A case of otocephaly with anencephaly and meningomyelocele

A case of otocephaly with anencephaly and meningomyelocele: Otocephaly is a rare lethal syndrome with microstomia, aglossia, agnathia, and synotia as major clinical features due to arrest in development of the first branchial arch. Some associated anomalies may be present as cyclopia, holoprosencephaly, cerebellar hypoplasia, situs inversus, and other visceral anomalies. We describe a case of fetus, spontaneously aborted in the 14th week of gestation with otocephaly complex (agnathia, synotia, microstomia) and associated anencephaly and meningomyelocele.     

Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology

This paper provides an updated, comprehensive, critical review of the epidemiology, genetics, and syndromic aspects of holoprosencephaly and is divided into four parts. In the first part, epidemiologic aspects are discussed under the following headings: prevalence, temporal trends, socioeconomic status, exposure to environmental teratogens, maternal and paternal ages, pregnancy histories, and birth weights. The second part analyzes the facial phenotypes because the genetic and syndromic aspects of holoprosencephaly cannot be understood without knowledge of facial variability and its meaning. Topics discussed include cyclopia, ethmocephaly, cebocephaly, median cleft lip, and less severe facial dysmorphism. The third section, on genetics, analyzes associated anomalies, chromosomal and non-chromosomal holoprosencephaly, family studies, twin studies, genetics of nonsyndromic holoprosencephaly, and recurrence risks. The final section on syndromology summarizes 48 conditions in which some degree of holoprosencephaly may be a feature.     

二维及实时三维超声对胎儿全前脑畸形的诊断价值探讨

目的：探讨二维及实时三维超声联合诊断胎儿全前脑畸形的价值。方法：二维超声系统检查发现胎儿颅脑结构异常者进行胎儿颅脑和颜面部实时三维成像,并将超声诊断结果与引产后尸检结果进行对照分析。结果：在20918例孕16~41周的胎儿中,经引产后尸检证实的全前脑畸形5例,其中无叶全前脑3例,半叶全前脑2例,均与产前超声检查结果相符合,二维联合实时三维超声检查对胎儿全前脑畸形诊断符合率为100%。结论：二维超声联合实时三维超声检查是诊断胎儿全前脑畸形可靠有效的方法,两者联合应用可提高产前全前脑的诊断率。     

Holoprosencephaly in a fetal macaque (Macaca nemestrina) following weekly exposure to ethanol

Previous studies in rodents have indicated that the facial changes of fetal alcohol syndrome (FAS) closely resemble those of a mild form of holoprosencephaly. In order to examine this relationship in non-human primates, we evaluated a 133-day gestation macaque (Macaca nemestrina) with holoprosencephaly, median cleft lip and palate, and encephalocele. The mother had been given ethanol once per week (1.8 g/kg body weight) from weeks 2 to 19 postconception. Diagnosis of holoprosencephaly was made following ultrasound evaluation for polyhydramnios and delivery of the female fetus by caesarean section. Another fetus of identical age was delivered by caesarean section for use as a control. Both fetuses were studied by anthropometric, gross, radiographic, and histologic techniques. In the fetus exposed to alcohol, no extracranial anomalies were identified and the karyotype was normal. The brain was micrencephalic, with absent olfactory bulbs, tracts, optic nerves and chiasma, fused frontal lobes, and a single, dilated lateral ventricle; a parietooccipital encephalocele consisted of thin, dysplastic cortex bordering the ventricle; the cerebellum was dysplastic and superiorly displaced. Within the craniofacial complex, anophthalmia was bilateral; premaxillary components were absent, palatal shelves separate, the maxillae closeset, and the ethmoid bone small and deformed. Most of these defects are similar to those encountered in humans with holoprosencephaly and support the hypothesis of shared etiologic and pathogenetic relations between the facial anomalies of fetal alcohol syndrome and holoprosencephaly.     

Microcephaly in familial holoprosencephaly

The holoprosencephaly sequence (HS) is characterized by abnormalities in forebrain cleavage and midface development. Familial holoprosencephaly has been reported in several families and there appears to be variable expression of the disorder in those who inherit the gene. Previous investigators have suggested hypotelorism and/or missing central incisors as mild manifestations of autosomal dominant HS. We evaluated a large kindred with three individuals with severe brain anomalies and 12 individuals with minor manifestations of the disorder. The most consistent sign in those mildly affected was microcephaly. We suggest that head circumference is an important part of the evaluation of the relatives of a patient with holoprosencephaly.     

