Number of axons in the corpus callosum of the Mature macaca nemestrina: increases caused by prenatal exposure to ethanol.

The effects of prenatal exposure to ethanol on the number of callosal axons were examined. Pregnant Macaca nemestrina were treated with ethanol (1.8 g/kg b.wt.) 1 day per week during the first 6 weeks (Et6) or full 24 weeks (Et24) of gestation. Control macaques were intubated with an isocaloric amount of sucrose water (Ct). The mid-sagittal area of the corpus callosum in 4- to 5-year-old offspring was examined in magnetic resonance (MR) images and in fixed brains. The number of callosal axons was determined by using electron microscopy. In both MR images and fixed brains of macaques treated with ethanol, the corpus callosum was 26% larger than in the controls. The rostral portion was particularly affected by ethanol; it was 55% larger in Et6- and Et24-treated macaques. Axonal size and myelin thickness were unaffected by ethanol, but ethanol-treated macaques had more callosal axons (13.7 x 10(7)) than did controls (9.4 x 10(7) axons). The increase in the rostral corpus callosum suggests that parietal and frontal cortices are particularly susceptible to ethanol. The altered callosal connectivity may be a component of the structural abnormalities that underlie executive processing problems associated with fetal alcohol syndrome.

Analysis of facial shape in children gestationally exposed to marijuana, alcohol, and/or cocaine.

The association between fetal marijuana and/or alcohol exposure and facial features resembling fetal alcohol syndrome was investigated in a sample of 80 children. Standardized lateral and frontal facial photographs were taken of 40 children, 5 to 7 years of age, whose mothers reported frequent use of marijuana during the first trimester of pregnancy and 40 children whose mothers reported no use of marijuana during pregnancy. The marijuana-exposed and unexposed children were group-matched on alcohol exposure prior to and during pregnancy, sex, race, and age at the time of assessment. The photographs were assessed clinically by a study staff dysmorphologist and morphometrically by computerized landmark analysis. Fetal alcohol syndrome-like facial features were not associated with prenatal marijuana exposure in this study sample. No consistent patterns of facial features were identified among the marijuana-exposed group. Maternal consumption of two or more ounces of alcohol per day, on average, in early gestation was found to be associated with fetal alcohol syndrome-like facial features identified both clinically and morphometrically. Cocaine use reported by 13 of the 80 women was independently associated with mild facial dysmorphic features of hypertelorism and midfacial flattening. The results demonstrate the usefulness of this diagnostic technique for quantifying anomalies apparently unique to fetal alcohol syndrome and for targeting clusters of anomalies in new conditions for future evaluation.

Isolated tibial hemimelia in sibs: an autosomal-recessive disorder?

Isolated tibial hemimelia is generally considered to occur sporadically. We report on isolated tibial hemimelia in two sibs born to phenotypically normal parents and review a similar case from the literature. These cases suggest autosomal-recessive inheritance. Whether isolated tibial hemimelia represents a discrete syndrome or an expression of a disorder with wider phenotypic variability remains unclear.

Brief clinical report: the del(4) (q31) syndrome- a recognizable disorder with atypical Robin malformation sequence.

Deletions of the terminal region of the long arm of chromosome 4 have been reported previously in 6 patients. With the addition of our patient with 46,XX,del(4) (pter leads to q31:), it becomes clearer that this is a recognizable syndrome. None of the 7 patients has had prenatal growth deficiency, while postnatal growth deficiency has been variable. The syndrome is typified by a Robin malformation sequence without apparent catch-up growth of the mandible, anomalous auricles, a short nasal septum with a depressed nasal bridge, absent 5th finger creases, clinodactyly, and displacement of the toes. Mental retardation has been found consistently.

Extending the Pallister-Hall syndrome to include other central nervous system malformations.

Hall-Pallister syndrome is defined by specific facial anomalies, post axial polydactyly, imperforate anus, and brain anomalies including a rare diencephalic mass, hypothalamic hamartoblastoma. In this article, two patients are described with the usual features of Hall-Pallister syndrome, including diencephalic anomalies, but without hamartoblastomas. These patients may suggest an appropriate extension of the definition of the Hall-Pallister syndrome.

Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly--a new syndrome? Part II: Neuropathological considerations.

