Atelencephalic microcephaly: craniofacial anatomy and morphologic comparisons with holoprosencephaly and anencephaly.

This is the first detailed report of the craniofacial anatomy of atelencephaly. Comparisons were made with a control specimen and others with holoprosencephaly, anencephaly, and anencephaly with holoprosencephalic facial features. In the atelencephalic fetus, severe microcephaly, flattened calvaria, and partial synostosis of the metopic suture were apparent. The cranial fossae were much smaller than usual; lesser wings of the sphenoid were folded into a rounded basal mass. Facial features were pronounced, and orbits were hyperteloric, lowset, and rounded. Ethmoidal cartilages, nasal bones, and maxillary structures were distorted and elongated. The secondary palate was displaced inferiorly and cleft. Because major components of the craniofacial complex were generally present, although misshapen, changes in the atelencephalic skull seem to be deformations rather than malformations. Differences in the cranial morphology of associated disorders--holoprosencephaly and anencephaly--can be construed as aberrations of separate developmental fields. Relationships between atelencephaly and these fields are unclear.

Atelencephalic microcephaly in a 21-week human fetus.

Atelencephalic microcephaly, a rare and extreme disorder, is known morphologically by only six cases. Derivatives of the telencephalon are absent or dysplastic, while more caudal structures are normal or mildly deformed. A more extensive form, aprosencephaly, involves structures of the diencephalon and may be associated with holoprosencephalic facies. Extracranial anomalies may be present in both atelencephaly and aprosencephaly. We describe the seventh and youngest specimen, a 21-week female with atelencephaly. Maternal and gestational histories were unremarkable; the fetus was obtained by therapeutic abortion following diagnosis of a severe cranial malformation by ultrasound. A small and depressed, but intact, calvarium covered the brain. The forebrain was rounded and showed fused hemispheres, absent gyri, olfactory bulbs, and tracts. Caudal structures were mildly deformed. An oval mass of bone filled much of the middle cranial fossa. By light microscopy, several dysplastic changes were apparent in the forebrain. Ventricles were not present; small round cells resembling those of the germinal matrix were prominent in the forebrain. Pyramidal tracts were absent at all levels. The process responsible for these changes cannot be established with certainty; the changes are, however, in keeping with previous damage, such as that accepted for other encephaloclastic disorders. The insult in atelencephaly presumably occurs after closure of the rostral neuropore; earlier damage, with more widespread consequences, is possible for aprosencephaly. As with other destructive processes, etiology in atelencephaly and aprosencephaly is most likely heterogeneous.

Management of spina bifida and associated anomalies.

Myelomeningocele and its accompanying deformities are among the most complex and frequent of the malformations to which the developing nervous system is subject. a multidisciplinary approach to management of the patient with myelomeningocele is essential, and with aggressive and continuous care, the results may be extremely gratifying.

Arteriovenous malformations of the brain: a teratologic challenge.

Congenital arteriovenous malformations of the brain are lesions which are well-known to neurologists and neurosurgeons but are puzzling to teratologists because they occur sporadically and are unassociated with congenital malformations outside the central nervous system. They are recommended to teratologists as a field of etiologic and pathogenetic research.

Laissez-faire in research.

These were informal remarks in an after-dinner speech about nutritional and pediatric research as it was initiated 50 years ago when the Cincinnati Children's Hospital Research Foundation was opened. Although from the beginning there were "divisions" in the institute, the success of the organization was due to cooperation rather than division and to the freedom of the investigators to alter their directions according to their change of interests and to changes of needs and opportunities. A plea is made to let capable investigators choose their topics and their methods of research; they are most likely to have success when they are left alone and free of outside pressures.

Congenital malformations of the central nervous system and transplacental carcinogenesis: modification of ethylnitrosourea-induced brain tumors in rats by pretreatment with methylazoxymethanol.

X-irradiation of rat fetuses prior to exposing them transplacentally to the neurotropic carcinogen ethylnitrosourea (ENU) greatly reduces the frequency of offspring that develop neurogenic tumors. Since the tumor inhibition may have been related to the teratogenic effects of the irradiation of the fetal brain, it was of interest to learn whether another means of causing such brain damage would also interfere with the development of ENU-induced neurogenic tumors. For this purpose methylazoxymethanol (MAM), known to produce microencephaly, was used. Pregnant Sprague-Dawley rats were injected i.p. with 20 or 30 mg MAM/kg on the 15th day of gestation and 10 mg ENU/kg on the 16th or 20th day of gestation, or with either chemical alone. The offspring were observed during their life-span for the appearance of neurogenic tumors. MAM produced the expected microencephaly, but when administered alone caused no neurogenic tumors. ENU had no effect on brain size; and when administered alone produced high rates of offspring with neurogenic tumors (68 and 72% after treatment on the earlier and later day of gestation, respectively). The combined treatments resulted in significantly reduced frequencies of brain tumors, but did not modify the frequencies of non-brain tumors. The treatments caused relatively little or no excess pre- and postnatal mortality and for the most part had little effect on postnatal growth. Mean time of appearance of neurogenic tumors and mean number of neurogenic tumors per affected animal were unchanged by the dual treatments. There were no sex differences in tumor frequency, latency, or multiplicity. As noted, MAM reduced cerebral hemisphere size, but did not affect spinal cord size. The site of tumor inhibition by MAM thus appears to be correlated with the site of teratogenic damage. Nevertheless, various considerations led us to conclude that reduced number of target cells does not entirely explain the modifications in the frequency of tumors caused by MAM.

Experimental spina bifida and associated malformations.

Seven litters and 17 near-term rats of mothers treated with teratogens during gestation were analyzed for concordance and discordance of congenital malformations of the central nervous system. In animals with spina bifida a firm association with Arnold-Chiari malformation was found but only in fetuses near term. Associations with aqueduct stenosis and hydrocephalus were poor. In general, the findings support the theory that the components of the spina bifida complex develop from a common teratogenic disturbance but independent from each other.

Dose-related reduction by prenatal x-irradiation of the transplacental neurocarcinogenicity of ethylnitrosourea in rats.

Pregnant Sprague-Dawley rats were X-irradiated on the 16th day of gestation with 5 to 250 rads and given i.p. injections 4 days later with 10 mg ethylnitrosourea per kg. The offspring were observed over their life span for the appearance of neurogenic tumors. The frequency of animals surviving beyond 4 weeks of age that developed tumors was inversely related to X-ray dose. About 15% developed tumors after exposure to the largest doses, 39 to 46% after the intermediate doses, and 58 to 65% after the smallest doses; 69% tumors occurred after treatment with ethylnitrosourea alone. The reductions in tumor frequency were not due to the increased mortality rate of tumor-prone animals, either before or after the onset of tumor appearance. Mean offspring weight at 4 weeks and 4 months of age was inversely related to X-ray dose but was not significantly different in those animals later developing tumors from that in animals remaining tumor free. Mean time of tumor appearance and mean number of tumors per affected animal were unrelated to tumor frequency. It does not seem that the destruction of target cells is by itself sufficient to explain the results.

The medical profession and congenital malformations (1900-1979).

Physicians' interest in congenital malformations has varied greatly during the last two centuries. After an acme in the 19th century, teratology was of little inteerest to the medical profession during the first four decades of the 20th century. Since then a variety of events have again made birth defects important. An attempt is made to explain the waxing and waning of the physicians' attention to this age-old problem.