Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies.

Intermicrovillar areas and apical vesicles characterized by an extensive clathrin coat can be identified in some epithelial cell types. We describe a 280-kD protein, characteristic of these areas in the proximal tubule brush border and epithelial cells of the visceral yolk sac. When injected to 9-d pregnant rats, mAbs to the 280-kD protein regularly induced fetal resorption and/or malformations. Antibodies to a 330-kD protein that is also coated-pit-restricted had no effect. Our observations point to a key function for p280 and suggest that immunity to specific constituents of the receptor-mediated endocytotic system may be involved in the induction of fetal abnormalities.

Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses.

OBJECTIVE: To estimate the prevalence of in utero transmission of HIV-1 through the second trimester. MATERIAL AND METHODS: One hundred consecutive, unselected, intact fetuses, beyond 15 weeks gestational age (mean, 22.4 weeks) were studied. These were obtained following spontaneous intrauterine deaths (n = 4), miscarriages (n = 4), and elective mid-trimester terminations (n = 92), eight of which were fetuses with malformations from HIV-1-positive pregnancies. Coded DNA extracts from the fetal thymuses were tested blindly by polymerase chain reaction in three laboratories using a total of six different primer pairs. RESULTS: Two thymuses tested positive [95% confidence interval (Cl), 0.2-7]. Results from the three laboratories were consistent in all 100 cases. The two fetuses with HIV in the thymus both tested positive in other organs, demonstrating systemic HIV infection. The first fetus, whose mother had advanced AIDS, had died in utero and had diffuse toxoplasmosis. The second died following extremely premature delivery in a pregnancy complicated by repeated bleeding. HIV infection was observed in none of the 92 fetuses that resulted from elective mid-trimester terminations (95% Cl, 0-4). CONCLUSION: The frequency of early in utero HIV infection appears to be low, compared with transmission rates in infants born to HIV-1-infected mothers, suggesting that transmission occurs mostly later in pregnancy and/or at delivery. Specific risk factors may have implications in the occurrence of early as opposed to late transmission.

Vasoactive intestinal peptide receptor activity in human fetal enterocytes.

Functional and specific receptors for vasoactive intestinal peptide (VIP) (determined by their capacity to bind 125I-VIP and activate adenylate cyclase) and cyclic AMP-dependent phosphodiesterase activities were characterized in enterocytes of human fetal small intestine between 18 and 23 weeks of gestation. Half-maximal stimulation of the cyclase and inhibition of 125I-VIP binding in membrane preparations were respectively observed at 1.4 and 5 X 10(-10) M VIP. The peptides structurally related to VIP activated the cyclic AMP generating system at pharmacological doses (10(-7) M and above) in the following order of potency: VIP greater than PHI greater than GRF greater than secretin. Other peptides or test substances, including GIP, pancreatic glucagon, somatostatin-14, gastrin, CCK, neurotensin, pancreatic polypeptide, PYY, substance P, histamine and isoproterenol are inactive in this system, while the ubiquitous adenylate cyclase activators NaF, forskolin and prostaglandins were effective. These results, combined with the appearance of intestinal VIP in nerve fibers at 8 weeks and with the morphological and enzymatic maturation at 9-12 weeks of the intestinal mucosa, indicate that this neuropeptide may regulate either the differentiation or function of enterocytes during the early development of human intestinal mucosa.

Role of cholesterol in embryonic development.

We showed previously that 3 distal inhibitors of cholesterol synthesis are highly teratogenic in rats. AY 9944 and BM 15766 inhibit 7-dehydrocholesterol reductase, which catalyzes the last step of cholesterol synthesis, and triparanol inhibits Delta(24)-dehydrocholesterol reductase, which catalyzes the last step in another pathway. These molecules cause holoprosencephalic brain anomalies. Under certain experimental conditions, other anomalies (of the limbs and male genitalia) are also observed. Assays performed by gas chromatography-mass spectrometry (GC-MS) show hypocholesterolemia and an accumulation of precursors. These data indicate that this animal model can be considered a model of Smith-Lemli-Opitz syndrome. Smith-Lemli-Opitz syndrome is a recessive autosomal genetic disease characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive. The syndrome has been attributed to a deficit in 7-dehydrocholesterol reductase. As assayed by GC-MS, the sterol status of these patients indicates severe hypocholesterolemia and an accumulation of precursors: 7-dehydrocholesterol, 8-dehydrocholesterol, and oxidized derivatives. The presence of 7-dehydrocholesterol in the serum of patients is pathognomonic of the disease. The developmental gene Shh (sonic hedgehog) plays a key role in brain, limb, and genital development; it was shown recently that the Shh protein has to be covalently linked to cholesterol to be active. This is the first time that a posttranslational function has been attributed to cholesterol. There is an obvious relation between Shh dysfunction and the malformations observed in our experiments and in patients with Smith-Lemli-Opitz syndrome. However, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account.

Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women.

Pathological abnormalities of the thymus were found in 3 of 37 fetuses aborted from human immunodeficiency virus (HIV)-infected mothers. These lesions were located predominantly in the thymic cortex, which contains mostly immature lymphocytes. Areas of focal lymphocyte depletion were infiltrated with CD4+ macrophages and were associated with abnormalities of the epithelial stromal network. No evidence of extensive HIV infection in any of the 37 thymuses was detected by either immunofluorescence or in situ hybridization techniques, although rare cells that expressed HIV antigens were found in 3 fetuses. Although less extensive, this thymic fetopathy was similar to that described in postnatal acquired immunodeficiency syndrome thymuses, strongly suggesting that the lesions were related to HIV infection. Thymic fetopathy might represent the initial injury to the lymphoid system in HIV-infected infants in whom early and severe immunosuppression develops.

Restrictive dermopathy, a lethal form of arthrogryposis multiplex with skin and bone dysplasias: three new cases and review of the literature.

Restrictive dermopathy is a rare, lethal autosomal recessive syndrome. We report on 3 unrelated affected stillborn infants of consanguineous parents. Clinical findings include a tight, thin, translucent, taut skin, which tears spontaneously in flexion creases, arthrogryposis multiplex congenita (including the temporomandibular joint), enlarged fontanelles, typical face and dysplasia of clavicles and long bones. Histologic abnormalities include hyperplastic, abnormally keratinized epidermis, reduced tonofilaments, thin, compact dermis with hypoplasia of the elastic fibres, and abnormal subcutaneous fat. Fifteen previous cases are reviewed.

Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome.

We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes.

Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form.

We report on congenital hypothalamic hamartomas, discovered at autopsy in 3 unrelated fetuses. In the first 2 patients, the tumor was associated with skeletal dysplasia only. In the third patient, it was part of a non-random congenital malformation association, suggestive of Meckel syndrome. In one family, a previous boy died soon after birth with similar craniofacial and skeletal abnormalities. As far as we know, the association between isolated skeletal dysplasia and congenital hypothalamic hamartomas has not yet been documented in the literature. Nevertheless, a spectrum of skeletal abnormalities has been described in association with congenital hypothalamic "hamartoblastoma" and a constellation of variable visceral malformations under the eponym of "Pallister-Hall syndrome" (PHS). A detailed analysis of the PHS reported cases shows that only skeletal dysplasia and oro-facial abnormalities are present constantly. They show similarities with those found in our first 2 cases. These findings prompt us to consider skeletal dysplasia and oro-facial abnormalities as common denominator and minimum criteria required to define a nosologically distinct, possibly familial entity, which we suggest calling "congenital hypothalamic hamartoma syndrome" (CHHS).

Serotonin deficiency in phenylketonuria embryopathy.

The development and evolution of PKU can be prevented by prescribing an appropriate diet at an early age. A systematic neonatal screening has been set up in most countries. However, young women suffering from PKU give birth to very severely malformed children (PKU embryopathy: microcephaly, mental retardation, hypotrophy, cardiopathy) unless they again take up the specific diet, until the PHE level has lowered down to normal, before the beginning of gestation. The treatment has to be continued at least during the first months of gestation. This management is very unpleasant and sometimes not easily accepted. The mechanism of this embryopathy is still unknown. It is possible that (1) the excess of PHE or the presence of abnormal metabolites, or (2) serotonin deficiency (which is a feature of PKU) could be responsible for the maldevelopment of the embryo. Some authors consider that serontonin has a morphogenetic role in normal embryogenesis. Previously we described an experimental animal model using in vitro culture of rat embryos in human PKU sera. Mouse embryos have been subsequently used, since they show a greater sensitivity. Malformations, consisting essentially of neural tube defects, were present in almost 100% of the embryos cultured in serum from PKU patients. Using this animal model, we tested the hypothesis of serotonin deficiency. For this purpose, mouse embryos were cultured in human serum depleted of serotonin. Under these conditions, 100% of the embryos showed oculo-neural malformations characteristic of the experimental embryopathy. These results indicate the importance of serotonin deficiency in the occurrence of PKU embryopathy.

