Prenatal sonographic diagnosis of autosomal recessive polycystic kidney disease (arpkd) during the early second trimester

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary disease with a high neonatal mortality. Currently, prenatal diagnosis is possible only during the second half of pregnancy, when bilaterally enlarged, echogenic kidneys are visible by ultrasound. We describe a case in which a diagnosis of ARPKD was sought in the first half of pregnancy. High-resolution ultrasonography revealed echogenic, normal-sized kidneys at 15+4 weeks. Microsatellite DNA analysis of a chorionic villus sample, parental blood, and blood of an affected sibling showed that the fetus had the maternal haplotype and a recombination of the paternal haplotype. Thus, no distinction between homo- and heterozygosity for the ARPKD mutation in the fetus was possible. A further ultrasound examination at 19+4 weeks confirmed the previous results, indicating that the fetus was likely to be affected. After termination of the pregnancy, the diagnosis was confirmed on microscopic examination.     

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.     

Prenatal ultrasound diagnosis of Apert's syndrome

A mother affected with Apert's syndrome was diagnosed by ultrasound scan at 16–17 weeks to have a fetus similarly affected. The typical features of acrocephaly and symmetrical syndactyly were seen. This is probably the first time that this condition has been diagnosed at such a gestation by ultrasound scan. The patient decided to continue the pregnancy, and intrauterine death occurred at 34 weeks. The diagnosis was confirmed by pathological examination.     

Early prenatal detection of diastrophic dysplasia

Diastrophic dysplasia, an autosomal recessive disorder, results in severe short-limbed dwarfism, progressive spinal and joint problems, and secondary psychosocial disability. The results of treatments are unsatisfactory. Four pregnant mothers at risk for an affected fetus were studied with an ultrasound scanner at 16 and 19 weeks of gestation. Each mother had a previous child with diastrophic dysplasia. The biparietal distance and the length of the long bones of the extremities were normal in three fetuses, whereas in one fetus there was a 30 per cent shortening of all long bones. The biparietal distance corresponded with the gestational age in all fetuses. In one fetus, diastrophic dysplasia was confirmed by fetoscopy and fetal radiograph at 19 weeks of gestation after the parents had decided to terminate the pregnancy. The skeletal radiograph and autopsy findings of the fetus verified the diagnosis. All other mothers were followed with repeated ultrasound examinations, and they delivered healthy babies. The retrospective follow-up of the four previous pregnancies and of the present one with affected fetuses disclosed that two mothers had had vaginal bleeding, two lymphedema, one abdominal pains, and one mother had had polyhydramnios. These complications were, however, mild and transient, and they could not be regarded as specific for pregnancies with affected fetuses.     

Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester

This is the first report of a fetus affected with campomelic acampomelic dysplasia presenting with increased nuchal translucency. Ultrasonography at 13 weeks of amenorrhea showed a nuchal translucency 5.6 mm thick. The karyotype performed on amniotic fluid cells was normal (46,XY). Ultrasonography at 22 weeks revealed a normal femoral length and female genitalia. A second amniocentesis was performed to confirm the karyotype and for dosage of steroid hormones. Testosterone dosage was low, corresponding to a female fetus. Ultrasonography at 32 weeks showed growth retardation of the long bones (<3rd centile) that were not curved. A severe malformation syndrome was suspected and the pregnancy was terminated at 33 weeks. The fetus displayed macrocephaly, facial dysmorphism and female external genitalia. X ray showed straight and thickened long bones, hypoplastic scapulae and moderate platyspondyly. In view of the association of sex reversal, hypoplasia of the scapulae, and the presence of straight long bones, campomelic acampomelic dysplasia was suspected and confirmed by the finding of a SOX9 mutation. This case shows the importance of a careful echographic survey in a fetus with a nuchal translucency > 4 mm, especially if there is discordance between phenotypic and genotypic sex, since growth retardation may occur later during the pregnancy. Copyright © 2004 John Wiley & Sons, Ltd.     

Prenatal diagnosis of congenital adrenal hyperplasia (21-OH deficiency type) by HLA typing

The close genetic linkage between HLA-B and congenital adrenal hyperplasia due to 21-hydroxylase deficiency permits prenatal diagnosis of an affected fetus by HLA typing of amniotic fluid cells in pregnancies at risk. Some families at risk, especially those with an affected girl with ambiguous genitalia, will only plan another pregnancy if a prenatal diagnosis is possible. After HLA typing of the index case, parents and eventually grandparents, the family were informed of the possibility of a prenatal diagnosis. Fibroblast cell lines were initiated from skin biopsies of the index cases and parents and were used as controls in the tests. HLA typing of the fetus was done on amniotic fluid cells grown in vitro using first, a microcytotoxicity test and second quantitative microabsorption test. Ten prenatal diagnoses are reported. In two cases the HLA genotype indicated an affected fetus, examination of the aborted fetuses was in agreement with the diagnosis. In one case an affected male fetus was diagnosed, the pregnancy is in progress. In seven cases an unaffected infant was predicted (four carriers and three homozygous normal infants).     

