Cases Of Holoprosencephaly Research Articles

Dual white matter pathology in fetal holoprosencephaly featuring concurrent malformative and destructive features: A case series.

Holoprosencephaly (HPE) is a classic brain malformation involving defective forebrain induction and patterning. Cases of HPE bearing white matter abnormalities have not been well documented, with only rare cases exhibiting hypoxic-ischemic damage. However, neuroradiologic studies of HPE using diffusion tensor imaging have suggested the presence of white matter architectural disarray. Described in this case series are the clinicopathologic features of 8 fetuses with HPE who underwent autopsy at BC Children's Hospital. All 8 cases exhibited subacute to chronic, periventricular leukomalacia (PVL)-like white matter pathology, with 7 of 8 cases also demonstrating aberrant white matter tracts, one of which manifested as a discreet bundle crossing the midline within the ventral aspects of the fused deep gray nuclei. In 6 of these 7 cases, the PVL-like pathology resided within this aberrant white matter tract. Original workup, alongside an additional HPE-focused next-generation sequencing panel identified a likely etiologic cause for the HPE in 4 cases, with an additional 2 cases exhibiting a variant of unknown significance in genes previously suggested to be involved in HPE. Despite our in-depth clinicopathologic and molecular review, no unifying etiology was definitively identified among our series of fetal HPE bearing this unusual pattern of white matter pathology.

Post-mortem rapid aneuploidy testing for holoprosencephaly.

Abortion and fetal death are common in fetuses with holoprosencephaly, so genetic examinations often have to be made in a post-mortem setting. The efficiency of the conventional karyotyping using cultured fibroblasts in these situations is limited due to frequent culture failure. In the current study, archived cases of holoprosencephaly, where post-mortem genetic evaluation was requested and sufficient frozen material was available, were reevaluated using the quantitative fluorescence polymerase chain reaction (QF-PCR) technique. Testing for aneuploidies of chromosomes 13, 15, 16, 18, 21, 22, X, and Y with the QF-PCR technique was carried out on DNA isolated from archived frozen chorionic villi in seven cases of holoprosencephaly. QF-PCR was successful in all seven cases. Two cases of trisomy 13, two cases of triploidy, and one case of trisomy 18 was found meaning a 71% diagnostic yield. The success rate of QF-PCR (100%, 7/7) was superior compared to conventional karyotyping (43%, 3/7). Rapid aneuploidy testing using the QF-PCR technique is a simple, reliable, time- and cost-effective method sufficient to conclude the etiologic investigation in the majority of holoprosencephaly cases post-mortem.

Rare manifestations of alobar holoprosencephaly and the potential causes: a report of two cases.

Herein, we report two cases of holoprosencephaly's rarest manifestations, albeit cebocephaly in the first case, and cyclopia with a probocis in the second. Cebocephaly, (hypotelorism with a single nostril and a blind-ended nose) was present in the first case; a Syrian newborn girl for a 41-year-old mother who works in collecting Capparis spinosa, and cyclopia with skull vault absence and posterior encephalocele in the second case; a Syrian newborn girl for a 26-year-old mother, the parents here where second-degree relatives. Early diagnosis through ultrasound is preferred in such cases and management options should be assessed and discussed with the parents due to poor prognosis. Adherence to pregnancy follow-up programs is essential to detect malformations and disorders as early as possible, especially when risk factors exist. Also, this paper may suggest a potential correlation between C. spinosa and holoprosencephaly. Therefore, we suggest that more research should be done.

Antenatal and Postnatal Diagnosis of Semilobar Holoprosencephaly: Two Case Reports

Holoprosencephaly (HPE) is a rare birth defect that occurs during the first few weeks of pregnancy. It results from a disturbance in the usual signaling pathways required for separation of the embryonic prosencephalon into 2 separate cerebral hemispheres. Classically four subtypes have been recognized: alobar, semilobar, lobar, and middle interhemispheric holoprosencephaly. The cause of HPE is unknown but may include genetic disorders. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. We report 2 cases of semilobar holoprosencephaly, diagnosed in Children's Hospital of Rabat: the first one was a fetus diagnosed by ultrasonogram at 25 weeks of gestation. The second one was a newborn at 15 days of life diagnosed by brain scan.

