Acalvaria and hydrocephalus: a case report and discussion of the literature.
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Adult↗
Biomedical subjects
J R Siebert
Publications and source records attributed to J R Siebert.
Spontaneous cleft palate in a newborn gorilla (Gorilla gorilla gorilla).
OBJECTIVE: We report the first case of cleft palate in a newborn male gorilla (Gorilla gorilla gorilla). CASE HISTORY AND RESULTS: The full-term infant was born to clinically healthy, wild-caught parents and survived 5 days. Autopsy disclosed a unilateral cleft palate, moderate scalp hemorrhage (birth versus postnatal trauma), cerebral edema, and a sterile fibrin vegetation in the heart. The palate was also shorter and narrower than expected, and the biorbital breadth was reduced; otherwise, growth and development appeared normal. Standard cranial and intraoral radiographs and three-dimensional reconstructions of computerized tomographic (CT) scans provided thorough and noninvasive methods of studying the craniofacial complex and extracranial skeleton. By this technique, major findings were: intact premaxilla, interpremaxillary, and premaxillary/maxillary sutures; intramaxillary cleft with ipsilateral choanal atresia; mildly asymmetric inferior turbinates; and normal nasal septum and vomer. CONCLUSIONS: Except for choanal atresia, cleft palate was not associated with other major craniofacial or extracranial anomalies in this case. Choanal atresia has been observed at times with cleft palate, but to our knowledge, the association has not been reported in nonhuman primates. Cleft palate, with or without cleft lip, has been recognized in a variety of nonhuman primates, including the lemur, marmoset, tamarin, squirrel monkey, and macaque. Some occurrences are spontaneous, while others are syndromic and/or arise from genetic or teratogenic influences. Each mode of presentation is poorly understood in nonhuman primates, but in this case, the absence of relevant environmental or parental history suggests that the occurrence was spontaneous. Anatomic studies of nonhuman primates are particularly valuable when they involve endangered species and will hopefully increase our understanding of the pathogenesis and etiology of congenital disorders, as well as other relationships between nonhuman primates and humans.
Animals↗
Neuropathology: art and science.
So many examples of computer-designed (rather than human-designed) displays occurred at a recent meeting of the American Association of Neuropathologists that we were stimulated to develop simple guides to help improve presentation. Various color combinations provide examples of the best (and worst) contrast between the message and the medium (background).
Art↗
Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice.
Dominant megacolon (Dom) is a mutation in an uncharacterized murine gene which is associated with intestinal aganglionosis and the focal absence of melanocytes in heterozygous animals. The phenotype of Dom/+ heterozygotes is similar to the lethal spotted and piebald lethal mutations, which are due to defects in endothelin-mediated intercellular signals. In this study, the DbetaH-nlacZ transgenic marker for enteric neural crest cells is used to study the distribution of enteric neurons and their precursors in Dom/+ mice and embryos. Vagal neural crest-derived cells in wild-type embryos colonize the gut in a cranial-to-caudal progression. In Dom/+ embryos, colonization was retarded from the earliest stages examined (embryonic Day 11.0), including progression through the small intestine. The early onset of this defect contrasts with impaired neural crest colonization associated with the lethal spotted and piebald lethal mutations which manifest only in the large intestine. Analysis of Dom/+ - +/+ aggregation chimeras indicated that defective colonization is not an autonomous (intrinsic) property of Dom/+ neuroblasts, but like lethal spotted and piebald lethal, the Dominant megacolon mutation directly or indirectly affects microenvironmental signals which influence the migration, proliferation, and/or survival of enteric neural crest cells.
Animals↗
Intercellular signals downstream of endothelin receptor-B mediate colonization of the large intestine by enteric neuroblasts.
Mice homozygous for the piebald lethal (sl) mutation, which have a complete deletion of endothelin receptor-B, fail to form ganglion cells in the distal large intestine and are nearly devoid of cutaneous melanocytes. These phenotypic features stem from incomplete colonization of the hindgut and skin by neural crest-derived neuroblasts and melanoblasts, respectively. We have used expression of a transgene, dopamine-beta-hydroxylase-nlacZ, to study colonization of the enteric nervous system in sl/sl embryos and sl/sl <--> wild-type chimeric mice. Enteric neuroblasts derived from the vagal neural crest colonize the developing foregut, midgut and distal small intestine of sl/sl embryos in a cranial-to-caudal manner indistinguishable from sl/+ or +/+ embryos. However, colonization of the large intestine is retarded and the distal large intestine is never colonized, a developmental defect identical to that observed in lethal spotted (endothelin-3 deficient) embryos. The coat pigmentation and relative distributions of mutant and wild-type ganglion cells in sl/sl <--> wild-type chimeras indicate that the defect associated with endothelin receptor-B gene deletion is not strictly neuroblast autonomous (independent of environmental factors). Instead, intercellular interactions downstream of the endothelin receptor-B mediate complete colonization of the skin and gut by neural crest cells.
