Congenital heart disease in CHARGE association

Summary This study reviews the spectrum of congenital heart disease and associated anomalies in 59 patients with the CHARGE association. We have analyzed our clinical experience in managing the cardiovascular anomalies and have reviewed outcome and risk factors for mortality. This study also highlights problems of cardiac management in children born with multiple system involvement. Twenty patients have died; actuarial survival was 78% at 1 year and 60% at 10 years. In only four of the nonsurvivors could their demise be ascribed to their underlying congenital heart disease. We found the outlook for survival was poor if more than one of the following three features were present; cyanotic cardiac lesions, bilateral posterior choanal atresia, or tracheoesophageal fistula. However, mortality was largely due not to the structural heart or choanae abnormalities, but instead reflected the underlying pharyngeal and laryngeal incoordination which resulted in aspiration of secretions. Furthermore, outcome is likely to be improved if collaboration between specialist surgical teams allows necessary procedures to be performed using the minimum of anesthetics. Examination of both the short-and long-term management of these children has stressed the importance of a multidisciplinary approach to their care. The pattern of cardiac defects was not random; lesions within the Fallot spectrum accounted for 33% of their congenital heart disease. Atrioventricular septal defects were also overrepresented. Not all cardiovascular defects could be explained by hypothesizing a neural crest etiology.     

Contemporary Approaches Toward Understanding the Pathogenesis of Hirschsprung Disease

Hirschsprung disease (HD), or congenital aganglionosis coli, is a birth defect with heterogeneous causes. In an effort to understand the molecular and cellular bases for this disorder, researchers have investigated enteric neurodevelopment in normal animals and compared these findings with observations of inbred animal strains that develop aganglionosis coli due to mutations at specific genetic loci. Recent technological advances, including use of retroviral and fluorescent lineage makers, immunohistochemical probes, and transgenic mice, have provided insights into the origins, behavior, and properties of enteric neuroblasts. Experiments with mutant murine embryos indicate that aganglionosis coli results from primary failure of neural crest-derived neuroblasts to colonize the distal colon. In at least one model, impaired colonization by neuroblasts may be secondary to environmental defects restricted to colonic mesenchyme. The discovery that human piebald trait, a hereditary disorder with a high incidence of HD, is caused by mutations in a growth factor receptor highlights the importance of regulatory intercellular interactions between nonneuroblastic mesenchyme and neuroblasts during normal development of the enteric nervous system. These observations, coupled with advances in molecular genetics, set the stage for dramatic progress in this field of research in the near future.     

颅底卵圆孔的观测

本文就广东出土的颅骨108个,计216侧卵孔的形态,位置和位置关系以及与三叉神经节穿刺有关的距离进行观测,见到卵圆孔呈卵圆形者占大多数(93.98±1.62%)。从卵圆孔外侧缘中点到颞下颌关节结节前根外侧缘的距离36.41±1.94mm、至颧下嵴切迹的距离47.98±3.07mm其两侧相互关系相对稳定,差异甚小。     

The appearance, density and distribution of melanocytes in human embryonic and fetal skin revealed by the anti-melanoma monoclonal antibody, HMB-45

Summary The presence, densities, and patterns of distribution of melanocytes in the epidermis of human embryos and fetuses, ranging in age from 40 d to 140 d estimated gestational age (EGA), were studied using the HMB-45 monoclonal antibody that recognizes an antigen in melanoma cells and fetal melanocytes. Immunostained sections of skin and epidermal sheets revealed dendritic melanocytes within the basal or intermediate layers of 50 d EGA and older skin. Melanocytes could not be identified by immunostaining or electron microscopy in younger (40–50 d EGA) epidermis or in cultured epidermal cells from these specimens. However, skin from a 45 d EGA embryo grown in organ culture for 11 d stained positively with HMB-45, suggesting that melanocytes are present at that age either in the epidermis or dermis of the explant. Double-labeling experiments using ATPase and HMB-45 confirmed the specificity of HMB-45 for melanocytes and demonstrated that melanocytes and Langerhans cells are nonoverlapping populations. Melanocytes were present in the embryonic epidermis in relatively high numbers (mean value of 1050 cells/mm²); they increased in density to 2300 cells/mm² during the late first trimester and early second trimester, then declined during later stages of development to a density of 800 cells/mm², within the range of values for the newborn child and young adult. Equivalent numbers of melanocytes were recognized by silver staining and with the HMB-45 antibody in an 87 d EGA test sample, indicating that HMB-45 reacted with the total melanocytic population. Melanocytes appeared to be distributed in epidermal sheets in a regular pattern. Statistical tests used to evaluate the randomness of a population revealed a tendency toward a non-random distribution in specimens younger than 80 d EGA, just prior to appendage formation and epidermal stratification into multiple layers, however there was variability in the degree of randomness for any given age. The results of this study have closed the gap in timing between the conclusion of neural crest formation and migration (around 6 weeks) and the appearance of melanocytes in the skin between 40–50 d EGA.Portions of this work were presented at the annual meeting of the Society for Investigative Dermatology, May, 1987 and at the 37th Annual Symposium on the Biology of Skin, October, 1987     

