X-连锁无汗性外胚层发育不良一家系产前诊断

目的基因诊断方法及连锁分析对一X连锁无汗性外胚层发育不良（XLHED）家系进行产前诊断。方法提取患儿、患儿母亲外周血以及胎儿脐血中的基因组DNA,PCR扩增该疾病相关基因EDA的五个外显子,并直接测序;选择与该基因连锁的STR位点,位于基因上游的一个（CA）n进行家系内的连锁分析。结果患儿的基因突变未发现,连锁分析提示胎儿为男性未携带风险X染色体,出生后证实胎儿正常。结论基因检测及多态性连锁分析在XLHED家系中进行产前诊断是一种较好的方法。     

Prenatal diagnosis of 48,XYY, + 21 ascertained through ultrasound anomalies

During a routine ultrasound study on a fetus at 21 weeks, nuchal edema was noted. At 21 weeks, repeat ultrasound study at our unit showed scalp and neck edema and a femur length/biparietal diameter ratio below the mean. Transabdominal chorionic villus sampling identified a 48.XYY, + 21 chromosome constitution. The fetus had normal internal/external genitalia and signs of Down syndrome.     

Prenatal diagnosis in Becker muscular dystrophy

Prenatal diagnosis in a pregnancy at risk for Becker muscular dystrophy is reported. The diagnosis was made prior to 12 weeks of gestation by typing a CVS sample for DNA markers.     

Trisomy 9 confined to the placenta: Prenatal diagnosis and neonatal follow-up

Chorionic villus sampling (CVS), performed on a woman in the 23rd menstrual week because of bilateral fetal hydronephrosis and suspected intrauterine growth retardation (IUGR), documented trisomy 9 in all cells examined. Chromosomes of amniocytes and fetal blood lymphocytes were normal. The ongoing pregnancy was monitored closely, and at 37 weeks, a phenotypic normal male infant was delivered. Multiple placental biopsies showed 47,XY,+9, while a repeat chromosome analysis of the infant and biopsies from the amniotic membrane were normal (46,XY). This case further emphasizes the association between placental aneuploidy and IUGR. To our knowledge, nonmosaic trisomy 9 in CVS confined to the chorionic villi and later confirmed in the placenta has not been reported previously.     

Facial morphometrics in the identification of gene carriers of X-linked hypohidrotic ectodermal dysplasia

Roentgenographic measurements and morphometric analysis were employed in the investigation of contrasting patterns of craniofacial variation between normal individuals and those affected by X-linked hypohidrotic ectodermal dysplasia (HED). The research objective was to identify and describe the facial characteristics of heterozygous gene carriers who show minor expression of the disorder. In this study of 13 HED families with 16 affected males, 12 carriers, and 12 normal individuals, affected individuals had at least 3 of the following 4 clinical signs and symptoms: a) hypodontia, b) hypohidrosis, c) hypotrichosis, and d) clinically distinct facial physiognomy. By contrast, the gene carriers manifested only one or 2 or none of the 4 clinical manifestations. In a preliminary comparison of gene carriers vs. normal individuals, we have generated 2 discriminant functions (each based on 3 facial measurements taken either from the lateral or frontal cephalograms). These 2 functions correctly diagnose 100% of the gene carriers and normal HED relatives. Facial anomalies characteristic of the gene carriers were 1) abnormally narrow and short maxillary width and palatal depth dimensions; 2) very small and retrusive malar and maxillary regions; 3) markedly reduced lower facial depth, height and width dimensions; 4) small head height, prominent forehead, and high-set orbits; 5) a generalized, symmetric reduction of the whole craniofacial complex.     

Expression of X-linked hypohidrotic ectodermal dysplasia in six males and in their mothers

Six male patients with confirmed X-linked hypohidrotic ectodermal dysplasia and their mothers were studied to determine the variation of expressivity in patients and heterozygotes, major problems of the patients, and to find a clue to pathogenesis. The number of teeth, conic in shape, in patients varied from none to 14. In addition to hypohidrosis and hypotrichosis, dry skin, reduced salivation, hoarseness and hypoplasia of the nipples were common signs. Five patients had frequent respiratory infections. The mothers lacked more than four permanent teeth, one mother had hypodontia in the deciduous dentition. The sweat pore counts were low in patients, and lower than normal in the mothers. All patients carried beta-hemolytic streptococci, four of them group A either in nose or pharynx, without symptoms. Immunoglobulin values, including IgA were normal in serum and saliva. Unexpectedly, serum parathyroid hormone concentrations both in patients and mothers were low. The major problem of the families was the risk of hyperpyrexia due to hypohidrosis, but the patients' concern was mostly because of their facial appearance.     

