In utero fetal muscle biopsy for the diagnosis of Duchenne muscular dystrophy

Deoxyribonucleic acid techniques can be used to diagnose Duchenne muscular dystrophy prenatally in male fetuses that are at risk. Deoxyribonucleic acid-based prenatal diagnosis can be impossible when there is only one prior affected male and there is no identifiable deletion or alteration. We performed fetal muscle biopsy in utero in such a case and documented the presence of dystrophin, thereby confirming normality in a male fetus at risk. This first in utero experience adds fetal muscle biopsy to the available procedures for fetal tissue diagnosis.     

In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy.

Prenatal diagnosis for Duchenne muscular dystrophy can usually be performed using DNA analysis. This approach would be impossible when there is only one prior affected male and no identifiable gene deletion. Therefore, in utero fetal thigh muscle biopsy with direct examination of muscle by dystrophin analysis may provide the only means of prenatal diagnosis. We report such a case in which fetal muscle biopsy was able to exclude Duchenne muscular dystrophy. A detailed literature review of the topic is provided.     

Status of prenatal diagnosis using direct interventions on the fetus

Prenatal diagnosis has developed into a large flourishing multidisciplinary branch of medicine. At present prenatal diagnosis is world-wide possible in the second trimester of pregnancy by analysis of both amniotic fluid obtained by amniocentesis or amniotic cell cultures. Ultrasound plays a central role in prenatal diagnosis, and has revolutionized obstetric practice. Without dealing with all aspects of prenatal diagnosis we have discussed the following invasive procedures, which give the prenatal diagnosis its forward thrust: fetal blood sampling including intravascular transfusion, fetal skin-, liver- and muscle biopsy, chorion biopsy, selective birth in twin pregnancies, and fetal therapy including fetal surgery. In utero surgery is in its earliest stages. Such simple procedures as decompression of the hydronephrotic kidney in obstructive uropathy, of the fetal lungs in pleural effusions caused by chylothorax, or of the hydrocephalic ventricle may be useful, but the possible success rate for such efforts remains still uncertain. The possibilities of first-trimester prenatal diagnosis especially by DNA-technology or direct chromosomal and biochemical analysis has stimulated the development of a multiplicity of methods for taking chorion biopsies. Compared with second trimester amniocentesis, the introduction of prenatal diagnosis by chorionic villi sampling would reduce the psychic trauma for patients waiting on results and allow earlier and safer termination of pregnancy.     

Increased AFP as an indicator of ovarian carcinoma and fetal kidney carcinoma--case report

We examined a young primipara with increased alpha-fetoprotein (AFP) values and cystic tumefaction of the right ovary. Having in mind a mild decrease in ovarian artery resistance index (RI) and suspected findings of fetal kidney, this situation was delicate due to its double pathology which was later confirmed. Wilms' tumor is the most common urogenital tumor in childhood, and it is detectable in the prenatal period by ultrasound examination. In utero kidney biopsy confirms diagnosis and facilitates decisions concerning the course of pregnancy. Relative risk of intervention limits this diagnostic procedure for indicated cases.     

Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis with no specific treatment or prenatal diagnosis available at present. The recent identification of SPINK5, which encodes a serine protease inhibitor, as the defective gene enables DNA based prenatal diagnosis to be carried out. Here we report the first direct molecular prenatal diagnosis of a lethal form due to a recurrent SPINK5 mutation in three consanguineous Turkish families. XmnI restriction enzyme digestion and DNA sequencing demonstrated that each deceased affected child was homozygous for mutation 153delT inherited from each parent. Analysis of fetal DNA from amniotic fluid cells in Family 1 and from a chorionic villus sampling in Family 3 showed that the fetus was heterozygous for 153delT in both cases. The pregnancies were carried to term and the newborns were unaffected. In Family 2, fetal DNA analysis from chorionic villus biopsy showed in a first pregnancy that the fetus was homozygous for 153delT. The pregnancy was terminated at 13 weeks and DNA analysis of fetal keratinocytes confirmed the prenatal prediction. In a second pregnancy in Family 2, fetal DNA analysis showed heterozygosity for 153delT, and the pregnancy was continued. Direct SPINK5 mutation analysis in families at risk for NS represents the first early, rapid and reliable method for prenatal diagnosis of this life threatening form of ichthyosis.     

