The teratogenicity of N(omega)-nitro-L-ariginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats.

Exposure of gravid rats to the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water or by implanted osmotic minipumps significantly elevates maternal blood pressure, reducing uteroplacental perfusion. Administration by either route causes fetal growth retardation, but oral exposure also causes hind limb reduction malformations. The present study employed both oral and intraperitoneal routes to determine the period of sensitivity to developmental toxicity, dose-response, and possible fetotoxic mechanisms. Hind limb hemorrhage occurred only in litters from dams exposed to oral doses of 1 to 2 mg/mL from gestational days 15 through 17. In contrast to oral exposure, single intraperitoneal injections caused both fore and hind limb reductions at doses of 25 mg/kg and above administered on gestational day 16 and later. Many other exposures that reduce uteroplacental perfusion have been associated with vascular disruptive dysmorphogenesis. These exposures include phenytoin, calcium channel inhibitors, cocaine, and uterine vascular clamping. Limb hemorrhage induced by these exposures is usually limited to distal structures, typically phalanges, and the incidence of affected fetuses rarely exceeds 50%. By contrast, hemorrhage caused by L-NAME frequently involves entire limbs, extending into adjacent flank in severe instances, and 100% of fetuses from treated dams may be affected. The basis of this difference and the differing defect patterns associated with the various routes of exposure are unclear, but the generation of reactive oxygen species during resumption of normal perfusion may play a role in this vascular disruption.

Epidemiology, etiologic factors, and prenatal diagnosis of open spinal dysraphism.

The caudal neural tube closes late in the first month after fertilization and failure of it results in myelomeningocele. Epidemiologic studies have shown differences in prevalence at birth based on ethnic-racial backgrounds and geography. Etiologic factors include the drug valproic acid or carbamazepine. Periconceptional folic acid supplementation appears to decrease the prevalence of neural tube defects. Numerous modalities allow for prenatal diagnosis of myelomeningocele. A cesarean section, before rupture of amniotic membranes and onset of labor, decreases the degree of paralysis.

Aberrant morphogenesis of the central nervous system.

This overview of congenital defects of the CNS has emphasized pathogenesis. As developmental pathways continue to be elucidated, this approach remains to an extent hypothetical. When, however, an understanding of the features of morphogenesis and dysmorphogenesis helps to indicate time of onset or to elucidate causal factors, important steps toward the prevention of birth defects are taken.

Management and long-term follow-up review of children with lipomyelomeningocele, 1952-1987.

The medical records of patients at Children's Hospital and Medical Center treated for lipomyelomeningocele repair were reviewed to assess the long-term outcome of surgery. In total, 108 children were cared for between 1952 and 1987, and long-term data are available for 80 of 96 children who underwent surgery. Cutaneous manifestations and associated malformations were common. Surgical repair was performed at ages 1 week to 17 years; there was no operative mortality. Thirty-five of 38 children with normal preoperative examination were without deficits on long-term follow-up review. Bowel and bladder paralysis was present in 42 children and did not recover after release of cord tethering. Eleven children had return of symptoms and were reexplored 3 to 8 years after initial surgery. Surgical repair with release of cord tethering at the time of diagnosis is advocated, regardless of patient age.

Anencephaly: its spectrum and relationship to neural tube defects.

Anencephaly patients are of renewed interest because they are regarded as a potential source of organ donation. While there has been a longstanding scientific curiosity on this subject, studies have frequently included such cases as part of the larger spectrum of neural tube defects (NTDs). This paper will discuss some unusual features of anencephaly. Following a review of classification and pathogenesis, associated malformations, growth parameters (organ size and anthropometric measurements), and associations with other entities are discussed. Finally, the relationship of anencephaly to NTDs is presented.

Pathophysiology of isolated lateral ventriculomegaly in shunted myelodysplastic children.

Eight myelodysplastic children developed isolated lateral ventriculomegaly following shunt insertion for progressive hydrocephalus after closure of a myelomeningocele. In all patients a low-pressure distal slit valve (Uni-shunt) system preceded development of an isolated contralateral ventricle. Six of 8 children required a second contralateral shunt for a symptomatic isolated ventricle. Magnetic resonance imaging demonstrated a collapsed ventricle ipsilateral to the shunt secondary to distortion of the foramen of Monro. This was clearly depicted using three-dimensional color reconstructions of the ventricular anatomy. Low-pressure distal slit valves should be avoided in myelodysplastic children to prevent postshunt ventricle isolation.

Hemangioblastoma of the conus medullaris associated with cutaneous hemangioma.

A 6-month-old infant is reported with a spinal cord hemangioblastoma located in the conus medullaris associated with an overlying congenital dermal sinus and cutaneous capillary hemangioma. There were no neurologic deficits either preoperatively or following removal of the tumor. The skin and spinal cord lesions were believed to represent an isolated vascular malformation. This spinal cord hemangioblastoma is unusual because of the age of the patient, manner of clinical presentation, location in the caudal spinal cord, and pathologic characteristics. We review the literature and discuss the associations of spinal cord hemangioblastomas with cutaneous and other lesions.

Neural tube defects.

Neural tube defects (NTDs) are a group of malformations of the brain and spinal cord that originate at various times during gestation. The most common NTDs are anencephaly and meningomyelocele, which arise during the process of neurulation, a well-defined period between the 17th and 30th day after ovulation. These NTDs are clinically apparent by being open, ie, leaving nervous tissue exposed, in contrast to postneurulation NTDs that are skin covered. The incidence of NTDs is declining in several areas of the world, including the United States. While the reasons for this are unclear, there seems to be some effect from prenatal diagnosis, genetic counseling, and possibly nutritional supplementation.

