Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease.

We describe four prenatal diagnoses in a family with autosomal dominant polycystic kidney disease. Two pregnancies were terminated following the detection of enlarged echogenic fetal kidneys with cysts. Histopathological examination confirmed the diagnosis of polycystic kidney disease. Linkage to PKD1 was obtained by the analysis of DNA from relatives in three generations and from paraffin blocks and formalin fixed fetal tissues. Prenatal DNA analysis in subsequent pregnancies identified one unaffected fetus and one fetus carrying the high risk PKD1 allelle. Information on survival and subsequent outcome of PKD cases presenting in utero was requested by this family before prenatal testing was performed. Of 83 reported cases of ADPKD presenting in utero (excluding termination of pregnancy) or in the first few months of life, 43% died before 1 year. Longitudinal follow up of 24 children in two studies showed that 67% of survivors developed hypertension, of whom three had end stage renal failure at a mean age of 3 years.     

Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (2) Invasive Diagnostic Testing for Fetal Chromosomal Abnormalities

The Korean Society of Maternal Fetal Medicine proposed the first Korean guideline on prenatal aneuploidy screening and diagnostic testing, in April 2019. The clinical practice guideline (CPG) was developed for Korean women using an adaptation process based on good-quality practice guidelines, previously developed in other countries, on prenatal screening and invasive diagnostic testing for fetal chromosome abnormalities. We reviewed current guidelines and developed a Korean CPG on invasive diagnostic testing for fetal chromosome abnormalities according to the adaptation process. Recommendations for selected 11 key questions are: 1) Considering the increased risk of fetal loss in invasive prenatal diagnostic testing for fetal genetic disorders, it is not recommended for all pregnant women aged over 35 years. 2) Because early amniocentesis performed before 14 weeks of pregnancy increases the risk of fetal loss and malformation, chorionic villus sampling (CVS) is recommended for pregnant women who will undergo invasive prenatal diagnostic testing for fetal genetic disorders in the first trimester of pregnancy. However, CVS before 9 weeks of pregnancy also increases the risk of fetal loss and deformity. Thus, CVS is recommended after 9 weeks of pregnancy. 3) Amniocentesis is recommended to distinguish true fetal mosaicism from confined placental mosaicism. 4) Anti-immunoglobulin should be administered within 72 hours after the invasive diagnostic testing. 5) Since there is a high risk of vertical transmission, an invasive prenatal diagnostic testing is recommended according to the clinician''s discretion with consideration of the condition of the pregnant woman. 6) The use of antibiotics is not recommended before or after an invasive diagnostic testing. 7) The chromosomal microarray test as an alternative to the conventional cytogenetic test is not recommended for all pregnant women who will undergo an invasive diagnostic testing. 8) Amniocentesis before 14 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 9) CVS before 9 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 10) Although the risk of fetal loss associated with invasive prenatal diagnostic testing (amniocentesis and CVS) may vary based on the proficiency of the operator, the risk of fetal loss due to invasive prenatal diagnostic testing is higher in twin pregnancies than in singleton pregnancies. 11) When a monochorionic twin is identified in early pregnancy and the growth and structure of both fetuses are consistent, an invasive prenatal diagnostic testing can be performed on one fetus alone. However, an invasive prenatal diagnostic testing is recommended for each fetus in cases of pregnancy conceived via in vitro fertilization, or in cases in which the growth of both fetuses differs, or in those in which at least one fetus has a structural abnormality. The guidelines were established and approved by the Korean Academy of Medical Sciences. This guideline is revised and presented every 5 years.     

Prenatal diagnosis of glycogenosis type II (Pompe''s disease) using chorionic villi biopsy

Glycogenosis type II (Pompe's disease) has been diagnosed using cultured amniotic cells for several years. In this paper, we present three prenatal diagnoses based on chorionic villi biopsy in three families at risk for Pompe's disease juvenile form: a normal fetus that was diagnosed and confirmed by enzymatic assay on amniotic cells; two affected fetuses that were diagnosed and confirmed on post-abortion fetal tissues. In one case a residual acid alpha-glucosidase activity was found; we concluded that the residual activity was due to maternal contamination. Prenatal diagnosis of Pompe's disease is therefore possible using chorionic villi biopsy.     