X连锁隐性遗传性少汗性外胚层发育不全一家系EDA基因突变分析

目的 对1个X连锁隐性遗传性少汗性外胚层发育不全(X-linked hypohidrotic ectodermal dysplasia,XLHED)家系进行EDA基因检测,分析基因突变类型,探讨其遗传学因素及发病原因.方法 对该XLHED家系进行家系调查,收集家系患者及部分成员和50名无亲缘关系的正常个体的外周血标本并提取基因组DNA,应用聚合酶链反应扩增EDA基因8个外显子,DNA直接测序进行突变检测.结果 该家系中患者检出EDA基因第3外显子存在c.467G＞A突变,导致R156H错义突变.先证者的母亲及姨妈携带c.467G＞A杂合突变,家系中正常个体和正常对照个体均未检测到该突变.结论 EDA基因的R156H突变可能是引起该XLHED家系先证者少汗性外胚层发育不全的致病原因.     

Manifestation of the lines of Blaschko in women heterozygous for X-linked hypohidrotic ectodermal dysplasia

For the detection of the carrier state of X-linked hypohidrotic ectodermal dysplasia, sweat pore counts on fingertips or palms have been used in the past. The results obtained, however, were sometimes difficult to interpret. We here describe a more reliable method, using the entire back as a test area. We provide evidence that the distribution of sweat pores in carriers is not simply patchy. In four heterozygous women we were able to demonstrate a linear distribution of hypohidrotic areas. This pattern followed the lines of Blaschko, forming a typical V-shape over the spine. Apparently, these lines reflect the dorsoventral outgrowth of two functionally different populations of cells during early embryogenesis.     

两个X连锁少汗性外胚层发育不良家系的基因突变分析

目的 对两个X连锁隐性遗传少汗性外胚层发育不良(X-linked hypohidrotic ectodermal dysplasia,XLHED)家系进行ED1基因突变分析,为罹患家庭提供遗传咨询及产前诊断.方法 综合应用序列分析及多重连接依赖性探针扩增方法,对两个家系的先证者进行ED1基因突变分析,并针对检测到的突变位点对女性成员进行检测.采集家系1胎儿的羊水细胞进行产前诊断,包括致病突变位点的分析、ED1基因内4个短串联重复序列(short tandem repeat,STR)位点的单倍型连锁分析、性别鉴定及核型分析.结果 家系1先证者缺失ED1基因第1外显子及下游2个STR位点DXS8269,DXS1422区域,其余外显子序列分析未见异常,其女儿为该缺失突变的携带者;结合连锁分析、性别鉴定及核型分析结果,家系1胎儿为男性非ED1基因缺失突变携带者,胎儿足月分娩后随访,为健康个体.家系2先证者经序列分析检测到ED1基因第3外显子c.463C＞T(R155C)错义突变,母亲为c.463C＞T(R155C)杂合突变携带者.结论 ED1基因第1外显子区域缺失和错义突变R155C是导致2个少汗性外胚层发育不全家系患者临床表型的主要原因,ED1基因的突变检测结合单倍型分析,能准确地对该类家系提供产前诊断.     

X-linked hypohidrotic ectodermal dysplasia and t(X;12) in a female

A female patient with features of hypohidrotic ectodermal dysplasia (HED) was found to be a carrier of a de novo t(X;12) with a breakpoint in Xq13.1. This is the second instance of an X/autosome translocation, with apparently the same X breakpoint, reported in HED.     

Correlation between the phenotypes and genotypes of X-linked hypohidrotic ectodermal dysplasia and non-syndromic hypodontia caused by ectodysplasin-A mutations

Mutations in the ectodysplasin-A (EDA) gene can cause both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic hypodontia (NSH). The correlation between the phenotypes and genotypes of these two conditions has yet to be described. In the present study, 27 non-consanguineous Chinese XLHED subjects were screened and 17 EDA mutations were identified. In order to investigate the correlation between genotype and phenotype, we also reviewed related studies on NSH subjects with confirmed EDA mutations and compared the differences in the clinical manifestations and EDA mutations of the two conditions. Tooth agenesis was observed in addition to abnormalities of other ectodermal organs. Tooth agenesis was more severe in XLHED subjects than in NSH subjects, and there were statistically significant differences in 10 tooth positions in the XLHED and NSH subjects, including canines, premolars, and molars. With the exception of one splicing mutation, all mutations in the NSH subjects were missense mutations, and these were most likely to be located in the tumor necrosis factor (TNF) domain. Further, more than half of the mutations in the XLHED subjects were speculated to be loss of function mutations, such as nonsense, insertion, and deletion mutations, and these mutations were distributed across all EDA domains. Our results show that there exists a correlation between the phenotypes and genotypes of XLHED and NSH subjects harboring EDA mutations. Further, our findings suggest that NSH is probably a variable expression of XLHED. This finding might be useful for clinical diagnosis and genetic counseling in clinical practice, and provides some insight into the different manifestations of EDA mutations in different ectodermal organs.     

