Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

[Autopsy findings related to Down's syndrome: 101 cases]. / Fréquence des malformations associées à la trisomie 21: à propos de 101 cas foetopathologiques.

OBJECTIVES: To analyze the spectrum of congenital malformations among fetuses with Down's syndrome sent for necropsy. Materials and methods. Necropsies following medical termination of pregnancy during the second and third trimester were performed during a 4 year period. RESULTS: The incidence of each malformation was determined. Talipes equinovarus and aberrant lobation of the lung were present in 6% of cases. We are able to state precisely the incidence of 11 pairs of ribs: 11%. CONCLUSION: A precise knowledge about Down's syndrome associated malformations is essential for genetic counselling. The exact incidence of each sign is important to lead ultrasound examination when this syndrome is revealed.

Congenital erythropoietic porphyria: prenatal diagnosis and autopsy findings in two sibling fetuses.

Congenital erythropoietic porphyria is an autosomal recessive disease characterized by a deficiency of uroporphyrinogen III cosynthetase activity, with diffuse tissue accumulation of specific type I porphyrins. The diagnosis of this disease was made in two fetuses, who were siblings, and from a Caucasian nonconsanguinous family. The first fetus died in utero with hydrops fetalis and anemia, but without an etiopathogenic diagnosis. In the second case, the diagnosis was based on pink fluorescence of the amniotic fluid examined fortuitously in sunlight. DNA analysis showed that the fetus was heteroallelic for the mutation C73R. The autopsy showed brown skin, and at histological examination, porphyrin pigment was deposited in many tissues. Retrospectively, similar deposits were found in the tissues of the first fetus.

Twin-to-twin transfusion syndrome. Role of the fetal renin-angiotensin system.

The twin-to-twin transfusion syndrome (TTS) results from an unbalanced blood supply through placental anastomoses in monochorionic twins. It induces growth restriction, renal tubular dysgenesis, and oliguria in the donor and visceromegaly and polyuria in the recipient. A better understanding of its pathophysiology could contribute to improving the management of TTS, which still carries a high perinatal mortality in both twins. As well as several other candidates, the renin-angiotensin system might be involved in TTS. To evaluate its role in the pathogenesis of the syndrome, we studied the kidneys of 21 twin pairs who died from TTS at 19 to 30 weeks, compared with 39 individuals in a control group, using light microscopy, immunohistochemistry, and in situ hybridization. The overexpression of the renin protein and transcript with frequent evidence of renin synthesis by mesangial cells was observed in the donor kidneys, presumably as a consequence of chronic renal hypoperfusion. This upregulation of renin synthesis might be beneficial to restore euvolemia. In severe cases of TTS, however, angiotensin-II-induced vasoconstriction acts as an additional deleterious factor by further reducing the renal blood flow in donors. In recipients, renin expression was virtually absent, possibly because it was down-regulated by hypervolemia. However, in addition to congestion and hemorrhagic infarction, there were severe glomerular and arterial lesions resembling those observed in polycythemia- or hypertension-induced microangiopathy. We speculate that fetal hypertension in the recipient might be partly mediated by the transfer of circulating renin produced by the donor, through the placental vascular shunts.

Prenatal diagnosis of a satellited non-acrocentric chromosome derived from a maternal translocation (10;13)(p13;p12) and review of literature.

We identified a familial balanced translocation involving chromosomes 10 and 13 through the finding of a satellited 10p chromosome in a fetus. The phenotype of two unbalanced products of the translocation resulting in pure monosomy 10p13 and trisomy 10p13 is described. This familial case and two of our unreported cases are discussed in the light of other prenatal observations with satellited non-acrocentric chromosomes reported in the literature.

A new lethal syndrome of exomphalos, short limbs, and macrogonadism.

