De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

Phenotype-genotype correlations in patients with Marinesco-Sjögren syndrome.

Marinesco-Sjögren syndrome (MSS; MIM 248800) is an autosomal recessive disorder characterized by congenital cerebellar ataxia, early cataracts, developmental delay, myopathy and short stature. Alterations in the gene SIL1 cause MSS in some patients with typical findings. In this study, molecular investigations including sequencing of the SIL1 gene, western blotting and microscopic investigations in fibroblast cultures were carried out in a cohort of 15 patients from 14 unrelated families, including the large, inbred family reported by Superneau et al., having the clinical features of MSS to provide insights into the pathophysiology of the disorder. A total of seven different mutations were found in eight of the patients from seven families. The mutations caused loss of the BIP-associated protein (BAP) protein in four patients by western blot. Novel clinical features such as dental abnormalities, iris coloboma, eczema and hormonal abnormalities were noticed in some patients, but there was no clear way to distinguish those with and without SIL1 mutations. Cultured fibroblasts contained numerous cytoplasmic inclusion bodies, similar to those identified in the brain of the whoozy mouse in five unrelated patients, three with and two without SIL1 mutations, suggesting some SIL1 negative patients share a common cellular pathogenesis with those who are SIL1 positive.

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.

Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.

The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.

Penile biometry on prenatal magnetic resonance imaging.

OBJECTIVE: In view of the implementation of magnetic resonance imaging (MRI) as an adjunct to ultrasonography in prenatal diagnosis, this study sought to demonstrate normal penile growth on prenatal MRI. METHODS: This was a retrospective study of MRI of 194 male fetuses (18-34 weeks' gestation) with normal anatomy or minor abnormalities. On sagittal T2-weighted MRI sequences, we measured penile length from the glans tip to the scrotal edge (outer length) and from the glans tip to the symphyseal border (total length). Descriptive statistics, as well as correlation and regression analysis, were used to evaluate penile length in relation to gestation. T-tests were calculated to compare mean outer/total length on MRI with published ultrasound data. RESULTS: Mean length values, including 95% CIs and percentiles, were defined. Penile length as a function of gestational age was expressed by the following regression equations: outer mean length = - 5.514 + 0.622 × gestational age in weeks; total mean length = - 8.865 + 1.312× gestational age in weeks. The correlation coefficients, r = 0.532 and r = 0.751, respectively, were statistically significant (P < 0.001). Comparison of outer penile length on MRI with published ultrasound penile length data showed no significant differences, while total penile length on MRI was significantly greater than ultrasound penile length (P < 0.001). CONCLUSION: Our MRI results provide a reference range of fetal penile length, which, in addition to ultrasonography, may be helpful in the identification of genital anomalies. Outer penile length on MRI is equivalent to penile length measured on ultrasound, whereas total length is significantly greater.

Male sexual development in utero: testicular descent on prenatal magnetic resonance imaging.

OBJECTIVE: To visualize in utero male fetal testicular descent on magnetic resonance imaging (MRI) and to correlate it with gestational age. METHODS: This retrospective study included 202 MRI examination results of 199 male fetuses (17-39 gestational weeks) with normal anatomy or minor congenital abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, multiplanar T2-weighted sequences were applied using a standard protocol to image and identify the scrotal content. The relative frequencies of unilateral and bilateral testicular descent were calculated and correlated with gestational age. RESULTS: Between 17 and 25 gestational weeks, neither unilateral nor bilateral testicular descent was visualized on MRI. Testicular descent was first observed at 25 + 4 weeks, in 7.7% of cases. 12.5% of 27-week fetuses showed unilateral descent and 50% showed bilateral descent. Bilateral descent was observed in 95.7% of cases, on average, from 30 to 39 weeks. CONCLUSIONS: Our results chart the time course of testicular descent on prenatal MRI, which may be helpful in the identification of normal male sexual development and in the diagnosis of congenital abnormalities, including the early detection of cryptorchidism.

Abnormalities of the upper extremities on fetal magnetic resonance imaging.