Prenatal diagnosis of congenital anomalies--present status and future problems

Technical advances continue to expand the number of genetic disorders that can be diagnosed in utero. The current methods for prenatal diagnosis are as follows: Amniocentesis, fetoscopy, fetal blood sampling, biopsy of fetal skin, and chorionic villus sampling (CVS). The method for growing fetal cells obtained by amniocentesis in short term culture and karyotyping has opened a new area to chromosomal anomalies. By using cultured amniotic fluid cells in larger numbers, it is also possible to diagnose many metabolic disorders. Fetoscopy has been developed which permits the perinatologist to enter the uterus and obtain tissue sample or to actually view the fetus. However, it is very difficult to visualize the fetus directly through fetoscope. Only specific parts of the fetus can be readily identified, but a total examination of surface anatomy is rarely possible. Now ultrasonography with improved resolution can clearly define many major anatomical abnormalities without apparent risk. And also, fetal blood sampling and skin biopsy have been successfully performed under ultrasound guidance rather than under direct fetoscopic visualization. Recently, the advent of fetal blood sampling has made it possible to diagnose genetic disorders which have hitherto been impossible to recognize in the fetus. The main applications are for the prenatal diagnosis of the fetal infection, coagulopathies, hemoglobinopathies, and muscular dystrophies. Several severe genodermatoses result in early death or are associated with significant morbidity. Some of these disorders can be diagnosed in utero with skin biopsies. Harlequin Ichthyosis is a typical case. A positive prenatal diagnosis of Harlequin Ichthyosis was reported.(ABSTRACT TRUNCATED AT 250 WORDS)     

A fetus with Prader-Willi syndrome showing normal diurnal rhythm and abnormal ultradian rhythm on heart rate monitoring

Clinical features of Prader-Willi syndrome in neonates are marked hypotonia with the absence of crying and feeding difficulty so that prenatal diagnosis of Prader-Willi syndrome is strongly hoped in order to provide appropriate medical and psychological care for neonates and their families. However, the clinical picture of Prader-Willi syndrome in utero has not been well described. We report a pregnancy associated with Prader-Willi syndrome manifesting polyhydramnios, large biparietal diameter of the fetus and characteristic fetal heart rate pattern: prolonged inactive periods and diurnal variation of the incidence of heart rate accelerations. These findings may offer a clue to the prenatal diagnosis of Prader-Willi syndrome, although molecular cytogenetics is mandatory for the definite diagnosis.     

DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and/or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester. The identification of mutations in the genes encoding keratins K5 and K14 as the cause of EBS opens up the possibility of much earlier diagnosis of the disease. We report here four cases in which prenatal testing was performed. In three of the cases the genetic lesions were unknown at the start of the pregnancy, requiring the identification of the causative mutation prior to testing fetal DNA. In two of the four cases novel mutations were identified in K14 and in the two remaining families, a previously identified type of mutation was found. Fetal DNA, obtained by chorionic villus sampling or amniocentesis, was analysed for the identified mutations. Three of the DNA samples were found to be normal; a mutant K14 allele was identified in the fourth case and the pregnancy was terminated. These results demonstrate the feasibility of DNA-based prenatal testing for EBS in families where causative mutations can be found.     

Fetal echocardiography: are we getting it right?

OBJECTIVE: To determine the diagnostic accuracy of prenatal fetal echocardiography. METHODS: The study was a retrospective chart review of 190 consecutive patients over a 3-year period from November 1998 to February 2002 of all women referred to the Maternal Fetal Medicine unit, Mater Mothers Hospital, for fetal echocardiography. The prenatal diagnosis was compared with the postnatal diagnosis made by postnatal echocardiography, surgical findings or post-mortem. The accuracy of prenatal diagnosis was described on a predetermined 4-point scale. RESULTS: Of the 89 patients, for whom complete diagnostic follow-up was available, there was complete agreement between the prenatal and postnatal diagnosis in 63 cases, minor discrepancies in 25 cases and major disagreement in 1 case. CONCLUSIONS: In experienced hands, fetal echocardiography is accurate and allows medical staff and patients information in order manage a pregnancy appropriately.     