Prenatal diagnosis of purine nucleoside phosphorylase deficiency in the first and second trimesters of pregnancy

Prenatal diagnosis was performed in two successive pregnancies of a mother with a previous child with purine nucleoside phosphorylase (PNP) deficiency. In one pregnancy, an affected fetus was diagnosed in the 18th week of gestation after the demonstration of PNP deficiency in cultured amniotic fluid cells. Also an abnormal purine nucleoside profile was found in the amniotic fluid. The diagnosis of an affected fetus was confirmed by the analysis of cultured fetal skin fibroblasts and placental villi. The complete deficiency of PNP activity in placental villi confirms that the prenatal diagnosis of this disorder is possible by the direct investigation of chorionic villi. In the subsequent pregnancy, a heterozygous fetus was predicted in the tenth week of pregnancy by using chorionic villi.     

Prenatal diagnosis of metabolic diseases on chorionic villi obtained before the ninth week of pregnancy

Nine pregnancies at risk for various metabolic disorders were monitored by prenatal diagnosis on chorionic villi obtained between the sixth and ninth weeks of pregnancy. A diagnosis of an affected fetus was made in five cases (Sandhoff, Tay—Sachs (2), Pompe's, GMI), while metachromatic leukodystrophy, GM1 (2), and Pompe's were excluded in four cases. It is concluded that chorionic villi are a reliable tissue for prenatal diagnosis of metabolic disorders also when obtained before the ninth week.     

Pitfalls in the prenatal diagnosis of peroxisomal β-oxidation defects by chorionic villus sampling

Variability in the level of expression of very long chain fatty acids (VLCFAs) is documented in cultured chorionic villus (CV) cells derived from two fetuses, one at risk for an unusual peroxisomal fatty acid β-oxidation defect, and the other at risk for the X-linked form of adrenoleucodystrophy (ALD). Cells from early subcultures of chorionic cells from both cases gave normal values for VLCFA ratios. The results for the fetus at risk for the β-oxidation defect were interpreted to indicate that the fetus was not affected; however, at birth, the infant was clinically and biochemically affected. In the case of the fetus at risk for X-linked ALD, although VLCFAs were normal in subculture 1, the levels of these fatty acids increased dramatically in subculture 3, suggesting an abnormal fetus. Termination of the pregnancy and subsequent biochemical and morphological follow-up confirmed that the fetus was indeed affected by ALD.     

Cystic hygroma simulating an encephalocele

An ultrasound examination at 17 weeks gestation on a woman with a family history of spina bifida suggested that the fetus had a closed encephalocele. Amniotic fluid alphafetoprotein, rapidly adhering cells and acetylcholinesterase gel electrophoresis were normal. The pregnancy was terminated and the fetus was found to have a large cystic hygroma. It is suggested that in counselling parents of an infant or fetus with a cystic hygroma and with a normal chromosome constitution, ultrasound examination in future pregnancies is advisable, because of the possibility of autosomal recessive inheritance.     

Prenatal ultrasound diagnosis of fetal scoliosis with termination of the pregnancy: Case report

Gross scoliosis of the fetal thoracic spine was diagnosed at 18 weeks gestation. The pregnancy was terminated and the fetus found to have webbing of the neck and an imperforate anus in addition to vertebral defects.     

First-trimester prenatal diagnosis of aspartylglucosaminuria

Fetal aspartylglucosaminuria (AGU) was studied during the first trimester of pregnancy in six at-risk pregnancies using chorionic villus samples. The activity of aspartylglucosaminidase (AGA) was high in five cases, indicating an unaffected fetus. This was confirmed through delivery of healthy newborns with a normal pattern of urinary oligosaccharides. Low enzyme activity in an uncultured biopsy specimen and in cultured amniotic fluid cells in one case demonstrated that the fetus was affected. The pregnancy was terminated and the prenatal diagnosis was confirmed by showing reduced AGA activity in cultured fibroblasts of the fetus.     

Evaluation of inorganic pyrophosphate in amniotic fluid as a mode of prenatal diagnosis of osteogenesis imperfecta

Using a modified procedure by Solomons and Styner (1969), an evaluation of inorganic pyrophosphate (PPi) was performed on the amniotic fluid of two fetuses at risk for osteogenesis imperfecta (OI) at 14½ weeks gestation. The parents of both cases had a previous child with OI, Type II. The normal control group at 14–16 weeks gestation had PPi values ranging from 22.0–59.2 ug/100 ml, with a mean of 38.6±9.51 ug/100 ml. In each at-risk fetus, the amniotic fluid PPi value was within normal range. The first baby was born phenotypically normal at term. Intrauterine radiographic and fetal sonograms were done on the second fetus at approximately 19 weeks gestation. Both showed evidence of OI, Type II. The pregnancy was terminated at 21 weeks. Radiologic studies of the aborted fetus were consistent with OI, Type II. Our results indicate that the evaluation of PPi levels in amniotic fluid is not the method of choice for prenatal diagnosis of IO.     

