Prenatal diagnosis of congenital cystic adenomatoid malformation of the lung by fetal lung biopsy

A case of type III congenital cystic adenomatoid malformation of the lung was successfully diagnosed prenatally by fetal lung biopsy. We performed this procedure at 22 weeks of gestation, using a biopsy gun system under ultrasound guidance. The pregnancy was undisturbed by the procedure but as the condition was incompatible with life, an abortion was performed. The diagnosis was confirmed at post-mortem examination. Fetal lung biopsy appears to be a useful method for prenatal diagnosis of fetal lung disorders.     

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. Copyright © 2002 John Wiley & Sons, Ltd.     

Activity and multiple forms of α-L-fucosidase and hexosaminidase in chorion biopsy specimens and some fetal organs

It was shown that activities and isoenzyme patterns of x-L-fucosidase and hexosaminidase were similar in biopsy specimens of chorion obtained immediately before induced abortion in normal pregnancy and in chorion tissue itself. A comparative study of isoenzyme patterns of these glycosidases showed their similarity in chorion and human fetal kidney, liver and lungs. The data obtained may be applied to the investigation of the multiple forms of α-L-fucosidase and hexosaminidase in chorion biopsy specimens for the prenatal diagnosis of fucosidosis (α-L-fucosidase deficiency). Tay-Sachs diseases (hexosaminidase A deficiency) and Sandhoff disease (deficiency of hexosaminidase A and B).     

Prenatal diagnosis of tyrosinase-negative oculocutaneous albinism by an electron microscopic dopa reaction test of fetal skin

An electron microscopic DOPA reaction test of fetal skin was used for the prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA). The subject was a 34-year-old Japanese woman in her second pregnancy. Her first child, born in 1982, had been previously examined and confirmed to have tyrosinase-negative OCA. The parents requested a prenatal diagnosis and we sampled skin from the upper trunk of the fetus. On conventional electron microscopy, the development of melanosomes in interfollicular melanocytes had progressed no further than stage II. Fetal skin samples incubated with L-DOPA solution indicated a lack of tyrosinase activity and showed that the melanosomes had not progressed beyond stage II. In skin samples from the trunks of three Japanese fetuses aborted for other reasons at 19–20 weeks of gestation, most premature melanosomes were further melanized to stage IV after incubation with L-DOPA solution. A prenatal diagnosis of tyrosinase-negative OCA was made. The parents requested a termination and skin biopsies of the abortus confirmed the diagnosis. This study shows that tyrosinase is normally present in melanocytes of the fetal epidermis at 20 weeks' gestation, and that the electron microscopic DOPA reaction test of a fetal skin biopsy specimen is safe and practical, and provides reliable information for making a prenatal diagnosis of tyrosinase-negative OCA in the second trimester.     

The prenatal diagnosis of the cerebro-hepato-renal syndrome of Zellweger

The prenatal diagnosis of the cerebro-hepato-renal syndrome of Zellweger (CHRS) was made by assaying the levels of very long chain fatty acids (VLCFAs) in amniotic fluid cell cultures, obtained by amniocentesis at 16 1/2 weeks of pregnancy. The family-at-risk, because they had previously borne a child with CHRS, accepted these results as indications of an affected fetus, and chose to terminate the pregnancy at 20 1/2 weeks of gestation. The diagnosis was confirned by the phenotype of the aborted fetus and the presence of markedly elevated levels of VLCFAs in fetal liver homogenates. The prenatal diagnosis of CHRS, which can now readily be determined from amniotic fluid cell cultures, is an important step in genetic counselling of families-at-risk for this disease.     

Molecular prenatal diagnosis of 3-hydroxy−3-methylglutaryl coa lyase deficiency

We report the first molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. The proband had a classic but severe presentation with hypoketotic hypoglycaemia and acidosis, secondary mental retardation, and epilepsy, and HL deficiency was documented in cultured fibroblasts. We found him to be homozygous for the frameshift mutation N46fs (+1), which yields a distinct pattern on single-strand conformation polymorphism (SSCP) analysis. In two subsequent pregnancies, molecular prenatal diagnosis was performed using SSCP. In the first, chorionic villus biopsy was normal. In the second pregnancy, amniocentesis revealed an affected fetus. In both pregnancies, the diagnosis was confirmed enzymatically. HL activity was less than 7 per cent of control values in amniocytes and fetal liver of the affected pregnancy. In the second pregnancy, amniotic fluid metabolite measurements by stable isotope dilution-selected ion monitoring mass spectrometry showed greater than 100-fold increases of 3-hydroxy-3-methylglutaric acid and of 3-methylglutaconic acid levels compared with controls.     