Prenatal detection and molecular characterization of a de novo duplication of the distal long arm of chromosome 19

A tandem duplication of the distal long arm of chromosome 19 was identified in a 10 week fetus by analysis of chorionic villi. The fetal karyotype from two primary cultures was 46,XY,dir dup(19)(q13.2q13.4). The origin of the extra material was confirmed by fluorescence in situ hybridization using a chromosome 19 whole chromosome probe. Parental chromosomes were normal, indicating a de novo origin of the extra chromosome material. This is the first case of dup(19q) detected by prenatal diagnosis. Molecular studies demonstrated that the duplication involved a maternal chromosome 19. Am. J. Med. Genet. 71:325–328, 1997. © 1997 Wiley-Liss, Inc.     

X-linked hypohidrotic ectodermal dysplasia. Genetic and dental findings in 67 Danish patients from 19 families

This study aimed to investigate genotype and phenotype in males affected with X-linked hypohidrotic ectodermal dysplasia (HED) and in female carriers, to analyse a possible genotype–phenotype correlation, and to analyse a possible relation between severity of the symptoms and the X-chromosome inactivation pattern in female carriers. The study group comprised 67 patients from 19 families (24 affected males and 43 female carriers). All participants had clinical signs of ectodermal dysplasia and a disease-causing EDA mutation. The EDA gene was screened for mutations by single-stranded conformational polymorphism and direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) analysis was used to detect deletions/duplications in female probands. Sixteen different EDA mutations were detected in the 19 families, nine not described previously. The MLPA analysis detected a deletion of exon 1 in one female proband. No genotype–phenotype correlations were observed, and female carriers did not exhibit a skewed X-chromosome inactivation pattern. However, in two female carriers with pronounced clinical symptoms, in whom the parental origin of each allele was known, we observed that mainly the normal allele was inactivated.     

Difficulties encountered in a randomization trial of CVS versus amniocentesis for prenatal diagnosis

In April 1985, having completed a study of the short-term complications of chorionic villus sampling (CVS), we began a randomized comparison of CVS versus amniocentesis. Our study continued over a 15-month period, and during that time we had difficulty recruiting patients, with only 10.6% of 1254 women referred for prenatal diagnosis fully participating in this study. However, 30.2% of those eligible by dates and indication chose to enter the study. CVS was available in our province only through this study, and the two most common reasons for such a low rate of recruitment were reporting too late in pregnancy and the concern about the potential risks of CVS. Patients continued to seek counselling too late for CVS despite direct and continuous contact with regional physicians. Our patients' concern about risk might well vary with the attitude of their physicians towards CVS, and with the information provided at the time of pre-test counselling. The small number of patients actually enrolled did not permit any meaningful comparison of amniocentesis to CVS. However, our experience with pregnancies lost post-CVS suggests that a pregnancy with an apparent low implantation at the time of sampling may be at a higher risk of loss.     

B超引导下经腹腔绒毛取材进行染色体培养的研究

目的研究早孕期B超引导下经腹绒毛取材以及绒毛细胞长期培养和染色体制备方法,评价早孕期细胞遗传学分析在产前诊断中的应用价值。方法采用绒毛细胞长期培养法对312例B超引导下经腹绒毛取材的产前诊断病例进行染色体培养制作、核型分析。结果建立一种快速简便的孕早期绒毛细胞长期培养和染色体制备方法,在312例孕早期绒毛膜细胞中,除12例因培养失败外,其余均获得成功,成功率达96.15%。结论孕9周后行B超引导下经腹绒毛取材是一项安全可行的早孕期介入性产前诊断方法。     

Use of decision analysis to evaluate patients' choices of diagnostic prenatal test