Prenatal diagnosis of Hunter syndrome using fetal plasma

The X-linked Hunter syndrome or mucopolysaccharidosis II was diagnosed in a male fetus by demonstrating a severe deficiency of iduronate 2-sulphate sulphatase activity in fetal plasma obtained by umbilical fetal blood sampling at 23 weeks of pregnancy. The diagnosis was confirmed after termination of pregnancy.     

First trimester prenatal diagnosis of Sanfilippo disease (MPSIII) type B

Two pregnancies of a family at risk for Sanfilippo disease type B were monitored in the first trimester. In one case an affected fetus was diagnosed on chorionic villi by the assay of N-acetyl-a-D -glucosaminidase and confirmed on cultured fibroblasts from the aborted fetus. Pathological findings are also reported and compared with changes observed later in life. The disease was excluded in the second pregnancy.     

Fetal cardiac scanning today

The ability to examine the structure of the fetal heart in real-time started over 30 years ago now. The field has seen very great advances since then, both in terms of technical improvements in ultrasound equipment and in dissemination of operator skills. A great deal has been learnt about normal cardiac function in the human fetus throughout gestation and how it is affected by pathologies of pregnancy. There is increasing recognition of abnormal heart structure during routine obstetric scanning, allowing referral for specialist diagnosis and counselling. It is now possible to make accurate diagnosis of cardiac malformations as early as 12 weeks of gestation. Early diagnosis of a major cardiac malformation in the fetus can provide the parents with a comprehensive prognosis, enabling them to make the most informed choice about the management of the pregnancy. Copyright © 2010 John Wiley & Sons, Ltd.     

Prenatal diagnosis of lethal osteogenesis imperfecta (OI) by ultrasonography

Ultrasonography was performed during the second trimester (17 weeks) in a pregnancy at risk for osteogenesis imperfecta congenita (OI). The scan showed that the femur was short, bent and dense. Radiologic examination of the fetus after interruption of pregnancy showed typical X-ray changes of OI.     

Human chorionic gonadotropin levels in pregnancies with aneuploid fetuses

Maternal serum human chorionic gonadotropin (hCG) and the free alpha-hCG subunit were evaluated in 249 women from 9 to 11 weeks gestation who subsequently underwent chorionic villus sampling for determination of fetal karyotype and in 20 women of 18 or more weeks gestation who were ascertained to have an aneuploid fetus by genetic amniocentesis. Seven of the first-trimester pregnancies were determined to be aneuploid and six had hCG levels in the normal range (one triploid pregnancy had elevated hCG levels) whereas 12 of the 20 secondtrimester cases had abnormal hCG levels and an additional three had elevated levels of alpha-hCG. This study confirms the previous report of abnormal maternal serum hCG levels in women with an aneuploid fetus at ≥ 18 weeks gestation and demonstrates that hCG evaluation is not useful at 9–11 weeks gestation for selecting pregnancies at risk for fetal aneuploidy.     

Prenatal diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency

A fatal case of medium-chain acyl-coenzyme A dehydrogenase deficiency is described in a patient who presented with hypoglycaemia and a gross non-ketotic dicarboxylic aciduria. Cultured skin fibroblasts released ¹⁴CO₂ from [1–¹⁴C] octanoic acid at half the normal rate. Prenatal diagnosis was undertaken in a subsequent pregnancy in which cultured amniotic fluid cells revealed a marked reduction in octanoate oxidation indicative of an affected fetus. The pregnancy was terminated and the diagnosis was confirmed by enzyme analysis of skin fibroblasts taken from the fetus. The high residual octanoate oxidation by affected fibroblasts together with the absence of any characteristic abnormality of amniotic fluid organic acids are a potential limitation to the reliability of this type of prenatal diagnosis.     

Early sonographic diagnosis of body stalk anomaly

Ultrasonographic features of a fetus at 18 weeks of gestation suggesting a body stalk anomaly are presented. These included a large abdominal anterior wall defect in apparent continuity with the placenta, severe kyphoscoliosis of the lower spine, the absence of one kidney, and a very short umbilical cord with only one umbilical artery. The amniotic fluid was reduced and the fetus was almost immobile at short-interval ultrasound examinations. The pregnancy was terminated and autopsy of the fetus showed abnormalities compatible with maldevelopment of both cephalic and caudal embryonic folds.