Cardiovascular abnormalities in thoracopagus twins: embryological interpretation and review.

The cardiovascular abnormalities of two sets of thoracopagus twins with conjoined heart and liver are described and compared with 27 well documented cases. An embryological interpretation of the cardiovascular abnormalities is suggested. The common heart in both sets showed a common atrium and two ventricles. In case 1 the great arteries were L. malposed in twin A. In case 2 the great arteries originated from their respective double outlet single ventricle. The systemic and pulmonary veins drained directly into the common atrium in case 1 and indirectly via systemic veins in case 2. The type of cardiovascular abnormalities are complex and discordent from one set to another and in the same set. However among 27 published cases of thoracopagus twins, cardiac union, including atrial union with separate ventricles, or atrial and ventricular union, was encountered in 16 cases. Approximately 90% of them are not suitable for surgical separation because of the high degree of cardiac union and the complexity of cardiovascular abnormalities. Surgical separation could be attempted in only two cases, but at the cost of the life of one of the twins.

Fetal hydrocephalus. Clinical significance of associated anomalies and genetic counseling: a pathological approach.

We report on a consecutive series of 94 cases of fetal hydrocephalus. Pathological and neuropathological findings have been thoroughly analysed in order to define more precisely the clinical significance of associated anomalies and their implications in genetic counseling. In 90.5% of cases, hydrocephalus was associated with other central nervous system (84%) or extra neural (56%) anomalies. True aqueductal stenosis occurred only twice in our series. In only 9 fetuses, hydrocephalus was an isolated finding, secondary to haemorrhage or infection. Since fetal hydrocephalus is an etiologically heterogeneous disorder, its recurrence varies greatly. Without a final diagnosis, based on well documented pathological data and cytogenetic studies, accurate genetic counseling and prenatal diagnosis in subsequent pregnancies would be impossible.

[The incidence of congenital malformations. A five-year study carried out in a Paris maternity unit (author's transl)]. / Fréquence des malformations à la naissance. Etude d'une maternité parisienne pendant cinq ans.

The congenital malformations arising out of 13,335 deliveries that occurred over the course of five years in the University Clinic of Gynecology and Obstetrics in the hospital of Saint-Antoine were recorded. Their overall frequency was 3.37%. Details are given of each malformation. Often malformations are linked to perinatal mortality (14.2% of stillbirths are malformed). There was no difference to be found between different ethnic groups. Pathological developments in previous pregnancies were not particularly frequent. Bleeding in the first trimester of pregnancy was significantly more frequent in congenital abnormalities.

[Prevention of congenital toxoplasmosis. Results at the maternity department of the Hôpital Saint-Antoine in 1972]. / Prophylaxie de la toxoplasmose congénitale. Bilan à la maternité de l'hôpital Saint-Antoine 1972

The authors report the results of checking for toxoplasmosis in a maternity hospital in Paris in one year. 3,409 women were checked. 19 cases of toxoplasmosis were detected and treated. 4 of these were cogenital toxoplasmosis, of which 3 were obvious. We have to point out that sero-conversion did not occur during the survey after we had started to prescribe hygienic diets to patients in the survey. The difficulties accompanying this form of prophylaxis have been analysed.

[Toxoplasmosis and pregnancy. Evaluation of 2 years of prevention of congenital toxoplasmosis in the maternity ward of Hôpital Saint-Antoine (1973-1974)]. / Toxoplasmose et grossesse. Bilan de deux ans de prophylaxie de la toxoplasmose congénitale à la maternité de l'hôpital Saint-Antoine (1) (1973-1974)

The authors report the results of prophylaxis of congenital toxoplasmosis in a maternity hospital in Paris for a two years period (1973-1974). 6269 pregnant women were surveyed. 18 toxoplasmosis were detected in evolution at the first prenatal examination, 10 seroconversions were identified among the first examination antibody negative women, when re-examined during the pregnancy. 25 of these 28 women were treated regularly. The seroconversions of the 3 other women were detected only at delivery. In addition 25 women were treated because of high antibody titers (Dye-Test greater than or equal to 300. U.I/ml). 6 congenital toxoplasmosis, 2 of them were manifest, were observed among the children whose mothers were treated for confirmed toxoplasmosis. The extremely low level of seroconversions may be in relation to hygienic and dietetic prescriptions. The difficulties of this prophylaxis are analysed: they are due to studied population and to problems of interpretation or serologic examinations.