We report a new lethal multiple congenital abnormality (MCA) syndrome of exomphalos, short limbs, nuchal web, macrogonadism, and facial dysmorphism in seven fetuses (six males and one female) belonging to three unrelated families. X rays showed enlarged and irregular metaphyses with a heterogeneous pattern of mineralisation of the long bones. Pathological examination showed adrenal cytomegaly, hyperplasia of Leydig cells, ovarian stroma cells, and Langherans cells, and renal microcysts. We suggest that this condition is a new autosomal recessive MCA syndrome different from Beckwith-Wiedemann syndrome, especially as no infracytogenetic deletion or uniparental disomy of chromosome 11 was found.

Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature.

The prenatal diagnosis of an 8p23.1 deletion is reported. The diagnosis was ascertained at 22 weeks of gestation because of the discovery of a diaphragmatic hernia at ultrasound. Following cytogenetic studies and counselling, the pregnancy was terminated. An autopsy confirmed the presence of a diaphragmatic hernia and revealed also the existence of an atrio-ventricular canal (AVC) and an atrial septal defect (ASD). The clinical features of this antenatally diagnosed case are compared with those observed in 16 previously reported cases with an identical deletion of the short arm of chromosome 8. This suggests that a deletion 8p23.1 should be considered whenever a diaphragmatic hernia and/or an AVC is detected on ultrasound.

Severe brain and limb defects with possible autosomal recessive inheritance: a series of six cases and review of the literature.

Six fetuses with normal chromosomes were found to have severe craniofacial, limb, and visceral malformations during the second trimester of pregnancy. Two of these fetuses were monozygotic twins while a third one had a healthy dizygotic twin brother. A case with familial recurrence was also observed. Autopsy and skeletal radiographs suggested several diagnoses such as neural tube defect with limb defects or XK aprosencephaly. The development of these severe conditions in monozygotic twins and familial recurrence emphasize the difficulties of genetic counseling in such situations. These cases may suggest autosomal recessive inheritance.

Development of human fetal kidney in obstructive uropathy: correlations with ultrasonography and urine biochemistry.

In utero urethral obstruction results in bilateral hydronephrosis and severe fetal and post-natal morbidity and mortality. Obstetrical management depends on the indirect evaluation of fetal renal function by ultrasonography and biochemical analysis. No direct evaluation of the severity and possible reversibility of renal lesions is available. In this paper we analyzed kidneys from 34 fetuses (14 to 37 gestational weeks) in which (1) isolated bilateral urinary tract obstruction had been detected in utero by sonography, and (2) the severity of sonographic and biochemical prognostic indicators led to the indication of termination of pregnancy or to perinatal death. Pure hydronephrosis was observed in two young fetuses [14 and 20 gestational weeks (GW)] and was associated with regressive changes in two others. In contrast, a wide spectrum of dysplastic renal lesions was present in 30 fetuses and was classified into four subgroups according to the association of dysplasia, hypoplasia and cysts. They had the following characteristics in common: (1) premature cessation of nephrogenesis assessed by the medullary ray counting method; (2) early disappearance or myofibroblastic differentiation of metanephric blastema; (3) early increase in interstitial mesenchyme with widespread expression of alpha-smooth muscle actin by mesenchymal cells; (4) frequent absence of classical criteria of dysplasia (nests of cartilage were observed in only 5 fetuses); (5) an identification, based upon the detection of alpha-smooth muscle actin expression, of the muscular phenotype of mesenchymal cells encircling primitive ducts. In conclusion, (1) the value of prognostic markers in fetuses less than 20 GW should be reconsidered; (2) after 20 GW there is a good correlation between markers predicting poor prognosis and the severity of renal lesions; (3) hypoplasia with disappearance of blastema cells, dysplasia and early interstitial fibrosis are evidence of the irreversibility of renal lesions and preclude any possibility of new nephron formation; (4) these findings suggest that most surgical in utero procedures are performed when irreversible renal lesions have developed.

Distribution of alpha-integrin subunits in fetal polycystic kidney diseases.

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by beta 1-integrins, a subfamily of integrin receptors, formed by the association of the beta 1-chain with different alpha-subunits. To date, no study on alpha-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of alpha-integrin subunits (alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in alpha 1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits alpha 2, alpha 3, and alpha 6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the alpha 1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of alpha 2, alpha 3, and alpha 6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases.

