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The pathologic anatomy of the central nervous system is described in a patient with Apert's syndrome. Multiple developmental anomalies of the brain were noted including disturbances of rhinencephalic organization. The association between maldevelopment of the rhinencephalon and the face is well known. Cranial vault malformations may also be associated with maldevelopment of the rhinencephalon.
INTRODUCTION: Fetal central nervous system (CNS) abnormalities have diverse etiologies, with genetic factors as a major contributor. Prenatal exome sequencing (ES) is a powerful tool for precise molecular diagnosis of CNS anomalies, but its diagnostic yield varies among studies. This study aimed to evaluate the additional diagnostic yield of prenatal ES compared with chromosomal microarray analysis (CMA) in fetuses with CNS anomalies detected by prenatal imaging. MATERIAL AND METHODS: We collected ES results from fetuses diagnosed with CNS anomalies by prenatal imaging (2019-2024) who had negative results. Subgroup analyses assessed phenotype-specific ES diagnostic yield for associated genes and variants. A systematic review and meta-analysis incorporating our data and published studies further explored the association between phenotype and diagnostic yield. RESULTS: In the cohort study of 219 cases, ES identified pathogenic/likely pathogenic single nucleotide variations in 36 cases (16%). The highest diagnostic yield of ES was in cases with multisystem malformations (25%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomalies (13%, 20/151). The most commonly identified isolated CNS anomaly was agenesis of the corpus callosum (31%, 5/16). Neural tube defects with urogenital anomalies were associated with a positive ES finding in 57% (4/7) of cases. The meta-analysis of 989 cases from 22 studies showed a pooled diagnostic yield of ES of 27% (95% CI, 21%-34%). The highest diagnostic yield of ES was in cases of corpus callosum anomalies with facial abnormalities (75%, 8/11) and neural tube defects with urogenital malformations (80%, 12/15). The diagnostic yield of ES for three or more CNS abnormalities was 43% (95% CI, 31%-58%), significantly higher than that for only two abnormalities (10%, 95% CI, 4%-18%). No significant difference in diagnostic yield was found between cases identified by prenatal MRI combined with ultrasound (27%, 95% CI, 20%-36%) and those identified by ultrasound alone (25%, 95% CI, 17%-35%). CONCLUSIONS: ES provided a significantly higher diagnostic yield than CMA for fetal CNS abnormalities, with diagnostic yields varying by phenotype. The systematic review and meta-analysis confirmed that the complexity and combination of malformations are key factors associated with differences in ES diagnostic yield.
Five patients with Down syndrome (DS) and infantile spasms were examined in a four-year interval. Previous reports of this association have been infrequent except during experimental treatment with 5-hydroxytryptophan, a precursor of serotonin. Malformations of the brain in DS are associated with an increased incidence of epilepsy, and both gross and cytoarchitectural anomalies have been described. The severity and distribution of these central nervous system anomalies presumably predispose to the infantile spasms. The contribution of altered serotonin metabolism is uncertain.
Meckel syndrome was diagnosed prenatally by alpha-feto protein and beta-trace protein determinations in amniotic fluid. No central nervous system anomalies were detected in the affected fetus, who presented with large polycystic kidneys and polydactyly. An excessive synthesis of these fetal proteins by the dysplastic kidneys is suggested, allowing for the possibility of prenatal diagnosis of polycystic kidneys in families at risk for this disease. The present family emphasized the importance of amniocentesis in pregnancies at risk for Meckel syndrome, regardless of the presence of a defect in neural tube closure.
The author presents cases of dysmorphic children born to alcoholic mothers to illustrate his discussion of the "fetal alcohol syndrome". The fact that this malformative syndrome has not been recognized before 1968 is amazing, particularly if one considers the high frequency of alcohol addiction and the relative specificity of the birth defects making up the syndrome. Newborns from severely alcoholic mothers are small for date, microcephalic, and they have abnormal facial features, as well as an increased frequency of other malformations (heart, genitalia, extremities). Neurological and mental deficiencies are recognized early in most of these children. Central nervous system anomalies are beginning to be described by the neuropathologists, which correspond to these clinical findings.