Unusual and virtually identical hypothalamic tumors were recently studied in three unrelated neonates with a similar complex malformation syndrome. Previous reports of either the hypothalamic tumors or the syndrome as a whole have not been found. Each tumor was apparent on the inferior surface of the cerebrum and extended from the optic chiasma to the interpeduncular fossa. The tumor replaced the hypothalamus and other nuclei which originate in the embryonic hypothalamic plate; it was principally composed of cells resembling primitive, undifferentiated germinal cells. The term "hamartoblastoma" is used to designate these tumors in order to emphasize the malformational and neoplastic aspects. In addition, short olfactory tracts suggest a relation to the arrhinencephaly field defect.

Partial deletion of the long arm of chromosome 11 [del(11)(q23.3----qter)] with abnormal white matter.

A patient with partial deletion of the long arm of chromosome 11[del(11)(q23.3----qter)] had macrocephalic trigonocephaly, growth and mental retardation, congenital heart defect, and characteristic facial appearance familiar to that of 33 other reported patients with this deletion. Computed tomography (CT) and magnetic resonance imaging of this infant's brain demonstrated abnormality of the supratentorial white matter. This may represent either deficiency or delay in myelination or possibly a demyelination process. No abnormalities in white matter were described in seven of 33 previously reported patients whose brains were examined by ultrasound, CT, or autopsy.

Facial effects of fetal alcohol exposure: assessment by photographs and morphometric analysis.

This study was designed to assess the limits of alcohol-related facial dysmorphogenesis. Standard full face and lateral facial photographs were obtained on 21 7-year-old children who had been exposed gestationally to known, heavy quantities of ethanol. Only two of these children had been previously considered to have definite fetal alcohol syndrome (FAS). Similar photographs of 21 other 7-year-old children with negligible gestational ethanol exposure were obtained for control purposes. Copies of the 42 photographs were given to each of seven expert clinicians who were asked to select any child with an FAS-related facial appearance. Six of seven judges were accurate in identifying children with high levels of alcohol exposure as having a fetal alcohol-affected face. A set of homologous points on the photographs were then digitized and analyzed by newly developed morphometric methods to determine the facial shape characteristics that distinguish the selected photographs of highly exposed children. The analysis confirmed that the judges specifically identified children with facial changes consistent with those previously published as defining the face of the FAS: short palpebral fissures, a relatively long and flat midface, and a retrusive mandible. This methodology may be useful in more accurately delineating the facial phenotype in other conditions diagnosed primarily on the basis of subjective clinical criteria.

Verification of the fetal valproate syndrome phenotype.

We have evaluated 19 children who were exposed to valproic acid (VPA) in utero to look for manifestations of a fetal valproate syndrome (FVS), as proposed by Di Liberti et al. [1984]. We found no consistent alterations of pre- or postnatal growth with exposure to VPA monotherapy. Postnatal growth deficiency and microcephaly were present however, in two thirds of children exposed to VPA in combination with other anticonvulsants. Developmental delay or neurologic abnormality was found in 71% of those exposed to VPA monotherapy, and in 90% of those exposed to VPA and other anticonvulsants. Craniofacial anomalies, which can be seen with other anticonvulsant exposures, including midface hypoplasia, short nose with a broad and/or flat bridge, epicanthal folds, minor abnormalities of the ear, philtrum or lip, and micrognathia were also found in infants whose mothers used VPA. Prominent metopic ridge and outer orbital ridge deficiency or bifrontal narrowing and certain major anomalies such as tracheomalacia, talipes equinovarus (with intact spine) and lumbosacral meningomyelocele seem to be peculiar to infants with VPA exposure. Other defects such as urogenital anomalies, inguinal or umbilical hernias, and minor digital anomalies that are common to other prenatal anticonvulsant exposures are also occasionally found in those exposed to VPA. Heart defects have been found in infants exposed to nearly every class of anticonvulsant although the types of defects associated with maternal VPA use may be clarified when classified by pathogenetic mechanism. Our findings overall are in agreement with the report of Di Liberti et al. [1984].

Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly--a new syndrome? Part I: clinical, causal, and pathogenetic considerations.

We report on six infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some, but not all, patients had laryngeal cleft, abnormal lung lobulation, renal agenesis and/or renal dysplasia, short 4th metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congenital heart defect, and intrauterine growth retardation. The infants also had hypopituitarism and hypoadrenalism. All were sporadic cases, parents were not consanguineous, chromosomes were apparently normal. Family histories were unremarkable. There was insecticide and/or herbicide exposure in several of the cases, but no exposures were common to all 6 mothers. Five of the patients were born within an 8-month period, but all in different geographic locations. It is postulated that this is a previously apparently unreported syndrome of presently unknown cause.