Animals↗
Diamniotic placentation associated with omphalopagus conjoined twins: implications for a contemporary model of conjoined twinning.
We have studied omphalopagus conjoined twins with a diamniotic monochorionic placenta. Although conjoined twins usually present in a single amniotic sac, one other example of diamniotic placenta has been reported in omphalopagus twins [Weston et al., 1990: Am J Med Genet 37:558-561]. Most theories concerning the pathogenesis of conjoined twinning exclude the possibility of diamniotic placentation. However, Spencer [1992: Teratology 45:591-602] recently elaborated a model for conjoined twinning based on duplication of organizing centers (primitive streaks) during gastrulation. We have considered the fate of embryonic membranes according to this model of omphalopagus twinning and show that diamniotic placentation is a predictable outcome.
Abnormalities, Multiple↗
Nitrofen-induced congenital diaphragmatic defects in CD1 mice.
In previous clinical reports, we have documented the association of several morphologic changes with congenital diaphragmatic hernia or, perhaps more appropriately termed, congenital diaphragmatic defect (CDD). These anomalies include decreased cardiac mass with left ventricular hypoplasia in infants with left-sided CDDs (Siebert et al., '84), enlarged, asymmetric chests (Siebert and Benjamin, '87), and extrathoracic anomalies (Benjamin et al., '88), including urinary tract anomalies and elevated kidney weights in otherwise normal kidneys (Glick et al., '90; Siebert et al., '90). Hypoplastic lungs and hearts and enlarged chests are thought to result from the herniation of abdominal viscera into the thoracic cavity, but for the renal abnormalities, pathogenesis is unclear. The findings are intriguing, for they could mirror unrecognized developmental relationships between the diaphragm, lung, heart, and kidney. In order to further examine these issues and to test the applicability of experimentally produced CDDs to human disease, we administered nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether), an herbicide known to produce diaphragmatic defects in rodents, to time-mated CD1 mice by gavage feeding on gestational days 8 and 9. Dosages were 200 (low dose) or 500 (high dose) mg/kg body weight, and fetuses were studied on gestational day 18. Diaphragmatic defects occurred in a dose-response fashion: 0% (0/48) control or sham-fed, 5% (5/104) in the low-dose group, and 25% (19/75) in the high-dose group. Several fetuses with cleft palate, renal agenesis, exencephaly/encephalocele, and/or Di-George sequence were noted at the high dose, the latter a previously undescribed finding. Diaphragmatic defects were primarily right sided and only associated with herniation of abdominal viscera in animals exposed to 500 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormalities, Drug-Induced↗
Relationship between epidemiologic risk factors and clinicopathologic findings in the sudden infant death syndrome.
The risk of sudden infant death syndrome (SIDS) is said to be enhanced by factors such as prematurity, low birth weight, and perinatal distress. The significance of risk factors for SIDS research was questioned because the majority of SIDS victims seem to lack them. Therefore, postmortem records of 1144 infants who died suddenly and unexpectedly in King County, Washington, over a 25-year period were studied. Deaths were classified as "explained" if a cause was apparent, "classic" SIDS if the history and autopsy were unrevealing or, where the diagnosis of SIDS was doubtful, as "probable" or "possible" SIDS. The infants' birth certificates were compared with those of 3647 infants born during a similar period. Seventy-nine deaths (7%) were explained. The 1065 previously certified as SIDS were reclassified classic SIDS (82%), probable SIDS (13%), and possible SIDS (5%). Low birth weight, small size for gestational age, prematurity, and low 5-minute Apgar scores each form a "continuum"; the possible-SIDS group had the highest proportion of such infants, followed by the probable- and classic-SIDS groups, which exhibit extensive overlap with the control population. A 5-minute Apgar score of less than 7 and delayed postnatal growth rate are not risk factors for classic SIDS. Risk factors are more prevalent in SIDS infants where the diagnosis may be doubtful. The great majority of SIDS victims possess fewer risk factors. To avoid the bias of confounding variables, SIDS research should focus on as "pure" a SIDS population as is possible.
Adult↗
Holoprosencephaly in a fetal macaque (Macaca nemestrina) following weekly exposure to ethanol.
