Likely pathogenic variant in the BICD2 gene in fetus presenting with non-immune hydrops

Trio exome sequencing was performed on a fetus presenting with severe hydrops fetalis at 21 + 0 weeks gestation. A novel de novo BICD2 missense variant was identified in the fetus. Pathogenic variants in the BICD2 gene are associated with lower extremity-predominant spinal muscular atrophy. The variant was initially classified as a variant of uncertain clinical significance (VUS) as at the time of analysis and initial report, pathogenic variants in the BICD2 gene specifically had not been associated with fetal hydrops and no other abnormalities had been detected. It was agreed in multidisciplinary team discussions to include the variant in the report as a VUS recommending phenotypic follow-up. The pregnancy was terminated and post-mortem findings were in keeping with a BICD2-pathogenic variant. In addition, a paper was published reporting another case with a pathogenic BICD2 variant presenting with fetal hydrops. The variant classification was then upgraded to class 4 likely pathogenic and reported as consistent with the diagnosis. This case demonstrates the importance of reporting these new gene/phenotypes in enabling others in the classification of variants, staying up-to-date with literature and following up phenotype for class 3 variants of interest.     

Prenatal diagnosis of Myhre syndrome with a heterozygous pathogenic variant in SMAD4 gene presented with thick nuchal translucency and cardiac abnormalities

Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.     

Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction,skeletal, cerebral and vascular anomalies

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.     

Prenatal findings on ultrasound and X-ray in a case of overgrowth syndrome associated with increased nuchal translucency

A case of prenatal diagnosis of an overgrowth syndrome at 30 weeks of gestation is reported. The diagnosis was suggested on the basis of increased fetal growth from 16 weeks onwards, advanced bone age, and characteristic facial features such as hypertelorism, broad forehead and small chin. The fetus presented at 12 weeks with a markedly increased nuchal translucency thickness and generalized skin edema, but normal karyotype. Serial ultrasound scans revealed brain abnormalities including mild unilateral ventriculomegaly and a cyst in the cavum septi pellucidi. The pregnancy was terminated at the parents' request at 32 weeks of gestation and postmortem examination confirmed the prenatal findings. This case demonstrates the possibility of prenatal diagnosis of early overgrowth syndromes and highlights the dilemma arising from the prenatal diagnosis of a non-lethal condition associated with an uncertain prognosis and poorly documented in utero. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of congenital my asthenia with arthrogryposis in a myasthenic mother

We studied two children born to a myasthenic mother. The first child, a female, had multiple flexion contractures. She died 1 h after birth. In the second pregnancy, 3 years later, ultra-sonographic examination at 20 weeks showed decreased fetal movements and multiple flexion contractures. The pregnancy was interrupted. Eight other cases of congenital rnyasthenia with arthrogryposis are known; four of them are siblings. The recurrence risk may be as high as 100 per cent. Our second case demonstrates that prenatal diagnosis is possible early enough to allow termination of pregnancy.     

Persistently elevated AFP and AChE in amniotic fluid from a normal fetus following demise of its twin

Intrauterine fetal demise (IUFD) in one of twins at 12 weeks of gestation was accompanied by markedly elevated maternal serum alpha-fetoprotein (AFP) at 17 and 18 weeks. Amniotic fluid AFP from the healthy surviving twin's sac at 18·5 and 23 weeks was also greatly increased along with a positive acetylcholinesterase (AChE) band. Persistently elevated AFP and positive AChE so long after fetal demise–-6·5 and 11 weeks post IUFD–-has not, to our knowledge, been previously described. In similar cases, high level ultrasound and careful placental examination at birth should be utilized to search for fetal abnormalities or multiple pregnancy with IUFD.     

口服二苯胂酸在小鼠小脑蒲肯野细胞诱发氧化和氮化应激

为了研究口服化学战剂降解产物二苯胂酸(DPA)导致小脑功能异常与诱发小鼠小脑蒲肯野细胞氧化和氮化应激之间的关系,利用硫代巴比妥酸反应物(TBARS)法和免疫组织化学方法检测脑组织丙二醛(MDA)和3-硝基酪氨酸(3-NT)的变化情况.同时,通过在体外合成3价DPA的模型化合物二苯胂酸碘(DPI),并用Western-blot检测3-NT的生成.研究发现,在小鼠一次口服15mg·kg-1DPA以及连续5d口服5mg·kg-1 DPA的情况下,小脑组织TBARS上升,蒲肯野细胞MDA和3-NT染色阳性.体外实验检测到DPI和NO反应可以生成3-NT,这表明DPA会导致小鼠小脑功能异常,这与其在体内代谢过程中产生的砷相关活性物质在小脑蒲肯野细胞诱发氧化和氮化应激密切有关.     

