Prenatal Diagnosis Of Holoprosencephaly Research Articles

VP53.04: Prenatal diagnosis of holoprosencephaly

VP53.04: Prenatal diagnosis of holoprosencephaly

Prenatal diagnosis of holoprosencephaly.

Holoprosencephaly is a spectrum of congenital defects of forebrain development characterized by incomplete separation of the cerebral hemispheres. In vivo diagnosis can be established with prenatal brain imaging and disease severity correlates with extent of abnormally developed brain tissue. Advances in magnetic resonance imaging (MRI) over the past 25 years and their application to the fetus have enabled diagnosis of holoprosencephaly in utero. Here, we report on the prenatal diagnosis of holoprosencephaly using MRI as part of a diagnostic and management evaluation at a tertiary and quaternary referral center. Using an advanced MRI protocol and a 1.5-Tesla magnet, we show radiographic data diagnostic for the holoprosencephaly spectrum, including alobar, semilobar, lobar, middle interhemispheric, and septopreoptic variant. Accurate prenatal evaluation is important because the severity of imaging findings correlates with postnatal morbidity and mortality in holoprosencephaly. Therefore, this work has implications for the evaluation, diagnosis, management, and genetic counseling that families can receive during a pregnancy.

Prenatal diagnosis of holoprosencephaly with proboscis and cyclopia caused by monosomy 18p resulting from unbalanced whole-arm translocation of 18;21

Abstract A case of holoprosencephaly (HPE) with proboscis, fused eyes in one orbit, and cyclopia was diagnosed by fetal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Ultrasonographic examination at 28 weeks of gestation showed fusion of the frontal part of the brain and ventricular dilation. Subsequent CT and MRI examinations confirmed this anomaly as alobar HPE. Amniocentesis followed by chromosome analysis demonstrated karyotype as de novo 45,XY, der (18;21)(q10;q10), with deletion of a short arm of chromosome 18. The pregnancy ended in a premature delivery of a male neonate weighing 1716 g at 34 weeks. Macroscopically, there were mid-frontal proboscis and single orbit with two eyes without normal nasal structures. He died 1 h after birth.

Biparietal diameter at 11 to 13 weeks' gestation in fetuses with holoprosencephaly

Studies have suggested that fetuses with holoprosencephaly have smaller head size, demonstrated as early as the first trimester. However, the majority of these cases were diagnosed in the second or third trimesters. The aim of this study was to investigate biparietal diameter (BPD) measured at 11 to 13 weeks' gestation in fetuses with holoprosencephaly. This was a retrospective study in which BPD was measured at 11 to 13 weeks in 34 fetuses with prenatal diagnosis of holoprosencephaly and 7775 unaffected controls. BPD values were converted into multiples of the expected median (MoM) after adjustment for crown-rump length and maternal characteristics. The median gestational age at the BPD recording was 12.6 (interquartile range 12.3-13.0) weeks. The nuchal translucency was increased (≥3mm) in 58.8% of the cases. Aneuploidy was confirmed in 73.5% of the cases; the commonest was trisomy 13 (50.0%). BPD values at 11 to 13 weeks were below the 5(th) centile in 32.4% of cases and below the 50(th) centile in 67.6%. BPD MoM values were significantly smaller than in the control group (median: 0.98; interquartile range: 0.90-1.06 vs 1.00; 0.96-1.04 MoM, p = 0.03). Fetuses with holoprosencephaly have a smaller BPD in the first trimester. This property may be useful in early diagnosis.

P15.11: Holoprosencephaly at prenatal ultrasound: different etiologies for the same ultrasound finding

Objectives: To assess the possibility of finding an etiology in a prenatal diagnosis of holoprosencephaly. Methods: From 1996–2009, 11116 prenatal diagnoses through CVS or amniocentesis were performed in a single center. Every diagnosis of holoprosencephaly at ultrasound was considered. Gestational age, ultrasound findings and karyotype were recorded. When relevant, molecular diagnosis or parental karyotype was studied. Results: 22 fetuses were diagnosed with holoprosencephaly (0.19%). Mean gestational age was 19 weeks. All cases had additional ultrasound findings (100%). A definitive etiology was found in 18 cases (81.8%): Karyotype was abnormal in 14 cases (63.6%) and normal in 8 (36.4%). There were 10 free trisomies (9 trisomies 13 and 1 trisomy 18), 4 structural chromosomal anomalies (3 inherited from parental balanced translocations and one de novo). In the group with normal karyotype: one autosomal dominant mutation of gene SIX was diagnosed. Both parents tested negative. One case had a postnatal diagnosis of dysgnathia complex. Two fetuses had Smith Lemli Opitz: low cholesterol levels at cordocentesis and 2 mutations at the gene DHCR were found. Both parents were carriers. In four cases with normal karyotype no etiology was found: in one case, no results were achieved due to a cytogenetic culture failure and in three other cases no etiology could be found. Conclusions: Our results showed that a definitive etiology can be achieved in 8 out of 10 cases when holoprosencephaly is found at a prenatal ultrasound. The fact that holoprosencephaly is strongly associated with chromosomal anomalies was supported with our data. However, in euploid fetuses, the searching for a molecular diagnosis is warranted since different genes with different patterns of inheritance may be responsible for this malformation. The finding of parents carrying mutations or structural chromosome balanced rearrangements is crucial for planning PGD in future pregnancies.

Genetic counseling and “molecular” prenatal diagnosis of holoprosencephaly (HPE)

Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype-phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case.