Microvillar enzyme assays in amniotic fluid and fetal tissues at different stages of development

A systematic study of microvillar enzyme activities in the amniotic fluid in correlation with their values in different fetal tissues during development has been undertaken. Microvillar enzymes appeared in the amniotic fluid at the time of disappearance of the anal membrane, 12–13 weeks, and declined from the 18th week until the 24th week. The study of fetal tissues and fluids has shown that gamma-glutamyltranspeptidase is mainly of liver origin. The significant decrease of the activities of these amniotic fluid enzymes has been the basis of prenatal diagnosis of cystic fibrosis. These assays may be useful for the diagnosis of certain digestive tract abnormalities at later stages of pregnancy.     

Comparative study of 15 lysosomal enzymes in chorionic villi and cultured amniotic fluid cells. Early prenatal diagnosis in seven pregnancies at risk for lysosomal storage diseases

A large number of chorionic villi samples obtained from women undergoing elective first trimester termination of pregnancy was analysed by enzyme assays similar to those applied to cultured amniotic cells. The levels of 15 lysosomal enzymes were compared to those observed in tissue cultures of amniotic cells obtained through amniocentesis at 16-18 weeks of pregnancy and the results were discussed in order to assess the usefulness of trophoblast biopsy for first trimester diagnosis of hereditary lysosomal diseases. The data suggest the applicability of this source of fetal cells for prenatal diagnosis of fifteen respective genetically determined enzyme deficiencies with the probable exception of α-L -iduronidase deficiency. Enzyme determinations were performed on chorionic villi samples of two pregnancies at risk for Tay-Sachs disease, three pregnancies for GM₁ gangliosidosis type 1, one for mucopolysaccharidosis type VI and one for Wolman's disease.     

Prenatal diagnosis of isolated bilateral microphthalmia with confirmation by evaluation of products of conception obtained by dilation and evacuation

We describe the prenatal diagnosis of isolated bilateral fetal microphthalmia in a woman at increased risk of having a fetus with microphthalmia. Ultrasound examinations at 161 and 19-5 weeks' gestation demonstrated bilateral fetal microphthalmia with no other associated structural defects. The patient elected to terminate her pregnancy at 19.5 weeks. Pathological evaluation of the products of conception obtained by dilation and evacuation confirmed the prenatal diagnosis of isolated bilateral fetal microphthalmia.     

Rapid karyotyping for prenatal diagnosis in the second and third trimesters of pregnancy

Direct chromosome preparations were performed on placental villi obtained by ultrasoundguided needle aspiration between 18 and 37 weeks of pregnancy in 53 patients. The sampling yielded a sufficient amount of tissue with a maximum of two, and in most cases one, insertions. Placental biopsy is easily performed in cases of severe oligohydrammnios, where fetal blood sampling is usually more difficult. Direct karyotyping of placental villi is faster than chromosome analysis from fetal blood or application of the pipette method on amniotic fluid cells, and currently represents the most rapid approach to prenatal diagnosis of chromosomal abnormalities from the first to the third trimester of pregnancy.     

Prenatal diagnosis of Apert syndrome: report of two cases

Two de novo cases with Apert Syndrome detected prenatally are presented herein. In the first, fetal ultrasound findings of syndactyly of the hands, craniosynostosis and proptosis resulted in a prenatal diagnosis in the nineteenth week of gestation. This is the earliest prenatal diagnosis of this syndrome in a not-at-risk case. Following counseling, this pregnancy was terminated and subsequent pathological examination and DNA analysis confirmed the diagnosis of Apert Syndrome and coarctation of the aorta. In the second case, fetal ultrasound at 21 weeks' gestation revealed a hypoplastic left heart and clover-leaf skull. Following counseling, this pregnancy was also terminated. Further examination of the fetus and DNA analysis led to a diagnosis of Apert Syndrome. These cases emphasize the need to complete a thorough fetal ultrasound in cases with potentially lethal cardiac abnormality and the importance of incorporating a fetal pathologist, as well as a medical geneticist, in the investigations performed after delivery or pregnancy termination when a fetal abnormality is detected on ultrasound. Copyright © 2003 John Wiley & Sons, Ltd.     