Previous studies in rodents have indicated that the facial changes of fetal alcohol syndrome (FAS) closely resemble those of a mild form of holoprosencephaly. In order to examine this relationship in non-human primates, we evaluated a 133-day gestation macaque (Macaca nemestrina) with holoprosencephaly, median cleft lip and palate, and encephalocele. The mother had been given ethanol once per week (1.8 g/kg body weight) from weeks 2 to 19 postconception. Diagnosis of holoprosencephaly was made following ultrasound evaluation for polyhydramnios and delivery of the female fetus by caesarean section. Another fetus of identical age was delivered by caesarean section for use as a control. Both fetuses were studied by anthropometric, gross, radiographic, and histologic techniques. In the fetus exposed to alcohol, no extracranial anomalies were identified and the karyotype was normal. The brain was micrencephalic, with absent olfactory bulbs, tracts, optic nerves and chiasma, fused frontal lobes, and a single, dilated lateral ventricle; a parietooccipital encephalocele consisted of thin, dysplastic cortex bordering the ventricle; the cerebellum was dysplastic and superiorly displaced. Within the craniofacial complex, anophthalmia was bilateral; premaxillary components were absent, palatal shelves separate, the maxillae closeset, and the ethmoid bone small and deformed. Most of these defects are similar to those encountered in humans with holoprosencephaly and support the hypothesis of shared etiologic and pathogenetic relations between the facial anomalies of fetal alcohol syndrome and holoprosencephaly.
Animals↗
Possible trophic relationship between the growth of the lungs and kidneys in congenital diaphragmatic hernia (CDH)
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Hernia, Diaphragmatic↗
Urinary tract anomalies associated with congenital diaphragmatic defects.
Anomalies of the urinary tract occur in some 13-27% of infants with congenital posterolateral diaphragmatic defect (CDD) and are often severe (renal agenesis, dysplasia, hypoplasia, or hydronephrosis). To test the hypothesis that urinary and diaphragmatic anomalies share elements of pathogenesis, we reviewed 60 autopsy cases of CDD studied at our institution. Sixteen patients (27%) manifested anomalies of the urinary tract: 12 had markedly altered kidneys, 8 of which were unilateral and ipsilateral to the diaphragmatic defect. Among 27 patients free of gross urinary tract anomalies, kidney weights formed a skewed distribution, with most values above published norms for body weight; by analysis of covariance, kidney weight (as a function of body weight) was significantly greater in CDD than in a control population of infants free of chronic illnesses and congenital anomalies who died suddenly and unexpectedly. Differences in glomerular number and diameter could not be identified between the latter groups. In 71% of patients with isolated left CDD, the left kidney was heavier than the right, a reversal of the usual condition in infancy. These findings demonstrate that both marked and subtle changes of the urinary tract in CDD are generally ipsilateral to the diaphragmatic defect and suggest that the pathogenetic mechanisms responsible for urinary and diaphragmatic anomalies may overlap topographically. Aberrant morphogenesis within a developmental field or fields is one explanation for this.
Abnormalities, Multiple↗
Central nervous system malformations in the CHARGE association.
Of 144 patients with the CHARGE association (literature 136, new patients 8), 47 (33%) had either a postmortem examination (30) or computerized axial tomography scan (17) of the head. Twenty-six of 47 (55%) had definite central nervous system (CNS) malformations; arhinencephaly, with or without other defects (11), holoprosencephaly (2), holoprosencephaly with arhinencephaly (1), other forebrain defects (3), hindbrain defects (3), or other defects (6). The presence of CNS malformation was most strongly associated with choanal atresia. This review demonstrates a predominance of forebrain anomalies, particularly arhinencephaly and holoprosencephaly, which may provide a clue to the mechanism of abnormal morphogenesis involved in CHARGE association.
Abnormalities, Multiple↗
An anatomic comparison of cebocephaly and ethmocephaly.
Cebocephaly (hypotelorism, single-nostril nose) and ethmocephaly (hypotelorism, interorbital proboscis) lie in the middle of the spectrum of craniofacial changes associated with holoprosencephaly. Because these defects and thorough anatomic studies of them are rare, knowledge concerning morphologic as well as pathogenetic relationships is lacking. We report the autopsy findings and anatomic features of the dried skull of a 31 week fetus with cebocephaly and the craniofacial dissection of a 36 week fetus with ethmocephaly. Both manifested dysplastic changes of the ethmoid bone and anterior portion of the sphenoid bone, with concomitant hypotelorism and defects of the medial orbital walls. Through these latter defects, the eyes were joined in the ethmocephalic fetus (synophthalmia). Other changes of bone (single optic foramen, approximated maxillae, choanal atresia, thickened palate) and soft tissue (eccentric or fused extraocular muscles, single optic nerve) in both fetuses resembled those reported in other cases of cebocephaly and ethmocephaly, as well as cyclopia. In the 19th century, both cebocephaly and ethmocephaly were classified as two-orbit variants of cyclopia, a view supported by the present study.