A case is presented of a new eight-month-old infant with congenital anophthalmos and ipsilateral absence of cerebral tissue. Various central nervous system anomalies are described as associated with anophthalmos. Therapy is directed toward enlargement of the socket by expansion and/or surgical techniques. Early expansion therapy within the first year of life appears warranted in view of differential orbital growth rates.
A variety of anomalies of the central nervous system are observed in trisomy 18. The present case describes an infant having a type II Arnold-Chiari malformation without spina bifida. One previous case of an Arnold-Chiari malformation was reported in trisomy 18 but that infant also had a lumbar meningomyelocoele. Abnormalities of cerebral gyration, hydrocephalus, and agenesis of the corpus callosum were also found in the present case.
Cavernous hemangioma of the retina is an unusual vascular hamartoma whose coexistence with vascular anomalies of the skin and central nervous system has been recognized recently. A 39-year-old woman, who had an acute palsy of the right third cranial nerve, had a history of seizures, cutaneous vascular anomalies, and a cavernous hemangioma of the retina of the right eye. One of her daughters demonstrated bilateral retinal cavernous hemangiomas, and another daughter, who developed seizures when febrile, displayed cutaneous vascular anomalies. A four-generation pedigree showed a number of cutaneous vascular anomalies, seizures, and stroke-related deaths. The pedigree suggests further support for considering this disorder an authentic oculoneurocutaneous triad.
A survey of all anaesthetists in the West Midlands region--that is, 10% of all the anaesthetists in England and Wales--showed that one in 10 of their children had been referred to a consultant because of a congenital or nonacquired anomaly. Abortions among anaesthetists' families were also common but more so when the mother was an anaesthetist. The anomalies were concentrated particularly in the central nervous system and musculoskeletal system, and girls were worst affected. The mean birth weights were below normal, more so when the mothers were anaesthetists. Girls with anomalies were particularly underweight. Other effects observed were unexpected infertility, cancer both in the adults and in the children, and, possibly, impaired intellectual development in the children. Many anaesthetising areas were inadequately ventilated, and scavenging devices despite their inefficiency are recommended as a stopgap measure. The results of the study closely resemble those of other studies with similar high response rates to requests for information.
Ribavirin, when given to pregnant hamsters in relatively small single doses, induces congenital anomalies of limbs, ribs, eyes, and central nervous system, as well as fetal deaths. On the basis of these findings, caution should be used in giving ribavrin to women of child-bearing age.
Review of 11 cases of agenesis of the corpus callosum studied at our institution revealed a high incidence of associated anomalies. None patients had associated malformations of the central nervous system, 6 involving the pyramidal system. Eight cases were associated with malformations in the rest of the body. Review of completely examined cases from the literature yielded 47 examples of associated malformations. These were varied and without consistent pattern, with the possible exception of facial abnormalities.
Fetal abnormalities involving the skeletal system, central nervous system or soft tissue may be diagnosed by radiologic methods, as may fetal death. Occasionally standard X-ray is used, but often invasive techniques are required, and should be limited to those patients with valid indications. X-rays of specific fetal anomalies are presented.
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Deep hypothermic circulatory arrest facilitates repair of congenital cardiac anomalies in infants. It is known empirically that hypothermia protects against central nervous system (CNS) ischemic damage. The Q10O2 is only 2.2 for brain and thus a decrease in metabolic rate does not fully account for protective effects of hypothermia. Since enthalpy of dissociation of H2O is high (approximately 7 kcal/mole), its pH is temperature dependent (7.0 at 25 degrees C, 7.4 at 20 degrees C) and hypothermia may in part protect by its influence on hydrogen ion concentration. A manifestation of CNS susceptibility to ischemia is an obstruction of the microcirculation [no-reflow lesion (NRL)] demonstrated by infusion of carbon black into the cerebral circulation after a period of circulatory arrest. White lesions (NRL) against a gray background on cut section of brain increase in size with increasing time of arrest. The effect of anoxia versus circulatory arrest, brain temperature, and extracellular brain pH on NRL was studied in 45 mongrel dogs, subjected to varying periods of N2-induced anoxia on cardiopulmonary bypass (CPB) at 37 degrees C or 20 degrees C. In some studies jugular venous pH was adjusted by infusion of NaHCO3 or HCl. Control groups included normothermic CPB without anoxic and normothermic CPB, anoxia, and equimolar NaCl infusion. NRL was quantified by planimetry of photographs of cut sections of brain. These results confirm that NRL is abated by hypothermia and suggest that (1) NRL is a function of anoxia and not arrested circulation since perfusion with N2 at 37 degrees C does not protect the brain (i.e., NRL is not solely related to "critical reopening pressure") and (2) NRL is in part a function of extracellular pH.
