Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome.

PURPOSE: CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary tract abnormalities, and Ear abnormalities and deafness) is the second-leading cause of deaf-blindness after Usher syndrome. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients. We tested the hypothesis that tissue-specific mutant mice provide models for molecularly dissecting CHD7 functions during eye development. METHODS: The conditional Chd7flox allele was mated together with tissue-specific Cre transgenes. Immunohistochemistry was used to determine the normal CHD7 pattern in the early eye primordia and to assess Chd7 mutants for expression of region-specific protein markers. RESULTS: CHD7 is present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm results in severely dysmorphic eyes generally lacking recognizable optic cup structures and small lenses. Deletion from the neural ectoderm results in similar defects. Deletion from the surface ectoderm results in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm are present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depends on the Chd7 gene dose within the neural ectoderm. CONCLUSIONS: Eye development requires CHD7 in multiple embryonic tissues. Lens development requires CHD7 in the surface ectoderm, whereas optic cup and stalk morphogenesis require CHD7 in the neural ectoderm. CHD7 is not absolutely required for specification of the major subdivisions within the neural ectoderm. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. These data indicate the Chd7 mutant mice are models for determining the molecular etiology of ocular defects in CHARGE syndrome.

Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research.

In this review, our work on CHARGE syndrome will be used to exemplify the role of rare cases in birth defects research. The analysis of 29 cases with mutations of CHD7, the causative gene for CHARGE syndrome, clarified the relative importance of the cardinal features, including facial nerve palsy and facial asymmetry. Concurrently, in situ hybridization using chick embryos studies were performed to delineate the expression pattern of Chd7. The Chd7-positive regions in the chick embryos and the anatomical defects commonly seen in patients with CHARGE syndrome were well correlated: expression in the optic placode corresponded with defects such as coloboma, neural tube with mental retardation, and otic placode with ear abnormalities. The correlation between expression in the branchial arches and nasal placode with the clinical symptoms of CHARGE syndrome, however, became apparent when we encountered two unique CHARGE syndrome patients: one with a DiGeorge syndrome phenotype and the other with a Kallman syndrome phenotype. A unifying hypothesis that could explain both the DiGeorge syndrome phenotype and the Kallman syndrome phenotype in patients with CHARGE syndrome may be that the mutation in CHD7 is likely to exert its effect in the common branch of the two pathways of neural crest cells. As exemplified in CHARGE syndrome research, rare cases play a critical role in deciphering the mechanisms of human development. Close collaboration among animal researchers, epidemiologists and clinicians hopefully will enhance and maximize the scientific value of rare cases.