Teratogenic effect of AY 9944 in rats: importance of the day of administration and maternal plasma cholesterol level

An inhibitor of cholesterol synthesis, AY 9944 (trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride) is teratogenic. A single dose of AY 9944 (50 mg/kg or 75 mg/kg) given to Wistar pregnant rats on the second, fourth, sixth, seventh, or eighth day of gestation induced malformations such as holoprosencephaly. They were often limited to isolated pituitary agenesis. The highest percentage of holoprosencephalic fetuses was found when AY 9944 was given on the fourth day of gestation. Whatever the dose and the day of administration, the lower the maternal plasma cholesterol level, the more frequent were holoprosencephalic fetuses. Therefore, it is suggested that the decrease in maternal plasma cholesterol level is at least one of the factors provoking holoprosencephaly.     

Unique Alterations of an Ultraconserved Non-Coding Element in the 3'UTR of ZIC2 in Holoprosencephaly

Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.     

Holoprosencephaly as a genetic model for normal craniofacial development

Holoprosencephaly is a common developmental defect of the forebrain and midface in humans. Clinical expression is variable, extending in unbroken sequence from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial holoprosencephaly. Significant aetiological heterogeneity in holoprosencephaly has been demonstrated including both genetic and environmental causes. Genetic approaches, such us positional cloning of genes involved in holoprosencephaly will result in a better understanding of normal development of the brain and face and, ultimately, elucidate the basic genetic defects which programme the abnormal formation seen in holoprosencephaly.     

Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencepahly

A fetus with a severe variant of the agnathia malformation complex (AMC) was delivered following prenatal diagnostic evaluation with ultrasonography. The constellation of anomalies that accompanied the agnathia included holoprosencephaly, hydranencephaly, situs inversus, and polysplenia. Recently, several authors have reported the association between the agnathia, holoprosencephaly, and situs inversus. We present evidence which suggests that, when hydranencephaly is also present, this may represent the most severe variant of the AMC. Our case is presented, the literature is reviewed, and a hypothesis regarding the embryopathologic mechanism is discussed.     

Holoprosencephaly: clinical, anatomic, and molecular dimensions

Holoprosencephaly is addressed under the following headings: alobar, semilobar, and lobar holoprosencephaly; arrhinencephaly; agenesis of the corpus callosum; pituitary abnormalities; hindbrain abnormalities; syntelencephaly; aprosencephaly/atelencephaly; neural tube defects; facial anomalies; median cleft lip; minor facial anomalies; single maxillary central incisor; holoprosencephaly-like phenotype; epidemiology; genetic causes of holoprosencephaly; teratogenic causes of holoprosencephaly; SHH mutations; ZIC2 mutations; SIX3 mutations; TGIF mutations; PTCH mutations; GLI2 mutations; FAST1 mutations; TDGF1 mutations; and DHCR7 mutations.     

Genetics of ventral forebrain development and holoprosencephaly

The disease holoprosencephaly is the basis of the most common structural anomaly of the developing forebrain in humans. Numerous teratogens when administered during early gastrulation, have been associated with this condition. Recent studies have characterized molecules expressed in the prechordal plate which are critical for normal brain formation. Perturbation of signaling pathways involving these molecules have been shown to cause holoprosencephaly in humans and other organisms.     

The Ubiquitin E3 Ligase NOSIP Modulates Protein Phosphatase 2A Activity in Craniofacial Development

Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans.     

Selected clinical research involving the central nervous system

This paper updates three clinical research projects involving the central nervous system. Discussions of conditions with encephalocele include several associations: encephalocele/craniostenosis, transsphenoidal encephalocele/hypothalamic-pituitary dysfunction, encephalocele/oculo-auriculo-vertebral spectrum, and encephalocele/frontonasal dysplasia. The relationship between oculo-auriculo-vetebral spectrum with encephalocele and frontonasal dysplasia with epibulbar dermoids and ear tags is also discussed and an explanation for encephalocele formation in the Apert syndrome is provided. Studies of the central nervous system in Apert syndrome indicate that distortion ventriculomegaly is common, but progressive hydrocephalus occurs infrequently. A recurrent pattern of abnormalities was discerned consisting of megalencephaly, gyral abnormalities, and defects of the corpus callosum and limbic structures. Five neuropathologic studies lend further support to this pattern of CNS anomalies in the Apert syndrome. In a study of holoprosencephaly, eight principles governing associated facial dysmorphism were derived. Each diagnostic category was shown to have its own frequency and range of holoprosencephalic faces. Some categories, such as del(13q), have narrow ranges; others, such as trisomy 13 syndrome, have broad ranges. However, no broad diagnostic range is known to include agnathia-holoprosencephaly and other severe forms of facial dysmorphism without agnathia. Absent maxillary incisors and a single maxillary central incisor are extremely common in holoprosencephaly with severe facial dysmorphism and may occur on occasion as a striking microform of holoprosencephaly, most commonly in the autosomal dominant form.     