Neurocutaneous melanosis associated with Hirschsprung's disease in a male neonate

Hirschsprung's disease is an inherited disorder characterized by the absence of ganglion cells in the distal bowel. Neurocutaneous melanosis is a rare congenital syndrome characterized by proliferation of melanin-producing cells in the skin and leptomeninges. The authors described a newborn patient with neurocutaneous melanosis associated with Hirschsprung's disease. This male baby had congenital hydrocephalus, large and multiple pigmented skin nevi, and severe abdominal distension. He showed marked hydrocephalus at birth and underwent a ventriculo-peritoneal shunt at the age of 5 days. Investigations for gut motility disorders revealed typical findings consistent with Hirschsprung's disease involving the rectosigmoid colon. He was surgically treated for Hirschsprung's disease after transanal endorectal pull-through at the age of 7 months. After settlement of the ventriculo-peritoneal shunt, the transanal approach was of significant value for keeping the intraperitoneal catheter clean. The association of developmental disorders of melanocytes and enteric ganglia, both of which originated from the neural crest, suggested the presence of mutual pathogenetic factors in the patient.     

Origins of avian ocular and periocular tissues

The mesenchyme which surrounds the avian embryonic eye and forms all periocular skeletal and connective tissues, including the orbit and part of the cornea, is derived from two sources, the ectodermal neural crest and the mesoderm. Due to difficulties in distinguishing cells of these separate origins, the precise contributions of each to periocular tissues has not been defined. By transplanting labeled neural creast or mesoderm cells into unlabeled host embryos we have been able to catalogue first the migratory patterns of these populations and then their precise derivatives. Some donor tissues were labeled with [³H]thymidine; in other cases embryonic quail cells, which contain a replicating heterochromatin marker, were grafted into chick hosts. As the optic vesicle forms, its caudal (future temporal) surface is contacted by a sparse population of mesodermal mesenchyme; the rest of the eye is closely surrounded by superficial ectoderm. Shortly thereafter neural crest cells migrate over the caudal and rostral surfaces of the eye, forming the maxillary and frontonasal processes as well as presumptive scleral and choroidal cells. Neural crest cells form all of the skeletal and connective tissues adjacent to the medial, fnasal, ienrior, and lateral parts of the eye, including the endothelial and stromal cells of the cornea and much of the orbit. Most of the tissues behind the eye are derived from mesoderm, with the exception of the squamosal (temporal) bone. The myofibers of extrinsic ocular muscles are mesodermal, but connective tissues associated with these muscles are of neural crest origin. The ciliary muscles are formed from neural crest cells. Periocular vascular endothelial cells are all mesodermal, but peri-vascular connective tissues, including associated smooth muscles cells, are of neural crest origin. By performing heterotopic transplantations, for example replacing the chick prosencephalic neural crest with quail metencephalic crest, we have proved that neural crest cells from other regions of the head can mimic the development of periocular crest cells. This proves that the environment through which these cells migrate plays an essential role in establishing the timing and spatial patterns of their movement. Included in the environment are the basement membranes associated with epithelial tissues, such as the optic vesicle and superficial ectoderm. We have described several instances in which basement membranes underlying these epithelia become tightly apposed and appear to act as barriers to cell migration. The patterns of basement membrane apposition and subsequent separation are described and correlated with patterns of mesenchymal cell migrations.     

The acetabular reamer: a unique tool for anterior iliac crest bone graft harvesting

Bone grafting is often required in craniofacial reconstruction. Morselized corticocancellous bone grafts are particularly useful in applications such as filling and contouring irregular bony defects. Obtaining grafts of this consistency by traditional methods is difficult. An efficient harvesting method that can produce such grafting material in clinically useful quantities is needed. We report the use of a mechanical acetabular reamer for the purpose of harvesting a bone graft from the iliac crest.     