OBJECTIVE: In view of the increasing use of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography, we sought to demonstrate the visualization of upper extremity abnormalities and associated defects on MRI, with regard to fetal outcomes and compared with ultrasound imaging. METHODS: This retrospective study included 29 fetuses with upper extremity abnormalities visualized with fetal MRI following suspicious ultrasound findings and confirmed by postnatal assessment or autopsy. On a 1.5-Tesla unit, dedicated sequences were applied to image the extremities. Central nervous system (CNS) and extra-CNS anomalies were assessed to define extremity abnormalities as isolated or as complex, with associated defects. Fetal outcome was identified from medical records. MRI and ultrasound findings, when available, were compared. RESULTS: Isolated upper extremity abnormalities were found in three (10.3%) fetuses. In 26 (89.7%) fetuses complex abnormalities, including postural extremity disorders (21/26) and structural extremity abnormalities (15/26), were demonstrated. Associated defects involved: face (15/26); musculoskeletal system (14/26); thorax and cardio/pulmonary system (12/26); lower extremities (12/26); brain and skull (10/26); and abdomen (8/26). Of the 29 cases, 18 (62.1%) pregnancies were delivered and 11 (37.9%) were terminated. MRI and US findings were compared in 27/29 cases: the diagnosis was concordant in 14 (51.9%) of these cases, and additional findings were made on MRI in 13/27 (48.1%) cases. CONCLUSIONS: Visualization of upper extremity abnormalities on fetal MRI enables differentiation between isolated defects and complex ones, which may be related to poor fetal prognosis. MRI generally confirms the ultrasound diagnosis, and may provide additional findings in certain cases.

Female external genitalia on fetal magnetic resonance imaging.

OBJECTIVES: To characterize the normal development of the female external genitalia on fetal magnetic resonance imaging (MRI). METHODS: This retrospective study included MRI examinations of 191 female fetuses (20-36 gestational weeks) with normal anatomy or minor abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, the bilabial diameter was measured on T2-weighted sequences. Statistical description, as well as correlation and regression analyses, was used to evaluate bilabial diameter in relation to gestational age. MRI measurements were compared with published ultrasound data. The morphological appearance and signal intensities of the external genitalia were also assessed. RESULTS: Mean bilabial diameters, with 95% CIs and percentiles, were defined. The bilabial diameter as a function of gestational age was expressed by the regression equation: bilabial diameter = - 11.336 + 0.836 × (gestational age in weeks). The correlation coefficient, r = 0.782, was statistically significant (P < 0.001). Bilabial diameter on MRI was not significantly different from that on ultrasound (P < 0.001). In addition, on MRI we observed changes in morphology of the external genitalia and in signal intensities with increasing gestational age. CONCLUSIONS: We have provided a reference range of fetal bilabial diameter on MRI, which, in addition to ultrasound findings, may be helpful in the identification of genital anomalies.

A Vaccine to Prevent Egg Layer Peritonitis in Chickens.