Women with a family history of a chromosomal or genetic abnormality must weigh several factors in choosing between amniocentesis and chorionic villus sampling. We compared the prenatal test choices of three such women with those of decision analytic models that incorporated their prefernces. Patient preferences were assessed using visual linear rating scales. Threshold analysis was used to determine preference ranges, and stochastic sensitivity analysis to provide confidence levels, for each choice of test. The test choices of patients and decision analytic models agreed in one case, and disagreed in two cases. In one of the latter two cases, stochastic and threshold analyses showed the disagreement to be slight; for small shifts in prefernce differences for first-vs. second-trimester diagnosis, or firstvs. second-trimester therapeutic abortion, patient and decision model would have agreed. In the other, stochastic analysis showed their differences to be large; there were no thresholds for early diagnosis, or for early therapeutic abortion, that would have led to agreement between patient and model. In the two cases in which patient and decision model agreed or slightly disagreed, the patients had made their own choice of prenatal test. In the case in which patient and decision model strongly disagreed, the patient's physician had shared in the choice of test. Decision analysis can be useful in analyzing prenatal test choices based on individual prefernces for pregnancy outcomes. When choices of patients and decision models do not agree, examination of the locus of decision making (patient vs. physician) may help resolve apparent differences. © 1995 Wiley-Liss, Inc.     

Effect of chorionic villus sampling on utilization of prenatal diagnosis in women of advanced maternal age

The effect of the introduction of chorionic villus sampling on the utilization rate of prenatal diagnosis in advanced maternal age was studied during the period 1 January 1985-1 January 1991. On the first of January 1985, the age limit for prenatal diagnosis in The Netherlands was lowered from 38 to 36 years of age. The overall uptake rate during the studied period increased significantly, but only because of the increased uptake rate in the group 36 and 37 years. In the maternal age group of 42 years and older, an uptake rate as low as 15.9% was established. This was mainly determined by the relatively high percentage (73.0%) of women from ethnic minorities in this age group. The number of CVS procedures increased significantly during the study period, but the utilization rate was not influenced, since the number of amniocenteses decreased accordingly. An increase in acceptability of prenatal diagnosis by women of advanced maternal age due to early testing and early termination of pregnancy could not be substantiated in the present study.     

有汗型外胚层发育不良家系基因突变分析及孕早期产前诊断

目的 对1个中国汉族有汗型外胚层发育不良家系进行了基因突变分析,并在此基础上对该家系中已孕11周的胎儿进行了产前诊断,为遗传咨询提供依据.方法 应用PCR扩增和直接双向测序对1个有汗型外胚层发育不良家系2例患者及6名正常成员的GJB6基因(Cx30基因)的全编码区序列进行突变分析.在确定突变后,取胎盘绒毛活检样本进一步行产前诊断.结果 在该家系的2例患者中检测出GJB6基因c.31G＞A的点突变,该突变导致了GJB6蛋白N-末端区域第11位甘氨酸被精氨酸替代(p.G11R),6名正常家系成员均未检测到该突变.产前诊断结果显示胎儿也携带有GJB6基因c.31G＞A突变.在终止妊娠后,流产物突变分析的结果与产前诊断结果一致.结论 GJB6基因c.31G＞A(p.G11R)错义突变是该有汗型外胚层发育不良家系的致病原因,通过基因诊断和产前诊断可以有效阻止致病基因的传递.     

Confined placental chimerism: Prenatal and postnatal cytogenetic and molecular analysis,and pregnancy outcome

The presence of two cell lines in chorionic villi sampling (CVS) represents a significant complication in CVS analysis, interpretation, and counseling. We report on the cytogenetic and molecular analysis of a pregnancy that was conceived on clomiphen citrate. Two cell lines (46,XX and 47,XY, + 9) were discovered in CVS analysis done for maternal age; 94% of the cells in the culture were 46,XX and 6% were 47,XY, + 9 (the direct preparation was 46,XX). As neither line could have derived from the other, chimerism and not mosaicism was suspected, with the 47,XY, + 9 cells deriving from a co-twin whose demise was the result of the autosomal trisomy. At a subsequent amniocentesis, only normal female cells were observed and a normal female infant was delivered at term. Cytogenetic analysis done on the infant's peripheral blood and on a sample of an umbilical vessel showed only 46,XX cells, while amnion and a fibrotic area of the placenta contained 2 cell lines, 46,XX and 47,XY, + 9. Molecular analysis of 3 different tissues was done by the polymerase chain reaction (PCR) and Southern blotting, using Y specific primers and probes, respectively. The presence of Y specific DNA was detected in the placenta and amnion, but not in the umbilical blood vessel. These data excluded true chimerism in the fetal tissues at the level of about 1 in 10⁵ cells and have defined for the first time probable confined placental chimerism (CPC), the result most likely of a “vanishing twin.” Whenever two cell lines are found in CVS, especially in the setting of pharmacologically stimulated ovulation, the possibility of CPC should be considered. The effects of CPC on placental function and fetal outcome merit further study. © 1994 Wiley-Liss, Inc.