Complete hydatidiform mole in twin pregnancy

Six cases of hydatidiform mole associated with normal chorionic villi and a normal embryo/fetus (in five cases) were investigated with interphase cytogenetic and DNA cytometric analyses for diagnostic purposes. DNA probes specific for the pericentromeric regions of chromosomes 1 and X and for the long arm of chromosome Y were used. In four cases a dizygotic twin pregnancy could be proven. In these cases, the histologically normal chorionic villi showed an XY DNA-diploid pattern, consistent with a normal male conceptus, and the molar chorionic villi a XX pattern. In the other two cases an identical sex chromosomal pattern was found in the normal and in the molar villi (XX/XX and XY/XY respectively). In all six cases the molar placental tissues showed prominent trophoblastic hyperplasia with DNA-polyploidy, consistent with a complete hydatidiform mole. In two cases persistent gestational trophoblastic disease developed. It is emphasized that twin pregnancies composed of a normal conceptus and a complete mole have a relatively high risk for the development of persistent trophoblastic disease and therefore, should be carefully differentiated from triploid partial moles with a relatively low risk of persistent gestational trophoblastic disease. These case reports indicate that additional interphase cytogenetic and DNA cytometric analyses are useful in this differential diagnosis.     

Prenatal diagnosis of sickle cell anemia. Hemoglobin electrophoresis versus DNA analysis

The prenatal diagnosis of sickle cell anemia (hemoglobin SS) can be established by DNA analysis using two highly sensitive techniques (Southern blot and polymerase chain reaction [PCR]). Hemoglobin electrophoresis provides a third, simpler and more rapid, technique to analyze blood from a fetus at risk for sickle cell anemia. The authors present examples of prenatal diagnostic studies using both DNA analysis techniques and hemoglobin electrophoresis. Hemoglobin electrophoresis of fetal hemolysate can provide a simple and rapid alternative method to PCR analysis for the prenatal exclusion of sickle cell anemia, and it is especially useful in cases in which rapid results are needed because of advanced gestational age.     

Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique

BACKGROUND: Fetal DNA circulating in maternal serum offers a possibility for non-invasive prenatal diagnosis but its kinetics during very early pregnancy is still unclear. In order to clarify this point, the studies on the kinetics of fetal DNA appearance in maternal serum were conducted on patients undergoing assisted reproduction. METHODS: Using a quantitative real time PCR assay, the presence of SRY gene sequences was evaluated in the serum of patients at the onset of pregnancy. RESULTS: Twenty-seven patients were originally studied but first trimester abortion occurred in five cases. Among the 22 ongoing pregnancies, ten were found to bear at least one male fetus and all sera from these women gave positive results for SRY gene detection. The SRY gene was found to be detectable as soon as day 18 after embryo transfer in one case and it had been found in the other nine patients by day 37. CONCLUSIONS: Fetal DNA is found in maternal serum even before the fetal circulation is established, which is highly suggestive that it is released, at least in part, from the trophoblast. Detection of fetal DNA in maternal serum very early in pregnancy may have clinical implications such as with the management of pregnant women carrying a fetus at risk for congenital adrenal hyperplasia.     

Prenatal diagnosis of Pena-Shokeir syndrome type 1

This report describes the sonographic diagnosis of the Pena-Shokeir syndrome type 1 during the second trimester of a pregnancy which was electively terminated. The mother had previously delivered a macerated, hydropic infant with multiple congenital anomalies. The diagnosis was based on the recurrence of hydramnios and nonimmune hydrops in a fetus with normal chromosomes, normal amniotic fluid alpha-fetoprotein, normal fetal echocardiography, and lack of evidence of a lysosomal storage disease. These observations suggest that serial sonography during the second trimester in pregnancies at risk may allow for the prenatal diagnosis of the Pena-Shokeir syndrome type 1. Without further experience, it would not be prudent to suggest to couples at risk that the prenatal diagnosis of a recurrence can be assured with a high degree of accuracy.     

2473例双胎妊娠的无创产前检测结果分析

目的:分析探讨无创产前检测(non-invasive prenatal testing,NIPT)对于双胎妊娠胎儿非整倍体的检测价值。方法:选取2016年1月至2019年12月在本中心接受NIPT检测的2473例双胎孕妇,利用高通量测序和生物信息学分析测算胎儿染色体非整倍体的风险率,为高风险孕妇提供羊膜腔或绒毛穿刺,并...     

Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: Case report and literature review

The molecular basis of the myotonic dystrophy (MD) kinase gene is expansion of the CTG repeat at the 3′-untranslated region of the MD gene. Variability of the CTG repeat size in different tissues of affected individuals has been demonstrated. The objective of this report was to examine and review the feasibility of prenatal diagnosis of congenital myotonic dystrophy (CMD) in pregnant women with MD using CTG repeat sizes in amniocytes or villi. We present a case of a pregnant woman with MD who underwent prenatal diagnosis of MD using amniocytes. The repeat size in the amniocytes was smaller than the repeat size in the maternal leukocytes and smaller than the repeat size in the infant blood. The infant had CMD. We also reviewed the literature for reports on MD cases that were prenatally tested for CTG repeat size using amniocytes or chorionic villi. Data were tabulated based on the number of maternal CTG repeats, prenatal procedure [amniocentesis or chorionic villus sampling (CVS)], CTG repeat size in fetal tissue, fetal/infant blood, and pregnancy outcome. Twenty-seven pregnancies at risk for MD that underwent prenatal diagnosis were reported. Eleven (40.7%) of the 27 pregnancies underwent amniocentesis, and 16 (59.3%) underwent CVS. Fourteen patients (61%) demonstrated an increase in CTG repeat size in the amniocytes or villi compared with the maternal repeat size. Nine (33%) of the 27 pregnancies were terminated because of CMD risk. The outcomes of 11 (40.7%) pregnancies were consistent with diagnosis of CMD. CMD was diagnosed in fetuses demonstrating expansion or contraction of the CTG mutation in the amniocytes. Prenatal diagnosis of MD is possible by using mutation analysis on maternal and fetal DNA and detection of the CTG repeat expansion. Prenatal diagnosis of CMD is more complex. The possible lack of correlation between CTG repeat size in amniocytes, villi, and other fetal tissues is a potential limitation in prenatal diagnosis and counseling of CMD using CTG repeat size. Thus, prenatal diagnosis of CMD should be based on a combination of factors, including maternal pregnancy history, clinical findings, and cautious interpretation of maternal and fetal DNA analysis. Am. J. Med. Genet. 78:250–253, 1998. © 1998 Wiley-Liss, Inc.     

Importance of accurate diagnosis in counseling for neural tube defects diagnosed prenatally

In cases of fetal neural tube defects (NTD), termination of pregnancy without ascertainment of specific etiology may lead to provision of incorrect recurrence risks and erroneous diagnosis in future pregnancies. Four patients are presented who illustrate the etiologic diversity of neural tube defects. The patients were referred for prenatal diagnosis because of elevated maternal serum alphafetoprotein (AFP). All four chose pregnancy termination. Diagnostic methods included fetal ultrasound, amniocentesis for fetal karyotyping and amniotic fluid AFP/acetylcholinesterase (AChE) and/or fetal karyotyping after delivery, and dysmorphology evaluation of the fetus after intact delivery. These cases highlight the benefits of fetal karyotype analysis and of an intact delivery and thorough clinical examination of the fetus when patients choose to terminate pregnancies with fetal anomalies.     

Abnormal maternal serum levels of human chorionic gonadotropin free subunits in trisomy 18

We have measured maternal serum levels of free alpha and beta subunits of human chorionic gonadotropin between 8 and 12 weeks of gestation in 704 women at increased risk for trisomy. This group was studied because of advanced maternal age or a previous birth with chromosomal abnormality. All sera had been collected prior to chorion villus biopsy for prenatal diagnosis. Serum levels of free alpha and beta hCG were determined by specific monoclonal antibody-based immunoradiometric assays. Analysis of chorionic tissue showed that in 38 of 704 (5.4%) pregnancies the fetus had a chromosome abnormality. There were 8 fetuses with trisomy 18 (1.1%) and 9 (1.3%) with trisomy 21. In all pregnancies carrying a trisomy 18 fetus, we observed either high levels of free alpha hCG or low levels of free beta hCG or both. More importantly, the calculated ratio of free beta hCG/alpha hCG was less than 0.25 multiples of the median (MoM) in 6 of 8 (75%) trisomy 18 cases. Only 21 of 666 mothers (3.2%) carrying a normal fetus had a ratio less than 0.25 MoM (P less than 0.0001). There was no difference between this ratio in trisomy 21 and normal pregnancy. Thus, when adjusted for gestational age, a low free beta hCG/alpha hCG ratio in maternal serum indicates a pregnancy at high risk [RR = 72 (95% CI 32, 162)] for trisomy 18.     