Holoprosenzephalie: Kriterien und Konsequenzen der pränatalen Diagnostik

Two cases of prenatal diagnosis of holoprosencephaly are described. The characteristic sonographic findings in the second trimester were: microcephaly, absence of the midline echo, hypotelorism and typically flattened profile without sufficient configuration of the nose. Both foetuses had midline facial clefts, one of which was diagnosed prenatally. One case demonstrated a dorsal intracranial cyst. Analysis of the karyotype after foetal blood sampling and amniocentesis revealed translocation trisomy 13 in one case. The mother of this foetus had a balanced translocation 13/14. This foetus also had many extracranial abnormalities in contrast to the other foetus, which had a normal karyotype. Additionally we report of the prenatal diagnosis of a third case with cyclopia and trisomy 13. The findings of the autopsy of the foetuses are described and the criteria for prenatal diagnosis are compared to those found in the literature.

An epidemiological study of holoprosencephaly from a regional congenital anomaly register: 1995–2004

Adequate contemporary information to counsel patients with a prenatal diagnosis of holoprosencephaly is lacking. We addressed this using data from the West Midlands Congenital Anomaly Register (WMCAR), a population-based malformation register, during a time where technological improvements have been stable and anomaly screening is well established. Cases were defined using the ICD 10 code for holoprosencephaly. Cases of livebirths, stillbirths and termination at all gestations were included in the study. The diagnosis was verified by a pathology or definitive radiological report with cross validation from the regional pathology, clinical genetics, cytogenetics and fetal medicine databases. There were 113 cases reported of holoprosencephaly for the years 1995-2004. This represents a prevalence of 1.7 per 10,000 births and terminations, with no change in prevalence over time. There was a decreased risk of holoprosencephaly in the white population [white vs. nonwhite; RR 0.53(0.36-0.79)]. Karyotypical abnormality was noted in 46% of cases where the karyotype was known. Trisomy 13 was the most common chromosomal abnormality. Correct allocation of a diagnosis of holoprosencephaly by ultrasound occurred in 77% of cases, with another 12% having a severe intracranial abnormality but was not reported as holoprosencephaly. In 4%, a prenatal diagnosis of holoprosencephaly was not made. Termination of pregnancy was performed in 80% of all cases. Holoprosencephaly is a morbid condition associated with significant secondary etiologies.

P03.09: Reversed end‐diastolic wave of middle cerebral artery in prenatal diagnosis of holoprosencephaly

P03.09: Reversed end‐diastolic wave of middle cerebral artery in prenatal diagnosis of holoprosencephaly

Prenatal diagnosis of holoprosencephaly with ethmocephaly via 3-dimensional sonography

We present the prenatal 3-dimensional (3D) sonographic findings in a case of holoprosencephaly with ethmocephaly at 32 weeks' gestation. The sonographic diagnosis was based on the intracranial findings of a single ventricle and bulb-shaped appearance of the thalami and facial abnormalities, including hypotelorism with proboscis. Chromosome study of the fetus revealed a normal female karyotype (46,XX). Postmortem examination confirmed the 3D sonographic findings. This case demonstrates that the use of 3D sonography improves the imaging and the understanding of the condition of the intracranial abnormalities and the facial anomalies.

Prenatal Diagnosis of Holoprosencephaly With Cyclopia

The authors report a case of holoprosencephaly with cyclopia, diagnosed prenatally at a gestational age of 19 weeks. The patient’s clinical history was normal, except for aspirin usage for her headache. The sonographic diagnosis was based on the intracranial finding of fused thalami with no visible midline structures and facial abnormalities, including cyclopia, proboscis, and absence of the nose. These findings are characteristic of alobar holoprosencephaly. With the informed consent of the patient, the pregnancy was terminated by induction after proper counseling. Postmortem examination of the abortus material confirmed the presence of cyclopia and a proboscis.

Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England

Objective: This study was undertaken to provide epidemiologic data on the prevalence of holoprosencephaly and to assess the sensitivity of routine ultrasonographic screening in a low-risk population. Study Design: A population-based register of congenital abnormalities was used to identify reported cases of holoprosencephaly between 1985 and 1998. Sources included fetal losses, termination for fetal anomaly, stillbirths, and live births. Prenatal diagnoses and pregnancy outcomes were determined. Results: Sixty-eight cases of holoprosencephaly were found among 531,686 births. The total prevalence (including pregnancy terminations) was 1.2 cases/10,000 registered births, and the birth prevalence (affected live births and stillbirths at >24 weeks’ gestation) was 0.49 cases/10,000 births. Prenatal diagnosis was achieved in 71% of cases, rising to 86% during the second half of the study period; the mean gestational age at diagnosis was 19.8 weeks’ gestation. Chromosomal abnormalities (75% of which were trisomy 13) were present in 38% of cases in which a karyotype was established. All those with aneuploidy (80% diagnosed prenatally) had other nonfacial anomalies; additional anomalies were also common in the euploid group (61% diagnosed prenatally), with 90% having facial abnormalities and 70% having other abnormalities. Conclusion: The prevalence of holoprosencephaly in second-trimester pregnancies was about 1 in 8000. Prenatal detection reached 86% with a routine anomaly scanning program. The etiology could usually be determined, which has important implications for recurrence risks. (Am J Obstet Gynecol 2001;184:1256-62.)

Prenatal Diagnosis of Holoprosencephaly by Sonography

Prenatal Diagnosis of Holoprosencephaly by Sonography