Studying alcohol teratogenesis from the perspective of the fetal alcohol syndrome: methodological and statistical issues.

Alcohol is a teratogenic drug and the effects appear to be grossly dose related. The severest effects are observable clinically as the fetal alcohol syndrome and are associated with heavy prenatal alcohol exposure and a history of chronic maternal abuse of alcohol. Hypotheses for subtler behavioral effects associated with lower levels of exposure can be generated from observation of the behavioral effects in FAS. Behavioral effects associated with various levels of prenatal alcohol exposure in humans include poor sucking and poor habituation in the newborn, poorer mental and motor development in infancy, and attentional and reaction time effects at four and seven years of age. Human behavioral teratology studies are necessarily complex due to the large number of covariates that affect behavior, modify the effects of teratogens, and influence interpretation. Challenging problems exist in assessing exposure, outcomes, and covariates. Common to assessment of all these classes of variables are the multiplicity of measurement and the indirect nature of the measurement. Answering specific questions about timing and dose effects demands careful statistical modeling procedures and large, complex data bases. Large data bases and indirect measurement problems suggest factor analytic extensions of current regression methodology, which we have proposed in this paper.

Neuropathologic findings in the spinal cords of 10 infants with arthrogryposis.

The lumbosacral cord segments of 10 infants with varying clinical forms of neurogenic arthrogryposis were compared with similar spinal cord segments from an infant with congenital contractures secondary to uterine constraint, 8 infants with Werdnig-Hoffman syndrome, and 11 age-matched controls. Neuronal numbers, sizes, and distribution were measured within the anterior horns. In addition to the classical reduction in the numbers of alpha motor neurons in both pathologic states, this study found the smaller neurons of the anterior horn were absent or diminished in Werdnig-Hoffman syndrome, while those cells were present in increased numbers with abnormal histology in all the patients with arthrogryposis. In 5 of the patients with arthrogryposis, the pathologic pattern was consistent throughout each cord segment; in 5 others, normal alpha neurons were retained and unequally distributed in the anterior horn segments. This unequal distribution predicted the muscle group involvement and suggested the mechanism for intrauterine joint fixation in these patients. The pathologic changes in the patients with arthrogryposis appear to be unique in spite of the heterogeneity of etiology and the clinical presentation.

Neuroanatomic examination of spina bifida aperta and the Arnold-Chiari malformation in a 130-day human fetus.

A 130-day human female fetus with the Arnold-Chiari malformation and thoracolumbar myeloschisis revealed evidence of neuroectodermal-mesodermal spatial dyssynchrony. The rhombencephalon and the cervico-medullary junction appear most affected. The phylogenetic and ontogenetic development of the transition zone between brain and spinal cord is reviewed. It is hypothesized that the etiologic event responsible for the Arnold-Chiari malformation is the caudal "displacement" of the site of initial fusion of the neural folds. This is believed to result in the posterior displacement of the cervico-medullary junction and myeloschisis (the Arnold-Chiari malformation, type II).

Magnetic resonance imaging and spectroscopy in fetal ethanol exposed Macaca nemestrina.

Magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) offer noninvasive ways to observe structural and biochemical changes which might serve as valuable diagnostic markers for detecting brain damage from prenatal ethanol teratogenesis. Cranial MR imaging and spectroscopy were performed on 20 nonhuman primates (Macaca nemestrina) with known prenatal ethanol exposures and well-documented cognitive and behavioral levels of performance. The choline: creatine ratio detected by 1H-MRS in the brain increased significantly with increasing duration of in utero ethanol exposure. These signal alterations occurred in the absence of gross structural brain anomalies (detectable by MRI) and were significantly correlated with alcohol-related cognitive and behavioral dysfunction. These observations are consistent with reports of elevated choline: creatine ratios associated with various neurologic insults and disease states. The association observed between brain choline:creatine ratios and in utero ethanol exposure suggest a role for 1H-MRS in elucidating mechanisms of ethanol teratogenicity.

The origin of prenatal and postnatal deformities.

Deformities are abnormalities of shape or form caused by abnormal or imbalanced mechanical forces. In prenatal deformation, most infants are intrinsically normal and the deformation results from extrinsic constraining forces. Most prenatal deformities will resolve spontaneously or with the application of counteracting forces. In contrast, postnatal deformities result from either extrinsic pathologic processes, affecting the bones, nervous system, or muscle and resulting in the application of abnormal forces to bone, or normal forces acting on intrinsic diseases of bone. While many postnatal deformities can be contained or corrected by the application of counteracting forces, aggressive physical therapy, casting, or surgery is often required for correction.