Stereology of the myocardium in human foetuses.

The rate of cellular proliferation and hypertrophy of the cardiac myocytes in the human perinatal period is still controversial. This work uses stereology to evaluate the prenatal quantitative changes of the myocardium. The hearts of 36 human foetuses, ranging from the 2nd trimester to the 3rd trimester, were studied. Fifteen random microscopic fields were analyzed in each heart. The following stereological parameters were determined: Vv[myocyte] and Vv[interstitium] (the volume densities of the cardiac myocyte and interstitium, respectively) and the Nv[myocyte] (the numerical density of the cardiac myocytes). The total number of myocytes (N[myocyte]) and the mean myocyte volume (V[myocyte]) were also determined. All differences between the second and the third trimester of gestation, tested with the Mann-Whitney test, were statistically significant (P < 0.05). The Vv[myocyte] decreased 8.69% and the Vv[interstitium] increased 49.83% in this period. Simultaneously, the Nv[myocyte] decreased 16.64%, the V[myocyte] increased 16.39%, the cardiac weight increased 366.67% and the N[myocyte] increased 272.06%. In conclusion, during the last two gestational trimesters the human heart increases in weight more than 4.5 times, the volume density of myocytes decreases while the volume density of the cardiac interstitium increases. The numerical density of myocytes per myocardium volume decreases but the myocytes became greater in mean volume (more than 16%).

Distribution and ontogenesis of tenascin in normal and cystic human fetal kidneys.

BACKGROUND: Tenascin is a mesenchymal extracellular matrix glycoprotein transiently expressed during development, mainly at the site of epithelial-mesenchymal interactions. It is thought to play a key role in morphogenesis. Little is known about the distribution of tenascin in normal human fetal kidney, and, so far, no data have been reported concerning the distribution of the protein in fetal cystic kidneys. EXPERIMENTAL DESIGN: Using specific mAb and the immunofluorescence technique, we analyzed the distribution of tenascin in normal human embryonic (n = 3), fetal (n = 15), and mature kidneys (n = 4) and in fetuses affected with autosomal recessive polycystic disease (n = 3), autosomal dominant polycystic disease (n = 3), and cystic dysplasia (n = 3). We compared the distribution of this protein with that of fibronectin and types I, III, V, and VI collagens. RESULTS: In normal developing kidneys, tenascin is present in the uninduced blastema and in the mesenchyme around differentiating nephrons. It is homogeneously distributed in the inner cortex and in the medulla. During maturation, tenascin expression persists in the medulla but progressively decreases in the cortex. Tenascin is present in the mesangial area from the S-shaped body stage. Both types of polycystic diseases are characterized by a marked and diffuse increase in cortical and medullary expression of tenascin as well as types III, V, and VI collagen. In cystic dysplasia, two types of changes were observed: (a) increased tenascin and interstitial collagen expression in the subcapsular strips of condensed mesenchyme; and (b) heterogeneous medullary tenascin distribution with positive labeling of the condensed mesenchyme surrounding cysts and primitive ducts and negative labeling of the loose interstitial mesenchyme, contrasting with the diffuse accumulation of types III, V, and VI collagen. CONCLUSIONS: In the human fetal kidney, tenascin is expressed by blastema cells and disappears when converted to epithelium. In polycystic diseases, an early increase in tenascin and interstitial collagen expression suggests that renal mesenchyme per se may contribute to the progressive alteration of the kidney. In cystic dysplasia, phenotypic changes in metanephric blastema indicate inappropriate commitment of blastema cells into interstitial cells, leading to the definitive arrest of nephrogenesis; the heterogeneity in tenascin medullary expression underlines the heterogeneity in the mesenchymal cell population.

Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome.

