Horst Müntefering

Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)-Re-evaluation of chromosome aberration rates in early spontaneous abortions.

Comparative genomic hybridisation (CGH) represents an alternative molecular-cytogenetic technique capable of detecting chromosomal imbalances by reverse fluorescence in situ hybridisation. As the technique uses genomic DNA for assessment it does not rely on metaphase chromosomes in the test material and thus circumvents technical problems associated with tissue culturing. In the present study, we applied CGH to identify chromosome anomalies in 60 spontaneous abortions of the first trimester, that had failed to grow in culture. In 57 out of 60 cases CGH analyses were successful. The overall aneuploidy rate detected was 72%. Trisomy was the predominant chromosome anomaly accounting for 68.0% of abnormal abortions, followed by triploidy (17.1%) and monosomy X (9.8%). An unbalanced structural rearrangement was found in one (2.4%) abortion. Most frequently involved in trisomies were chromosomes 16 (32.1%), 7 and 22 (10.7% each), 4, 13, 15, and 21 (7.2 % each). Three triploid cases and one complete mole were detected by microsatellite analysis as supplementary method. CGH data on culture failures were compared with data derived from 4693 successfully karyotyped first trimester spontaneous abortions, resulting in a chromosome aberration rate of 64.8%. The distribution of the different chromosome anomalies was similar with the exception of a higher rate of trisomies 7 and of XYY-triploidies in the culture failures. Based on our data we suggest that the genetic contribution to pregnancy loss is still underestimated. Investigating abortion tissues hitherto unassessed by conventional methods, we suggest that the contribution of chromosome aberrations to first trimester pregnancy loss is nearly 70%.

Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome.

We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth that resulted in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis (DMS). Clinically obvious eye abnormalities were recognized in six of the eight patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large appearing corneae in some cases suggesting buphthalmos, and extremely narrow, nonreactive pupils (microcoria). Pathological examination of the eyes of two aborted fetuses revealed a more complex ocular maldevelopment including posterior lenticonus as well as anomalies of cornea and retina. On the basis of these observations and other cases in the literature, we delineate a previously unrecognized distinct entity characterized by congenital nephrotic syndrome, DMS, and eye abnormalities with microcoria as the leading clinical feature. Pedigrees of affected families with parental consanguinity support autosomal recessive inheritance. We propose that this syndrome should be designated microcoria‐congenital nephrosis syndrome or Pierson syndrome. Possible overlap with Galloway–Mowat syndrome and relations to other oculo‐renal syndromes are discussed.

Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining

Chronic villitis is almost always present in intrauterine infection with human cytomegalovirus (HCMV). The inflammatory response to this virus has been described in detail. However, little is known about the types of placental cells that may be infected by HCMV and six cases of HCMV placentitis were thus investigated to identify the vulnerable cell types. Immunohistochemical double staining analyses were performed using antibodies to HCMV immediate early antigens and to specific cellular marker proteins. Fixed connective tissue cells could be demonstrated to be the predominantly infected cell type in each placental tissue. Endothelial cells and macrophages were also found to be infected in all six cases, whereas evidence of trophoblast infection was obtained in four cases. It is concluded that release of infectious virus by connective tissue cells, macrophages and endothelial cells may play a critical role in transplacental transmission of HCMV. The findings further suggest that the cytopathic effect of HCMV infection on these cells might be involved in the pathogenesis of intrauterine HCMV disease.

Immunohistochemical expression analysis of inhibin-alpha and -beta subunits in partial and complete moles, trophoblastic tumors, and endometrial decidua.

The expression of inhibin-&agr; subunit has been described in normal placentas, hydatidiform moles, and trophoblastic tumors. We performed a double immunohistochemical expression analysis of inhibin-&agr; and inhibin-&bgr; subunits in a cytogenetically well characterized series of 21 complete and 22 partial hydatidiform moles, 2 placental site trophoblastic tumors, and one choriocarcinoma. Syncytiotrophoblastic cells were consistently inhibin-&agr; and inhibin-&bgr; positive in all hydatidiform moles and in the one choriocarcinoma. Cytotrophoblast was negative for both subunits in all trophoblastic lesions studied. While villous intermediate trophoblastic cells were consistently inhibin-&agr; negative in all hydatidiform moles, focal inhibin-&bgr; immunoreactivity was detected in villous intermediate trophoblast in approximately one third of complete and partial hydatidiform moles. Decidual stromal cells in 40 hydatidiform moles were inhibin-&agr; and inhibin-&bgr; positive in approximately one third of cases. Both placental site trophoblastic tumors were inhibin-&agr; positive but inhibin-&bgr; negative. Our findings indicate that inhibin-&agr; and -&bgr; subunits are consistently coexpressed in syncytiotrophoblast in complete and partial moles. Immunohistochemical detection of inhibin subunits may be useful in the differential diagnosis of trophoblastic lesions.

