelong salt replacement therapy. We describe a male newborn of consanguineous parents with CLD. Postnatally, frequent watery diarrhoea and electrolyte disturbances were noted from the day 8 of his life. At molecular level, a homozygous mutation was detected in the solute carrier family 26 member A3 gene (SLC26A3), confirming the clinical diagnosis of CLD. CONCLUSION: The relatively late onset of persistent clinical and laboratory signs may demonstrate a new clinical course of CLD. These findings support the need of a tight follow-up and monitoring if such a diagnosis is considered.     

Japanese neonate with congenital chloride diarrhea caused by SLC26A3 mutation

Congenital chloride diarrhea (CCD) beginning in utero is a rare autosomal recessive inherited disorder characterized by impairment of Cl^?/HCO₃^? exchange in an otherwise normal distal ileum and colon. Life‐long secretory diarrhea is caused by mutations in solute carrier family 26, member 3, (SLC26A3), which disrupt epithelial Cl^?/HCO₃^? transport in the ileum and colon. Although 55 mutations in SLC26A3 have been identified throughout the world, few Japanese cases have been confirmed on genetic analysis. We report the successful treatment of a Japanese neonate with CCD caused by SLC26A3 mutation.     

Congenital hypothyroidism caused by a novel homozygous mutation in the thyroglobulin gene

Congenital hypothyroidism (CH) due to thyroglobulin (TG) deficit is an autosomal recessive disease (OMIM #274700) characterized by hypothyroidism, goiter, low serum TG, and a negative perchlorate discharge test. The aim of this study was to perform the genetic analysis of the TG gene in two sisters born from consanguineus parents and affected by CH and low serum TG levels. The index patient and her sister were identified at neonatal screening for CH and treated with L-thyroxine (L-T4). After discontinuation of L-T4 therapy, hypothyroidism was confirmed, serum TG was undetectable, and no organification defect after ¹²³I scintigraphy and perchlorate test was shown; thyroid ultrasound showed a eutopic gland of normal size. DNA was extracted from peripheral white blood cells of the two sisters and the father. All 48 exons of TG gene were amplified by polymerase chain reaction and subjected to direct sequencing. A novel homozygous point mutation in exon 10 of TG gene was identified in the patient and her sister. The mutation determined a stop codon at position 768 (R768X) resulting in an early truncated protein or in the complete absence of the protein. The father (euthyroid) was heterozygous carrier of the mutation. Conclusion: Genetic analysis of TG gene was performed in two sisters affected by CH. A novel point mutation of the TG gene determining a stop codon at position 768 of the protein was identified. The early truncated nonfunctioning protein or the absence of the protein due to the premature degradation of abnormal mRNA may be responsible of the observed phenotype.