Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10-12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.

Large hepatic mesenchymal hamartoma leading to mid-trimester fetal demise.

This report describes a fetus with a large multiloculated cystic liver mass. Two small abdominal cysts were seen on ultrasound at 19 weeks of gestation but the patient was referred to us at 23 weeks, after the mass had grown to 8.0 x 5.6 x 7.0 cm, displacing intra-abdominal organs, heart and diaphragm. There was a small amount of ascites but no hydrops. There was polyhydramnios and a thick hyperechoic placenta. After detailed sonograms and MRI suggested the diagnosis of cystic mesenchymal hamartoma of the liver, cyst decompression was favored and consent was obtained. Unfortunately, absence of fetal cardiac activity was noted on the day of the planned intervention. Autopsy confirmed the diagnosis and demonstrated placental changes consistent with mesenchymal stem villous hyperplasia of the placenta. Large fetal cystic abdominal masses that compress the heart, lungs and other organs may benefit from prenatal decompression. This is the first report of cystic hamartoma of the liver apparent on second-trimester sonography, and the fourth time such a lesion is associated with fetal or neonatal death out of 11 cases diagnosed prenatally.

Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.

AIMS/HYPOTHESIS: Neonatal diabetes is a rare disease with several identified molecular aetiologies. Despite associations with other malformations, neonatal diabetes with intestinal and biliary anomalies has not been described. The current study aims to describe a new syndrome, and to examine a possible link with one of three genes known to cause neonatal diabetes. METHODS: Five clinical cases are described. Immunohistochemical staining for pancreatic islet hormones was performed on three of the infants. DNA from one infant was analysed for abnormalities of the PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes. RESULTS: Five infants (two sibling pairs from two families, and an isolated case) presented with neonatal diabetes, hypoplastic or annular pancreas, jejunal atresia, duodenal atresia and gall bladder aplasia or hypoaplasia. One sibling pair was born to consanguineous parents. One patient with a milder form is surviving free of insulin. Four children died in the first year of life despite aggressive medical management. Pancreatic immunohistochemistry revealed few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon and somatostatin. Exocrine histology was variable. In one case from the consanguineous family, molecular analysis showed no duplication or uniparental isodisomy of PLAGL-1 at 6q24, no contiguous gene deletion involving the glucokinase gene, and no mutation in the coding sequences or splice sites of PDX-1. CONCLUSIONS/INTERPRETATION: This combination of multiple congenital abnormalities has not been previously described and probably represents a new autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development and whose aetiology is as yet unknown.

Pericardial hemangioma presenting as thoracic mass in utero.

Pericardial hemangiomas are rare lesions. We present the case of an infant who was referred to our fetal diagnosis and treatment group for the presence of a left thoracic mass, pleural effusion, and mediastinal shift on fetal ultrasound. The characteristics of the lesion suggested the presence of a pulmonary sequestration. A chest radiograph done at birth was normal. At 2 weeks of age, an enhancing lesion of the left pericardium was identified on chest CT. A cardiac MRI demonstrated enhancement of the mass on T2-weighted images. The patient underwent thoracoscopic assessment of the mass for diagnostic purposes. Multiple lesions were identified along the left pericardium and diaphragm. A frozen section biopsy revealed a hemangioma. The natural history for hemangiomas is gradual regression; however, they may increase acutely in size and cause symptoms prior to involution. Investigations should be performed to identify the involvement of other organs. This case illustrates the need to closely follow all patients with prenatally diagnosed thoracic masses with CT imaging, even when they are asymptomatic and have a normal chest radiograph at birth.

Comparative genomic hybridization: a new approach to screening for intrauterine complete or mosaic aneuploidy.

In the practice of clinical genetics chromosomal aneuploidy in both mosaic and nonmosaic forms has long been recognized as a cause of abnormal prenatal and postnatal development. Traditionally, cytogenetic analysis of cultured lymphocytes has been used as a standard test for detection of constitutional aneuploidies. As lymphocytes represent only one lineage, chromosomal mosaicism expressed in other tissues often remains undetected. The purpose of this study was to assess the utilization of molecular cytogenetic analysis for detection of chromosomal aneuploidy in placental tissues. Using placentas from 100 pregnancies with viable nonmalformed livebirths, both trophoblast and chorionic stroma were analyzed using comparative genomic hybridization (CGH). In all cases with an indication of chromosomal imbalance by CGH, fluorescence in situ hybridization (FISH) analysis was performed to confirm the presence of aneuploidy. To differentiate between constitutional aneuploidy and confined placental mosaicism (CPM), amniotic membrane was analyzed by CGH and FISH techniques. Our results demonstrated five placentas with CPM for chromosomes 2, 4, 12, 13, and 18, respectively, and two constitutional nonmosaic aneuploidies (47,XXX and 47,XXY). Molecular cytogenetic studies of human placental tissues enables easy analysis of both embryonic (amnion) and extraembryonic (chorion) cell lineages. Detection at birth of chromosomal defects affecting intrauterine placental and fetal development is important because these chromosomal defects may continue to have an influence on postnatal development.