A series of studies was undertaken in specific-pathogen-free white leghorn chickens for the development of a chicken model of avian pathogenic Escherichia coli (APEC) peritonitis. Once established, this model was then used to measure the effectiveness of a siderophore receptor and porin proteins (SRP®) APEC vaccine. Initially, five pilot studies were performed to compare the E. coli serotype, challenge route, and dose of inoculum that resulted in pathologies characteristic of the peritonitis observed in commercial layer facilities, such as widespread organ infection, atrophy, discoloration, corrugation of yolk sacs, and the presence of caseous exudate. Isolates of serotypes O1, O2, and O78 were tested by intravenous, intravaginal, intratracheal, and intraperitoneal routes and were compared at various levels of challenge inoculum. Daily observations of mortality and morbidity were made, and at necropsy, gross lesion scores were collected and bacterial colonization of internal organs determined. Outcomes varied from a complete lack of mortality or detectable pathology and low, or no, organ colonization in the case of intravaginal and intratracheal routes with each E. coli serotype to moderate to high levels of mortality, pathology, and colonization after challenge via the intravenous and intraperitoneal routes with O2 and O78 serotypes, respectively. The O78 serotype was found to result in pathologies consistent with field observations of peritonitis, and therefore, subsequent studies were performed only with O78. In addition to the relative failure with both the intratracheal and intravaginal routes of challenge, the intravenous route was found to be inconsistent and often resulted in lameness not observed with the intraperitoneal route. A final pilot study confirmed that the dose (∼ 8 log 10 CFU) administered by the intraperitoneal route replicated peritonitis, and therefore, all vaccination/challenge studies were conducted in this manner. Five vaccination/challenge studies are reported here in which variables of chicken age, vaccination interval, and vaccination to challenge interval were examined. In all studies, vaccine effectiveness was dramatic and was shown to completely protect against mortality and substantially against tissue colonization and pathology typical of APEC infections. The vaccine elicited a rapid onset of immunity with both narrow and broad vaccination intervals and in both young and mature chickens. Additionally, the vaccine was demonstrated to sustain robust effectiveness against mortality over 3 months. The SRP APEC vaccine should provide effective protection of young and mature chickens from E. coli under broadly flexible conditions of use in commercial operations.

Artíclo regular­Vacuna para prevenir la peritonitis de gallina de postura. Se llevó a cabo una serie de estudios en aves tipo Leghorn blancas libres de patógenos específicos para el desarrollo de un modelo en pollo para la peritonitis causada por Escherichia coli patógena aviar (APEC). Una vez establecido, este modelo se utilizó para medir la eficacia de una vacuna con proteínas del receptor de sideróforo y de porina (SRP®) de E. coli patógena aviar. Inicialmente, se realizaron cinco estudios piloto para comparar el serotipo de E. coli, la ruta de desafío y la dosis de inóculo que resultaron en patologías características de las peritonitis observadas en instalaciones comerciales de ponedoras, como la infección generalizada de órganos, atrofia, decoloración, ondulación de saco vitelino y la presencia de exudado caseoso. Los aislamientos de los serotipos O1, O2 y O78 se analizaron por vías intravenosa, intravaginal, intratraqueal e intraperitoneal y se compararon a varios niveles de inóculo de desafío. Se realizaron observaciones diarias de mortalidad y morbilidad, en la necropsia, se registraron puntuaciones de lesiones macroscópicas y se determinó la colonización bacteriana de los órganos internos. Los resultados variaron desde una ausencia total de mortalidad o patología detectable y una colonización de órganos baja o nula en el caso de las rutas intravaginal e intratraqueal con cada serotipo de E. coli hasta niveles de mortalidad, patología y colonización de moderados a altos después del desafío por vía intravenosa e intraperitoneal con los serotipos O2 y O78, respectivamente. Se encontró que el serotipo O78 dio como resultado patologías consistentes con las observaciones de campo de la peritonitis y por lo tanto, los estudios posteriores se realizaron solo con el serotipo O78. Además del fracaso relativo con las rutas de desafío intratraqueal e intravaginal, se descubrió que la vía intravenosa era inconsistente y a menudo, provocaba cojera que no se observaba con la vía intraperitoneal. Un estudio piloto final confirmó que la dosis (∼8 log10 UFC) administrada por vía intraperitoneal reproducía la peritonitis y por lo tanto, todos los estudios de vacunación/desafío se realizaron de esta manera. En este estudio se reportan cinco estudios de vacunación/desafío en los que se examinaron las variables de edad del pollo, intervalo de vacunación e intervalo de vacunación al desafío. En todos los estudios, la eficacia de la vacuna fue muy evidente y se demostró que protege completamente contra la mortalidad y sustancialmente contra la colonización de tejidos y la patología típica de las infecciones por E. coli patógena aviar. La vacuna provocó un rápido inicio de la inmunidad con intervalos de vacunación tanto estrechos como amplios y tanto en aves jóvenes como maduras. Además, se demostró que la vacuna mantiene una sólida eficacia contra la mortalidad durante tres meses. La vacuna con proteínas del receptor de sideróforo y de porina de E. coli patógena aviar debería proporcionar una protección eficaz de las aves jóvenes y maduras contra E. coli en condiciones de uso ampliamente flexibles en operaciones comerciales.

Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Classical conditioning: induction of luteinizing hormone and testosterone secretion in anticipation of sexual activity.

A classical conditioning paradigm was used to demonstrate that male rats can learn to secrete luteinizing hormone and testosterone in anticipation of sexual activity. Sexually naïve males were exposed to a neutral stimulus and then to a sexually receptive female once daily. After exposure to the paired stimuli for 14 trials, the neutral stimulus was as effective as the female in triggering luteinizing hormone and testosterone secretion. These findings provide two novel perspectives on the control of reproductive hormone secretion in male rats: (i) environmental cues, which males learn to associate with sexual activity, induce the secretion of hormones that regulate pituitary-testis function, and (ii) classical conditioning may be used as a noninvasive method to evoke functional alterations in the secretion of luteinizing hormone and presumably the neuroendocrine pathways that mediate its release.

Cross-modal plasticity underpins language recovery after cochlear implantation.

Postlingually deaf subjects learn the meaning of sounds after cochlear implantation by forming new associations between sounds and their sources. Implants generate coarse frequency responses, preventing place-coding fine enough to discriminate sounds with similar temporal characteristics, e.g., buck/duck. This limitation imposes a dependency on visual cues, e.g., lipreading. We hypothesized that cross-modal facilitation results from engagement of the visual cortex by purely auditory tasks. In four functional neuroimaging experiments, we show recruitment of early visual cortex (V1/V2) when cochlear implant users listen to sounds with eyes closed. Activity in visual cortex evolved in a stimulus-specific manner as a function of time from implantation reflecting experience-dependent adaptations in the postimplant phase.

Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro alpha 1(I) chains of type I collagen determines the clinical phenotype.

Skin fibroblasts grown from three individuals with osteogenesis imperfecta (OI) each synthesized a population of normal type I collagen molecules and additional molecules that had one or two alpha 1(I) chains that contained a cysteine residue within the triple-helical domain, a region from which cysteine normally is excluded. The patients had very different phenotypes. One patient with OI type I had a population of alpha 1(I) chains in which glycine at position 94 of the triple helix was substituted by cysteine; a patient with OI type III had a population of alpha 1(I) chains in which glycine at position 526 of the triple helix was substituted by cysteine; and the third patient, with OI type II, had a cysteine for glycine substitution at position 718 of the alpha 1(I) chain. From all three patients, molecules that contained two mutant chains formed interchain, intramolecular disulfide bonds, and although less stable to thermal denaturation than normal molecules, they were more stable than molecules that contained only a single mutant chain. These findings indicate that substitutions for glycine within the triple-helical domain of the alpha 1(I) chain are not invariably lethal and that their phenotypic effect largely depends on the nature of the substituting residue and its location in the chain.

Glycolipid glycosyl transferases of a hamster cell line in culture. II. Subcellular distribution and the effect of culture age and density.

The activities of two galactosyl transferases catalysing the formation of di- and tri-glycosyl ceramides in NIL-2 hamster cells have been studied with respect to culture age and density, subcellular distribution, and transformation of cells by virus. The activity of the transferases was found to increase considerably as culture density increased, although maximal activities were found before appreciable cell contact occurred. The highest transferase activities were found in the endoplasmic reticulum. Virus transformation reduces the activity of the transferase catalysing triglycosyl ceramide synthesis, while the transferase catalysing diglycosyl ceramide synthesis is slightly increased. There is no evidence that the transformed cells produce a dialysable soluble inhibitor of transferase activities.

Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson's disease.