Holoprosencephaly in a fetus with a 46,XX,der(7), t(7;8)(q36.1;p12) mat karyotype

In this report we present a female fetus with hemilobar holoprosencephaly and 46,XX,der(7)t(7;8)(q36.1;p12) mat karyotype. The holoprosencephaly-sequence is apparently related with the distal 7(q36.1----qter) deficiency.     

Major malformation syndrome and apparently balanced chromosomal abnormality: holoprosencephaly and 5p; 12q translocation

Observation of holoprosencephaly associated to chromosomic aberration (balanced translocation 5p; 12q); genetic council may be difficult in case of familial translocation.     

Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies.

This paper presents an updated analytic review of the holoprosencephalic disorders. Central nervous system findings and craniofacial anatomy are discussed in depth. Associated anomalies and syndromes are updated with a syndrome commentary that attempts to separate durable syndromes from associated anomalies and spurious entities. The differential diagnosis of various conditions that may simulate the holoprosencephalic disorders is also discussed. Various experimental approaches to holoprosencephaly are reviewed, indicating that holoprosencephaly appears to be both etiologically and pathogenetically heterogeneous.     

Production of identical twin and triplet mice by nuclear transplantation

Transplantation of a single nucleus from two- or four-cell embryos into one of the enucleated blastomeres of a two-cell embryo resulted in successful production of identical triplet and twin mice. The proportion of reconstituted embryos that developed in blastocysts was 71% (84/118) when four-cell embryos were used as donors of nuclei; 10 sets of quadruplet and nine sets each of triplet and twin blastocysts were obtained by this technique. After transfer to recipients, 30% (18/61) developed to term, and one set of identical triplet and four sets of identical twin mice were obtained. When two-cell embryos were used as donors of nuclei, 79 (95%) sets of twin embryos developed to blastocysts. Of 38 twin blastocysts transferred to recipients, 21 sets (55%) developed to term as identical twin mice. These results demonstrate that the enucleated two-cell embryo develops in vitro after transfer of a nucleus from a two- or four-cell embryo and the resultant blastocyst has high potential for development to term after transfer to a recipient.     

Production efficiency of Japanese black calves by transfer of bovine embryos produced in vitro

The objective of this study was to examine the production efficiency of Japanese Black beef calves after transfer of bovine embryos derived from an in vitro procedure. In vitro-produced (IVP) embryos were obtained from in vitro maturation and fertilization and in vitro development by co-culture with cumulus cells until 7 or 8 days after insemination. In vivo-developed (IVD) embryos from superovulated Japanese Black heifers and cows 7 days after artificial insemination were used as a control group. Bovine embryos were transferred nonsurgically to recipient cows on Day 7 +/- 1 of the estrous cycle. Pregnancy was diagnosed by palpation per rectum at Day 60 to 70 after estrus. Pregnancy, abortion, perinatal accident and birth rates were examined according to the origin of embryos (IVP or IVD), the number of transferred embryos (single or twin) and the storage status (fresh or frozen-thawed). In Experiment 1, production efficiency by twin transfer of fresh IVP embryos was examined. Higher pregnancy rates (52 1% vs 42 9%, P < 0.05) and birth rates (47.0% vs. 33.0%, P < 0.05) were obtained by twin transfer than by single transfer of fresh IVP embryos. Thus, the twin transfer of fresh IVP embryos was effective for production of calves, although the birth rates for single and twin transfers of fresh IVD embryos were still higher (55.5% and 76.1%, P < 0.05). But the abortion and perinatal accident rates for twin transfer of fresh IVP embryos were also significantly greater than those for single and twin transfer of fresh IVD embryos (P < 0.05). In Experiment 2, production efficiency by twin transfer of frozen-thawed IVP embryos was examined. Either single or twin transfer of frozen-thawed IVP embryos resulted in a similar pregnancy rate (41.3% vs. 46.7%, P > 0.05) and birth rate (34.1% vs. 41.1%, P>0.05). Thus, in combination with frozen-thawed IVP embryos, the twin transfer did not enhance production efficiency. In conclusion, Japanese Black beef calves could effectively produce calves by twin transfer to Holstein recipients when using fresh IVP embryos, and by single transfer when using frozen-thawed IVP embryos.