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Purpose: To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal, or early infant death., Methods: ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines., Results: A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1), or abdominal (1) abnormalities., Conclusion: This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.

Chromosomal abnormalities are a significant cause of pregnancy loss. Solid tissue fetal and neonatal pathology samples are routinely examined by karyotype analysis after cell culture. However, there is a high failure rate, and this approach is expensive and labor intensive. We have therefore evaluated a new molecular strategy involving quantitative fluorescent polymerase chain reaction (QF-PCR) and subtelomere multiplex ligation-dependent probe amplification (MLPA) analysis. A retrospective audit showed that less than 4% of abnormal cases may not be detected by this molecular strategy. We validated this strategy in parallel with cytogenetic analysis on 110 patient samples, which included cases of fetal loss, still birth, neonatal death, termination of pregnancy, recurrent miscarriage, and sudden unexpected death in infancy. This validation showed that 55 of the 57 samples that gave a result for both strategies were concordant. During the 1st year of diagnostic testing, we analyzed 382 samples by the molecular strategy. A 16% abnormality rate was observed. These included trisomies 13, 18, 21, monosomy X, and triploidy detected by QF-PCR (77%), and 23% were other trisomies and subtelomere imbalances detected by MLPA. This strategy had a 92% success rate in contrast to the 20%-30% failure rate observed with cell culture and cytogenetic analysis. We conclude that QF-PCR and subtelomere MLPA is a suitable strategy for analysis of the majority of fetal and neonatal pathology samples, with many advantages over conventional cytogenetic analysis.

The human placenta is an underexamined organ. The clinical indications for placental examination have no gold standards. There is also inconsistency in the histological reports and the quality is variable. There is great interobserver variability concerning the different entities. Although there are still grey areas in clinicopathological associations, a few mainstream observations have now been clarified. The histopathological examination and diagnosis of the placenta may provide crucial information. It is possible to highlight treatable maternal conditions and identify placental or fetal conditions that can be recurrent or inherited. To achieve optimal benefit from placental reports, it is essential to standardise the method of placenta examination. This article summarises the clinical indications for placenta referral and the most common acknowledged clinicopathological correlations.

Introduction: Rather few papers are about first trimesters pathology. The reason of this roots in the technical difficulties. The first trimesters pathology can not be separated from prenatal diagnostics., Objectives: The authors summarized the molecular basis of embryology, malformations, and published cases that had been diagnosed prenatally., Materials and Methods: In the I. Department of Obstetrics and Gynecology, Semmelweis University in Budapest between 1995. and 2000. altogether sixty embryos 70 gms or smaller were examined., Results: Malformations included neural tube defects, disorders of twinning, body stalk defect, chromosome aberrations, hydrops, omphalocele and gastroschisis., Conclusions: Examination of early embryos may discover many results on the fields of prenatal diagnosis and the pathomechanism of developmental abnormalities.

Hypoplastic left heart syndrome (HLHS) is the most common cause of death from heart disease in the first week of life. There are reports about familial concordance by presumed morphogenetic mechanisms of abnormal embryonic blood flow with phenotypes of varying severity. The risk of having a child with a left heart lesion after a previously affected child may be as high as 5% to 12%. We present case reports from four families in which sustained fetal arrhythmia (three ectopic atrial tachycardias and one severe bradycardia due to excessive ectopic atrial beats) was demonstrated. Within these four families a close relative of the mother (a previous child, a brother, or a nephew) had severe left heart abnormality (three with HLHS and one with severe aortic valve stenosis). The association of sustained fetal arrhythmia of ectopic atrial origin and severe left heart abnormalities could be expected to occur by chance in a very low percentage of cases. We conclude that sustained fetal atrial ectopic arrhythmia is a congenital abnormality and should be considered as a risk factor for inherited congenital heart abnormalities.

The authors report two families with two affected siblings of heterotaxy syndrome. Ivemark syndrome with asplenia and complex cardiovascular malformation occurred in two siblings of the first family. The first affected sibling in the second family had situs inversus, transposition of the great arteries with spleen on the right side of the abdomen. Ivemark syndrome with polysplenia and cardiovascular malformation were present in the second affected sibling of the second family. Autosomal recessive inheritance of Ivemark syndrome was reported in the most of the cases, but there are several cases of autosomal dominant inherited Ivemark syndrome. X-linked inheritance of heterotaxy syndrome is also known. Heterotaxy syndromes could also occurred in chromosomal translocation or deletion in sporadic cases. The molecular genetic studies were not able to find the mutation responsible for heterotaxy syndrome. The diagnosis of heterotaxy syndrome could be made by foetal echocardiography until molecular genetic methods are available. Therefore, in the case of positive anamnesis, foetal echocardiography on the 18-20 weeks of gestation is essential diagnostic method.

Calcification of the heart and vessels in fetuses is a rare condition. It may be dystrophic or metastatic. An extremely rare form of vascular calcification has been termed 'idiopathic arterial calcification of infancy', which is inherited in an autosomal recessive pattern. We report four cases of myocardial calcifications of different origin diagnosed in utero. The correct diagnosis is very important in regard to genetic counselling.

Prenatal diagnosis of fetal trisomies is usually performed by cytogenetic analysis on amniotic fluid. This requires lengthy laboratory procedures and high costs, and is unsuitable for large scale screening of pregnant women. An alternative method, which is both rapid and inexpensive and suitable for diagnosing trisomies even from single fetal cells, is the fluorescent polymerase chain reaction using polymorphic small tandem repeats (STRs). In this paper we present the preliminary results of a larger study comparing parallel prenatal diagnoses of trisomies 21 and 18 using cytogenetics with quantitative fluorescent polymerase chain reaction using STR markers. The results obtained by the two techniques were concordant in all cases. This is the first study reporting significant numbers of prenatal diagnoses using the quantitative fluorescent polymerase chain reaction. We believe that further studies on greater numbers of samples will determine the absolute reliability of this technique. These results also provide a model for diagnosis of trisomy from single fetal cells isolated from maternal blood.

A case of multifocal hemangioendothelioma of the liver, adrenal gland, and placenta is reported. The histological appearance of the tumor is consistent with an infantile hemangioendothelioma, type 2. Multifocal development is the most obvious explanation for the disease but the possibility that this represents malignant placental neoplasm with metastases requires consideration.