DNA-based carrier detection and prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA1A)

We describe molecular prenatal diagnosis and carrier detection of tyrosinase-negative oculocutaneous albinism (OCA1A) in two families. In one family, we carried out DNA-based prenatal diagnosis of OCA1A. In the other family, mutation analysis and carrier detection obviated the need for prenatal diagnosis. Molecular analysis is safer and probably more accurate than fetoscopy and fetal scalp biopsy, and should become the method of first choice for prenatal diagnosis of OCA1.     

The MRI spectrum of congenital cytomegalovirus infection

Human cytomegalovirus (CMV) is an ubiquitous pathogen, with a high worldwide seroprevalence. When acquired in the prenatal period, congenital CMV (cCMV) is a major cause of neurodevelopmental sequelae and hearing loss. cCMV remains an underdiagnosed condition, with no systematic screening implemented in pregnancy or in the postnatal period. Therefore, imaging takes a prominent role in prenatal diagnosis of cCMV. With the prospect of new viable therapies, accurate and timely diagnosis becomes paramount, as well as identification of fetuses at risk for neurodevelopmental sequelae. Fetal magnetic resonance imaging (MRI) provides a complementary method to ultrasound (US) in fetal brain and body imaging. Anterior temporal lobe lesions are the most specific finding, and MRI is superior to US in their detection. Other findings such as ventriculomegaly, cortical malformations and calcifications, as well as hepatosplenomegaly, liver signal changes and abnormal effusions are unspecific. However, when seen in combination these should raise the suspicion of fetal infection, highlighting the need for a full fetal assessment. Still, some fetuses deemed normal on prenatal imaging are symptomatic at birth or develop delayed cCMV-associated symptoms, leaving room for improvement of diagnostic tools. Advanced MR sequences may help in this field and in determining prognosis, but further studies are needed.     

Progressive neuronal degeneration of childhood: prenatal diagnosis by MRI

We report two cases in the same family of progressive neuronal degeneration of childhood—Alpers syndrome—with prenatal MRI findings in one case. The first infant presented at birth with severe microcephaly, then rapidly evolved to progressive encephalopathy with refractory epilepsy, leading to death at 10 months. Biochemical investigations including liver function tests were normal. CT and MRI showed severe diffuse brain atrophy. The diagnosis of progressive neuronal degeneration of childhood was made on the clinical and imaging data. The second pregnancy was marked by gradual decrease of fetal cerebral biometry and a prenatal MRI performed at 32 weeks showed diffuse cortical atrophy, as observed in the sibling. The infant died at 5 months. Neuropathological findings were consistent with Alpers syndrome. Copyright © 2005 John Wiley & Sons, Ltd.     

Maternal age in the epidemiology of common autosomal trisomies

The birth prevalence rate of each common autosomal trisomy generally increases with advancing maternal age and there is a substantial fetal loss rate between late first trimester and term. The literature is reviewed in order to provide the best estimates of these rates, taking account where possible of biases due to prenatal diagnosis and selective termination of pregnancy. There is an almost exponential increase in Down syndrome birth prevalence between ages 15 and 45 but at older ages the curve flattens. There is no evidence of the claimed relatively high birth prevalence at extremely low ages. Gestation-specific intra-uterine fetal loss rates are estimated by follow-up of women declining termination of pregnancy after prenatal diagnosis, comparison of observed rates with those expected from birth prevalence and comparison of age-specific curves developed for prenatal diagnosis and birth. Down syndrome fetal loss rates reduce with gestation and increase with maternal age. Edwards and Patau syndrome birth prevalence is approximately 1/8 and 1/13 that of Down syndrome overall, although the ratio differs according to maternal age, particularly for Patau syndrome where it reduces steadily from 1/9 to 1/19. Fetal loss rates are higher for Edwards and Patau syndromes than for Down syndrome.     