Effects of phenobarbital, potassium bromide and topiramate on intractable epilepsies in two cases of holoprosencephaly

We describe the courses of treatment for epilepsies in two patients with semilobar type holoprosencephaly (HPE); a 5-year-old girl and a 30-year-old man. Seizure semiology included eye fixation, upward or lateral gaze, horizontal or vertical nystagmus, eyelid flutter, and grinning facial distortion, which frequently evolved to generalized tonic convulsions. In both patients, ictal electroencephalography revealed seizure onset with rhythmic activity in bilateral frontopolar areas. Administration of phenobarbital with subsequent elevation of blood levels to 30–40 μg/ml alleviated the clustered tonic seizures. This allowed dosage reduction of other antiepileptic drugs that had sedative and/or respiratory adverse effects causing significant distress in these patients. Potassium bromide 20–50 mg/kg/day and topiramate 1–3 mg/kg/day were also beneficial in these patients. A combination regimen of these three antiepileptic drugs could be a promising treatment option for intractable epilepsy in HPE.

Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly.

Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.

The assessment of holoprosencephaly cases in the last 10 years

Holoprosencephaly is a disorder of cleavage failure or incomplete differentiation of the forebrain structures. Chromosomal anomalies and environmental teratogenic factors play a role in its development. We reported 22 cases of holoprosencephaly diagnosed between the years 2011-2020 in our clinic.

Increasing Number of Unusual Brain Abnormalities Seen in Rural West Virginia

The incidence rate of schizencephaly is 1.5 in 100,000 live births and the rate of holoprosencephaly is 1 in 16,000 live births. Both malformations are rare, but our institution has seen a dramatic increase in both malformations in recent years with no known cause. Schizencephaly is the most severe cortical malformation and holoprosencephaly is the most common defect in the prosencephalon during development however, it is still not very common to see a fetus with this defect live to delivery. Our institution seen four cases of schizencephaly and three cases of holoprosencephaly within two years. No two neonates seem to share a common factor. All had different co-morbidities and presentations, all mothers were different ages and showed few risk factors if any for these deformities. This paper is a report of the cases found of these rare birth defects seen at our institution in recent years.

Nationwide epidemiological survey of holoprosencephaly in Japan.

Holoprosencephaly (HPE) is a congenital malformation with an estimated prevalence of 0.10-6.06 per 10000 births but with no nationwide data specific to Japan. This nationwide retrospective questionnaire survey was conducted from 2011 to 2013. All 467 training hospitals for perinatal and neonatal care certified by the Japan Society of Perinatal and Neonatal Medicine were contacted. The birth prevalence rate (BPR) was assessed from the primary survey and clinical characteristics from the secondary survey. We received valid responses from 253 hospitals in the primary survey (54.6%). Of 390342 live births, 60 were diagnosed with HPE (23 males and 37 females), resulting in an actual BPR of 1.54 per 10000 live births. The point estimate for HPE cases was 100 (95% confidence interval [CI]: 80.7-120), and the estimated BPR of HPE was calculated to be 0.32 per 10000 live births (95% CI: 0.26-0.38) based on 3117853 live births according to Japanese national statistics during the study period. In the secondary survey, we obtained data for 49 cases (19 males and 30 females). Of these, 20 were alobar (40.8%), 20 were semilobar (40.8%), five were lobar (10.4%), and four were of unknown type. Genetic examination was performed in 37 of the 49 HPE patients and revealed that chromosomes 13, 18, and 7 were affected in eight, six, and four patients, respectively. This is the most extensive survey on holoprosencephaly to date in Japan. The estimated BPR was consistent with that reported in previous research.