Some patients with idiopathic Parkinson's disease experience hallucinations as a result of treatment with levodopa and dopamine agonists. There is evidence for some heterogeneity in these hallucinating patients based on duration of Parkinson's disease at onset of hallucinations. We compared the frequency of polymorphisms in the dopamine D2 and D3 receptor genes between patients with drug-induced hallucinations and non-hallucinating patients. Two polymorphisms close to DRD2 and one in DRD3 were studied. No association was found with the whole group of hallucinating patients and their controls. However, an association was found with late-onset hallucinations and the C allele of the TaqIA polymorphism, 10.5 kb 3' to DRD2. This polymorphism may be in linkage disequilibrium with a mutation in DRD2 or a nearby gene that predisposes to drug-induced hallucinations which occur later in the course of idiopathic Parkinson's disease.

A novel method for the rapid separation of plasma lipoproteins using self-generating gradients of iodixanol.

We describe a new method for the rapid fractionation of plasma lipoproteins, which makes use of a new non-ionic, iodinated, density gradient medium, iodixanol, commercially available as Optiprep(TM). The method is simple: plasma or serum is mixed with iodixanol followed by centrifugation in a vertical or near vertical rotor. Separation of VLDL, LDL and HDL can be achieved in 3 h and the lipoprotein fractions are comparable in density and composition with those prepared using conventional salt based gradients. Each class of lipoprotein can be removed in a single fraction, or a profile of lipoprotein distribution can be obtained using a gradient fractionator. Because the medium is inert, fractions from the gradient can be analysed by agarose gel electrophoresis or assayed for lipid content or apolipoprotein composition by SDS-PAGE without removing the iodixanol. Small differences in electrophoretic mobility of HDL and LDL across several gradient fractions suggest that subfractionation of these classes may occur. The new method is simple, rapid and versatile with potential application for preparation of lipoproteins and for analysis of lipoprotein profiles in the research or clinical laboratory.

A quick, easy and inexpensive method for the isolation of human peripheral blood monocytes.

A commercial monocyte isolation technique based on the OptiPrep density-gradient medium was up-scaled with respect to sample and reagent volumes. The results of 7 isolations are reported in which the average purity ranged from 87.9 to 96.4%. In all but the initial isolation, monocytes were defined as CD15+ dim CD4+ dim as assessed by flow cytometric analysis; in the first isolation, monocytes were defined by the traditional CD14+ CD4+ dim combination. The mean yield (the number of isolated monocytes relative to the number present in the buffy coat) of all isolations was 26.1%, with the individual yields ranging from 10.8 to 41.4%. The mean number of isolated monocytes per experiment was 3.6 x 10(6) monocytes for those isolations performed using 14 ml of buffy coat/OptiPrep mixture (n = 4). The isolated cells were viable (> 95%) and were not activated, according to HLA-DR expression. This technique is a convenient, tast (less than 2 h), relatively simple, and inexpensive alternative to traditional monocyte isolation techniques. The up-scaled version of this method also results in significantly higher numbers of monocytes per isolation than some traditional techniques. Furthermore, this is the first literature report of the use of the OptiPrep density-gradient medium for the isolation of monocytes.

Metopic craniostenosis as a consequence of fetal head constraint: two interesting experiments of nature.

Two instances of metopic craniosynostosis provide dramatic experiments of nature which implicate fetal head constraint as one cause of early sutural fusion. The presumed restriction of growth stretch at the metopic suture in one instance was due to a bicornuate uterus in which the fetal head was markedly constrained. The second instance was in one of monozygotic triplets reared in a small mother in which the affected fetal head had been wedged between the hips of the two unaffected siblings.

Central nervous system and facial defects associated with maternal hyperthermia at four to 14 weeks' gestation.

An analysis of 28 dysmorphic offspring with a retrospectively ascertained history of maternal hyperthermia during the first trimester of pregnancy showed a similarity in their pattern of CNS dysfunction and facial dysmorphogenesis. All survivors had mental deficiency and most of them demonstrated altered muscle tone, including hypotonia with increased deep tendon reflexes. Those exposed at four to seven weeks' gestation showed an increased prevalence of facial dysmorphogenesis. The duration of the high fever was usually one or more days, an unusual occurrence during the first trimester of pregnancy. The nature of these defects in relation to the relative timing of hyperthermia exposure is similar to that previously noted in animal studies. The morphogenetic implications of these findings are explored and the need for larger, controlled studies is suggested.