Prenatal exclusion testing for Huntington''s disease: a problem of too much information.

At eight weeks of pregnancy a couple were informed that the prospective father's mother had died of Huntington's disease (HD). There were no living affected members in the immediate family to confirm the diagnosis. By inspection of the local genetic register, it was established that it was indeed HD segregating in the extended family. Genotyping of the prospective mother and father, the father's unaffected father, and his unaffected maternal grandmother was carried out using a battery of polymorphic DNA markers, including a new probe which has a very low recombination rate with the HD locus. Analysis of DNA from a chorionic villus sample taken at 10 weeks of pregnancy showed that the fetus must have inherited a chromosome from its father's affected mother. Its risk of developing HD was 47%. If the genotype of the unaffected maternal grandmother was taken into account, the risk was reduced to 42%. Neither risk was considered acceptable by the prospective parents and the pregnancy was terminated at 12 weeks' gestation. Prospects for future pregnancies are good, with a 50% chance of having a child whose risk of inheriting the HD gene is less than 1.5%. In retrospect it was noted that although genotyping of the maternal grandmother had refined the fetal risk, it had also nearly contributed to an inadvertent and unwanted predictive test for HD on the father. This case makes the point that in prenatal exclusion testing, linkage information must be generated with considerable care.     

Prenatal diagnosis of Fanconi anemia

Prenatal diagnosis was performed on a fetus at risk for Fanconi anemia. A high spontaneous (0.30 breaks/cell) and diepoxybutane-induced (0.69 breaks/cell) chromosome breakage rate indicated an affected fetus and the pregnancy was terminated. The anatomic findings in the aborted fetus together with cytogenetic findings in cultured fetal skin fibroblasts confirmed the prenatal diagnosis.     

Prenatal diagnosis of a hypermethylated full fragile X mutation in chorionic villi of a male fetus.

Fragile X syndrome, one of the most common human genetic diseases, is characterised by a unique genetic mechanism which involves dynamic mutation because of a heritable unstable DNA sequence and abnormal DNA methylation. Direct detection of the dynamic mutation and its methylation status at the DNA level would facilitate reliable tests for prenatal and postnatal diagnosis of the disease and for carrier detection. However, it has been suggested that DNA methylation can not be used as the basis for prenatal diagnosis as the CpG island is not always methylated in chorionic villus DNA. We report here a male fetus exhibiting both extensive somatic heterogeneity and abnormal hypermethylation of the full fragile X mutation in chorionic villus DNA as well as in fetal tissue DNA. Our results indicate that both somatic heterogeneity and hypermethylation of the full fragile X mutation are events that are clearly detectable in the 11th to 12th week of pregnancy.     

First-trimester diagnosis of metachromatic leucodystrophy

Two pregnancies at risk for late infantile metachromatic leucodystrophy were monitored by assaying arylsulphatase A at 0 degrees C in homogenates of chorionic villi. In one, the very low activity recorded indicated the fetus to be affected, and this was confirmed by demonstration of low arylsulphatase A activity in cultured villi and cultured fetal fibroblasts after termination. In the other pregnancy, normal activity was found in the villi and the pregnancy is continuing. This simple chromogenic assay appears to be reliable for first-trimester diagnosis of metachromatic leucodystrophy. However, there is a probability of mis-diagnosis if the standard assay at 37 degrees C is used.     

Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis

Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia was previously performed by the direct histological analysis of fetal skin obtained by late second trimester fetoscopy. The recent gene mapping of the locus for the disorder to the region of Xq11-21.1 now permits the indirect prenatal diagnosis of the disorder by the method of linkage analysis, based on closely linked marker loci, during the first trimester of pregnancy. We report the prenatal diagnosis of a male fetus with a high probability of the disorder by a linkage analysis utilizing restriction fragment length polymorphisms at the DXS159, PGK1, and DXS72 loci, from a DNA sample obtained by a chorionic villus biopsy at 9 weeks gestation. After further counseling, the pregnancy was terminated but the diagnosis could not be confirmed by histological analysis, even though analysis of skin samples by light and electron microscopy showed lack of hair germs, primary dermal ridges, and sweat gland primordia, due to the early developmental stage of the fetus. The use of DNA-based linkage analysis now offers the opportunity for an earlier diagnosis of X-linked hypohidrotic ectodermal dysplasia by a method other than fetal skin sampling. However, families must also fully understand the present limitations of the method prior to undertaking the procedure.     