Spontaneous rupture of fetal sacrococcygeal teratoma

With recent advances in technology, fetal sacrococcygeal teratoma is being diagnosed increasingly during the early prenatal period by ultrasound examination. In addition, early detection of tumor related complications such as polyhydramnios, congestive heart failure, hydrops, hemorrhage, urinary tract or bowel obstruction can be followed closely in utero. Active prenatal management can improve fetal perinatal outcome by allowing planned delivery for neonatal surgery [Chisholm, C.A. et al.: Am J Perinatol 1999;16:47-50] or in some cases, fetal intervention. Additionally, families can be counseled appropriately regarding the range of outcomes. We report a case of fetal sacrococcygeal teratoma Type I diagnosed at 20 weeks with a prominent vessel supplying the tumor mass. At 23 weeks, there was a sudden appearance of an additional lobular mass, consistent with intrauterine spontaneous ruptured of a sacrococcygeal teratoma mass.     

Prenatal diagnosis of long QT syndrome using magnetocardiography: a case report and review of the literature

OBJECTIVES: To investigate the usefulness of magnetocardiography (MCG) in the prenatal diagnosis of fetal long QT syndrome. METHODS: Fetal MCG was recorded in a case of fetal long QT syndrome suspected in utero. The literature on the prenatal diagnosis of fetal long QT syndrome was also reviewed. RESULTS: The MCG was performed at 36 weeks' gestation because sustained fetal bradycardia of 110-120 bpm was detected by cardiotocography. The 64-channel MCG revealed a prolonged fetal corrected QT-interval of 0.57 s. The postnatal electrocardiogram coincided with prenatal MCG. CONCLUSION: An accumulation of cases of prenatally diagnosed long QT syndrome using MCG indicates that MCG may be the most reliable tool for the prenatal diagnosis of long QT syndrome.     

Fetal hematopoietic stem cell transplantation

In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising approach for the treatment of a potentially large number of fetuses affected by congenital hematologic disorders. With technical and molecular advances in prenatal diagnosis, the majority of these diseases can now be diagnosed early in gestation, allowing consideration of prenatal treatment. In addition, technical advances in fetal imaging and intervention make it possible to perform the transplants with relatively minimal risk. It, therefore, stands to reason that there is increasing interest in performing in utero hematopoietic stem cell transplantation at many fetal treatment centers. Although the approach remains experimentally promising, expansion of clinical application will depend on improved understanding of the biological barriers to engraftment in the fetus as well as the development of effective clinical strategies based on the hematopoietic biology of individual disorders. This article presents the current status of this emerging therapeutic approach.     

Prenatal immune status of fetuses of HIV-seropositive mothers

Human immunodeficiency virus (HIV) has been isolated from fetal tissues as early as 13 weeks and later from fetal blood. These findings have raised the possibility of prenatal diagnosis of infected fetuses by identification of the virus in the fetal compartment. Study of the fetal immune status has proved reliable in prenatal diagnosis of congenital immunodeficiency, and we have tested the possibility to diagnose acquired immunodeficiency in utero by this approach. We studied T lymphocyte subsets and their mitogenic response in fetal blood obtained after elective termination at midgestation in 8 cases and at delivery in 26 cases of maternal HIV infection. Results have been compared to appropriate normal controls. No significant difference was found in terms of total lymphocytes, CD4 and CD8 populations and phytohemagglutinin responses. This indicates either that immunological parameters currently used to assess postnatal immunodeficiency are not reliable during intrauterine life or that the intrauterine environment and the transplacental passage of maternal antibodies interfere with development of prenatal immunodeficiency.     

Fetal abdominal hyperechoic mass: diagnosis and management.

