C.S. von Kaisenberg

A Case of Fetal Parvovirus B19 Myocarditis, Terminal Cardiac Heart Failure, and Perinatal Heart Transplantation

We report a case of fetal cardiomegaly secondary to myocarditis as a result of intrauterine parvovirus B19 infection. The fetus was delivered through caesarean section because of increasing deterioration of cardiac function at 33 + 3 weeks with reverse flow in the ductus venosus. Four weeks later, a cardiac transplantation was carried out because of therapy-resistant dilative cardiomyopathy. This case shows that fetal parvovirus B19 infection may occur without anemia and myocarditis and does not always result in spontaneous reformation of a dilated heart and normal recovery. It may become the determining prognostic factor for the child.

Screening for trisomy 21 by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-14 weeks: a German multicenter study.

Objective: To examine the effectiveness of screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum biochemistry using free β-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks of gestation. Methods: This was a multicenter study of screening for trisomy 21 by a combination of maternal age, fetal NT and maternal serum free β-hCG and PAPP-A at 11-14 weeks of gestation, using the methodology developed by the Fetal Medicine Foundation. The distribution of estimated risks for trisomy 21 was determined and the sensitivity and false-positive rate for a risk cut-off of 1 in 300 were calculated. Results: In total, 3864 singleton pregnancies with live fetuses at 11-14 weeks were examined and the fetal NT and maternal serum free β-hCG and PAPP-A were successfully measured in all cases. The median maternal age was 33 (range 15-46) years and, in 1271 (35.8%), the age was 35 years or more, the median gestation at screening was 12 (11-14) weeks and the median fetal crown-rump length was 64 (range 45-84) mm. The fetal NT was above the 95th centile in 73.7% (14 of 19) of trisomy 21 and in 4.8% (169 of 3505) of normal pregnancies. The estimated risk for trisomy 21 based on maternal age, fetal NT and maternal serum free β-hCG and PAPP-A was 1 in 300 or greater in 6.6% (233 of 3505) of normal pregnancies, in 84.2% (16 of 19) of those with trisomy 21 and 88.9% (24 of 27) of those with other chromosomal defects. Conclusions: In Germany, the results of screening for chromosomal defects by measurement of fetal NT and maternal serum biochemistry, in centers with appropriately qualified sonographers, are similar to those reported in the UK using the same methodology.

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex associated with increased nuchal translucency

as at least 10 mm5,6, 3 mm2,3 or 1 mm4. The highest rate of aneuploidy was observed in studies which included only major separation. Bronshtein and Zimmer described major CAS as being associated with oligohydramnios in the early second trimester and the nine cases they report were interrupted within 8 days of the diagnosis5. In our case, at the initial scan we also observed a reduced amniotic fluid volume but it had normalized when the membranes were found to be fused 5 weeks later. CAS is rarely isolated (Table 1) and is more often associated with fetal anomalies suggestive of aneuploidy. Isolated CAS was associated more often with an aneuploidy when the separation between the membranes was large (> 10 mm) and complete. Some studies included CAS detected after amniocentesis1,4 while others included only spontaneous cases2,3,5. Levine et al. demonstrated that CAS occurring following amniocentesis was often a limited form with no specific consequences on the pregnancy4. Our observation of a spontaneous, complete, transient and isolated CAS associated with trisomy 21 corresponds to the most rarely reported form. It emphasizes the fact that the isolated or transient nature of CAS during the early second trimester cannot be considered as a reassuring finding and that karyotypic analysis is justified.

A familial disorder of altered DNA-methylation

Background In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. Purpose/objective We have investigated the clinical and molecular features of a familial DNA-methylation disorder. Methods Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed. Results In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene. Conclusions The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.

Cardiac Expression of Sarcoplasmic Reticulum Calcium ATPase in Fetuses with Trisomy 21 and Trisomy 18 Presenting with Nuchal Translucency

At 10-14 weeks of gestation about 80% of fetuses with chromosomal defects have abnormal accumulation of subcutaneous fluid in the nuchal region that is visualized by ultrasonography as nuchal translucency. A possible cause for this translucency is cardiac dysfunction due to the associated defects in the heart and great arteries. The aim of this study was to investigate whether in cardiac tissue from trisomic fetuses, compared to normals, there is an alteration in the steady state levels of expression of the genes encoding sarcoplasmic reticulum calcium ATPase (calcium ATPase), which is known to be downregulated in postnatal heart failure. After termination of pregnancy at 10-18 weeks of gestation, mRNA was extracted from cardiac tissue in 11 trisomy 21 and 4 trisomy 18 fetuses. Densitometric analysis of the Northern and slot blots was used to determine the steady state levels of expression of calcium ATPase and the values from the trisomic fetuses were compared to those of 30 normal controls at 10-18 weeks. Calcium ATPase gene expression did not change significantly with gestation at 10-18 weeks. In trisomic fetuses there was no significant decrease in calcium ATPase expression and expression levels of calcium ATPase were not related to increased nuchal translucency. However, the levels expressed in fetuses are already very low and cardiac dysfunction as a potential etiological factor cannot be excluded.

