Craniofacial

H. E. Ang, E. Deltour, T. E. Hayamizu, M. Zgombic-Knight and G. Duester, Retinoic acid synthesis in mouse embiyos during gasti ulation and craniofacial development linked to class IV alcohol dehydrogenase gene expression , /. Biol. Chem. 271 9526-9534(1996). 

Mice homozygous for an ETA receptor gene disruption show craniofacial malformations, such as cleft palate, micrognathia, microtia and microglossia. ETA (—/—) mice die shortly after birth due to respiratory failure. Mice with an ET-l-null mutation show the same cranciofacial malformations and, in addition, cardiovascular disorders (e.g. septal defects, abnormal cardial outflow tract, aortic arch and subclavian arteries). 

Balling, R., Mutter, G., Gruss, R, and Kessel, M. (1989). Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice. Cell 58 337-347. 

McLain, K., Schreiner, C., Yager, K., Stock, J., and Potter, S. (1992). Ectopic expression of Hox-2.3 induces craniofacial and skeletal malformations in transgenic mice. Mech. Dev. 39 3-16. 

Fetal alcohol syndrome (FAS) is a pattern of birth defects caused by maternal consumption of ethanol during pregnancy. It is recognized by growth deficiency, a characteristic set of craniofacial features and neurodevelopmental abnormalities leading to cognitive and behavioral deficits [85]. FAS is considered to be the most common non-hereditary cause of mental retardation. 

Prater, M.R. et al., Maternal treatment with a high dose of CpG ODN during gestation alters fetal craniofacial and distal limb development in C57BL/6 mice, Vaccine, 24, 263, 2006. 

National Institute of Dental and Craniofacial Research (NIDCR) guidelines available at... 

Craniofacial abnormalities, joint immobility, club-foot, claw-hand, scoliosis... 

As research in craniofacial abnormalities evolved, two key factors surfaced in the study of the mechanism of action and advancement of the biomedical research on the human cleft palate condition ... 

Steroidal alkaloids found in the Filiaceae family, primarily Veratrum and Zygadenus, have been responsible for large losses in livestock. Fluman and livestock deaths have occurred from accidental ingestion of death camas (Panter et al., 1987). Thousands of lambs have died or been destroyed because of Veratrum-indvLCQd malformations, most notably a craniofacial defect called cyclopia (Binns et al., 1965 James, 1999 Figure 2.8). Tracheal stenosis, skeletal malformations and early embryonic death are also common (Keeler and... 

Gaffield, W. and Keeler, R.F. (1996). Steroidal alkaloid teratogens molecular probes for investigation of craniofacial malformations, J. Toxicol. Toxin Rev., 15, 303-326. 

Toxicologists nowadays take a broad view of developmental toxicity they consider not only structural but also functional abnormalities to qualify as adverse, as long as they were produced as a result of exposures incurred in utero. Thus, for example, the developmental effects of chronic alcohol abuse by pregnant women, known as fetal alcohol syndrome (FAS), are characterized not only by the presence of certain craniofacial abnormalities, but also by a variety of disabilities such as shortened attention span, speech disorders, and restlessness. Although fully expressed physical deformities included in FAS are associated with heavy drinking, debate continues on the level of alcohol consumption, if any, that is without these more subtle effects on behavior. 

In 1963 J.H. Rubinstein and H. Taybi reported a rare human disease that induced mental retardation, an increased risk of neoplasia and physical abnormalities, including broad thumbs, big and broad toes, short stature and craniofacial anomalies. The molecular basis of the Rubinstein-Taybi syndrome (RTS) was later discovered to be a disruption of one copy of the human CREB binding protein (CBP or CREB-BP) gene that encodes the histone acetyltransferase CBP [3]. In addition to CBP, all mammals have a closely related acetyltransferase, p300. Retrospectively, RTS was the first disease found to be due to a defective acetylation process [1-3]. 

Several studies in rats, mice, and rabbits demonstrate that cycloheximide is embry-otoxic, fetotoxic, and teratogenic. Intraperi-toneal administration of doses as low as 250 pg/kg on day 10 of gestation produced central nervous system, craniofacial, and cardiovascular system abnormalities in rats. Musculoskeletal abnormalities were produced in mice after intraperitoneal administration of doses as low as 30mg/kg on day 9 of gestation. Subcutaneous administration of 5 mg/1 cycloheximide on day 11 caused postimplantation mortality in the mouse. Effects on fertility were observed in pregnant rabbits administered as little as 5 pg/kg on day 1 of gestation. 

A score of 3 is assigned when the nasal prominence is small, or in cases when there are small or misshapen optic or otic placodes (Fig. 14c, arrows). A score of 3 is also assigned when the mesencephalic flexure is irregularly shaped or it is small/narrow. Frequently, facial hypoplasia (reduced expansion/distance between the optic and otic placodes) accompanies this finding as the flexure abnormalities can indicate alterations in craniofacial mesenchyme populations. 

Cytochrome P450 inducer (oral contraceptive failure) Autoinduction Rare blood cell dyscrasias aplastic anemia, agranulocytosis Hepatotoxicity Rash risk, including Stevens-Johnson syndrome Risk for SIADH Teratogenicity risk neural tube defects, craniofacial defects... 

Because of the potential for hematological and hepatic toxicity, carbamazepine should not be administered to patients with liver disease or thrombocytopenia or to those at risk for agranulocytosis. For this reason, carbamazepine is strictly contraindicated in patients receiving clozapine. Because of reports of teratogenicity, including increased risks of spina bifida (Rosa 1991), microcephaly (Bertol-lini et al. 1987), and craniofacial defects (Jones et al. 1989), carbamazepine is relatively contraindicated in pregnant women. Pretreatment evaluation should include a complete blood count and determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 

Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis site specific malformations following exposure to serotonin uptake inhibitors. Teratology 1992 46 367-378. 

There is an increased risk of craniofacial defects, spina bifida, and developmental delay in children whose mothers received CBZ while pregnant. Thus, women of childbearing age should avoid this agent. If not practical, contraception should be diligently used to avoid pregnancy. In this context, dose adjustment of oral hormonal drugs may be necessary, since CBZ may accelerate their metabolism and compromise contraceptive effectiveness. 

Transient hypertrophic cardiomyopathy has been attributed to systemic glucocorticoid administration for a craniofacial hemangioma (28). 

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