In the last 2 years, we have had the opportunity to follow 12 cases diagnosed with hyperechoic abdominal masses. Four of the cases ended with a fetal demise, while 7 resulted in the birth of an anomalous or medically ill neonate. Only 1 case has shown spontaneous resolution of the hyperechoic mass with the birth of a normal neonate. The in utero diagnosis of a hyperechoic abdominal mass should encourage the clinician to further investigation since the differential diagnosis is quite diverse. Appropriate counselling for the patient is a necessary part of prenatal care.     

Perinatal outcomes of prenatal cases testing positive for trisomy 9 by noninvasive prenatal testing

ObjectivesTo evaluate the performance of non-invasive prenatal testing (NIPT) for the detection of fetal trisomy 9 in prenatal screening and to investigate the prenatal appearances and genetic counseling of trisomy 9 fetuses.Materials and methodsThe ultrasonography information, laboratory detection and pregnancy outcome of 16 cases of single pregnancy with trisomy 9 identified by NIPT who received amniocentesis in our prenatal diagnosis center from January 2018 to December 2020 were retrospectively analyzed.ResultsAmong the 16 cases, 2 cases of trisomy 9, 3 cases of trisomy 9 mosaicism, 2 cases reporting of regions of homozygosity and 9 cases of false positive were diagnosed. Among the true positive cases, 4 cases showed abnormal ultrasonic finding: 3 cases terminated pregnancy and 1 case was lost to follow-up. Another 1 case was in utero fetal demise in the second trimester without structural abnormality, and 2 cases were normal live birth without developmental abnormalities. In the 9 cases with normal kayrotyping, 1 case had termination of pregnancy and 1 case with mental retardation and poor cognitive ability, other 7 had good pregnancy outcomes.ConclusionOur results may be helpful for the selection of prenatal diagnostic strategies and genetic counseling for pregnant women with trisomy 9 revealed by NIPT.     

Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases

Three hundred and twenty-two percutaneous umbilical blood samplings were performed over 4 years in our prenatal diagnostic centre. A 3.5 MHz sector ultrasound transducer was used to guide a 22.5-gauge needle under local anaesthesia. Sampling was performed for rapid fetal karyotyping (within 72 h) in 120 cases, for diagnosis of fetal toxoplasmosis in 133 cases, for determination of the severity of Rh immunization in 15 cases, and for diagnosis of congenital rubella in 4 cases. Pure fetal blood was obtained in 98.7 per cent of the cases after two attempts. The approach to the cord was either transamniotic or transplacental. Puncturing was preferentially done at the placental insertion of the cord (72.2 per cent of the cases) and the mean blood sample volume was 3.5 ml. The rate of fetal death in utero was 1.9 per cent, including two cases of amnionitis, one trisomy 18, and one severe bradycardia. The failures were due to sampling at an early stage of pregnancy (before gestation week 18), to maternal obesity, oligohydramnios, and the inexperience of the operator.     

Comparison of ultrasound and magnetic resonance imaging in 100 singleton pregnancies with suspected brain abnormalities

OBJECTIVE: To compare the diagnostic accuracy of the current reference standard-ultrasound with in utero magnetic resonance imaging, in a selected group of patients. DESIGN: Prospective study. SETTING: Five fetal maternal tertiary referral centres and an academic radiology unit. SAMPLE: One hundred cases of fetuses with central nervous system abnormalities where there has been diagnostic difficulties on ultrasound. In 48 cases the women were less than 24 weeks of gestation and in 52 cases later in pregnancy. METHODS: All women were imaged on a 1.5 T clinical system using a single shot fast spin echo technique. The results of antenatal ultrasound and in utero magnetic resonance were compared. MAIN OUTCOME MEASURES: The definitive diagnosis was made either at autopsy or by postmortem magnetic resonance imaging, in cases that went to termination of pregnancy, or a combination of postnatal imaging and clinical follow up in the others. RESULTS: In 52 of cases, ultrasound and magnetic resonance gave identical results and in a further 12, magnetic resonance provided extra information that was judged not to have had direct effects on management. In 35 of cases, magnetic resonance either changed the diagnosis (29) or gave extra information that could have altered management (6). In 11 of the 30 cases where magnetic resonance changed the diagnosis, the brain was described as normal on magnetic resonance. CONCLUSIONS: In utero magnetic resonance imaging is a powerful tool in investigating fetal brain abnormalities. Our results suggest that in selected cases of brain abnormalities, detected by ultrasound, antenatal magnetic resonance may provide additional, clinically useful information that may alter management.     