Pax3 mRNA is decreased in the hearts of rats with experimental diaphragmatic hernia

Rats with nitrofen-induced congenital diaphragmatic hernia (CDH) have heart hypoplasia and cardiovascular malformations. The mechanism of action of nitrofen involves changes in neural crest signaling. Pax3 function is required for cardiac neural crest cells to complete their migration to the developing heart. The aim of this study was to examine whether Pax3 expression is changed at two gestational endpoints in rat embryos or fetuses exposed to nitrofen. On day E9.5 of gestation, pregnant rats received either 100 mg of nitrofen (n=10) or vehicle alone (control, n=10). The fetuses were recovered on E15 or E21. Their hearts were dissected out and weighed. Pax3 mRNA expression was determined by real-time polymerase chain reaction. We used two-tailed Students t-tests to compare groups, with a threshold of significance of p<0.05. Compared with controls, nitrofen-exposed fetuses had heart hypoplasia in terms of heart/body weight ratio (0.62±0.10% vs. 0.77±0.17%, p<0.05). Pax3 mRNA expression in the heart was significantly decreased on E15 in nitrofen-treated embryos (32.94±17.11 U vs. 55.09±11.56 U, p<0.05), and it was still decreased, although not significantly, in the hearts of nitrofen-exposed fetuses recovered on E21 (15.67±5.56 U vs. 20.51±5.92 U, not significant). In conclusion, Pax3 is underexpressed in the hearts of nitrofen-exposed embryonal rats before the end of gestation. The mechanism of action of Pax3 should be further investigated because it could be one of the targets for future prenatal transplacental intervention.Paper presented at the XVIIth International Symposium of Pediatric Surgical Research, Liverpool, United Kingdom, 1–2 October, 2004.     

Constitutive Activation of the Neuregulin-1/erbB Signaling Pathway Promotes the Proliferation of a Human Peripheral Neuroepithelioma Cell Line

Neuregulin-1 (NRG-1) proteins, acting through their erbB receptors, promote the differentiation, survival and/or proliferation of many cell types in the developing nervous system, including neural crest cells and neural crest-derived Schwann cells. We have recently found that the proliferation of a neoplastic Schwann cell line is dependent on constitutive activation of the NRG-1/erbB signaling pathway and that overexpression of NRG-1 in myelinating Schwann cells induces the formation of malignant peripheral nerve sheath tumors. These observations suggested that NRG-1 might similarly promote mitogenesis in a variety of neural neoplasms including peripheral neuroepitheliomas, aggressive neural crest-derived neoplasms that arise in nerves and soft tissues. To test this hypothesis, we examined the expression of NRG-1 and its erbB receptors in SK-N-MC neuroepithelioma cells. SK-N-MC cells expressed multiple NRG-1 proteins and mRNAs encoding several alpha and beta isoforms from the sensory and motor neuron-derived factor NRG-1 subfamily as well as the NRG-1 receptor subunits erbB2, erbB3, and erbB4. The erbB receptors expressed by SK-N-MC cells were constitutively tyrosine phosphorylated and inhibiting these kinases with the erbB specific inhibitor PD158780 reduced SK-N-MC DNA synthesis in a dose-dependent manner. We conclude that constitutive activation of the NRG-1/erbB signaling pathway promotes the proliferation of SK-N-MC neuroepithelioma cells in vitro and hypothesize that NRG-1/erbB autocrine, paracrine or juxtacrine signaling may contribute to the development and/or progression of neuroepitheliomas in vivo.     

Goldenhar syndrome and neuroblastoma: a chance association?

Oculoauriculovertebral dysplasia, also called Goldenhar syndrome, includes several anomalies: epibulbar dermoids or lipodermoids, microtia, mandibular hypoplasia, vertebral, skeletal, cardiac and kidney anomalies, among others. Tumours have also been observed in patients with oculoauriculovertebral dysplasia. We report the first case of oculoauriculovertebral dysplasia associated with a neuroblastoma. This tumour consists of cells identical to early migratory neural crest cells in the embryo. Several theories have been proposed regarding the pathogenetic explanation of oculoauriculovertebral dysplasia. Currently, some researchers have suggested a deficiency in mesodermal formation or defective interaction between neural crest and mesoderm as a possible aetiology. CONCLUSION: It is suggested that the case reported here is an additional argument for an anomaly in neural crest cell migration or interaction with the mesoderm in the pathogenesis of oculoauriculovertebral dysplasia.