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.

Coma scale for use in brain-injured children.

The association between admission coma score and eventual outcome was assessed using a coma scale developed for children with a variety of central nervous system injuries. As opposed to the Glasgow coma scale, this scale does not demand assessment of verbalization, and thus can be applied to the preverbal or previously intubated child. Cortical function is graded from 6 (purposeful, spontaneous movements) to 0 (flaccid), and brainstem function is graded from 3 (intact) to 0 (absent and apneic). Maximum total score is 9. In 91 children treated for intracranial hypertension, the association was moderately good. The scale was better in predicting the outcome of patients with hypoxic encephalopathy and head trauma than that of patients with Reye's syndrome, meningitis, or encephalitis. No child with a score of less than 3 survived in spite of intensive therapy. Most of these children were flaccid with depressed or absent brainstem reflexes. No child with flaccidity on admission survived.

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.

Neural tube defects: clinical correlations.

There are several approaches that can be applied to the analysis of malformations of the CNS. One practical way in making clinical correlations is to divide neural tube defects into those that arise during the period of neurulation and those that arise thereafter. This concept applies to cranial and spinal lesions and makes it possible to interpret clinical findings with embryological events. Malformations of the CNS that arise during the period of neurulation are not covered by skin and can be diagnosed prenatally by amniocentesis. Postneurulation CNS malformations are skin-covered and have differing patterns of associated malformation and etiologies. There is an overlap of the latter group with congenital tumors, and for the most part these malformations are not apt to be diagnosed prenatally.

Syndromes with cephaloceles.

Encephaloceles may occur as isolated malformations or together with other anomalies making up various syndromes or associations. With the possible exception of the aberrant tissue band syndrome and the Meckel syndrome, little attention has been paid to syndromes with encephaloceles as a group. This paper discusses syndromes of known genesis, including the aberrant tissue band syndrome, Chemke syndrome, cryptophthalmos syndrome, dyssegmental dwarfism, frontonasal dysplasia, Knobloch syndrome, Meckel syndrome, pseudo-Meckel syndrome, von Voss syndrome, and warfarin syndrome. Associations include a wide range of anomalies that may occur with encephalocele. Some abnormalities are secondary to encephalocele formation; others represent primary noncontiguous embryonic malformations. Associated anomalies include absent corpus callosum, orofacial clefting, craniostenosis, Dandy-Walker defect, Arnold-Chiari defect, ectrodactyly, hemifacial microsomia, hypothalamic-pituitary dysfunction, Klippel-Feil anomaly, iniencephaly, and myelomeningocele. Finally, several other conditions with encephalocele are discussed. Some may represent true low-frequency associations; others are spurious.

Pathogenesis of congenital tumors and malformations of the sacrococcygeal region.

Skin-covered lesions in the sacrococcygeal region include an unusual array of congenital tumors and malformations. Excluding the easily recognized meningomyelocele, there are over 50 other conditions that occur, many of which seem to be important in linking the disciplines of teratology and oncology. While it is impossible to precisely determine the manner in which these arise, there is suggestive evidence that early structures incorporated within the caudal cell mass of the embryonic tail may play an important role. The present paper reviews the basis for this speculation from both the literature and a series of 136 cases.

The facial features of holoprosencephaly in anencephalic human specimens. I. Historical review and associated malformations.

At least 19 human anencephalic specimens have been published which have the facial features of holoprosencephaly. All categories of holoprosencephaly are represented except ethmocephaly, the rarest form. Because of current scientific and clinical interest in both neural tube defects and holoprosencephaly it seems important to establish whether or not this association occurs by chance alone. The study of human embryos with holoprosencephaly by Matsunaga and Shiota ('78) and the anencephalic collection of Lemire et al ('78) suggests the association may be real.

The facial features of holoprosencephaly in anencephalic human specimens. II. Craniofacial anatomy.

The craniofacial anatomy of two anencephalic human specimens with the facial features of holoprosencephaly is reported. Many of the malformations have distinctly holoprosencephalic or anencephalic features. Absence of the entire ethmoid complex, observed in both specimens of the present study, has rarely been described and, to our knowledge, has never been confirmed histologically. The significance of agenesis of the ethmoid bone in the development of normal and holoprosencephalic facial features has not been considered previously. On the basis of several morphological variations in the two specimens described, it is evident that the ethmoid bone provides integral support in multiple planes for tissues of the median face. It is postulated that the spatial relationships of the bony and soft tissue components of the median face are guided and maintained by the ethmoid complex during morphogenesis. Specifically, hypotelorism and superiorly displaced structures of the nose and upper lip may well represent migration of embryonic tissues into areas normally occupied by the ethmoid bone. Absence of the sella turcica and pituitary gland is ascribed to the holoprosencephalic process. A variant of choanal atresia, due to collapse of the pterygoid plates, is described.

The association of spinal retroflexion with limb anomalies.

The spectrum of conditions in which retroflexion of the spine occurs includes anencephaly, iniencephaly, and Klippel-Feil syndrome. It was suggested by Gimour ('41) that a continuum may exist linking the latter two entities. The present paper attempts to reopen this question by reporting two specimens which have none of the above conditions, yet have spinal retroflexion and limb malformations. Combined with other isolated case reports, they show that spinal retroflexion can arise over a variable period of time.