Epidemiological characteristics of holoprosencephaly in China, 2007-2014: A retrospective study based on the national birth defects surveillance system.

ObjectiveTo describe the epidemiology of holoprosencephaly (HPE) in China with special reference to prevalence and associated anomalies.MethodsData were abstracted from the Chinese Birth Defects Monitoring Network for the period 2007–2014. Birth prevalence of HPE were assessed by birth year, fetal/infant sex, maternal age, and maternal residential area. Poisson regressions were used to calculate the crude and adjusted prevalence ratios (PR) and their 95% confidence intervals, and linear chi-square test was used to explore time trend for the prevalence of HPE.ResultsA total of 1222 HPE cases were identified in 13,284,142 births, yielding an overall prevalence of 0.92 per 10,000 births. The annual prevalence of HPE presented an upward trend (P<0.001), from 0.54 per 10,000 births in 2007 to 1.21 per 10,000 births in 2014. Higher prevalence was found in older maternal-age groups (30–34 years, adjusted PR: 1.19, 95% CI: 1.02–1.40; ≥35 years, adjusted PR: 1.53, 95% CI: 1.26–1.86) in comparison with the maternal-age group of 25 to 29 years. Higher prevalence was also found in infants born to mothers resided in urban areas (adjusted PR: 1.23, 95% CI: 1.08–1.39) and female infants (adjusted PR: 1.30, 95% CI: 1.15–1.47).ConclusionsHPE is an important perinatal health issue because of its poor prognosis. This is the first study depicting a picture of epidemiological characteristics of HPE in China, which can provide useful references for future studies.

Syndromes associated with holoprosencephaly.

Holoprosencephaly (HPE) is partial or complete failure of the forebrain to divide into hemispheres and can be an isolated finding or associated with a syndrome. Most cases of HPE are associated with a syndrome and roughly 40%-60% of fetuses with HPE have trisomy 13 which is the most common etiology of HPE. Other syndromes associated with HPE include additional aneuploidies like trisomy 18 and single gene disorders such as Smith-Lemli-Opitz syndrome. There are a number of syndromes such as pseudotrisomy 13 which do not have a known molecular etiology; therefore, this review has two parts: syndromes with a molecular diagnosis and syndromes where the etiology is yet to be found. As most HPE is syndromic, this review provides a comprehensive list and description of syndromes associated with HPE that may be used as a differential diagnosis and starting point for evaluating individuals with HPE.

Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature.

Holoprosencephaly (HPE) is a major structural birth defect of the brain that occurs in approximately 1 in 10,000 live births. Although some genetic causes of HPE are known, a substantial proportion of cases have an unknown etiology. Due to the low birth prevalence and rarity of exposure to many potential risk factors for HPE, few epidemiologic studies have had sufficient sample size to examine risk factors. A 2010 review of the literature identified several risk factors that had been consistently identified as occurring more frequently among cases of HPE, including maternal diabetes, twinning, and a predominance of females, while also identifying a number of potential risk factors that had been less widely studied. In this article, we summarize a systematic literature review conducted to update the evidence for nongenetic risk factors for HPE.

Clinical and Demographic Evaluation of a Holoprosencephaly Cohort From the Kyoto Collection of Human Embryos.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogeneous disorder involving developmental defects. HPE is a rare condition (1/10,000-20,000 newborns) but can be found as frequently as 1/250 among conceptions, suggesting that most HPE embryos are incompatible with postnatal life and result in spontaneous abortions during the first trimester of gestation. Beginning in 1961, the Kyoto University in Japan collected over 44,000 human conceptuses in collaboration with several hundred domestic obstetricians. Over 200 cases of HPE have been identified in the Kyoto collection, which represents the largest single cohort of HPE early stage embryo specimens. In this study, we present a comprehensive clinical and demographic evaluation of this HPE cohort prior to genomic analysis. The total percentage of the threatened abortion among HPE embryos in the Kyoto collection was 67%. Almost 20% of the women with embryos affected by HPE had experienced spontaneous miscarriage. In addition, there was a significant tendency that the mothers with HPE cases had fewer live births than the control. Moreover, in 70% of cases, the mother reported bleeding during pregnancy, a higher percentage than expected, indicating that most of the conceptions with HPE embryos tend to be terminated spontaneously. There were no differences in smoking between mothers with HPE affected and unaffected pregnancies; however, alcohol use was higher in women with pregnancies affected by HPE. In this study, we precisely characterize the phenotype and environmental influences of embryos affected by HPE allowing the future leveraging of genomic technologies to further understand the genetics of forebrain development. Anat Rec, 301:973-986, 2018. © 2018 Wiley Periodicals, Inc.

Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain

Human protein TGIF1 is an essential regulator of cell fate with broad roles in different tissues, and has been implicated in holoprosencephaly (HPE) and many cancers. The function of TGIF1 in transcriptional regulation depends on its three-amino acid loop extension (TALE) type of homeodomain (HD). Two missense mutations that led to P192A and R219C substitutions in TGIF1-HD were previously found in HPE patients and suggested to be the causes for these cases. However, how these mutations affected TGIF1 function has not been investigated from a structural view. Here, we investigated the roles of P192 and R219 in TGIF1-HD structure packing through determining the NMR structure of TGIF1-HD. Surprisingly, P192 and R219 were found to play roles in packing α1 and α2 to α3 together with A190 and F215 through side-chain interactions. Circular dichroism (CD) showed that P192A and R219C mutants displayed structural change and less folding compared with wild-type TGIF1-HD, and 1H-15N HSQC spectrum of P192A mutant exhibited chemical shift perturbations in all three helices of TGIF1-HD. Thus, it is suggested that P192A and R219C mutations led to structure disturbances of TGIF1-HD, which subsequently reduced the DNA-binding affinity of TGIF1-HD by 23-fold and 10-fold respectively, as revealed by the isothermal titration calorimetry (ITC) experiments. Our study provides structural insights of the probable pathogenesis mechanism of two TGIF1-related HPE cases, and evidences for the roles of P192 and R219 in HD folding.

ZIC2 in Holoprosencephaly.

The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.

Impact of holoprosencephaly, exomphalos, megacystis and increased nuchal translucency on first-trimester screening for chromosomal abnormalities.

To examine the prevalence of alobar holoprosencephaly, exomphalos, megacystis and nuchal translucency thickness (NT) ≥ 3.5 mm, the incidence and types of chromosomal abnormalities associated with these conditions and their overall impact on the rate of invasive testing and performance of screening at 11-14 weeks. This was a prospective screening study for trisomies 21, 18 and 13 by the first-trimester combined test at three maternity units in England. In the study population of 108 982 singleton pregnancies, 870 (0.8%) had abnormal karyotype, including 654 (75.2%) with trisomies 21, 18 or 13 and 216 (24.8%) with other chromosomal abnormalities. The prevalence of alobar holoprosencephaly, exomphalos, megacystis and NT ≥ 3.5 mm was 1 in 2945, 1 in 419, 1 in 1345 and 1 in 119, respectively. Chromosomal abnormalities were observed in 78.4% of cases of holoprosencephaly, 40.8% of exomphalos, 18.5% of megacystis and 48.5% of those with NT ≥ 3.5 mm. The most common chromosomal abnormality associated with holoprosencephaly was trisomy 13, with exomphalos and megacystis was trisomy 18 and with increased NT was trisomy 21. Fetal karyotyping of cases with major fetal defects or increased NT would potentially detect 57% of all chromosomal abnormalities at an invasive testing rate of 1.1%. Major fetal defects and increased NT at 11-13 weeks' gestation are associated with a high risk of chromosomal abnormalities and merit invasive fetal testing. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly.