OBJECTIVE: Fetal hyperchogenic bowel is associated with a variety of conditions, the incidence of which has yet to be studied. STUDY DESIGN: The outcomes of 182 cases of fetal hyperechogenic bowel were reviewed. Screening for maternal toxoplasmosis, fetal karyotyping, and amniotic fluid digestive enzyme assays were performed in all cases. Eight mutations associated with cystic fibrosis were analyzed in 116 cases. RESULTS: Of 135 newborns, 121 were normal, but nine underwent surgery for gastrointestinal obstruction, three had cytomegalovirus or parvovirus infection, one had a triple X chromosome, and one died from sudden infant death syndrome. In utero fetal death was observed in 24 cases. Elective termination of pregnancy was performed in 23 cases for associated anomalies. CONCLUSIONS: Hyperechogenic fetal bowel was associated with increased risk for adverse outcome. Prenatal management should include ultrasonographic surveillance, fetal karyotyping, amniotic digestive enzyme assays, and screening for cystic fibrosis and infectious disease.

Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and müllerian regression: further delineation of a new syndrome?

A 24-week-old fetus is described here with holoprosencephaly sequence (arhinencephaly and agenesis of the corpus callosum) associated with brain and meningeal dysplasia, microphthalmia with an ectopic pigmentary layer, hypothalamic hamartoblastoma, preaxial asymmetric limb reduction, lung hypoplasia, gastric hypoplasia, Müllerian regression, intestinal malrotation, asplenia, and normal chromosomes. The differential diagnosis includes the Cerebroacrovisceral-Early lethality (CAVE) phenotype, and the Pallister-Hall syndrome, but the anomalies best fit the severe form of microgastria-limb reduction syndrome. Together with a previous case reported by Meinecke, the pattern of anomalies appears to represent a combination of defects, related to but distinct from the microgastria-limb reduction syndrome.

Osteocraniostenosis.

We report a multiple congenital anomalies (MCA) syndrome in three unrelated fetuses consisting of extremely thin, dense, fishbone-like diaphyses, flared metaphyses, mild micromelic dwarfism, brachydactyly, facial dysmorphism, ocular malformations (microphthalmia, aniridia), cloverleaf skull deformity, and splenic hypoplasia. Histopathological investigations showed abnormalities of the metaphyseal cartilage and adjacent diaphyseal ossification, excessive modelling of the metaphyses, and, in one case, dysplasia of the epiphyseal cartilage. We review three previously reported cases. We suggest the name osteocraniostenosis to describe this radiological and clinical disorder, pinpointing its major clinical and radiological features.

Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin.

OBJECTIVE: The purpose of this study is to emphasize the high risk of renal failure and severe morphologic changes related to prolonged prenatal exposure to indomethacin. STUDY DESIGN: Referred renal specimens from six anuric neonates exposed in utero to indomethacin were studied. Clinical charts were retrospectively reviewed. Indomethacin dosages varied from 150 to 400 mg daily, and the drug was given for a 2- to 11-week period, until birth. RESULTS: All infants died in anuria, 4 of them after 7 to 39 days on peritoneal dialysis. In 5 infants cystic dilatations of superficial nephrons were associated with ischemic changes of the deep cortex. By immunohistochemical analysis intrarenal renin content was increased in 4 of 5 patients. CONCLUSION: Long-term indomethacin treatment during pregnancy may lead to the development of renal failure and irreversible renal damage with cystic dilatation of developing nephrons in an exposed fetus. Prior stimulation of the renin-angiotensin system may favor this complication.

Fetal enteroviral infection with cerebral ventriculomegaly and cardiomyopathy.

Fetal cerebral ventriculomegaly and cardiomyopathy were diagnosed prenatally at 35 weeks and resulted in fetal death. Although there was no post mortem pathological evidence of inflammatory lesions, fetal serum alpha interferon was abnormally high (25 IU/ml). Virologic investigations were therefore carried out on stored amniotic fluid, fetal and maternal blood samples. The presence of enterovirus was retrospectively demonstrated in amniotic fluid. The association of fetal birth defects with enteroviral infection is puzzling and suggests that more attention should be given to virologic studies in the diagnostic workup of fetal malformations otherwise considered as idiopathic.