[Anencephaly and diprosopy: 2 cases]. / Anencéphalie et diprosopie: deux cas.

We have seen two cases of diprosopy associated with anencephaly in Brittany between 1975 and 1984. Diprosopy is a partial or total duplication of the face. It consists of the phenomenon of late division in the embryo of the cephalic portion of the neural plate between the 16th and the 18th days. This gives rise to an incomplete type of monozygotic twinning or a conjoint twin. There are several different forms of the organs that are duplicated. We have seen a case of diprosopos distomos dirhinos diophthalmos and a case of disprosopos distomos dirhinos triophthalmos. These two cases were associated with anencephaly, the second also having a spina bifida and a diaphragmatic hernia. One can explain the incidence of anencephalies in cases of diprosopies by the desturbance created by the latter on the embryological events that succeed it. The delay in nerve formation makes it impossible for the neural tube to close completely, and this is why sometimes the anencephaly is associated with spina bifida. In more general terms one can postulate that all conjoint twins that are, of course, monozygotic and monochorial can interfere with early enbryological development and increase the risks of failure of the neural tube to close.

[Chromosomal study of 65 couples with spontaneous abortions]. / Etude chromosomique de 65 couples ayant eu des accidents gestationnels

A Robertsonian translocation and two reciprocal translocations were found in chromosome analysis of 65 couples attending for fetal wastage. The possible pathological significance of hyperdiploid cells which were observed is discussed.

[Acardiac fetus]. / Foetus acardiaque.

Acardiac fetus is a rare lethal fetopathy usually encountered in monozygous pregnancies. Ultrasound prenatal diagnosis has enabled an increasing number of observations and raised the need for an adequate therapeutic approach since the spontaneous prognosis for the healthy twin is unfavorable in half of the cases. An acardiac fetus was identified at 12 weeks gestation in a 36-year-old woman. Growth of the healthy fetus was carefully monitored and progressed normally to delivery by cesarean section of a 2.900 kg boy at 36 weeks. At delivery, the acardiac fetus was found to be totally free of any attachment, floating in the remaining fluids. Pathology examination showed a 16 g macerated fetus with a cephalic extremity, a ventral pedicle and a syrenomelic caudal extremity. The caryotype was not significative. Acardiac fetus occurs in less than 1% of multiple pregnancies and can develop in single pregnancies. Twin reversed arterial perfusion has been recognized as necessary for development of the perfused fetus. Genetic and immunologic theories have been proposed to explain the pathogenesis which remains unknown. Clinical management depends on the spontaneous development of the acardiac fetus and the deleterious consequences for the healthy twin resulting from heart failure, anasarca or prematurity. Medical management with digoxin, or selective extraction by hysterotomy may improve prognosis but results have been variable. Echoguided umbilical cord ligation has also been proposed to improve maternal mortality. Therapeutic abstention is no longer indicated at prenatal diagnosis of an acardiac fetus and a healthy twin despite the risk of invasive treatment.

[Teratogenesis and autoimmunity: significance of an experimental murine model for human pathology]. / Tératogenèse et auto-immunité: signification en pathologie humaine d'un modèle expérimental murin.

Fetal malformations constitute a major problem of public health. Unfortunately the known causes do not account for more than 50% of the cases observed. The potential role of immune mechanisms is suggested by experimental studies in the rat indicating that antibodies reactive with the yolk sac induce fetal malformations. In this study we show that these antibodies are specific for a 280 kDa protein expressed only in the kidney and the yolk sac by cell structures associated with the formation of endocytic vesicles. We further show that a similar protein is expressed in man by the yolk sac, the kidney and the trophoblasts. The possible role in pathology of antibodies against the human protein is discussed.