Congenital deformities.

Forty years ago Denis Browne wrote that the medical world was ignoring an important distinction among birth defects. There were, he said, a large group of abnormalities caused not by genetic errors or teratogens but simply by fetal constraint. These abnormalities, if recognized early, could be readily ameliorated with simple, conservative forms of therapy. Today the full range and frequency of deformations are still not well appreciated and yet the recognition of these deformities may be more important than ever. The public is becoming increasingly aware of environmental hazards and genetic risks to their unborn children. They know of the difficult problems faced by families when malformed children are born. The physician who can rapidly and accurately diagnose deformities treats a good deal more than the problems of aberrant fetal molding.

A periodic dosing model of fetal alcohol syndrome in the pig-tailed macaque (Macaca nemestrina).

A nonhuman primate on a periodic ethanol dosing schedule should provide a model of fetal alcohol syndrome (FAS) most relevant to the majority of pregnant women who are "social drinkers" and can exercise reasonable control over their ethanol intake. In this pilot study, four pregnant pig-tailed macaques (Macaca nemestrina) received ethanol once a week from 40 days' gestation. Doses were 2.5 gm/kg for three moderate-dose animals (MDAs) and 4.1 gm/kg for one high-dose animal (HDA). Peak blood ethanol levels reached a mean of 240-256 mg/dl for the MDAs and averaged 379 mg/dl for the HDA. Peak acetaldehyde did not vary with dose. One MDA aborted after the first dose. The other three pregnancies were compared with eight to ten control pregnancies, and the infants' development over the first six months was compared with that of the control offspring. Nutritional status of the pregnant females was normal. The fetal heart rate response to maternal restraint was absent in the HDA. Gestational duration and simian Apgar scores were normal. All three infants were abnormally large, and two were also abnormally heavy, with body weight appropriate to skeletal size. Skeletal maturation, judged by ossification and tooth eruption, was not accelerated. The high-dose infant (HDI) was scaphocephalic, with an underdeveloped cranial base and midface, and its brain was small and dysplastic; its reflex, motor, and cognitive development were retarded. One moderate-dose infant (MDI) had some brain abnormalities; it was hyperkinetic and showed developmental retardation on several behavioral measures. The other MDI was normal. We conclude that the periodic model offers an effective means of investigating FAS in M. nemestrina. Furthermore, when nutrition is maintained, intermittent intake of ethanol by the pregnant primate does not necessarily reatard fetal growth.

The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding.

The diagnosis and treatment of posterior plagiocephaly is one of the most controversial aspects of craniofacial surgery. The features of true lambdoid synostosis versus those of deformational plagiocephaly secondary to positional molding are inadequately described in the literature and poorly understood. This has resulted in many infants in several craniofacial centers across the United States undergoing major intracranial procedures for non-synostotic plagiocephaly. The purpose of this study was to describe the detailed clinical, imaging, and operative features of true lambdoid synostosis and contrast them with the features of positional plagiocephaly. During a 4-year period from 1991 to 1994, 102 patients with posterior plagiocephaly were assessed in a large multidisciplinary craniofacial program. During the same period, 130 patients with craniosynostosis received surgical treatment. All patients were examined by a pediatric dysmorphologist, craniofacial surgeon, and pediatric neurosurgeon. Diagnostic imaging was performed where indicated. Patients diagnosed with lambdoid synostosis and severe and progressive positional molding underwent surgical correction using standard craniofacial techniques. Only 4 patients manifested the clinical, imaging, and operative features of unilambdoid synostosis, giving an incidence among all cases of craniosynostosis of 3.1 percent. Only 3 among the 98 patients with positional molding required surgical intervention. All the patients with unilambdoid synostosis had a thick ridge over the fused suture, identical to that found in other forms of craniosynostosis, with compensatory contralateral parietal and frontal bossing and an ipsilateral occipitomastoid bulge. The skull base had an ipsilateral inferior tilt, with a corresponding inferior and posterior displacement of the ipsilateral ear. These characteristics were completely opposite to the findings in the 98 patients who had positional molding with open lambdoid sutures and prove conclusively that true unilambdoid synostosis exists as a specific but rare entity. Awareness of the features of unilambdoid synostosis will allow more accurate diagnosis and appropriate treatment of posterior plagiocephaly in general and in particular will avoid unnecessary surgical intervention in patients with positional molding.