The role of autopsy following pregnancy termination for fetal abnormality

OBJECTIVE: To review the frequency of autopsy following pregnancy termination for fetal anomaly and its contribution to subsequent counselling. METHODS: All medical pregnancy terminations for fetal anomaly performed after 14 weeks gestation from January 1997 to December 2006 were identified and the frequency of autopsy ascertained. The prenatal diagnosis prompting the termination was then compared with the autopsy data, and a diagnostic valuation was determined. The potential autopsy value ranged from no additional information provided, minor added value, significant added value, major added value to non-confirmation of the prenatal findings. RESULTS: During the ten-year study period, there were 1012 consecutive terminations for fetal abnormality. The principal indications for termination were: karyotypic (38.4%); neural tube defects (16.1%); cardiac (10.3%) and cerebral anomalies (7.5%). Autopsy was performed in 809 cases (79.9%). The autopsy rate progressively declined from 95.1% in 1997 to 67.5% in 2006 (P<0.001). Women declining autopsy were older (31 years (26,35) vs 32 years (27,37), P=0.005) and more likely to have a fetal chromosomal abnormality (30.6% vs 69.9%, P<0.001) (autopsy vs no-autopsy). In euploid cases, autopsy confirmed the prenatal diagnosis with no additional information in 63.5% (357 of 562). In 1.1% (six cases), autopsy added major diagnostic information, and in 15.1% (85 cases), significant information was provided. CONCLUSIONS: Although contemporary prenatal testing has improved the recognition of fetal abnormalities, autopsy remains a valued tool by providing diagnosis or clarification of some prenatal findings in 16% of cases. Fetal autopsy rates are declining and this trend may lead to a loss of diagnostic and recurrence risk-counselling information.     

Prenatal diagnosis of congenital cytomegalovirus infection

OBJECTIVE: To assess prospectively the diagnostic reliability and prognostic significance of prenatal diagnosis of cytomegalovirus (CMV) infection. METHODS: One hundred ten pregnant women (four with twin pregnancies) with a risk of congenital CMV infection were investigated. Prenatal diagnosis was carried out by amniocentesis and fetal blood sampling (n = 75) or amniocentesis alone (n = 35). Serial ultrasonographic examinations were performed from time of referral until pregnancy end. All infected neonates were given long-term follow-up. Autopsy was performed in all cases of termination of pregnancy. RESULTS: Nearly 23% (26 of 114) of fetuses were infected and prenatal diagnosis was positive in 20 cases. Sensitivity of prenatal diagnosis was 77% and specificity 100%. In eight cases, parents requested termination of pregnancy on the basis of abnormal ultrasonographic findings and/or biologic abnormalities in fetal blood. In 12 cases, parents decided to proceed with the pregnancy. In this group, one intrauterine and one neonatal death were observed. In one case, prenatal diagnosis revealed an abnormal cerebral sonography and the infant had bilateral hearing loss at birth. In 15 cases (nine positive and six false-negative prenatal diagnoses), no apparent lesion was present at birth, nor did it develop during the follow-up period (mean 31 months). In 88 (77.2%) of 114 infants, no evidence of vertical transmission was found during the pre- or postnatal period. CONCLUSION: Prenatal diagnosis provides the optimal means for both diagnosing fetal infection (amniocentesis) and identifying fetuses at risk of severe sequelae (ultrasound examination, fetal blood sampling), thus allowing proper counseling.     

Prenatal diagnosis of carbamoyl-phosphate synthetase deficiency by fetal liver biopsy

In a pregnancy at risk for carbamoyl-phosphate synthetase (CPS) deficiency, prenatal diagnosis was attempted by fetal liver biopsy, performed at 18 weeks of gestation. CPS activity was absent and the diagnosis was confirmed after termination of the pregnancy. The technique employed for fetal liver biopsy is described together with an evaluation of its possible role in prenatal diagnosis.