Renal tubular dysgenesis (RTD) - an important cause of the oligohydramnion-sequence: Report of 3 cases and review of the literature

Renal tubular dysgenesis (RTD) is a disorder characterized by neonatal renal failure and regular gross renal architecture, although the histological features of immature and shortened proximal tubules lead to neonatal death. The pathogenesis of this condition includes a congenital familial condition, a twin-twin transfusion syndrome, and an angiotensin-converting enzyme inhibitor intake by the mother. The clinical picture shows an association with oligohydramnia, pulmonary hypoplasia, and skull ossification defects. In the present paper, we report the occurrence of RTD in three infants of a consanguinous couple and compared our data with those of the literature. Our data confirm that late second trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney.

Placenta in gestational hypertension

ZusammenfassungDie schwangerschaftsinduzierte Hypertonie (SIH) ist mit einer Inzidenz von 3,2–4% weltweit die häufigste Erkrankung der Schwangerschaft. Da sie nicht nur für die Mutter, sondern auch für das Kind Risiken mit sich bringt, sollte die Plazenta in jedem Fall pathologisch-anatomisch untersucht werden. Es können dabei sowohl für die fetomaternale Grenzzone als auch für die fetale Plazenta pathomorphologische Befunde beschrieben werden, die allerdings nicht spezifisch oder diagnostisch beweisend sind.Pathomorphologische Befunde in der fetomaternalen Grenzzone sind: das Fehlen der physiologischen Invasion des extravillösen Zytotrophoblasten, hyperplastische Arterio-/Arteriolopathie, akute Atherose und fibrinoide Endothelnekrosen.Die fetale Plazenta kann folgende Fehlentwicklungen aufweisen: Infarkte/Mikrofibrinabscheidungen, Abruptio placentae, Endangiopathia obliterans/Zottenstromafibrose /-hyalinose, Synzytiotrophoblastzellknoten (Tenney-Parker-Phänomen) sowie Zottenreifungsstörungen/Retardierung bzw. Akzeleration.Eine Korrelation zwischen dem Schweregrad der Erkrankung und der Morphologie fehlt weitgehend; eine Ausnahme bilden in dieser Hinsicht nur die Befunde an den Gefäßen sowohl des Plazentabettes, als auch der Chorionzotten. Diese korrelieren gut mit dopplersonographischen Befunden.AbstractAt an incidence of 3.2–4% world-wide, pregnancy-induced hypertension (PIH) is the most common disease of pregnancy. Since this holds a risk, not only for the mother, but also for the child, the placenta should undergo pathological-anatomical examination in every case. Pathomorphological findings can be described in the feto-maternal border zone as well as in the fetal placenta. These are not, however, specific, nor do they offer diagnostic proof.Pathomorphological findings in the feto-maternal border zone: defective invasion of the extravillous cytotrophoblast, hyperplastic arterio-/arteriolopathy, acute atherosclerosis, and fibrinoid necrosis of endothelium.Disorders of the fetal part of placenta: infarctions/fibrin deposits, obliterative angiopathy, stromal fibrosis/fibrinoid degeneration, syncytiotrophoblastic nodes (Tenney-Parker-phenomenon), and disturbances of maturation of the villi.There is a general lack of correlation between the seriousness of the disease and the morphology. The only exception in this respect are the findings in the vessels both of the placental bed and of the chronic villi. These show a high correlation with doppler sonographic findings.At an incidence of 3.2-4% world-wide, pregnancy-induced hypertension (PIH) is the most common disease of pregnancy. Since this holds a risk, not only for the mother, but also for the child, the placenta should undergo pathological-anatomical examination in every case. Pathomorphological findings can be described in the feto-maternal border zone as well as in the fetal placenta. These are not, however, specific, nor do they offer diagnostic proof. Pathomorphological findings in the feto-maternal border zone: defective invasion of the extravillous cytotrophoblast, hyperplastic arterio-/arteriolopathy, acute atherosclerosis, and fibrinoid necrosis of endothelium. Disorders of the fetal part of placenta: infarctions/fibrin deposits, obliterative angiopathy, stromal fibrosis/fibrinoid degeneration, syncytiotrophoblastic nodes (Tenney-Parker-phenomenon), and disturbances of maturation of the villi. There is a general lack of correlation between the seriousness of the disease and the morphology. The only exception in this respect are the findings in the vessels both of the placental bed and of the chronic villi. These show a high correlation with doppler sonographic findings.