Prenatal exclusion of metachromatic leukodystrophy by estimation of arylsulphatase a activity in chorion and cultured amniotic fluid cells

Chorion biopsy specimens were used for prenatal assay of arylsulphatase A activity in a pregnant woman whose two children had died from metachromatic leukodystrophy (MLD). As in two subsequent pregnancies chorion arylsulphatase A was in the control range, it was concluded that both fetuses were healthy. Absence of MLD in the fetus from the first pregnancy was confirmed after assay of arylsuphatase A activity in fetal organs. The second pregnancy resulted in delivery of a healthy child.     

First-trimester diagnosis of conjoined twins

Conjoined twins are a rare and complex complication of monozygotic twinning, which is associated with high perinatal mortality. Early prenatal diagnosis of conjoined twins allows better counselling of the parents regarding the management options, including continuation of pregnancy with post-natal surgery, termination of pregnancy or selective fetocide in case of a triplet pregnancy. With the introduction of high-resolution and transvaginal ultrasound imaging, accurate prenatal diagnosis of conjoined twins is possible early in pregnancy. We have reviewed the medical literature on the early prenatal diagnosis of suspected conjoined twins using a MEDLINE search. Although first-trimester diagnosis of conjoined twins is feasible, false-positive cases are common before 10 weeks because, earlier in gestation, fetal movements are limited and monoamniotic twins may appear conjoined. As most parents opt for immediate termination of pregnancy at confirmation of the diagnosis, there are limited data on the prenatal follow-up of conjoined twins. When the parents opt for conservative management, half of the fetuses die in utero and another 44% will die during the neonatal period. A detailed analysis of case reports where 3D imaging was used indicates that this modality does not improve on the diagnosis made by 2D ultrasound. Overall, very early prenatal diagnosis and first-trimester 3D imaging provide very little additional practical medical information compared to the 11–14 weeks' ultrasound examination. Copyright © 2005 John Wiley & Sons, Ltd.     

Can infantile hereditary agranulocytosis be diagnosed prenatally?

Fetoscopy and fetal blood sampling were performed in an attempt at prenatal monitoring of a pregnancy at risk for infantile hereditary agranulocytosis (Kostmann's disease). In smears of fetal blood three segmented neutrophils were found out of 200 nucleated cells (1 2/ per cent). Their presence, although in a lower percentage than in six age-matched controls, was considered to indicate that the fetus was not affected. The newborn infant has developed normally and at the age of four months has a normal number of segmented neutrophils in his peripheral blood. Feasibility of prenatal diagnosis of infantile hereditary agranulocytosis is discussed.     

Fetal cells in the uterine cervix: a source for early non-invasive prenatal diagnosis

Various non-invasive techniques for prenatal diagnosis have been under investigation. We evaluated the success of fetal sexing using a non-invasive technique for obtaining fetal cells, uterine cervix brushing, in combination with FISH. Thirty pregnant women who completed between 6 and 10 weeks of gestation and who were scheduled to undergo pregnancy termination were included in the study. A Pap smear cytobrush was inserted through the external os to a maximum depth of 2 cm and removed while rotating it a full turn. The material that was caught on the brush was spread on four microscope slides. Two-color FISH was used for fetal sexing. Following pregnancy termination, a placental sample was used for full karyotyping. In 29/30 cases FISH diagnosis was confirmed by chromosomal analysis. The only male case in which a Y chromosome was not seen was from a pregnancy of 6 weeks 6 days gestational age. One case was mosaic of 46,XY/47,XXY (25%). In most cases (7/13) the Y chromosome was already identified in the first analyzed slide. With the use of a cytobrush fetal cells can be easily obtained for the purpose of prenatal diagnosis of chromosomal disorders. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal testing for inherited immune deficiencies by fetal blood sampling

We attempted to develop a prenatal diagnosis in fetuses at risk for immunodeficiency by fetal blood sampling performed under fetoscopy at 18–22 weeks of gestation. In order to obtain normal values, we first investigated thirty-five control fetuses whose blood punctures were undertaken for the diagnosis of haemoglobinopathies. Surface markers and in vitro mitogen-induced proliferation of the fetal lymphocytes were studied using micromethods. We then examined two fetuses at risk for two different types of severe combined immunodeficiency and established their immunological integrity, hence avoiding an unjustified termination of pregnancy. This immunological integrity was confirmed after birth.