The teratogenetic periods of the most important CNS malformations are defined and briefly discussed. The results are presented in a synoptic figure. The present study is based on the analysis of normal CNS development and on morphogenetic interpretations of the pertinent anomalies. The data compiled from the literature concerning normal development are presented in an analytical table and are also summarized in a synoptic figure.
We have seen that what must be applied to dysmorphology is the doctrine of multifactorial causality, ie dysmorphogenetic events have both genetic and nongenetic etiologic components to varying degrees. Complicating matters is the extent to which there is etiologic and/or mechanistic heterogeneity (Fig. 1). This is nicely illustrated by the holoprosencephaly anomaly. In addition, there are numerous CNS malformations that have major single gene, chromosomal, or environmental initiating agents of malformation mechanisms. Still a mystery is the common neural tube malformations. It is now clear that the "multifactorial/threshold" model is an inadequate explanation of the observed data and until the etiologic heterogeneity of these malformations is clearly defined, our knowledge remains primarily empiric. A potential area of fruitful investigation is likely to be the identification of maternal genotypes which do not allow detoxification of potential environmental teratogens.
The persistent cloaca in the female newborn is one of the most complex and challenging developmental malformations that the pediatric urologist will encounter. A review of 5 patients seen at this center and 34 completely documented cases was undertaken to characterize the defects and devise a logical diagnostic and therapeutic approach. Diagnostic steps include the search for associated anomalies, which were present in the upper urinary tract (33 per cent), gastrointestinal tract (13 per cent), cardiovascular system (13 per cent), central nervous system (10 per cent) and respiratory tract (5 per cent). Delineation of the cloaca and its anatomic relationships is determined by abdominal x-rays, injection of contrast material into the cloacal channel, excretory urography and endoscopy with selective catheterization. Surgical treatment begins with a diverting right transverse colostomy in the newborn period followed by rectal pull-through when the patient weighs 25 pounds. Vaginal pull-through should be performed at the same time as the rectal pull-through if the vagina enters the cloaca high. If the cloacovaginal communication is low a vaginoplasty by a posterior flap procedure can be done when the child is 10 to 12 years old. Even is anatomy is reconstructed in an ideal manner urinary and fecal continence cannot be assured since congenital neurologic dysfunction is not uncommon.
Maternal dose--fetal teratogenic response data were obtained for a variety of narcotic and related compounds by single subcutaneous injections of the drugs into pregnant hamsters during the critical periods of central nervous system organogenesis. The number of abnormal fetuses from females injected with diacetylmorphine (heroin), thebaine, phenazocine, pentazocine, propoxyphene, and methadone increased as the maternal dose of the compounds was increased. By contrast, morphine, hydromorphone, and meperidine produced an increase in the number (per cent) of fetal anomalies only up to a certain maternal dose level. Further increases in maternal dose levels did not produce additional fetal anomalies. Comparative studies of single and multiple maternal doses indicated that diacetylmorphine (heroin) and methadone produced a four- to sixfold increase in fetal anomalies with repetitive doses whereas the percentage of malformed fetuses remained the same with hydromorphone (Dilaudid). The narcotic antagonists nalorphine, naloxone, levallophan, and cyclazocine blocked the teratogenic effects of both single and multiple doses of the narcotics.