Congenital disorders of the colonic innervation. A diagnostic guide

ZusammenfassungDer Morbus Hirschsprung (MH, Aganglionose) ist die wichtigste Form der kongenitalen Innervationsstörungen des Darms mit Indikation zu einer chirurgischen Intervention. Die Hypoganglionose im Übergangssegment stellt die bedeutendste Entität von Krankheitswert dar. Die präoperative Klärung der Länge des innervationsgestörten Segments ist nach wie vor eine diagnostische Herausforderung für den Kliniker und Pathologen. Enzymhistochemische Untersuchungen stellen die Methode der Wahl dar, bei deren Anwendung jedoch bestimmte Einschränkungen zu beachten sind.Andere Dysganglionosen, insbesondere die so genannte neuronale intestinale Dysplasie (NID), lassen sich wegen einer zu großen Überlappung mit alterskorrelierten Normwerten nicht zweifelsfrei als Entität definieren. Die einzige Ausnahme bildet die als Teilsymptom einer genetisch bedingten Erkrankung auftretende Ganglioneuromatose.AbstractHirschsprung’s disease (HD, aganglionosis) is the most important form of congenital disturbance of intestinal innervation, requiring surgical intervention. Furthermore, hypoganglionosis of the transitional zone forms the most significant factor in morbidity. Pre-operative definition of the length of neuronally disturbed segment is still a diagnostic challenge for both clinical physician and pathologist. Enzyme histochemical studies form the method of choice, but certain limitations in their use must be observed.Other dysganglionoses, particularly the so-called “Intestinal Neuronal Dysplasia” (IND) cannot—because of an excessive overlapping with age-correlated normal values—unequivocally be defined as an entity on its own. The only exception to this, is the ganglionic neuromatosis, which arises as part of a genetic illness.

Kongenitale Innervationsstörungen des Kolon

ZusammenfassungDer Morbus Hirschsprung (MH, Aganglionose) ist die wichtigste Form der kongenitalen Innervationsstörungen des Darms mit Indikation zu einer chirurgischen Intervention. Die Hypoganglionose im Übergangssegment stellt die bedeutendste Entität von Krankheitswert dar. Die präoperative Klärung der Länge des innervationsgestörten Segments ist nach wie vor eine diagnostische Herausforderung für den Kliniker und Pathologen. Enzymhistochemische Untersuchungen stellen die Methode der Wahl dar, bei deren Anwendung jedoch bestimmte Einschränkungen zu beachten sind.Andere Dysganglionosen, insbesondere die so genannte neuronale intestinale Dysplasie (NID), lassen sich wegen einer zu großen Überlappung mit alterskorrelierten Normwerten nicht zweifelsfrei als Entität definieren. Die einzige Ausnahme bildet die als Teilsymptom einer genetisch bedingten Erkrankung auftretende Ganglioneuromatose.AbstractHirschsprung’s disease (HD, aganglionosis) is the most important form of congenital disturbance of intestinal innervation, requiring surgical intervention. Furthermore, hypoganglionosis of the transitional zone forms the most significant factor in morbidity. Pre-operative definition of the length of neuronally disturbed segment is still a diagnostic challenge for both clinical physician and pathologist. Enzyme histochemical studies form the method of choice, but certain limitations in their use must be observed.Other dysganglionoses, particularly the so-called “Intestinal Neuronal Dysplasia” (IND) cannot—because of an excessive overlapping with age-correlated normal values—unequivocally be defined as an entity on its own. The only exception to this, is the ganglionic neuromatosis, which arises as part of a genetic illness.