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss-of-function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.     

The prenatal diagnosis of joubert's syndrome of familial agenesis of the cerebellar vermis

The prenatal diagnosis by ultrasound examination of Joubert's syndrome of familial agenesis of the cerebellar vermis is described allowing termination of pregnancy ai 26 weeks gestation. The diagnosis was made by a comparison of the prenatal ultrasound examination with computerized axial tomography obtained from the siblings with the same condition.     

Prenatal diagnosis of mucopolysaccharidosis type VII facilitating treatment in neonatal period

Duo exome testing was performed on a fetus conceived via in vitro fertilization with an egg donor. The fetus presented with non-immune hydrops fetalis (NIHF) at 20 + 0 weeks gestation. Two variants were detected in the GUSB gene. Biallelic pathogenic variants cause mucopolysaccharidosis type VII (MPS-VII), which can present with NIHF prenatally. At the time of analysis and initial report, one variant was classified as likely pathogenic and the other as of uncertain clinical significance. Biochemical testing of the amniotic fluid supernatant showed elevated glycosaminoglycans and low β-glucuronidase activity consistent with the diagnosis of MPS-VII. This evidence allowed the upgrade of the pathogenicity for both variants, confirming the diagnosis of MPS-VII. The infant was born at 36 + 5 weeks and enzyme replacement therapy (ERT) using vestronidase was initiated at 20 days with planning for hematopoietic stem cell transplant ongoing. The ERT therapy has been well tolerated, with decreasing quantitative urine glycosaminoglycans. Long-term follow up is required to determine whether treatment has been successful. This case demonstrates the utility of alternative testing methods to clarify the pathogenicity of variants and the clinical utility of obtaining a diagnosis antenatally in facilitating treatment in the neonatal period, and specifically highlights MPS-VII as a treatable cause of NIHF.     

Performance of comprehensive first trimester fetal anatomy assessment

Objective

Ultrasound assessment of the fetal anatomy and fetal echocardiography are feasible in the first trimester of pregnancy. This study was designed to assess the performance of a comprehensive fetal anatomy assessment in a high-risk population at a tertiary fetal medicine unit.

Methods

A retrospective review of high-risk patients undergoing comprehensive fetal anatomy ultrasound assessment between 11 weeks and 13 + 6 weeks of gestation was conducted. Findings of the early anatomy ultrasound scan were compared with those of the second trimester anatomy scan, and birth outcomes or post-mortem results.

Results

Early anatomy ultrasounds were performed in 765 patients. The sensitivity of the scan for detecting fetal anomalies compared to the birth outcome was 80.5% (95% CI 73.5–86.3) and specificity was 93.1% (95%CI 90.6–95.2). Positive and negative predictive values were 78.5% (95% CI 71.4–84.6) and 93.9% (95% CI 91.4–95.8), respectively. The most missed and overdiagnosed abnormalities were ventricular septal defects. The second trimester ultrasound had sensitivity of 69.0% (95% CI 55.5–80.5) and specificity of 87.5% (95% CI 84.3–90.2).

Conclusions

In a high-risk population, early assessments had similar performance metrics as the second trimester anatomy ultrasound. We advocate for a comprehensive fetal assessment in the care of high-risk pregnancies.     

Cornelia de Lange Syndrome in association with a balanced reciprocal translocation involving chromosomes 3 and 5

We present a case report on a fetus with multiple malformations, diagnosed by ultrasound at 20 weeks' gestation. From the combination of intrauterine growth retardation and limb abnormalities that were observed, the most likely diagnosis was considered to be Cornelia de Lange Syndrome (CdLS). Following counselling, the mother opted to terminate the pregnancy. Chromosome analysis of cultured amniotic fluid cells showed a karyotype of 46,XX,t(3;5)(q21;p13). Postmortem examination of the baby confirmed the presence of features consistent with a diagnosis of CdLS. This case provides a report of a definitive diagnosis of Cornelia de Lange Syndrome, suspected on the basis of ultrasound imaging and confirmed by amniocentesis findings. Copyright © 2005 John Wiley & Sons, Ltd.     

Trisomy 12 mosaicism detected by mid–trimester amniocentesis

Trisomy 12 mosaicism was found in about 15 per cent of cultured amniocytes obtained from a 32-year-old white female at 17·6 weeks of gestation. Termination of pregnancy was elected and multiple tissues were obtained for chromosome analysis. Of 158 cells examined, only 1 cell in placenta was found with an extra number 12 chromosome. Pathological examination of the fetus did not reveal significant physical abnormalities. This report illustrates the difficulty of confirming trisomy 12 mosaicism which has been detected on prenatal diagnosis. The presence of trisomy 12 in one placental cell obtained from the curettage specimen suggests the possibility of confined placental mosaicism in this case.     