胎儿颈项透明层厚度在早孕期筛查胎儿畸形的研究进展

孕11-13＋6周胎儿颈项透明层（NT）厚度已经成为早孕期筛查唐氏综合征的重要指标。NT增厚除了与染色体病密切相关外,还与先天性心脏病、胎儿畸形、贫血、感染等因素相关。但是,仍有相当一部分NT增厚的胎儿,出生后是完全正常的。因此,如何对胎儿NT增厚的孕妇进行产前诊断？如何对NT增厚但染色体核型正常的产前病例进行产科处理？NT一旦增厚是否不需要进行唐氏筛查而直接进行产前诊断？这些问题都是目前临床亟待解决的主要问题[1]。本文对国内外相关的文献进行综述,旨在从NT增厚的原因、病理基础、产科处理及妊娠结局等多个角度对NT增厚的产前咨询策略作一探讨,以期为NT测量的临床应用提供科学的理论依据。     

Parental decision following prenatal diagnosis of fetal chromosome abnormality

In the event of prenatal diagnosis of fetal chromosome abnormality, parents must choose between continuation and termination of the pregnancy. To determine whether parents are capable of understanding differences in severity among aneuploidy syndromes, we examined the outcome chosen for all pregnancies in which a fetal chromosome disorder was diagnosed at Northwestern Memorial Hospital between January, 1977 and June, 1986. Among amniocentesis cases, 88% with autosomal aneuploidy were terminated, but only 41% with sex chromosome abnormalities and none with de novo structural rearrangements were terminated. Among a smaller group of chorionic villus sampling cases, all with abnormal results were terminated. Similar patterns of parental behavior were noted in other prenatal diagnosis units. We conclude that parents do distinguish among, and respond specifically to, fetal chromosome disorders of differing severity, at least in the second trimester of pregnancy. However, parents appear more inclined to terminate all pregnancies with chromosome abnormalities when the diagnosis has been made in the first trimester.     

孕早期宫颈分泌物中获取胎儿细胞DNA进行产前诊断的可行性

目的：探索获取胎儿细胞DNA用于产前基因诊断的可行性，及能否用于预期胎儿性别。方法：收集92例孕早期人工流产妇女宫颈分泌物和绒毛组织，提取宫颈分泌物中DNA，扩增Y染色体特异重复序列DNA。短期培养制备绒毛染色体，分析核型确定流产胎儿性别。结果：92例经绒毛染色体核型分析的人工流产胎儿中，正确预期胎儿性别72例，准确率78％。结论：采集孕早期宫颈分泌物，可获得胎儿滋养层细胞DNA用于产前诊断，其准确性和可靠性有待进一步提高。     

Prenatal diagnosis of genetic disorders.

Three hundred and fifty pregnancies were monitored by transabdominal amniocentesis in the fourteenth to sixteenth week of gestation followed by karyotyping or biochemica assays of cultured amniotic fluid cells and analysis of alpha-fetoprotein in the amniotic fluid supernatant. The pregnancy was interrupted in 36 cases (10%) either becasue of a fetal abnormality or the presence of a male fetus in pregnancies at risk for an X-linked disease. Four chromosomal aberrations were found in 87 pregnancies tested because of advanced maternal age. In 101 pregnancies with a recurrence risk of Down's syndrome, 2 fetuses with an abnormal karyotype were detected. In 11 cases, in which 1 parent was a carrier of a balanced translocation, 2 unbalanced fetal karyotypes were found. Fetal chromosome studies in 43 pregancies at risk for an X-linked disease indicated the presence of a male fetus in 21 cases. Prenatal diagnosis of 11 different metabolic diseases was performed in a total of 34 cases. Microchemical techniques were used to allow completion of the diagnosis of seven different enzyme deficiencies within 9 to 22 days after amniocentesis. Alpha-fetoprotein assay in the amniotic fluid supernatant of 47 pregnancies at risk for an open neural tube defect resulted in the detection of 3 anencephalic fetuses during the second half of pregnancy. The safety and reliability of amniocentesis and the possible effects on the outcome of pregnancy are evaluated. Prenatal diagnosis offers a promising alternative for parents who are at risk of having a child with a genetic disease which can be detected in amniotic fluid or in cultured amniotic fluid cells.