Maternal Serum ADAM-12 as a Potential Marker for Different Adverse Pregnancy Outcomes

Objective: To investigate first-trimester ADAM-12 levels in pregnancies which later develop hypertensive and growth complications. Methods: First-trimester serum samples (11+0 to 13+6 weeks) were retrieved from frozen storage. 47 samples with at least one of the following adverse outcomes: pre-eclampsia (PE), small for gestational age, HELLP syndrome and gestational hypertension were analysed and 452 controls matched to the cases by gestational age and length of storage were analysed. ADAM-12 levels were measured by the automated AutoDELFIA immunoassay platform. Results: ADAM-12 was found to increase with gestational age (11+0 to 13+6 weeks) and decrease with increasing maternal weight and in women who smoked. After correction, ADAM-12 median multiples of the median were increased in cases with HELLP syndrome, all PE and PE only. Conclusion: The increased first-trimester levels of ADAM-12 in PE and HELLP are in contrast with previous findings. The usefulness of ADAM-12 as a marker for adverse outcomes is still unclear.

Congenital lobar emphysema and increased nuchal translucency.

Congenital lobar emphysema (CLE) is a malformation of the lung that is usually diagnosed postnatally. It is characterized by air trapping and/or overdistension of lung segments and lobes. In some cases there is respiratory distress, mediastinal shift and wheezing due to spontaneous overinflation of the affected areas. Prenatal diagnosis has been made in a number of cases, and such fetuses present with a congenital echogenic mass, including mediastinal shift and displacement of the heart, resulting in compression of the contralateral lung. Both macroand microcystic lesions have been reported. While the association with increased nuchal translucency (NT) has been made for lesions that lead to high intrathoracic pressure such as congenital diaphragmatic hernia (CDH)1, Fryns’ syndrome2 and congenital cystic adenomatoid malformation (CCAM)3, this is the first report of the association between CLE and increased NT. A 32-year-old primigravida, at 12 + 2 weeks, was referred to our fetal medicine unit because of an increased NT of 4.5 mm. Ultrasound examination was performed using an ATL HDI 5000 machine (software version HDI 5000 4252-0901-05 185.13, copyright 1997, Advanced Technology Laboratories, Solingen, Germany) with a 5-MHz transabdominal probe and this confirmed the findings. The results of first-trimester biochemistry (free beta human chorionic gonadotropin and pregnancyassociated plasma protein-A) were normal. Chorionic villus sampling showed a normal karyotype. A follow-up scan at 20 weeks’ gestation was performed, which showed an echogenic mass in the left upper lobe of the lung. The increased NT had resolved. Biometry was within normal ranges. Sagittal and transverse sections of the fetal thorax showed bright lung tissue of microcystic appearance (Figure 1). No macrocystic lesions, mediastinal shift or associated anomalies were observed and there was no sign of fetal compromise, features which together raised the suspicion of CCAM Type III4. Serial follow-up scans to exclude hydrops or mediastinal shift were normal. Spontaneous delivery occurred at term. Postnatal imaging using chest X-rays and both magnetic resonance imaging and computed tomography scans were also suggestive of CCAM. Histological studies, performed for suspected malignancy, were however consistent with the diagnosis of CLE. The differential diagnosis of a congenital chest mass includes CCAM, CLE, pulmonary sequestration and bronchogenic cysts5. Histological studies of lung masses obtained from postnatal thoracic surgery have shown that there may be more than one diagnosis attributed to the same lesion5. This has led to the assumption Figure 1 Fetal ultrasound scan at 20 weeks’ gestation. (a) Sagittal and (b) transverse sections of the fetal thorax showing bright lung tissue with a microcystic appearance resembling that associated with congenital cystic adenomatoid malformation Type III.

WS10: Chromosomopathies WS10‐01Pathophysiology of increased nuchal translucency‐abnormalities of the extracellular matrix

Objective