Middle interhemispheric variant of holoprosencephaly (MIH) is a rare brain malformation; hemispheric fusion does not occur at the rostral forebrain, but rather across the posterior frontal region. Barkovich and Quint1 first described and proposed MIH as part of the holoprosencephaly (HPE) spectrum in 1993. Although classic HPE and MIH share several similarities, they are related to different embryological mechanisms: classic HPE is caused by a defect in the formation of the embryonic floor plate, whereas MIH occurs after a disturbance to the roof plate formation.2 The gene ZIC2 is important for the differentiation of the roof plate in the dorsal midline of the neural tube of the developing embryo. In humans, ZIC2 mutations have been identified in 3%–4% of HPE cases, including individuals with MIH, thus confirming that MIH is a variant of HPE.3

Holoprosencephaly: antenatal and postnatal diagnosis and outcome.

The objectives of this study are to ascertain the clinical outcome and overall survival of holoprosencephaly (HPE) patients diagnosed antenatally and postnatally, to determine the accuracy of antenatal diagnosis and to determine the role of neurosurgical intervention in HPE. This is a retrospective review over a 10-year period. Sixty-three patients were included in the study, 45 were diagnosed by antenatal radiological imaging and 18 were diagnosed by postnatal radiological imaging. Patient data was drawn from Temple Street Children's University Hospital (the national paediatric neurosurgery centre), the National Maternity Hospital in Holle's Street, Dublin, and Our Lady of Sick Children Hospital, Dublin. The study was carried out through a review of antenatal and postnatal radiological imaging and reports, clinical charts, GP letters from patient follow-up and telephone conversations with parents of HPE patients. Four patients in the antenatal diagnosis group had follow-up foetal MRI confirming HPE. Twelve in this group had radiological follow-up postnatally, and in five of these, HPE was confirmed. The remaining seven were identified as false positive. Alobar HPE constituted 55% (21/38) of patients with 95% mortality. Fifty-one percent had a normal karyotype. The overall survival in the antenatal diagnosis group was 13%. In the postnatal group, 18 patients were identified, 67% (12/18) lobar and 33% (6/18) semilobar. Normal karyotype was found in 72% (13/18), with an overall survival rate of 56% (10/18). Neurosurgical intervention in both groups mainly consisted of CSF diversion in the form of ventriculoperitoneal (VP) or cystoperitoneal shunt (CP) (13/67). Foetal MRI should be routinely performed in suspected cases of HPE, and reliance on ultrasound alone in the antenatal period may not be sufficient. In our study, there is a high early mortality noted in severe cases of HPE, while milder forms of HPE in children tend to survive beyond infancy albeit with associated complications that required neurosurgical intervention and medical management for other associated systemic anomalies.

In Utero MR Imaging of Fetal Holoprosencephaly: A Structured Approach to Diagnosis and Classification.

Holoprosencephaly is a rare developmental brain abnormality with a range of severity. We describe our experience in diagnosing holoprosencephaly in the fetus with in utero MR imaging. We hypothesized that including in utero MR imaging in the diagnostic pathway will improve the detection of holoprosencephaly compared with ultrasonography and allow better assessment of the severity. We report on holoprosencephaly identified from ultrasonography and/or a diagnosis of holoprosencephaly made with in utero MR imaging. We compare the diagnoses made with sonography and in utero MR imaging in each case and compare the 2 methods of assessing the severity of holoprosencephaly. Thirty-five fetuses are reported, including 9 in which the diagnosis of holoprosencephaly was made on ultrasonography but not confirmed on in utero MR imaging. Of the 26 cases of holoprosencephaly diagnosed on in utero MR imaging, 12 were not recognized on ultrasonography. Our results show that in utero MR imaging has a major role in diagnosing or refuting a diagnosis of fetal holoprosencephaly made on ultrasonography. In utero MR imaging also assists in grading the severity of fetal holoprosencephaly.

Frequency of holoprosencephaly in Chile

Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. To estimate holoprosencephaly prevalence at birth. All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).