Plazenta bei Schwangerschaftshochdruck

ZusammenfassungDie schwangerschaftsinduzierte Hypertonie (SIH) ist mit einer Inzidenz von 3,2–4% weltweit die häufigste Erkrankung der Schwangerschaft. Da sie nicht nur für die Mutter, sondern auch für das Kind Risiken mit sich bringt, sollte die Plazenta in jedem Fall pathologisch-anatomisch untersucht werden. Es können dabei sowohl für die fetomaternale Grenzzone als auch für die fetale Plazenta pathomorphologische Befunde beschrieben werden, die allerdings nicht spezifisch oder diagnostisch beweisend sind.Pathomorphologische Befunde in der fetomaternalen Grenzzone sind: das Fehlen der physiologischen Invasion des extravillösen Zytotrophoblasten, hyperplastische Arterio-/Arteriolopathie, akute Atherose und fibrinoide Endothelnekrosen.Die fetale Plazenta kann folgende Fehlentwicklungen aufweisen: Infarkte/Mikrofibrinabscheidungen, Abruptio placentae, Endangiopathia obliterans/Zottenstromafibrose /-hyalinose, Synzytiotrophoblastzellknoten (Tenney-Parker-Phänomen) sowie Zottenreifungsstörungen/Retardierung bzw. Akzeleration.Eine Korrelation zwischen dem Schweregrad der Erkrankung und der Morphologie fehlt weitgehend; eine Ausnahme bilden in dieser Hinsicht nur die Befunde an den Gefäßen sowohl des Plazentabettes, als auch der Chorionzotten. Diese korrelieren gut mit dopplersonographischen Befunden.AbstractAt an incidence of 3.2–4% world-wide, pregnancy-induced hypertension (PIH) is the most common disease of pregnancy. Since this holds a risk, not only for the mother, but also for the child, the placenta should undergo pathological-anatomical examination in every case. Pathomorphological findings can be described in the feto-maternal border zone as well as in the fetal placenta. These are not, however, specific, nor do they offer diagnostic proof.Pathomorphological findings in the feto-maternal border zone: defective invasion of the extravillous cytotrophoblast, hyperplastic arterio-/arteriolopathy, acute atherosclerosis, and fibrinoid necrosis of endothelium.Disorders of the fetal part of placenta: infarctions/fibrin deposits, obliterative angiopathy, stromal fibrosis/fibrinoid degeneration, syncytiotrophoblastic nodes (Tenney-Parker-phenomenon), and disturbances of maturation of the villi.There is a general lack of correlation between the seriousness of the disease and the morphology. The only exception in this respect are the findings in the vessels both of the placental bed and of the chronic villi. These show a high correlation with doppler sonographic findings.At an incidence of 3.2-4% world-wide, pregnancy-induced hypertension (PIH) is the most common disease of pregnancy. Since this holds a risk, not only for the mother, but also for the child, the placenta should undergo pathological-anatomical examination in every case. Pathomorphological findings can be described in the feto-maternal border zone as well as in the fetal placenta. These are not, however, specific, nor do they offer diagnostic proof. Pathomorphological findings in the feto-maternal border zone: defective invasion of the extravillous cytotrophoblast, hyperplastic arterio-/arteriolopathy, acute atherosclerosis, and fibrinoid necrosis of endothelium. Disorders of the fetal part of placenta: infarctions/fibrin deposits, obliterative angiopathy, stromal fibrosis/fibrinoid degeneration, syncytiotrophoblastic nodes (Tenney-Parker-phenomenon), and disturbances of maturation of the villi. There is a general lack of correlation between the seriousness of the disease and the morphology. The only exception in this respect are the findings in the vessels both of the placental bed and of the chronic villi. These show a high correlation with doppler sonographic findings.

[A computer-assisted workplace for anatomical pathology investigations on human embryos].

Contrary to chromosomal aberrations, which can be recognized by cytogenetic procedures alone, monogenic inherited diseases are determined exclusively by evidence from anatomical-pathological investigations. We present a computer-assisted optical system providing not only efficient dissections of embryos, but also diagnosis of congenital defects, such as congenital heart deformities, neural tube defects and skeletal malformations. A stereomicroscope with an integrated camera as well as two cold light sources creates a three-dimensional image of the human embryo (size: e.g., 2.5 mm=23.-25.d), hence facilitating handling of the autopsy. Scenes of interest are photodocumented by a multifocusing camera. Its technique is based on serial pictures of predefined levels of the embryo, consecutively adding up to one photograph with minimized areas out of focus. The sequences, the rapid as well as exact calibration of the screened objects and digital archiving of the obtained photographs allow efficient diagnostic procedures. As the depth of field is broadened, the computer-assisted workplace improves the diagnosis as well as documentation, providing a base for genetic counseling.