Ethmoid Bone↗
Pathophysiology of congenital diaphragmatic hernia: I. Renal enlargement suggests feedback modulation by pulmonary derived renotropins--a unifying hypothesis to explain pulmonary hypoplasia, polyhydramnios, and renal enlargement in the fetus/newborn with congenital diaphragmatic hernia.
Survival of newborns with congenital diaphragmatic hernia (CDH) is largely dependent on the severity of pulmonary hypoplasia (PH) present at birth. Intrathoracic compression by the herniated abdominal viscera is thought to be the primary factor involved in the pathogenesis of the PH in CDH. Humoral and/or amniotic pulmonary growth factors (PGF) have been hypothesized to play a role in normal fetal pulmonary development and may be involved in the pathogenesis of CDH as well. The hypothesis of this paper is that growth of the fetal lung is stimulated by a PGF produced by the kidneys, which is modulated by a feedback signal from the lungs, a pulmonary derived renotropin (PDR). In the fetus with CDH, the lungs may be unable to respond to PGF due to compression by the herniated abdominal viscera. Theoretically, PH associated with CDH would maximally stimulate this feedback loop to release more PDR, resulting in continual stimulation of the kidneys and renal enlargement. If such a scheme plays a role in the in utero pathophysiology of CDH, then newborns with CDH should have enlarged kidneys. To investigate this hypothesis, we reviewed 30 autopsy cases of newborns with CDH and analyzed their kidney weights versus body weights, using historical data as control. Kidney weights in CDH cases were greater than the control population in 77% of the cases; 57% of kidney weights were more than one standard deviation above control values. Adjusted group mean kidney weights were 29.8 g (+/- 1.0 SE) in CDH cases and 25.9 g (+/- 1.5 SE) in the control population (P less than .04). These data support our hypothesis and demonstrate that in newborns with CDH and morphologically normal kidneys, there is significant renal enlargement associated with CDH. The presumed mechanism of this renal enlargement, as well as its relationship to normal and aberrant pulmonary growth and regulation are discussed. If such a selective PGF exists, its therapeutic implications for fetuses and newborns with PH are considerable.
Analysis of Variance↗
C-reactive protein and prealbumin in suspected sudden infant death syndrome.
This study investigated the levels of C-reactive protein (CRP) and prealbumin in 87 infants suspected of dying from sudden infant death syndrome (SIDS). These proteins change rapidly, within 24 hr, in patients who have an acute phase response, especially a response resulting from bacterial infection. In addition, prealbumin is sensitive to a recent reduction of protein or calorie intake. Eighty patients were determined to have typical SIDS. Only four of these had a minimal increase in CRP (0.8-2 mg/dl), and in none could an explanation be found. Seven patients were uncovered who had a significant infection, four of whom had prominent CRP elevations. Prealbumin was not decreased in the SIDS population. We conclude that there is no evidence that the acute inflammatory response is activated in infants dying of SIDS. An elevation of CRP above 2 mg/dl should prompt additional studies to find the cause. There is also no evidence of a recent, significant decrease in nutrition in these patients.
C-Reactive Protein↗
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.
Abnormalities, Multiple↗
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.
Central Nervous System↗
Ebstein's anomaly and extracardiac defects.
Ebstein's anomaly of the tricuspid valve occurs as an isolated defect with other forms of congenital heart disease such as transposition of the great arteries or tetralogy of Fallot or, rarely, in association with extracardiac malformations. Because so little is known about this latter group, we studied four cases clinically, at autopsy, and by means of a retrospective chart review. Major extracardiac changes most often involved the craniofacial region, central nervous system, and limbs. Karyotypes were normal, and no distinctive syndromes or anatomic patterns were identified. Since the timing of Ebstein's anomaly is quite precise, ascertainment of such cases on the basis of cardiac morphology may enhance the understanding of etiology and pathogenesis. Both causes and mechanisms may well be diverse, for the clinical histories and anatomic findings in present and previously reported cases vary considerably. Isolated Ebstein's anomaly may develop from topographically and temporally localized damage. Ebstein's anomaly with extracardiac defects may involve damage during a longer, and perhaps earlier, period.
Abnormalities, Multiple↗