Prenatal diagnosis and characterization of an analphoid marker chromosome 16

We report on a fetus with intrauterine growth retardation and multiple malformations diagnosed on ultrasound at 32 weeks. Examination of amniotic fluid cells in culture showed a 47,XY, i(16)(q10), +mar karyotype. Chromosome analysis of both parents was normal. Using spectral karyotyping, we identified the marker chromosome as a mitotically stable acentric marker chromosome derived from chromosome 16. Further studies using subtelomeric fluorescent probes confirmed the presence of an isochromosome for the long arm of chromosome 16 and showed that the acentric marker chromosome derived from the short arm of chromosome 16 leading to a trisomy for the long arm of chromosome 16. After genetic counseling, the parents decided to terminate the pregnancy. Fetal autopsy showed a male fetus with ambiguous external genitalia, cardiac malformation, megacystis and limbs anomalies as observed in other cases of trisomy for the long arm of chromosome 16. In addition, fetal brain examination showed vermian and olfactory bulb hypoplasia. Copyright © 2004 John Wiley & Sons, Ltd.     

First trimester diagnosis of sirenomelia

We present a case of sirenomelia diagnosed on a first trimester ultrasound at 10 weeks' gestation and confirmed on 3D-ultrasound and MRI. The pregnancy was terminated at 15 gestational weeks and the post-mortem examination, including RX and microscopy, is presented. The sirenomelia sequence is a rare and lethal anomaly characterized by fusion, rotation, hypotrophy or atrophy of the lower limbs and severe urogenital abnormalities leading to oligohydramnios in the second half of pregnancy. Our case illustrates that the diagnosis of sirenomelia can be reliably made in the first trimester. Copyright © 2006 John Wiley & Sons, Ltd.     

Fetal hydrops caused by a novel pathogenic MECOM variant

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.     

46,XY/47,XY,+ 17p+ mosaicism in amniocytes associated with fetal abnormalities despite normal fetal blood karyotype

46,XY/47,XY, + 17p + mosaicism was found in two primary amniotic fluid cultures (AFCs). Fetal blood karyotype was normal, but ultrasonography revealed Dandy-Walker malformation and bilateral choroid plexus cysts. Following termination of pregnancy, fetal examination revealed post-axial polydactyly and neuroblastoma-in-situ affecting both adrenals in addition to the cerebellar abnormalities. Mosaicism for the aberrant cell line was confirmed in all fetal tissues sampled and in the placenta.     

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Developmental brain abnormalities are complex and can be difficult to diagnose by prenatal imaging because of the ongoing growth and development of the brain throughout pregnancy and the limitations of ultrasound, often requiring fetal magnetic resonance imaging as an additional tool. As for all major structural congenital anomalies, amniocentesis with chromosomal microarray and a karyotype is the first-line recommended test for the genetic work-up of prenatally diagnosed central nervous system (CNS) abnormalities. Many CNS defects, especially neuronal migration defects affecting the cerebral and cerebellar cortex, are caused by single-gene mutations in a large number of different genes. Early data suggest that prenatal diagnostic exome sequencing for fetal CNS defects will have a high diagnostic yield, but interpretation of sequencing results can be complex. Yet a genetic diagnosis is important for prognosis prediction and recurrence risk counseling. The evaluation and management of such patients is best done in a multidisciplinary team approach. Here, we review general principles of the genetic work-up for fetuses with CNS defects and review categories of genetic causes of prenatally diagnosed CNS phenotypes.     

Abnormalities of the foetal cerebral cortex

Prenatal ultrasound has concentrated on readily visible cerebral structures including head size, shape, ventricles, CSP (cavum septi pellucidi), cerebellar size/vermian presence and cisterna magna. However, apart from these easily visible structures it is important to evaluate the brain itself. Patients who initially appear to have mild isolated findings such as borderline ventriculomegaly in fact can have many more subtle findings that significantly alter prognosis and management that can be detected on detailed examination of the brain. There has been rapid evolution in imaging these foetuses, especially with neurosonography and MRI, and a revolution in understanding the underlying genetic and biochemical mechanisms. There is increasing emphasis to detect cortical abnormalities as early as possible. This article reviews development of the cerebral cortex, the classification, aetiologies and clinical manifestations of cortical disorders, normal and abnormal appearances at ultrasound and MRI, and approaches to investigation. Copyright © 2009 John Wiley & Sons, Ltd.